JP7644713B2 - Abiraterone Prodrug - Google Patents

Description

This application claims the benefit of U.S. Provisional Patent Application No. 62/814,568, filed March 6, 2019, and U.S. Provisional Patent Application No. 62/849,259, filed May 17, 2019, the entire contents of each of which are incorporated herein by reference.

The present disclosure generally relates to novel prodrugs of abiraterone and long-acting depot-based parenteral formulations of abiraterone prodrugs. The disclosure is directed to a wide range of applications, such as intramuscular (IM) injections in patients with androgen or estrogen hormone-dependent benign or malignant diseases, including various cancers (such as prostate cancer, bladder cancer, hepatocellular carcinoma, lung cancer, breast cancer, and ovarian cancer), and for the treatment of non-neoplastic syndromes resulting from androgen overproduction (including classical and non-classical congenital adrenal hyperplasia, endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc.), or conditions such as Cushing's syndrome or Cushing's disease resulting from overproduction of glucocorticoids, typically cortisol.

Abiraterone ((3β)-17-(pyridin-3-yl)androsta-5,16-dien-3-ol; CAS number 154229-19-3); chemical formula: C ₂₄ H ₃₁ NO; molar mass: 349.5 g/mol) is an inhibitor of CYP17A1, a member of the cytochrome P450 superfamily of enzymes that catalyze the synthesis of cholesterol, steroids and other lipids and are involved in drug metabolism. CYP17A1 has both 17α-hydroxylase activity and 17,20-lyase activity. Abiraterone potently and selectively inhibits CYP17A1 17α-hydroxylase and 17,20-lyase enzyme activity. The 17α-hydroxylase activity of CYP17A1 is required for the production of glucocorticoids such as cortisol. However, both the hydroxylase and 17,20 lyase activities of CYP17A1 are required for the production of androgenic steroids (e.g., androstenedione, testosterone, and dihyrotestosterone) and estrogenic steroids (estrone, estradiol, estriol) through the conversion of 17α-hydroxypregnenolone to the sex steroid precursor, dehydroepiandrosterone (see FIG. 14D). Thus, abiraterone inhibits the synthesis of androgens and estrogens in the gonads (mainly the testes and ovaries) and extragonadally (the adrenal glands and their tumors).

Abiraterone itself is poorly absorbed, but can be administered orally as the abiraterone acetate prodrug. Abiraterone acetate is also poorly absorbed, but can be converted to abiraterone in the intestine, which results in poor absorption into the bloodstream after cleavage of the acetate ester prodrug. Abiraterone acetate ((3β)-17-(3-pyridyl)androsta-5, acetate ester; CAS number 154229-18-2) is approved in the United States under the trade name Zytiga® for the treatment of castration-resistant or castration-sensitive prostate cancer. Abiraterone acetate is currently available worldwide.

Orally administered abiraterone acetate is known not to be absorbed in the gastrointestinal tract (and not detectable in plasma). Instead, abiraterone acetate is hydrolyzed to abiraterone in the intraluminal environment, resulting in abiraterone supersaturation, which has been shown to play a role in generating a strong driving force for abiraterone absorption (Stappaerts et al., Eur. J. Pharmaceutics Biopharmaceutics 90:1, 2015 (Non-Patent Document 1)).

Abiraterone interferes with the normal physiological production of steroids by the adrenal glands, so its prodrug formulations are generally prescribed at low doses of steroids to prevent adrenal insufficiency. Indeed, Zytiga® tablets (250 mg) are approved in the United States in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer and patients with metastatic castration-sensitive prostate cancer. Prescribing information for Zytiga® recommends oral administration of 1000 mg (4 x 250 mg tablets) once daily in combination with oral administration of prednisone (5 mg) twice daily for patients with castration-resistant prostate cancer or once daily for patients with castration-sensitive prostate cancer. In Europe, Zytiga® is approved for use in combination with either prednisone or prednisolone.

Because administration of abiraterone acetate with food increases absorption of abiraterone acetate (and therefore potentially increases and significantly variability in exposure, potentially resulting in a variety of side effects, such as cardiovascular and/or liver toxicity), the prodrug must be taken on an empty stomach, at least 1 hour before or 2 hours after a meal. Indeed, the prescribing information for Zytiga® states that the drug must be taken on an empty stomach, with no food being consumed at least 2 hours before and at least 1 hour after oral administration.

The prescribing information explains that following daily oral administration of 1,000 mg of Zytiga® to patients with metastatic castration-resistant prostate cancer, the steady-state _Cmax value of abiraterone was 226±178 ng/mL (mean±SD) and the area under the curve (AUC) value was 1173±690 ng-hr/mL (mean±SD). A single-dose (1,000 mg) crossover study of Zytiga® in healthy subjects confirmed that systemic exposure of abiraterone was increased when Zytiga® was administered with food. Specifically, the _Cmax and AUC values of abiraterone were approximately 7-fold and 5-fold higher, respectively, when Zytiga® was administered with a low-fat meal (7% fat, 300 calories) and approximately 17-fold and 10-fold higher, respectively, when Zytiga® was administered with a high-fat meal (57% fat, 825 calories).

The currently approved oral solid formulation of the prodrug abiraterone acetate has several drawbacks. For example, it has very low bioavailability, which imposes a high daily dose burden on patients (4 x 250 mg tablets once daily). In addition, the combination of low bioavailability and high food effect results in high blood level variability in patients. Furthermore, abiraterone is rapidly excreted, so the approved dosage is C _min abiraterone per day, which is believed to be associated with loss of therapeutic effect in patients with metastatic castration-resistant prostate cancer.

Parenteral modes of administration (e.g., parenteral routes) have been explored for other classes of drugs; however, to date, no sustained-release injectable prodrug formulations of abiraterone exist.

Stappaerts et al. , Eur. J. Pharmaceutics Biopharmaceutics 90:1, 2015

In various embodiments, the present disclosure provides novel abiraterone prodrugs, long-acting abiraterone prodrug formulations, and methods of using the same in treating subjects having, for example, sex hormone-dependent benign or malignant diseases and/or syndromes resulting from androgen and/or glucocorticoid excess. Typically, the novel abiraterone prodrugs herein can be fatty acid esters of abiraterone that upon cleavage release abiraterone and a safe and degradable fatty acid moiety. As detailed herein, compared to oral abiraterone acetate formulations, the novel abiraterone prodrugs and formulations disclosed herein are groundbreaking in that they provide improved bioavailability, elimination of food effects, reduced dosage burden, reduced dosing frequency, and sustained effective plasma levels of abiraterone, e.g., continuous plasma exposure for at least one week, typically at least two weeks, following administration of the abiraterone prodrug formulation, that exceed the daily _Cmin levels observed with oral administration of abiraterone acetate. Furthermore, pharmacokinetic and pharmacodynamic studies of representative abiraterone prodrugs herein, such as abiraterone decanoate or abiraterone isocaproate, demonstrate that the novel abiraterone prodrugs and formulations disclosed herein are suitable for weekly, monthly, or even less frequent administration for treating subjects with sex hormone dependent benign or malignant diseases, androgen excess syndromes, and/or glucocorticoid excess syndromes described herein. This characteristic alone represents a highly significant improvement over the currently marketed Zytiga® tablets, which require a large daily dosage burden for patients (4 x 250 mg tablets once daily).

式中のＲ^１については、本明細書にて定義する。 Some embodiments of the present disclosure are directed to novel abiraterone prodrugs. In some embodiments, the abiraterone prodrug is a compound of formula I or a pharma- ceutically acceptable salt thereof:

wherein R ¹ is as defined herein.

式中のＲ^２については、本明細書にて定義する。いくつかの実施形態では、アビラテロンプロドラッグ製剤は、筋肉内注射、皮内注射、または皮下注射用に製剤化することができる。いくつかの実施形態では、式ＩＩの化合物またはそれらの薬学的に許容される塩は、約２５ｍｇ／ｍｌ～約５００ｍｇ／ｍｌの濃度で製剤中に存在し得る。 In one representative embodiment, an abiraterone prodrug formulation is provided for parenteral administration to a subject having a sex hormone-dependent benign or malignant disease, syndrome resulting from androgen excess, and/or syndrome resulting from glucocorticoid (e.g., cortisol) excess. In one aspect, the formulation comprises a lipophilic ester form of abiraterone and one or more pharma- ceutically acceptable carriers, diluents, or excipients (e.g., such that the prodrug formulation is present as a solution or suspension in a pharma- ceutically acceptable oil, such as an oil of vegetable origin or a synthetic oil, including synthetic mono- or diglycerides of fatty acids; e.g., such that the prodrug formulation is present as a solution or suspension in a vegetable oil and other co-solvents and excipients). In certain exemplary embodiments, the lipophilic ester form of abiraterone may be acetate, propionate, butanoate, valerate, caproate, enanthate, cypionate, isocaproate, buciclate, cyclohexanecarboxylate, phenylpropionate, decanoate, or undecanoate. In some embodiments, the abiraterone prodrug formulation may comprise a compound of Formula II or a pharma- ceutically acceptable salt thereof:

wherein ^R2 is as defined herein. In some embodiments, the abiraterone prodrug formulation may be formulated for intramuscular, intradermal, or subcutaneous injection. In some embodiments, the compound of formula II or a pharma- ceutically acceptable salt thereof may be present in the formulation at a concentration of about 25 mg/ml to about 500 mg/ml.

Typically, upon administration of the formulation (e.g., the abiraterone prodrug formulation herein), a therapeutic range plasma concentration of abiraterone is achieved and sustained for at least 1 week, e.g., at least 2 weeks and up to 4 weeks or more. In one aspect, the therapeutic range plasma concentration of abiraterone after parenteral administration of the prodrug formulation is at least 1 ng/ml, e.g., at least 1 ng/ml, at least 2 ng/ml, at least 4 ng/ml, or at least 8 ng/ml. In some embodiments, the therapeutic range plasma concentration of abiraterone may be about 0.5 ng/ml or greater. Parenteral administration may be via IM injection, intradermal injection, or subcutaneous injection. In one aspect, the formulation is suitable for the treatment of sex hormone-dependent benign or malignant diseases, such as androgen-dependent and estrogen-dependent diseases, such as androgen-dependent or estrogen-dependent cancers. Sex hormone-dependent benign or malignant diseases include prostate cancer and breast cancer. Prostate cancer includes castration-resistant prostate cancer and castration-sensitive prostate cancer. In some embodiments, sex hormone-dependent benign or malignant diseases include various cancers such as ovarian cancer, bladder cancer, hepatocellular carcinoma, and lung cancer. Inhibition of CYP17A1 is expected to reduce the overproduction of androgens and glucocorticoids (e.g., cortisol). The abiraterone prodrug formulations herein are not limited to the treatment of neoplastic conditions described herein, but may also be used to treat non-neoplastic syndromes resulting from androgen and glucocorticoid (e.g., cortisol) excess. In one aspect, the formulations are suitable for the treatment of non-neoplastic syndromes resulting from androgen excess, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), precocious puberty, hirsutism, and/or syndromes resulting from glucocorticoid (e.g., cortisol) excess, such as Cushing's syndrome or Cushing's disease.

Parenteral formulations fill a long-standing unmet need by providing an alternative to oral formulations that suffer from (1) low bioavailability, (2) interactions with ingested food, (3) delivery of unchanged drug at widely variable blood levels that can reduce efficacy and increase side effects, (4) the need for daily dosing and high dose burden, and (5) reduced patient compliance due to the need for daily dosing of supplemental prednisone or prednisolone taken with food due to the abstinence from food within hours of dosing, high dose burden, and inconsistent dosing schedules.

It is an object of the present disclosure to provide methods for inhibiting CYP17A1 activity, such as inhibiting 17α-hydroxylase activity and 17,20-lyase activity, by parenterally administering an effective dose of at least one abiraterone prodrug formulation to a subject in need thereof. In some embodiments, the subject suffers from a sex hormone-dependent benign or malignant disease as described herein, a syndrome resulting from androgen excess, and/or a syndrome resulting from glucocorticoid excess, such as hypercortisolism.

It is an object of the present disclosure to provide a method of reducing glucocorticoid (e.g., cortisol) levels by parenterally administering an effective dose of at least one abiraterone prodrug formulation to a subject in need thereof. In some embodiments, the subject suffers from a syndrome resulting from glucocorticoid excess, such as resulting from hypercortisolism as described herein. In some embodiments, the subject suffers from Cushing's syndrome disease or Cushing's disease.

An object of the present disclosure is to provide a method of reducing androgen (e.g., testosterone and/or dihydrotestosterone) and/or estrogen levels by parenterally administering an effective dose of at least one abiraterone prodrug formulation to a subject in need thereof. In some embodiments, the subject suffers from a syndrome resulting from androgen excess, such as classical or non-classical congenital adrenal hyperplasia, endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc. In some embodiments, the subject suffers from an androgen- and/or estrogen-related cancer, such as prostate cancer or breast cancer.

Another object is to provide a method for treating sex hormone dependent benign or malignant diseases, syndromes due to androgen excess and/or syndromes due to glucocorticoid excess such as hypercortisolism by parenterally administering an effective dose of at least one abiraterone prodrug formulation to a subject in need of such treatment . In one exemplary embodiment, the method is for treating sex hormone dependent benign or malignant diseases, such as androgen dependent or estrogen dependent diseases, such as androgen dependent or estrogen dependent cancers. Sex hormone dependent benign or malignant diseases include prostate cancer or breast cancer. Prostate cancer includes castration resistant and castration sensitive prostate cancer. In some embodiments, sex hormone dependent benign or malignant diseases include ovarian cancer, bladder cancer, hepatocellular carcinoma, lung cancer, and the like. In one exemplary embodiment, the method is for treating non-neoplastic syndromes resulting from androgen excess, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), precocious puberty, hirsutism, and/or syndromes resulting from glucocorticoid (e.g., cortisol) excess, such as Cushing's syndrome or Cushing's disease.

In some embodiments, the abiraterone prodrug formulation can include at least one compound of formula I or II or a pharma- ceutically acceptable salt thereof. In one aspect, the formulation includes a lipophilic ester form of abiraterone and one or more pharma- ceutically acceptable carriers, diluents, or excipients. In certain exemplary embodiments, the lipophilic ester form of abiraterone can be, for example, acetate, propionate, butanoate, valerate, caproate, enanthate, cypionate, isocaproate, bucclate, cyclohexanecarboxylate, phenylpropionate, decanoate, or undecanoate. Upon administration of the formulation to a subject in need thereof, a therapeutic plasma concentration of abiraterone is achieved and sustained for at least one week, for example, at least two weeks and up to four weeks or more. In one aspect, the therapeutic range plasma concentration of abiraterone after parenteral administration of the prodrug formulation is at least 1 ng/ml, e.g., at least 1 ng/ml, at least 2 ng/ml, at least 4 ng/ml, or at least 8 ng/ml. In some embodiments, the therapeutic range plasma concentration of abiraterone may be about 0.5 ng/ml or greater. Parenteral administration may be via IM injection, intradermal injection, or subcutaneous injection. In certain embodiments, the method may include monthly administration of at least one abiraterone prodrug formulation. In one aspect, the at least one abiraterone prodrug formulation may be administered in divided doses. In another exemplary embodiment, the at least one abiraterone prodrug formulation may be administered simultaneously with one or more different prodrug formulations and/or at least one other drug or agent (e.g., another cancer chemotherapy drug, hormone replacement drug, or hormone ablation drug). In certain aspects, the at least one abiraterone prodrug formulation may be administered prior to at least one other drug or agent. Alternatively, at least one abiraterone prodrug formulation may be administered after at least one other drug or agent. In other exemplary embodiments, two or more administrations of one or more formulations may be administered over a period of days, weeks, months, or years to provide initial and continuous treatment of sex hormone-dependent benign or malignant diseases (e.g., prostate cancer), syndromes due to androgen excess, and/or syndromes due to glucocorticoid excess, such as hypercortisolism. In other exemplary embodiments, at least one abiraterone prodrug formulation may contain at least two different lipophilic ester forms of abiraterone, and the formulation may be administered simultaneously with one or more different prodrug formulations and/or at least one other drug or agent (e.g., another cancer chemotherapy drug, a hormone replacement drug, or a hormone ablation drug). In certain aspects, at least one abiraterone prodrug formulation may contain at least two different lipophilic ester forms of abiraterone, and the formulation may be administered prior to at least one other drug or agent. Alternatively, at least one abiraterone prodrug formulation may contain at least two different lipophilic ester forms of abiraterone, and the formulation may be administered after at least one other drug or agent. In other exemplary embodiments, two or more administrations of one or more formulations containing at least two different lipophilic ester forms of abiraterone may be administered over a period of days, weeks, months, or years to provide initial and continuous treatment of sex hormone-dependent benign or malignant diseases (e.g., prostate cancer), syndromes due to androgen excess, and/or syndromes due to glucocorticoid excess, such as hypercortisolism. The lipophilic ester form of abiraterone may be selected from, for example, acetate, propionate, butanoate, valerate, caproate, enanthate, cypionate, isocaproate, bucclate, cyclohexanecarboxylate, phenylpropionate, decanoate, or undecanoate.

Another object is to provide a kit for treating a subject having a sex hormone-dependent benign or malignant disease (e.g., prostate cancer), a syndrome resulting from androgen excess, and/or a syndrome resulting from glucocorticoid excess, such as hypercortisolism. In an exemplary embodiment, the kit includes a container, such as a vial, an ampoule, or a pre-loaded syringe, containing one or more formulations. In another exemplary embodiment, the kit includes a container, such as a vial, an ampoule, or a pre-loaded syringe, containing one or more formulations and at least one other drug or agent that can enhance the efficacy of the formulation(s) or reduce the undesirable side effect(s) of the formulation(s). In another exemplary embodiment, the kit includes a container, such as a vial, an ampoule, or a pre-loaded syringe, containing one or more formulations and at least one other drug or agent that can enhance the efficacy of the formulation(s) or reduce the undesirable side effect(s) of the formulation. It is understood that the formulation may contain one lipophilic ester form of abiraterone or two or more different lipophilic ester forms of abiraterone. It will be appreciated by those skilled in the art that the kits and packages can be prepared to include one, all, or any combination of the formulation, diluents, buffers, adjuvants, pharma- ceutically acceptable carriers, and at least one other drug or agent that can enhance the efficacy of the formulation or reduce undesirable side effects of the formulation.

Another object is to provide a method for preparing an abiraterone decanoate formulation suitable for parenteral administration to subjects with sex hormone dependent benign or malignant diseases, syndromes resulting from androgen excess, and/or syndromes resulting from glucocorticoid excess, such as hypercortisolism.

These and other objects may be achieved in certain embodiments.

In some embodiments, the present disclosure provides:

式中、Ｒ^１は、Ｒ^１０、Ｏ－Ｒ^１０、またはＮＨＲ^１０であり、
前記Ｒ^１０は、
Ｃ_７－３０アルキル；Ｃ_７－３０アルケニル；Ｃ_７－３０アルキニル；総炭素数が５～１６の、シクロアルキルで置換されたアルキル；総炭素数が７～１６の、フェニルで置換されたアルキル；総炭素数が５～１６の、１つ以上のアルキルで任意的に置換されたシクロアルキル；及び

から選択される、前記化合物またはそれらの薬学的に許容される塩。 [1] A compound of formula I or a pharma- ceutically acceptable salt thereof,

In the formula, R ¹ is R ¹⁰ , O—R ¹⁰ , or NHR ¹⁰ ;
The ^R10 is
C _7-30 alkyl; C _7-30 alkenyl; C _7-30 alkynyl; alkyl substituted with cycloalkyl having a total of 5 to 16 carbon atoms; alkyl substituted with phenyl having a total of 7 to 16 carbon atoms; cycloalkyl optionally substituted with one or more alkyl having a total of 5 to 16 carbon atoms; and

or a pharma- ceutically acceptable salt thereof.

[2] The compound according to [1], wherein R ¹ is C _7-16 alkyl, or a pharma- ceutically acceptable salt thereof.

[3] The compound according to [1] or [2], wherein R ¹ is an alkyl having the formula -(CH ₂ ) _n -CH ₃ , where n is an integer selected from 6, 7, 8, 9, 10, 11, or 12, or a pharma- ceutically acceptable salt thereof.

��ある、［１］に記載の化合物またはそれらの薬学的に許容される塩。 [4] R ¹ is an alkyl having the formula -(CH ₂ ) ₈ -CH ₃ , or

The compound according to [1], or a pharma- ceutically acceptable salt thereof, wherein:

[5] A pharmaceutical composition comprising a compound according to any one of [1] to [4] or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable carrier.

を有するデカン酸アビラテロン、またはそれらの薬学的に許容される塩、及び薬学的に許容される担体を含む、医薬組成物。 [6] The following formula

or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical composition comprising:

[7] The pharmaceutical composition according to [5] or [6], which is formulated for intramuscular, intradermal, or subcutaneous injection.

[8] The pharmaceutical composition according to any one of [5] to [7], wherein the pharma- ceutically acceptable carrier comprises a pharma- ceutically acceptable oil and, optionally, a further pharma- ceutically acceptable solvent.

[9] The pharmaceutical composition according to [8], wherein the pharma- ceutically acceptable oil comprises a triglyceride (e.g., a long-chain and/or medium-chain triglyceride), and the further pharma-ceutically acceptable solvent, if present, comprises an alcohol, an ester, and/or an acidic solvent.

[10] The pharmaceutical composition according to any one of [8] to [9], wherein the pharma- ceutically acceptable oil is selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil, and the further pharma-ceutically acceptable solvent, if present, comprises benzyl alcohol, benzyl benzoate, or a combination thereof.

[11] The pharmaceutical composition according to any one of [6] to [10], comprising a sufficient amount of abiraterone decanoate or a pharma- ceutical acceptable salt thereof to provide a therapeutically effective plasma concentration of abiraterone, i.e., a plasma concentration of abiraterone of about 1 ng/ml or more, for a period of at least two weeks (e.g., at least three weeks, at least four weeks, and up to six or eight weeks or more) after a single administration to a subject having one or more diseases selected from sex hormone-dependent benign or malignant diseases, syndromes due to androgen excess, and syndromes due to glucocorticoid excess such as hypercortisolism.

[12] A method for treating one or more diseases selected from sex hormone dependent benign or malignant diseases, syndromes caused by androgen excess, and syndromes caused by glucocorticoid excess such as hypercortisolism, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to any one of [5] to [11].

[13] The method according to [12], wherein the administration is by intramuscular injection, intradermal injection, or subcutaneous injection.

[14] The method according to any one of [12] to [13], wherein the pharmaceutical composition is administered to the subject with or without food.

[15] The method according to any one of [12] to [14], wherein the one or more diseases are selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, lung cancer, endometriosis, polycystic ovary syndrome, Cushing's syndrome, Cushing's disease, classical congenital adrenal hyperplasia, non-classical congenital adrenal hyperplasia, precocious puberty, hirsutism, and combinations thereof.

[16] The method according to any one of [12] to [14], wherein the one or more diseases are sex hormone-dependent benign or malignant diseases selected from castration-resistant prostate cancer and castration-sensitive prostate cancer.

[17] The method according to any one of [12] to [14], wherein the one or more diseases are sex hormone-dependent benign or malignant diseases selected from metastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer.

[18] The method according to any one of [12] to [17], wherein the subject is treated with a gonadotropin releasing hormone analogue and/or bilateral orchiectomy.

[19] The method according to any one of [12] to [18], further comprising administering a corticosteroid to the subject .

[20] The method according to any one of [12] to [19], further comprising administering prednisone, prednisolone, and/or methylprednisolone to the subject .

[21] The method according to any one of [12] to [20], wherein the pharmaceutical composition is administered to the subject at a dosing frequency ranging from once a week or more than once a week, e.g., from once a week to once every several months, e.g., from once a week to once every eight weeks, or from once a week to once every three months.

[22] The method of any one of [12] to [21], wherein the administration provides: (a) a plasma concentration of abiraterone greater than 1.0 ng/ml for a period of at least two weeks; (b) a single dose or steady state C _max of abiraterone of about 10 ng/ml to about 400 ng/ml; or (c) both (a) and (b).

を有する治療上有効な量のデカン酸アビラテロン、薬学的に許容される油、及び薬学的に許容される溶媒を含み、前記デカン酸アビラテロンは、約２５ｍｇ／ｍｌ～約５００ｍｇ／ｍｌの濃度で存在するその塩基性形態であり、例えば単位製剤である前記医薬組成物は、筋肉内注射、皮内注射、または皮下注射用に製剤化され、例えば単位製剤である前記医薬組成物は、約５０ｍｇ～約２，０００ｍｇの量の前記デカン酸アビラテロンを含む、前記医薬組成物。 [23] A pharmaceutical composition, for example a unit dosage form, comprising the following formula:

a pharma- ceutical composition comprising a therapeutically effective amount of abiraterone decanoate having a formula of:

[24] The pharmaceutical composition, e.g., a unit dosage form, according to [23], wherein the pharma- ceutically acceptable oil comprises a triglyceride, and the pharma-ceutically acceptable solvent comprises an alcohol, an ester, and/or an acidic solvent.

[25] The pharmaceutical composition, e.g., a unit formulation, according to [23] or [24], wherein the pharma- ceutically acceptable oil comprises vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil, the pharma-ceutically acceptable solvent comprises benzyl alcohol and/or benzyl benzoate, and the abiraterone decanoate is present at a concentration of about 50 mg/mL to about 300 mg/mL, e.g., about 100 mg/mL to about 300 mg/mL.

[26] A method for treating prostate cancer, comprising administering to a subject in need thereof a pharmaceutical composition, e.g., a unit formulation, described in any one of [23] to [25] via intramuscular, intradermal, or subcutaneous injection at a dosing frequency ranging from once a month or more than once a month, e.g., once a month to once every several months, e.g., once a month to once every two months, or once a month to once every three months.

[27] The method according to [26], wherein the pharmaceutical composition, e.g., a unit dosage form, is administered via intramuscular injection.

を有するデカン酸アビラテロンを混合して、混合物を形成することと、
ｂ） 任意選択で、ａ）で形成した前記混合物を滅菌することと
を含む、前記方法。 [28] A method for preparing an abiraterone decanoate formulation suitable for parenteral administration to a subject having, for example, a sex hormone dependent benign or malignant disease, a syndrome due to androgen excess, and/or a syndrome due to glucocorticoid excess, such as hypercortisolism, comprising:
a) in a pharma- ceutically acceptable carrier,

to form a mixture; and
b) optionally sterilizing the mixture formed in a).

[29] The method of [28], wherein the mixing comprises mixing a crystalline form of abiraterone decanoate in the pharma- ceutically acceptable carrier, the crystalline form being characterized by an X-ray powder diffraction (XRPD) spectrum having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) of the following peaks at 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6, and 20.8 degrees 2Θ (±0.2°); a differential scanning calorimetry (DSC) pattern having an endothermic peak at an onset temperature of about 69.0°C; or a combination thereof.

[30] The method of [28] or [29], wherein the pharma- ceutically acceptable carrier comprises a pharma-ceutically acceptable oil and a pharma-ceutically acceptable solvent, the pharma-ceutically acceptable oil comprises vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil, the pharma-ceutically acceptable solvent comprises benzyl alcohol or benzyl benzoate, and the abiraterone decanoate is present at a concentration of about 50 mg/mL to about 300 mg/mL, for example, about 100 mg/mL to about 300 mg/mL.

[0013] Embodiments of the present disclosure may fulfill a long-standing need in the field of sex hormone dependent diseases and oncology, including chemotherapy for prostate cancer. Embodiments of the present disclosure may also fulfill a long-standing need in the field of treatment of syndromes resulting from androgen excess and/or syndromes resulting from glucocorticoid excess, such as hypercortisolism. [0014] Embodiments of the present disclosure may overcome major shortcomings and deficiencies of prior art formulations of abiraterone acetate (including commercially available oral formulations) by providing long-acting, sustained release depot-based parenteral formulations of abiraterone prodrugs, methods of making same, methods of treatment using same, and kits for convenient administration of the formulations to subjects in need of treatment for various diseases, including prostate cancer.

The features have been outlined in a broader manner in order to provide a better understanding of the details set forth below, and to provide a better understanding of the present contribution to the art. Naturally, additional features are further described below. Indeed, it should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the present disclosure.

In this regard, before describing at least one embodiment in detail, it is to be understood that the invention is not limited in its application to the details and arrangements of construction set forth in the following description or illustrated in the following drawings. The invention is capable of other embodiments and of being practiced or carried out in various ways. Moreover, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

Thus, those skilled in the art will appreciate that the concepts underlying this disclosure may be readily utilized as a basis for the design of other formulations, methods, systems, kits, and compositions for carrying out some of the purposes of this disclosure. It is therefore important that equivalent structures within the scope of this disclosure are included in this disclosure.

The accompanying drawings are included to provide a further understanding, are incorporated in and constitute a part of the invention, illustrate several embodiments, and together with the description serve to explain the principles thereof.

[0023] Figure 1 shows the mean plasma concentrations of abiraterone (ng/ml) in rats at different time periods (hours) after IM administration of various abiraterone or abiraterone acetate formulations. Figure 1 shows the profile obtained with abiraterone acetate in castor oil (70 mg/ml), abiraterone acetate in sodium phosphate buffer, 0.1% Tween suspension (70 mg/ml), abiraterone in castor oil suspension (62.5 mg/ml), and abiraterone in sodium phosphate buffer, 0.1% Tween suspension (62.5 mg/ml). [0023] Figure 2 shows the mean plasma concentrations of abiraterone (ng/ml) in dogs at different time periods (hours) following IM or intravenous (IV) administration of various abiraterone acetate formulations. Figure 2 shows the profiles obtained from an abiraterone acetate solution (33% HP-β-cyclodextrin in water) administered IV at a dose of 10 mg/kg, an abiraterone acetate solution in castor oil (66 mg/ml) administered IM at a dose of 21 mg/kg, an abiraterone acetate solution in 10% benzyl alcohol in castor oil (91 mg/ml) administered IM at a dose of 30 mg/kg, and an abiraterone acetate solution in 50% benzyl benzoate in castor oil (124 mg/ml) administered IM at a dose of 42 mg/kg. FIG. 1 shows the mean plasma concentrations (ng/ml) of abiraterone (top line) and abiraterone acetate (bottom line) in dogs at different time periods (hours) following IV administration of abiraterone acetate (administered at 10.3 mg/ml as a solution in 33% HP-β-cyclodextrin in water). FIG. 1 shows the mean plasma concentrations (ng/ml) of abiraterone (top line) and abiraterone acetate (bottom line) in dogs at different time periods (hours) following IM administration of abiraterone acetate in 10% benzyl alcohol in castor oil (91 mg/ml) at a dose of 30 mg/kg. 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone decanoate following IV administration of 1.2 mg/kg abiraterone decanoate to dogs, with error bars representing standard deviation. 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone propionate following IV administration of 1 mg/kg abiraterone propionate to dogs, with error bars representing standard deviation. 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone decanoate following IM administration of 50 mg/kg abiraterone decanoate (90% castor oil/10% benzyl alcohol) to dogs. Error bars represent standard deviation. 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone decanoate following IM administration of 50 mg/kg abiraterone decanoate (90% corn oil/10% benzyl alcohol) to dogs. Error bars represent standard deviation. 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone propionate following IM administration of 41 mg/kg abiraterone propionate (90% castor oil/10% benzyl alcohol) to dogs. Error bars represent standard deviation. 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone propionate following IM administration of 41 mg/kg abiraterone propionate (90% corn oil/10% benzyl alcohol) to dogs. Error bars represent standard deviation. 1 shows exemplary predicted human abiraterone plasma concentrations following intramuscular administration of abiraterone decanoate by computer modeling in humans using an input half-life assumed to be the same as that observed in dogs. Computer modeling predictions are shown following IM administration of 120 mg abiraterone decanoate every two weeks. The horizontal line represents the target C _min value of approximately 8 ng/ml of abiraterone. 1 shows exemplary predicted human abiraterone plasma concentrations following intramuscular administration of abiraterone decanoate by computer modeling in humans using an input half-life assumed to be the same as that observed in dogs. Computer modeling predictions are shown following IM administration of 350 mg abiraterone decanoate every 4 weeks. The horizontal line represents the target C _min value of approximately 8 ng/ml of abiraterone. 1 shows exemplary predicted human abiraterone plasma concentrations following intramuscular administration of abiraterone decanoate by computer modeling in humans using an input half-life assumed to be the same as that observed in dogs. Computer modeling predictions are shown following IM administration of 1000 mg abiraterone decanoate every 6 weeks. The horizontal line represents the target C _min value of approximately 8 ng/ml of abiraterone. 1 shows exemplary predicted human abiraterone plasma concentrations following intramuscular administration of abiraterone decanoate by computer modeling in humans using an input half-life assumed to be the same as that observed in dogs. Computer modeling predictions are shown following IM administration of 1700 mg abiraterone decanoate every two months. The horizontal line represents the target C _min value of approximately 8 ng/ml of abiraterone. FIG. 1 shows a representative X-ray powder diffraction (XRPD) spectrum of the abiraterone decanoate solid form prepared in Example 6A. FIG. 1 shows a differential scanning calorimetry (DSC) spectrum of the abiraterone decanoate solid form prepared in Example 6A. FIG. 1 shows a thermogravimetric analysis (TGA) of the abiraterone decanoate solid form prepared in Example 6A. 1 shows a plot of the solubility of abiraterone decanoate in corn oil in the presence of various amounts of benzyl alcohol and benzyl benzoate. 1 shows a contour plot of the solubility of abiraterone decanoate in corn oil in the presence of various amounts of benzyl alcohol and benzyl benzoate. Viscosity (Pa ^*s ) is shown for an oil vehicle containing no additive, an oil vehicle containing 10% benzyl alcohol, an oil vehicle containing 20% benzyl benzoate, or an oil vehicle containing a combination of 10% benzyl alcohol and 20% benzyl benzoate. Shown is the glide force (N) of an oil vehicle with no additive, an oil vehicle containing 10% benzyl alcohol, an oil vehicle containing 20% benzyl benzoate, or an oil vehicle containing a combination of 10% benzyl alcohol and 20% benzyl benzoate, tested in a 5 ml syringe with a 23 gauge needle. Shown is the glide force (N) of an oil vehicle with no additive, an oil vehicle containing 10% benzyl alcohol, an oil vehicle containing 20% benzyl benzoate, or an oil vehicle containing a combination of 10% benzyl alcohol and 20% benzyl benzoate, tested in a 5 ml syringe with a 27 gauge needle. 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone decanoate following IV administration of 1.2 mg/kg abiraterone decanoate (0.4 mg/ml solution in 40% HP-β-cyclodextrin, 25 mM sodium phosphate buffer, pH 7.4) to male cynomolgus monkeys (n=3). FIG. 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone decanoate following a single IM administration of an abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 192 mg/ml abiraterone decanoate) at a dose of 90 mg/kg of abiraterone decanoate to male cynomolgus monkeys (n=3). The observed time course data for steroid levels (progesterone, cortisol and testosterone levels) following this single IM administration are shown. As shown in FIG. 14C, prolonged CYP17A1 inhibition was achieved following a single IM injection, as evidenced by sustained elevated progesterone levels and reduced glucocorticoid (cortisol) and sex hormone (testosterone) levels. 14A depicts biochemical pathways showing the effect of CYP17A1 inhibition on the synthesis of androgens, estrogens, glucocorticoids, progesterone, and mineralocorticoids. As shown in FIG. 14D, inhibition of CYP17A1 17a-hydroxylase and C17,20-lyase activity results in (1) increased levels of progesterone and mineralocorticoids, (2) decreased levels of glucocorticoids such as cortisol, and (3) decreased levels of sex hormones, e.g., androgens such as testosterone and dihydrotestosterone, and estrogens such as estradiol. 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone decanoate following repeated IM administration of an abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 192 mg/ml abiraterone decanoate) to male cynomolgus monkeys (n=3) on days 0, 7, and 35. Each dose of abiraterone decanoate was 90 mg/kg. 1 shows time course data for mean plasma concentrations of abiraterone following repeated dosing of abiraterone decanoate Formulation 1 (90% corn oil, 10% benzyl alcohol, 207 mg/ml abiraterone decanoate) or Formulation 2 (70% corn oil, 10% benzyl alcohol, 20% benzyl benzoate, 209 mg/ml abiraterone decanoate) IM to male cynomolgus monkeys (n=1) on days 0, 7, and 14. Each dose of abiraterone decanoate is 100 mg/kg. 1 shows mean plasma concentration time course data for abiraterone and abiraterone decanoate following IV administration of 1.2 mg/kg abiraterone decanoate (0.4 mg/ml solution in 40% HP-β-cyclodextrin, 25 mM sodium phosphate buffer, pH 7.4) to male rats (n=5). FIG. 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone decanoate following a single IM administration of an abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 172 mg/ml abiraterone decanoate) to male rats (n=5) at a dose of 90 mg/kg abiraterone decanoate. 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone decanoate following repeated IM dosing of an abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 172 mg/ml abiraterone decanoate) to male rats (n=5) on days 0, 7, and 35. Each dose of abiraterone decanoate was 90 mg/kg. 1 shows allometric scaling of the volume of distribution (Vss) of abiraterone in rats, dogs, and monkeys, and predicted in humans. 1 shows the predicted plasma profile of abiraterone in humans following a single intramuscular dose of 1 mg abiraterone based on a bioavailability of 56%. 1 shows the predicted plasma profile of abiraterone in humans following repeated intramuscular administration of 1000 mg abiraterone decanoate every 4 weeks based on a bioavailability of 56%. 1 shows the predicted plasma profile of abiraterone in humans following repeated intramuscular administration of 1000 mg abiraterone decanoate every four weeks, assuming complete bioavailability. 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone isocaproate following IV administration of 1.0 mg/kg abiraterone isocaproate to dogs, with error bars representing standard deviation. 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone isocaproate following IM administration of abiraterone isocaproate to dogs, with error bars representing standard deviation. 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone decanoate following IM administration of abiraterone decanoate to dogs, with error bars representing standard deviation. 1 shows time course data for mean plasma concentrations of abiraterone following IM administration of abiraterone isocaproate or abiraterone decanoate to dogs, with error bars representing standard deviation.

DETAILED DESCRIPTION The present disclosure relates to compounds and compositions that deliver therapeutic plasma levels of the potent abiraterone to a subject over an extended period of time. Initial experiments in rats demonstrated that intramuscular injection of a suspension of the potent abiraterone did not achieve the desired therapeutic plasma levels. However, as detailed herein, representative novel abiraterone prodrugs and formulations have been found to achieve the desired therapeutic plasma levels over an extended period of time when administered parenterally (e.g., intramuscularly).

Thus, various embodiments of the present disclosure are directed to novel abiraterone prodrugs and formulations that have various advantages over existing abiraterone formulations, such as commercially available oral abiraterone acetate formulations. Such advantages include, but are not limited to, improved bioavailability, elimination of the food effect associated with oral abiraterone acetate formulations, reduced dosage burden, improved patient compliance, less frequent dosing, maintenance of stable blood levels of potent drug, and lower _Cmax that can reduce associated side effects. In some embodiments, methods of using the novel abiraterone prodrugs and formulations to treat, for example, sex hormone-dependent benign or malignant diseases (e.g., prostate cancer), syndromes due to androgen excess, and/or syndromes due to glucocorticoid excess, such as hypercortisolism, are also provided.

Compounds of Formula I In some embodiments, the present disclosure provides novel abiraterone prodrugs. In some embodiments, the novel abiraterone prodrugs are compounds of formula I or a pharma- ceutically acceptable salt thereof.

のような分枝鎖Ｃ５またはＣ６アルキルから選択される。 A variety of groups are suitable for R ¹ in formula I. In some embodiments, R ¹ can be selected such that the compound of formula I is an ester (e.g., a lipophilic ester), a carbamate ester, or a carbonate ester of abiraterone. In some embodiments, R ¹ is R ¹⁰ , O-R ¹⁰ , or NHR ¹⁰ , where R ¹⁰ is selected from C _7-30 alkyl; C _7-30 alkenyl; C _7-30 alkynyl; alkyl substituted with cycloalkyl, typically having a total of 5 to 16 carbon atoms; alkyl substituted with phenyl, typically having a total of 7 to 16 carbon atoms; cycloalkyl optionally substituted with one or more alkyl, typically having a total of 5 to 16 carbon atoms; and

and the like.

In some preferred embodiments, R ¹⁰ is a C _7-30 alkyl. As used herein, unless expressly stated to be substituted, alkyl should be understood to be unsubstituted. However, alkyl may be either straight or branched. In some embodiments, R 10 may be a straight chain C 7-30 alkyl. In some embodiments, R ¹⁰ may be a branched chain C _7-30 alkyl. In some embodiments, R ¹⁰ is a straight chain C _7-16 alkyl, e.g., R ¹⁰ may have the formula -(CH ₂ ) _n -CH ₃ , where n is an integer between 6 and 15 (e.g., between 6 and ₁₂ , such as 6 ^, 7, 8, 9, 10, 11, or 12). In some embodiments, R ¹⁰ may be a branched chain C _7-16 alkyl.

In some embodiments, R ¹⁰ may also be an alkyl substituted with a cycloalkyl. Typically, in such embodiments, R ¹⁰ has a total of 5-16 carbons, in other words, the total number of carbons in the alkyl and cycloalkyl portions is 5-16. The cycloalkyl is typically unsubstituted. However, in some embodiments, the cycloalkyl may be optionally substituted, for example, with one or two lower alkyls (e.g., C _1-4 alkyl). In some embodiments, R ¹⁰ is an alkyl substituted with a C 3-6 cycloalkyl, typically having a total of 6-12 carbons. In some embodiments, R ¹⁰ is a straight chain alkyl substituted with a C _3-6 cycloalkyl, e.g., R ¹⁰ may have the formula -(CH ₂ ) _n -Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) and Cy is a C _3-6 cycloalkyl (such as cyclopropyl, _cyclobutyl , cyclopentyl, or cyclohexyl). In some embodiments, R ¹⁰ may have the formula -(CH ₂ ) _n -Cy, where n is 1 or 2, and Cy is cyclopentyl or cyclohexyl. In some embodiments, R ¹⁰ may also be a branched alkyl (e.g., branched C _2-6 ) substituted with a C _3-6 cycloalkyl. As used herein, branched C2 alkyl should be understood to be a 1,1-disubstituted ethyl group, e.g., CH(CH ₃ )-Cy.

In some embodiments, R ¹⁰ may also be an alkyl substituted with a phenyl. Typically, in such embodiments, R ¹⁰ has a total of 7-16 carbons, in other words, the total number of carbons in the alkyl and phenyl portions is 5-16. In some embodiments, R ¹⁰ is a straight chain alkyl substituted with a phenyl, e.g., R ¹⁰ may have the formula -(CH ₂ ) _n -Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is phenyl. In some embodiments, R ¹⁰ may have the formula -(CH ₂ ) _n -Cy, where n is 1 or 2, and Cy is phenyl. In some embodiments, R ¹⁰ may also be a branched chain alkyl substituted with a phenyl (e.g., branched C _2-6 ). The phenyl is typically unsubstituted. However, in some embodiments, the phenyl may be optionally substituted, for example, with one or two lower alkyl (eg, C _1-4 alkyl).

であってよい。 In some embodiments, R ¹⁰ may be cycloalkyl optionally substituted with one or more alkyl. In such embodiments, R ¹⁰ typically has a total of 5 to 16 carbons, in other words, the total number of carbons in the cycloalkyl and its optional substituents is 5 to 16. In some embodiments, R ¹⁰ may be a C _3-6 cycloalkyl that is unsubstituted or substituted with a C _1-4 alkyl. In some particular embodiments, R ¹⁰ is

It may be.

であってよい。その他の分枝鎖Ｃ５またはＣ６アルキルもまた、好適である。 In some embodiments, R ¹⁰ can be a branched C5 or C6 alkyl. In some embodiments, R ¹⁰ can be:

Other branched C5 or C6 alkyls are also suitable.

In some embodiments, R ¹⁰ can be an unsaturated aliphatic group, such as a C _7-30 alkenyl or a C _7-30 alkynyl.

であってよい。いくつかの特定の実施形態では、式Ｉ中のＲ^１は

であってよい。Ｒ^１のその他の好適な基は、本明細書にて定義するＲ^１０のいずれかを含む。 In some preferred embodiments, the compound of formula I is an ester of abiraterone, e.g., R ¹ is R ¹⁰ , where R ¹⁰ is defined herein. In some embodiments, R ¹ in formula I can be a C _7-16 alkyl, e.g., alkyl has the formula -(CH ₂ ) _n -CH ₃ , where n is an integer between 6 and 12 (e.g., 6, 7, 8, 9, 10, 11, or 12). In some embodiments, R ¹ in formula I can be represented by the formula -(CH ₂ ) _n -Cy, where n is an integer between 1 and 6, and Cy is a C _3-6 cycloalkyl or phenyl, e.g., in more specific embodiments, n can be 1 or 2, and Cy is cyclopentyl, cyclohexyl, or phenyl. In some particular embodiments, R ¹ in formula I can be

In some particular embodiments, R ¹ in formula I may be

Other suitable groups for R ¹ include any of R ¹⁰ defined herein.

In some embodiments, R ¹ in formula I can also be OR ¹⁰ or NHR ¹⁰ , where R ¹⁰ is defined herein.

Typically, the compound of formula I may be present in the formulation, e.g., in a non-aqueous formulation, in its basic form. However, in some embodiments, pharma- ceutically acceptable salts of the compound of formula I are also useful. Unless specifically referred to as its salt form or unless otherwise contradicted by context, the compound of formula I may be in its basic form in the abiraterone prodrug formulations described herein.

Compounds of Formula I can be readily synthesized by one of skill in the art in light of the present disclosure. Exemplary syntheses of representative compounds are provided in the Examples section. For example, esters of Formula I can typically be prepared by reacting abiraterone with the corresponding carboxylic acid or with an activated form thereof, such as the corresponding acyl chloride, anhydride, etc. Exemplary reaction conditions using activated forms, such as acyl chlorides, are provided in the Examples section.

Abiraterone Prodrug Formulations The abiraterone prodrugs herein, including the compound of Formula I, are useful for delivering abiraterone to a subject in need thereof, for example, a subject having a sex hormone-dependent benign or malignant disease herein, a syndrome resulting from androgen excess, and/or a syndrome resulting from glucocorticoid excess, such as hypercortisolism. Typically , the abiraterone prodrug is formulated as a parenteral formulation, such as an intramuscular, intradermal, or subcutaneous formulation, and in some embodiments, can be formulated to deliver therapeutically effective plasma concentrations of abiraterone over an extended period of time, such as, for example, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, and up to 6 or 8 weeks or more.

Various abiraterone prodrugs, such as abiraterone esters, carbamates, carbonates, etc., are suitable for the compositions and methods of the present disclosure. In some embodiments, the present disclosure provides a pharmaceutical composition (alternatively sometimes referred to herein as an abiraterone prodrug formulation) comprising a compound of formula I (e.g., any one or more as defined herein), or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition can be formulated for parenteral administration, such as intramuscular, intradermal, or subcutaneous injection. The pharmaceutical composition typically includes a pharma- ceutically acceptable carrier. Suitable carriers include those known in the art, e.g., those listed in "Remington: The Science and Practice of Pharmacy" (formerly "Remington's Pharmaceutical Sciences" University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia, Pa. (2005)) and the Inactive Ingredients Database of FDA-Approved Drugs at the Center for Drug Evaluation and Research of the U.S. Food and Drug Administration. In some embodiments, a pharma- ceutically acceptable carrier can be a carrier approved for use by the FDA for intramuscular, intradermal, or subcutaneous drugs, e.g., one listed in the FDA's Inactive Ingredients Database. In some embodiments, the pharmaceutically acceptable carrier may be any suitable non-aqueous vehicle suitable for injection, such as those described in the United States Pharmacopoeia. In some embodiments, the pharmaceutically acceptable carrier may be a pharmaceutically acceptable oil, such as vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil. In some embodiments, the pharmaceutically acceptable oil may be an oil suitable as a vehicle for injection (e.g., as described herein), such as one that meets the criteria described in the corresponding monographs of the United States Pharmacopoeia. In some embodiments, the pharmaceutically acceptable oil may be a plant-derived oil suitable as a vehicle for injection. In some embodiments, the pharmaceutically acceptable oil may be a synthetic oil suitable as a vehicle for injection, such as a synthetic monoglyceride or diglyceride of fatty acid, for example, that is liquid, remains a clear liquid when cooled to 10° C., and has an iodine value of 140 or less. In some embodiments, the pharma- ceutically acceptable oil may be a natural oil, a synthetic oil, or a semi-synthetic oil, such as fractionated coconut oil and a medium chain triglyceride, such as that sold under the trademark Miglyol. In some embodiments, the pharma- ceutically acceptable carrier comprises a triglyceride derived from a fatty acid. In some embodiments, the pharma- ceutically acceptable carrier comprises a triglyceride derived from a long and/or medium chain fatty acid, which may be independently polyunsaturated, monounsaturated, or saturated. In some embodiments, two or more different pharma- ceutical acceptable oils may be used. In some embodiments, the pharmaceutical composition is a non-aqueous solution or suspension. In some embodiments, the pharmaceutical composition further comprises a pharma- ceutical acceptable solvent, such as benzyl alcohol. In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof may be present in the pharmaceutical composition at a concentration of about 25 mg/ml to about 500 mg/ml (e.g., about 25 mg/ml, about 50 mg/ml, about 100 mg/ml, about 150 mg/ml, about 200 mg/ml, about 250 mg/ml, about 300 mg/ml, about 400 mg/ml, about 500 mg/ml, or any of the ranges of values recited).

式中のＲ^２については、本明細書にて定義する。いくつかの実施形態では、医薬組成物は、筋肉内注射、皮内注射、または皮下注射用に製剤化することができる。いくつかの実施形態では、式ＩＩの化合物またはそれらの薬学的に許容される塩は、約２５ｍｇ／ｍｌ～約５００ｍｇ／ｍｌ（例えば、約２５ｍｇ／ｍｌ、約５０ｍｇ／ｍｌ、約１００ｍｇ／ｍｌ、約１５０ｍｇ／ｍｌ、約２００ｍｇ／ｍｌ、約２５０ｍｇ／ｍｌ、約３００ｍｇ／ｍｌ、約４００ｍｇ／ｍｌ、約５００ｍｇ／ｍｌまたは列挙した値の範囲のいずれか）の濃度で医薬組成物中に存在し得る。いくつかの実施形態では、医薬組成物は、非水性溶液または懸濁液である。いくつかの実施形態では、式ＩＩの化合物またはそれらの薬学的に許容される塩は、植物油、ヒマシ油、コーン油、ゴマ油、綿実油、ピーナッツ油、ケシ種子油、茶種子油、または大豆油などの（例えば、本明細書に記載されるような）薬学的に許容される油中に溶解または懸濁している。いくつかの実施形態では、医薬組成物は、ベンジルアルコールなどの薬学的に許容される溶媒をさらに含む。 In some embodiments, the disclosure also provides pharmaceutical compositions (alternatively sometimes referred to herein as abiraterone prodrug formulations) comprising a compound of formula II or a pharma- ceutically acceptable salt thereof.

wherein R ² is as defined herein. In some embodiments, the pharmaceutical composition can be formulated for intramuscular, intradermal, or subcutaneous injection. In some embodiments, the compound of formula II or a pharma- ceutically acceptable salt thereof can be present in the pharmaceutical composition at a concentration of about 25 mg/ml to about 500 mg/ml (e.g., about 25 mg/ml, about 50 mg/ml, about 100 mg/ml, about 150 mg/ml, about 200 mg/ml, about 250 mg/ml, about 300 mg/ml, about 400 mg/ml, about 500 mg/ml, or any of the ranges of values recited). In some embodiments, the pharmaceutical composition is a non-aqueous solution or suspension. In some embodiments, the compound of formula II or a pharma- ceutically acceptable salt thereof is dissolved or suspended in a pharma- ceutically acceptable oil (e.g., as described herein), such as vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil. In some embodiments, the pharmaceutical composition further comprises a pharma- ceutically acceptable solvent, such as benzyl alcohol.

A variety of groups are suitable for R ² in formula II. In some embodiments, R ² can be selected such that the compound of formula II is an ester, carbamate, or carbonate ester of abiraterone. In some embodiments, R ² is R ²⁰ , O-R ^{20, or NHR 20 ,} and R ²⁰ is selected from C _1-30 alkyl; C _2-30 alkenyl; C _2-30 alkynyl; alkyl substituted with cycloalkyl, typically having a total of 4 to 30 carbon atoms; alkyl substituted with phenyl, typically having a total of 7 to 30 carbon atoms; and cycloalkyl optionally substituted with one or more alkyl, typically having a total of 3 to 30 carbon atoms.

であってよい。いくつかの実施形態では、Ｒ^２０は、式－（ＣＨ_２）_ｎ－ＣＨ_３を有する場合があり、式中ｎは０～１２の間（例えば、６、７、８、９、１０、１１または１２などの６～１２の間）の整数である。 In some preferred embodiments, R ²⁰ is a C _1-16 alkyl. In some embodiments, R ²⁰ can be a straight chain C _1-16 alkyl. In some embodiments, R ²⁰ can be a branched chain C _3-16 alkyl. In some embodiments, R ²⁰ can be a branched chain C 5 or C 6 alkyl. In some embodiments, R ²⁰ is:

In some embodiments, R ²⁰ may have the formula -(CH ₂ ) _n -CH ₃ , where n is an integer between 0 and 12 (e.g., between 6 and 12, such as 6, 7, 8, 9, 10, 11, or 12).

In some embodiments, R ²⁰ may also be an alkyl substituted with a cycloalkyl. Typically, in such embodiments, R ²⁰ has a total of 4 to 30 carbons, such as a total of 5 to 16 carbons (in other words, the total number of carbons in the alkyl and cycloalkyl portions is 5 to 16). The cycloalkyl is typically unsubstituted. However, in some embodiments, the cycloalkyl may be optionally substituted, for example, with one or two lower alkyls (e.g., C _1-4 alkyl). In some embodiments, R ²⁰ is an alkyl substituted with a C _3-6 cycloalkyl, typically having a total of 6 to 12 carbons. In some embodiments, R ²⁰ is a straight chain alkyl substituted with a C _3-6 cycloalkyl, for example, R ²⁰ may have the formula -(CH ₂ ) _n -Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) and Cy is a C _3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, R ²⁰ may have the formula -(CH ₂ ) _n -Cy, where n is 1 or 2 and Cy is cyclopentyl or cyclohexyl. In some embodiments, R ²⁰ may also be a branched chain alkyl substituted with a C _3-6 cycloalkyl (e.g., branched C _2-6 ).

In some embodiments, R ²⁰ may also be an alkyl substituted with a phenyl. Typically, in such embodiments, R ²⁰ has a total of 7 to 30, such as a total of 7 to 16 carbons (in other words, the total number of carbons in the alkyl and phenyl portions is 7 to 16). In some embodiments, R ²⁰ is a straight chain alkyl substituted with a phenyl, e.g., R ²⁰ may have the formula -(CH ₂ ) _n -Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is phenyl. In some embodiments, R ²⁰ may have the formula -(CH ₂ ) _n -Cy, where n is 1 or 2, and Cy is phenyl. In some embodiments, R ²⁰ may also be a branched chain alkyl substituted with a phenyl (e.g., branched C _2-6 ). The phenyl is typically unsubstituted. However, in some embodiments, the phenyl may be optionally substituted, for example, with one or two lower alkyl (eg, C _1-4 alkyl).

であってよい。 In some embodiments, R ²⁰ may be cycloalkyl optionally substituted with one or more alkyl. In such embodiments, R ²⁰ typically has a total of 3 to 30, such as a total of 5 to 16 carbons (in other words, the total number of carbons in the cycloalkyl and its optional substituents is 5 to 16). In some embodiments, R ²⁰ may be a C _3-6 cycloalkyl that is unsubstituted or substituted with a C _1-4 alkyl. In some particular embodiments, R ²⁰ is

It may be.

In some embodiments, R ²⁰ can be an unsaturated aliphatic group, such as a C _2-30 alkenyl or a C _2-30 alkynyl.

であってよい。Ｒ^２のその他の好適な基は、本明細書にて定義するＲ^２０のいずれかを含む。いくつかの実施形態では、アビラテロンエステルは、アビラテロンの、酢酸エステル、プロピオン酸エステル、ブタン酸エステル、（バテレート（ｖａｔｅｒａｔｅ））ペンタン酸エステル、イソカプロン酸エステル、ブシクラート、シクロヘキサンカルボン酸エステル、フェニルプロピオン酸エステル、カプロン酸エステル（ヘキサン酸エステル）、エナント酸エステル（ヘプタン酸エステル）、シピオン酸エステル、オクタン酸エステル、ノンカノエート（ｎｏｎｃａｎｏａｔｅ）、デカン酸エステル、ウンデカン酸エステル、ドデカン酸エステル、トリデカン酸エステル、テトラデカン酸エステル、ペンタデカン酸エステル、またはヘキサデカン酸エステルであってよい。いくつかの実施形態では、アビラテロンエステルは、酢酸アビラテロン、プロピオン酸アビラテロン、及びデカン酸アビラテロンであってよい。いくつかの特定の実施形態では、アビラテロンエステルは、ペンタン酸アビラテロン、ヘキサン酸アビラテロン、ヘプタン酸アビラテロン、デカン酸アビラテロン、イソカプロン酸アビラテロン、またはシピオン酸アビラテロンであってよい。 In some preferred embodiments, the compound of formula II is an abiraterone ester, e.g., R ² is R ²⁰ , where R ²⁰ is defined herein. In some embodiments, R ² in formula II can be a C _1-16 alkyl, e.g., alkyl has the formula -(CH ₂ ) _n -CH ₃ , where n is an integer from 0 to 12. In some embodiments, R ² in formula II can be represented by the formula -(CH ₂ ) _n -Cy, where n is an integer from 1 to 6 and Cy is a C _3-6 cycloalkyl or phenyl, e.g., in more specific embodiments, n can be 1 or 2 and Cy is cyclopentyl, cyclohexyl, or phenyl. In some particular embodiments, R ² in formula II is

Other suitable groups for ^R2 include any of ^R20 as defined herein. In some embodiments, the abiraterone ester may be an acetate, propionate, butanoate, (vaterate) pentanoate, isocaproate, bucclate, cyclohexanecarboxylate, phenylpropionate, caproate (hexanoate), enanthate (heptanoate), cypionate, octanoate, noncanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate, or hexadecanoate ester of abiraterone. In some embodiments, the abiraterone ester may be abiraterone acetate, abiraterone propionate, and abiraterone decanoate. In some particular embodiments, the abiraterone ester may be abiraterone pentanoate, abiraterone hexanoate, abiraterone heptanoate, abiraterone decanoate, abiraterone isocaproate, or abiraterone cypionate.

In some embodiments, R ² in formula II can also be O--R ²⁰ or NHR ²⁰ , where R ²⁰ is defined herein.

Typically, the compound of formula II may be present in the formulation, e.g., in a non-aqueous formulation, in its basic form. However, in some embodiments, pharma- ceutically acceptable salts of the compound of formula II are also useful. Unless specifically referred to as its salt form or unless otherwise contradicted by context, the compound of formula II may be in its basic form in the abiraterone prodrug formulations described herein.

Compounds of formula II can be readily synthesized by one of skill in the art in light of the present disclosure. Exemplary syntheses of representative compounds are provided in the Examples section. For example, esters of formula II can typically be prepared by reacting abiraterone with the corresponding carboxylic acid or with an activated form thereof, such as the corresponding acyl chloride, anhydride, etc. Exemplary reaction conditions using activated forms, such as acyl chlorides, are provided in the Examples section.

Typically, the abiraterone prodrugs of the present disclosure are formulated as non-aqueous solutions or suspensions. In some embodiments, the non-aqueous solutions or suspensions provide higher concentrations of abiraterone in plasma for a longer period of time when compared to aqueous solutions or suspensions. For example, as detailed herein, IM injections of aqueous and vegetable oil solutions of abiraterone acetate prodrugs were evaluated in rats. Surprisingly, it was determined that the vegetable oil solution of abiraterone acetate prodrug (not the aqueous suspension) provided the highest plasma levels and the longest exposure of the potent abiraterone (see FIG. 1). Thus, in some embodiments, the abiraterone prodrug formulations herein may include the abiraterone prodrugs of the present disclosure (e.g., compounds of formula I or II) dissolved or dispersed in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier may be any suitable non-aqueous vehicle suitable for injection, such as those described in the United States Pharmacopeia. In some embodiments, the pharma- ceutically acceptable carrier may be a pharma- ceutically acceptable oil, such as vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil. In some embodiments, the pharma- ceutically acceptable oil may be an oil suitable as a vehicle for injection (e.g., as described herein), e.g., one that meets the criteria as described in the corresponding monographs of the United States Pharmacopeia. In some embodiments, the pharma- ceutically acceptable oil may be a plant-derived oil suitable as a vehicle for injection. In some embodiments, the pharma- ceutically acceptable oil may be a synthetic oil suitable as a vehicle for injection, such as a synthetic monoglyceride or diglyceride of fatty acids, e.g., a liquid, remains a clear liquid when cooled to 10° C., and has an iodine value of 140 or less. In some embodiments, the pharma- ceutically acceptable oil may be a natural oil, a synthetic oil, or a semi-synthetic oil, such as fractionated coconut oil and medium chain triglycerides, such as those sold under the trademark Miglyol. In some embodiments, the pharma- ceutically acceptable carrier comprises a triglyceride derived from a fatty acid. In some embodiments, the pharma-ceutically acceptable carrier comprises a triglyceride derived from a long-chain and/or medium-chain fatty acid, which may be independently polyunsaturated, monounsaturated, or saturated. In some embodiments, the pharma-ceutically acceptable oil may be any oil approved for use by the FDA for intramuscular, intradermal, or subcutaneous drugs, e.g., any oil listed in the FDA's Inactive Ingredients Database. In some particular embodiments, the pharma-ceutically acceptable oil is castor oil or corn oil. In some embodiments, two or more different pharma-ceutically acceptable oils may be used.

Other ingredients may also be optionally included in the abiraterone prodrug formulations herein. In some embodiments, the abiraterone prodrug formulation may further include a pharma- ceutically acceptable solvent, such as benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid, and ethyl acetate. It has been determined that the additives/co-solvents benzyl alcohol and benzyl benzoate not only increase the solubility of the prodrug, but also reduce the viscosity and/or glide force of the solution (see Figures 13A-13E and Tables 2A-2D), thereby resulting in a more concentrated solution that is easier to inject through gauge needles acceptable for IM injection (e.g., 20-27 gauge, e.g., 22-25 gauge). Co-solvents may be selected based on their ability to reduce the viscosity of the vehicle to allow injection through an appropriate needle or cannula. Benzyl alcohol as an additive for IM or subcutaneous injections has the advantage that it can act as a local anesthetic at the injection site (Wilson et al. Ann. Emer. Med. 33(5), 495, 1999). In some embodiments, the abiraterone prodrug formulation further comprises benzyl alcohol. In some embodiments, a co-solvent, if present, may be included at a level that does not cause irritation (i.e., minimal or tolerable irritation) at the injection site (e.g., about 0-50%, e.g., 10%).

In some embodiments, the abiraterone prodrug formulation may include benzyl benzoate as a co-solvent, e.g., about 0-50%, typically 0-35% or 0-30%, or about 20% of the solvent. In some embodiments, the abiraterone prodrug formulation may include a combination of benzyl alcohol and benzyl benzoate as co-solvents. In some embodiments, the benzyl alcohol may be present in an amount of about 0-20% (e.g., 0-15% or 0-10%, e.g., about 10%) of the solvent, and the benzyl benzoate may be present in an amount of about 0-50% (e.g., 0-35% or 0-30%, e.g., about 20%) of the solvent, with the remainder of the solvent being any one or more of the pharma- ceutically acceptable oils described herein, such as corn oil, castor oil, sesame oil, peanut oil, cottonseed oil, and/or Miglyol 812. As discussed in more detail in the Examples section, the inclusion of benzyl benzoate in various oil vehicles has been found to be advantageous in a variety of ways. See, e.g., Figures 13A-13E and Tables 2A-2D. For example, the combination of benzyl alcohol and benzyl benzoate has been shown to provide lower viscosity and glide force compared to the use of benzyl alcohol alone or benzyl benzoate alone. Additionally, unexpectedly, a representative abiraterone prodrug (abiraterone decanoate) formulation comprising oil (70% corn oil), benzyl alcohol (10%) and benzyl benzoate (20%) was found to provide higher abiraterone plasma exposure in monkeys compared to the same oil vehicle without benzyl benzoate, i.e., a formulation comprising 90% corn oil and 10% benzyl alcohol, containing substantially the same concentration of abiraterone decanoate and administered in the same amount.

While the oil vehicles described herein are typically used for the abiraterone prodrugs of the present disclosure, such oil vehicles are also contemplated for potential use in formulating other active ingredients. In some embodiments, the present disclosure also provides an oil vehicle that includes benzyl alcohol in an amount of about 0-20% (e.g., 0-15% or 0-10%, e.g., about 10%) of the oil vehicle, and benzyl benzoate in an amount of about 0-50% (e.g., 0-35% or 0-30%, e.g., about 20%) of the oil vehicle, with the remainder of the oil vehicle being any one or more of the pharma- ceutically acceptable oils described herein, such as corn oil, castor oil, sesame oil, peanut oil, cottonseed oil, and/or Miglyol 812.

The solubility of the abiraterone ester may be affected by the addition of a co-solvent to the vegetable oil vehicle. In some embodiments, the abiraterone ester is completely dissolved within the composition, while in other embodiments, the abiraterone ester is partially dispersed within the composition. In one embodiment, the abiraterone ester is completely dissolved in the vehicle.

Abiraterone prodrug formulations may also contain pharma- ceutically acceptable preservatives, polymers, antioxidants, antimicrobials, chelating agents, and other excipients, including but not limited to citric acid, dextrose, ascorbic acid, benzalkonium chloride, benzoic acid, betadex sodium sulfobutylether, calcium chloride, sodium carbomethoxycellulose, chlorobutanol, creatine, croscarmellose, potassium dibasic phosphate, docusate sodium, sodium edetate, glycerin, sodium hyaluronate, hydroxypropyl betadex, lactic acid, lactose, lecithin, maleic acid, mannitol, meglumine, methylcellulose, methylparaben, microcrystalline cellulose, miripitium chloride, methylcellulose, methylparaben, methylcellulose ... chloride), monothioglycerol, phenol, poloxamer 188, polyglactin, polysorbate 20, polysorbate 40, polysorbate 80, propylparaben, sodium acetate, sodium benzoate, sodium citrate, sorbitan monolaurate, sorbitol, sucrose, tartaric acid, trisodium citrate, tromantadine, tromethamine, and urea.

Abiraterone prodrug formulations may be sterilized by methods known to those of skill in the art (e.g., gamma irradiation, micron filtration, and autoclaving).

LONG-ACTING RELEASE OF ABIRATERONE The abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure (e.g., formulations containing a compound of Formula I or II as described herein) are typically formulated to provide a long-acting release form of abiraterone, preferably as a parenteral formulation, such as an intramuscular, intradermal, or subcutaneous formulation, to a subject in need thereof, such as, for example , having a sex hormone-dependent benign or malignant disease, syndrome resulting from androgen excess, and/or syndrome resulting from glucocorticoid excess, such as hypercortisolism. In some embodiments, the disclosed abiraterone prodrugs and abiraterone prodrug formulations (e.g., formulations containing a compound of Formula I or II as described herein) can be formulated to deliver therapeutic range plasma levels of abiraterone for extended periods of time (e.g., at least 1 week, e.g., at least 2 weeks, at least 3 weeks, at least 4 weeks, and up to 6 or 8 weeks or more) following a single administration to a subject having a hormone-dependent benign or malignant disease, a syndrome resulting from androgen excess, and/or a syndrome resulting from glucocorticoid excess, such as hypercortisolism. In some embodiments, the therapeutic range plasma concentration of abiraterone may be at a concentration of at least 1 ng/ml, e.g., at least 2 ng/ml, at least 4 ng/ml, at least 8 ng/ml. In some embodiments, the therapeutic range plasma concentration of abiraterone may be about 0.5 ng/ml or greater.

As shown herein, abiraterone acetate vegetable oil IM injection was evaluated in dogs. Solutions of abiraterone acetate in castor oil, co-solvents benzyl alcohol and benzyl benzoate were prepared at various strengths (66-124 mg/ml) and injected intramuscularly in dogs, and plasma levels of the parent abiraterone drug were measured over a 3-week period (see FIG. 2). Data from the dog study showed that abiraterone acetate given as a solution in castor oil (with or without benzyl alcohol) resulted in measurable blood levels for up to 504 hours. Absolute bioavailability results for these formulations ranged from 61.7-86.2%. This is the first demonstration that it is possible to deliver abiraterone to a subject over an extended period of time with a single injection, thus allowing for administration frequencies ranging from once per week to once more than once per week, for example, from once per week to once every several months, such as once per week to once every 8 weeks or once per week to once every 3 months.

Without wishing to be bound by theory, it is believed that the duration of action of the prodrug depends on the choice of prodrug (e.g., ester moiety) and the choice of oil vehicle, as it is controlled by both the rate of release of the prodrug from the oil vehicle into aqueous tissues and the rate of bioconversion of the ester prodrug to unchanged abiraterone. Unlike when abiraterone acetate is administered orally, where bioconversion occurs before the drug is absorbed (and therefore the prodrug is not observed in plasma), when the abiraterone prodrug is administered parenterally (either IV or IM) to dogs, the prodrug is converted to unchanged abiraterone, which is observed in plasma (see Figures 3-10). Thus, an aspect of the present disclosure is the selection of an ester prodrug and a vegetable oil/co-solvent vehicle that allows for suitable solubility of the ester prodrug in the vehicle to allow for injection, controlled release of the ester prodrug from the oily depot (dependent on the partition coefficient of the drug between the oil and aqueous phases), and subsequent bioconversion of the ester prodrug to unchanged abiraterone. Selected abiraterone prodrugs (acetate, propionate, butanoate, pentanoate, hexanoate, heptanoate, isocaproate, cypionate, and decanoate esters) were prepared and their solubility in several vegetable oils and co-solvents was measured (see Table 2).

Unit Dosage Forms In some embodiments, the abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure (e.g., formulations containing a compound of Formula I or II as described herein) can be formulated as unit dosage forms. In some embodiments, the unit dosage form can contain a sufficient amount of the corresponding prodrug such that after a single administration (e.g., intramuscular injection) to a subject , e.g., a subject with a sex hormone-dependent benign or malignant disease (e.g., metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer), a syndrome due to androgen excess, and/or a syndrome due to glucocorticoid excess, such as hypercortisolism, the unit dosage form provides a therapeutically effective plasma concentration of abiraterone in the subject for a period of at least 2 weeks, e.g., at least 3 weeks, at least 4 weeks, at least 5 weeks, and up to 6 or 8 weeks or more. In some embodiments, the therapeutic range plasma concentration of abiraterone can be at a concentration of at least 1 ng/ml, e.g., at least 2 ng/ml, at least 4 ng/ml, at least 8 ng/ml. In some embodiments, the therapeutic range plasma concentration of abiraterone may be about 0.5 ng/ml or more. In some embodiments, the unit formulation is a parenteral formulation, such as an intramuscular, intradermal, or subcutaneous formulation. In some embodiments, the unit formulation is a non-aqueous solution or suspension. In some embodiments, the unit formulation comprises an abiraterone prodrug (a compound of formula I or II) dissolved or suspended in a pharmaceutically acceptable oil, e.g., a vegetable oil, such as castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil. In some embodiments, two or more different pharmaceutically acceptable oils may be used in the unit formulation. In some embodiments, the unit formulation may further comprise a pharmaceutically acceptable solvent, e.g., an alcohol, ester, and/or acid, such as benzyl alcohol, benzyl benzoate, or a combination thereof. Other ingredients suitable for the unit formulation include those described herein.

The abiraterone prodrug (e.g., a compound of Formula I or II) is typically present in the unit formulation at a concentration of about 25 mg/ml to about 500 mg/ml (e.g., about 25 mg/ml, about 50 mg/ml, about 100 mg/ml, about 150 mg/ml, about 200 mg/ml, about 250 mg/ml, about 300 mg/ml, about 400 mg/ml, about 500 mg/ml, or any of the ranges of values recited). The amount of abiraterone prodrug in the unit formulation can vary depending on various factors, such as the clearance rate of the corresponding abiraterone prodrug, the desired dosing frequency, and the desired plasma level. Typically, the amount of abiraterone prodrug can range from about 50 mg to about 2000 mg, and when expressed as an equivalent to abiraterone, can usually range from about 25 mg to about 1750 mg. In some embodiments, to achieve less frequent dosing, e.g., once a month, the prodrug can be included in the unit dosage form at as high a concentration as is safe and tolerable to the intended user. Typically, the unit dosage form is formulated to have a viscosity suitable for parenteral injection, such as intramuscular, intradermal, or subcutaneous injection.

In some embodiments, the unit dosage form can be formulated to obtain a certain pharmacokinetic (PK) profile, for example, a PK profile that has a substantially flat curve after an initial rising period. Typically, after administration of the unit dosage form to a subject , the plasma concentration of abiraterone in the subject may rise over the first few hours to several weeks (e.g., 5 days or 1 week) after administration and then gradually plateau (see, e.g., Figures 2-4). In some embodiments, after this initial rising period, the plasma concentration of abiraterone in the subject may plateau and remain substantially constant for an extended period of time, for example, at least several days (e.g., 2, 3, 4, 5, or 6 days) or at least 1 week, at least 2 weeks.

In some embodiments, the unit dosage form is suitable for monthly (or more than monthly) administration, and after a single administration (e.g., intramuscularly) to a subject in need thereof, the unit dosage form achieves a PK profile characterized by one or more of the following (a)-(f): (a) the unit dosage form provides a therapeutically effective plasma concentration of abiraterone in a subject for at least 4 weeks; (b) a single-dose C _{max of abiraterone of about 10 ng/ml to about 400 ng/ml (e.g., about 50 ng/ml to about 100 ng/ml, or about 15 ng/ml to about 160 ng/ml); (c) no food effect; (d) a single-dose C max} of abiraterone that is at least 30% lower than the C _max of abiraterone observed at steady state when 1000 mg of _Zytiga® is administered orally once daily without food; (e) a single-dose C _min of abiraterone of about 1 ng/ml to about 8 ng/ml, or greater than about 8 ng/ml, at 28 days post-administration. (f) the plasma concentration of abiraterone remains substantially constant, e.g., for at least one week, e.g., one to three weeks, after administration. In some embodiments, substantially constant over a period of time may mean that the highest concentration observed on any one day (i.e., 24 hour period) during that period is no more than four-fold, e.g., no more than two-fold, the lowest concentration observed on that same day. The absence of food effect should be understood to mean that, generally, no significant differences in PK are observed when the unit dosage form is administered to a subject with or without food, e.g., in some embodiments, the absence of food effect may mean that the _Cmax and AUC of abiraterone are substantially the same (e.g., 80% to 125%) between subjects administered after a meal or in the fasted state. As used herein, single-dose _Cmax should be understood to be the Cmax achieved following a single _dose to a treatment-naive subject (generally meaning a subject who has not received any abiraterone drug treatment for at least three days, e.g., at least one week, prior to dosing and who has no observable abiraterone in their plasma prior to dosing). As used herein, single-dose _Cmin refers to the minimum concentration observed on a given day following a single dose to a treatment-naive subject , e.g., 28 days after dosing.

In some embodiments, the unit dosage form is suitable for monthly (or more than monthly) administration, such that after administration (e.g., intramuscularly) of the unit dosage form once a month to a subject in need thereof, the unit dosage form achieves the following (a)-(g): (a) a steady state C _{max of abiraterone of about 10 ng/ml to about 400 ng/ml (e.g., about 50 ng/ml to about 100 ng/ml, or about 15 ng/ml to about 160 ng/ml); (b) no food effect; (c) a steady state C max} of abiraterone that is at least 30% lower than the C _max of abiraterone observed at steady state when 1000 mg of Zytiga® is administered orally once daily without food; (d) a steady state C _min of abiraterone of about 1 ng/ml to about 8 ng/ml, or greater than about 8 ng/ _ml ; (g) the plasma concentration of abiraterone remains substantially constant after each administration, e.g., for at least one week, e.g., one week to three weeks. As used herein, steady state _Cmax or _Cmin should be understood to be the _Cmax or _Cmin observed after steady state is reached, typically after several administrations to a subject .

In some embodiments, the unit dosage form may be packaged in a container such as a vial or ampoule. In some embodiments, the unit dosage form may be included in a kit with a syringe, such as a prefilled or disposable syringe. Other packages and/or containers known to those of skill in the art are also useful. In some embodiments, kits are provided that include a plurality of the unit dosage forms described herein. In some embodiments, the kit may further include a syringe. Although in some embodiments, it may be advantageous to prepare the abiraterone prodrug formulation as a unit dosage form, in some embodiments, the present disclosure also provides abiraterone prodrug formulations that allow for multiple single-use or that can be divided into multiple unit dosage forms.

Specific Formulation Examples In some embodiments, the present disclosure also provides some specific abiraterone prodrug formulations, which in some embodiments may be unit dosage forms or multiple unit dosage forms. For example, the following tables (Tables A and B) show some representative abiraterone ester prodrug formulations in an oil vehicle. All numerical values in the tables should be understood as being preceded by the term "about". The concentration of abiraterone prodrug is expressed in mg of abiraterone prodrug per ml of final formulation, which may be a solution or suspension. The amount of oil (primary solvent) and co-solvent in the tables is expressed as a volume percent of the solvent, including both the oil and the co-solvent. Suitable oils include any of the pharma- ceutically acceptable oils as described herein. Suitable co-solvents also include any of those described herein, such as alcohols, esters, and/or acids, such as benzyl alcohol, benzyl benzoate, or combinations thereof (see, e.g., Table B). One example of a suitable co-solvent is benzyl alcohol. An example of a suitable co-solvent is a combination of benzyl alcohol and benzyl benzoate. In some embodiments, no co-solvent is included in the formulation. In some embodiments, the co-solvent does not include benzyl benzoate. Other optional ingredients are also described herein.
(Table A) Formulation examples

As shown in Figures 13A-13E and in the Examples section, benzyl alcohol and/or benzyl benzoate can improve the solubility of the abiraterone prodrug of the present disclosure in oily vehicles such as corn oil, and can reduce the viscosity and glide force of various oily vehicles, including corn oil, sesame oil, peanut oil, cottonseed oil, and Miglyol 812 (a mixture of medium chain triglycerides, primarily caprylic/capric triglycerides). In some embodiments, the present disclosure provides an abiraterone prodrug formulation comprising an abiraterone prodrug and a pharma- ceutically acceptable carrier, where the pharma-ceutically acceptable carrier comprises a pharma- ceutically acceptable oil (e.g., as described herein), benzyl alcohol, and benzyl benzoate. In some embodiments, the abiraterone prodrug can be abiraterone decanoate. In some embodiments, the abiraterone prodrug can be abiraterone isocaproate. Pharmaceutically acceptable oils typically include triglycerides derived from fatty acids. In some embodiments, the pharma-ceutically acceptable oils may be natural, synthetic, or semi-synthetic oils, such as fractionated coconut oil and medium chain triglycerides, such as those sold under the trademark Miglyol. In some embodiments, the pharma-ceutically acceptable oils may be selected from vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil. In some embodiments, the present disclosure provides certain exemplary formulations shown in Table B.
Table B: Further formulation examples

In some embodiments, the present disclosure also provides a solution of abiraterone acetate in castor oil at a concentration of about 50 mg/mL to about 200 mg/mL (e.g., 70 mg/mL); a 10% benzyl alcohol/90% castor oil solution of abiraterone acetate at a concentration of about 50 mg/mL to about 200 mg/mL (e.g., 90 mg/mL); a 50% benzyl benzoate/50% castor oil solution of abiraterone acetate at a concentration of about 50 mg/mL to about 200 mg/mL (e.g., 125 mg/mL); a 10% benzyl alcohol/90% castor oil solution of abiraterone propionate at a concentration of about 50 mg/mL to about 300 mg/mL (e.g., 168 mg/mL); a 10% benzyl alcohol/90% corn oil solution of abiraterone propionate at a concentration of about 100 mg/mL to about 300 mg/mL (e.g., 160 mg/mL or 170 mg/mL); a castor oil solution of abiraterone decanoate at a concentration of about 100 mg/mL to about 300 mg/mL (e.g., 160 mg/mL or 170 mg/mL); corn oil solutions of abiraterone decanoate at concentrations of about 100 mg/mL to about 300 mg/mL (e.g., 160 mg/mL or 170 mg/mL); 10% benzyl alcohol/90% castor oil solutions of abiraterone decanoate at concentrations of about 100 mg/mL to about 300 mg/mL (e.g., 160 mg/mL or 170 mg/mL); 10% benzyl alcohol/90% castor oil solutions of abiraterone decanoate at concentrations of about 100 mg/mL to about 300 mg/mL (e.g., 160 mg/mL or 170 mg/mL); Certain formulations are provided, such as: alcohol/90% corn oil solution; abiraterone decanoate in a concentration of about 150 mg/mL to about 300 mg/mL (e.g., 200 mg/mL or 240 mg/mL) in 70% corn oil, 10% benzyl alcohol, 20% benzyl benzoate; abiraterone isocaproate in a concentration of about 120 mg/mL to about 200 mg/mL (e.g., 150 mg/mL or 160 mg/mL) in 90% corn oil, 10% benzyl alcohol; In some embodiments, the disclosure also provides any of the specific formulations prepared herein, such as in Examples 3A-3J. In some embodiments, the disclosure also provides the formulation described herein in Example 1.

Methods of Treatment Some embodiments of the present disclosure relate to methods of delivering abiraterone to a subject in need thereof. In various embodiments, the present disclosure also provides methods of treating or preventing a disease or disorder in which administration of abiraterone is beneficial.

In some embodiments, the disclosure provides a method of delivering abiraterone to a subject in need thereof, comprising administering to the subject any of the disclosed abiraterone prodrugs or abiraterone prodrug formulations. In some embodiments, the subject suffers from a sex hormone-dependent benign or malignant disease, such as an androgen-dependent or estrogen-dependent disease, as described herein. In some embodiments, the subject suffers from a syndrome resulting from androgen excess and/or a syndrome resulting from glucocorticoid excess, such as hypercortisolism, as described herein. In any of the embodiments described herein, unless directly contradicted, the subject may be a human subject, such as a human patient having a hormone-dependent benign or malignant disease, such as a syndrome resulting from androgen excess, as described herein, and/or a syndrome resulting from glucocorticoid excess, such as hypercortisolism. As used herein, a hormone-dependent benign or malignant disease should be understood as a sex hormone-dependent benign or malignant disease, such as an androgen-dependent or estrogen-dependent disease, whether or not preceded by the term "sex".

As detailed herein, monkey PK studies have demonstrated that a single intramuscular injection of a representative abiraterone prodrug, abiraterone decanoate, can achieve long-term CYP17A1 inhibition with sustained elevated progesterone levels and reduced cortisol and testosterone levels for up to 8 weeks. As shown in FIG. 14D, inhibition of CYP17A1 17a-hydroxylase and C17,20-lyase activity is expected to result in: (1) elevated progesterone and mineralocorticoid levels; (2) reduced levels of glucocorticoids, such as cortisol; and (3) reduced levels of sex hormones, e.g., androgens, such as testosterone and dihydrotestosterone, and estrogens, such as estradiol. Thus, the abiraterone prodrugs and prodrug formulations of the present disclosure can be advantageously used to inhibit CYP17A1 activity, reduce glucocorticoid levels, such as cortisol levels, reduce sex hormone levels, such as androgen and estrogen levels, and/or treat diseases associated with high glucocorticoid levels, such as cortisol levels, and/or treat diseases caused by high sex hormone levels, such as androgen and estrogen levels.

In some embodiments, the disclosure provides methods of inhibiting CYP17A1 activity, such as inhibiting 17α-hydroxylase activity and 17,20-lyase activity, comprising administering to a subject any of the disclosed abiraterone prodrugs or abiraterone prodrug formulations. In some embodiments, the subject suffers from a sex hormone-dependent benign or malignant disease, e.g., as described herein. In some embodiments, the subject suffers from a syndrome resulting from androgen excess and/or a syndrome resulting from glucocorticoid excess, such as hypercortisolism, e.g., as described herein.

In some embodiments, the disclosure provides a method of reducing glucocorticoid (e.g., cortisol) levels in a subject in need thereof, the method comprising administering to the subject any of the disclosed abiraterone prodrugs or abiraterone prodrug formulations. In some embodiments, the subject suffers from a syndrome resulting from glucocorticoid excess, such as hypercortisolism as described herein, such as Cushing's syndrome or Cushing's disease.

In some embodiments, the present disclosure provides a method of reducing androgen (e.g., testosterone and/or dihydrotestosterone) and/or estrogen levels in a subject in need thereof, comprising administering to the subject any of the disclosed abiraterone prodrugs or abiraterone prodrug formulations. In some embodiments, the subject suffers from a syndrome resulting from androgen excess, such as congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc. In some embodiments, the subject suffers from an androgen- and/or estrogen-related cancer, such as prostate cancer or breast cancer.

In some embodiments, methods are provided for treating sex hormone-dependent benign or malignant diseases, syndromes resulting from androgen excess, and/or syndromes resulting from glucocorticoid excess, such as hypercortisolism. Typically, the methods comprise administering a therapeutically effective amount of any of the disclosed abiraterone prodrugs or abiraterone prodrug formulations to a subject in need thereof. In any of the embodiments described herein, unless directly contradicted, the subject may be a human subject , e.g., a human patient having a hormone-dependent benign or malignant disease, syndromes resulting from androgen excess, and/or syndromes resulting from glucocorticoid excess, such as hypercortisolism, as described herein.

The administration in the methods herein is not limited to any particular route. However, in some preferred embodiments, the administration may be parenteral, such as intramuscular, intradermal, or subcutaneous injection. Parenteral administration may be advantageous in some embodiments. For example, in some embodiments, the administration may be parenteral, such as intramuscular injection, which can be performed regardless of whether the subject has eaten or not. In other words, it does not matter whether the subject has eaten or is fasting. This eliminates the restriction on the currently marketed Zytiga® formulation, which states that the drug "must be taken on an empty stomach, at least 1 hour before a meal or 2 hours after a meal, with water." Thus, among other advantages, the methods herein may also improve patient compliance.

A variety of sex hormone dependent benign or malignant diseases can be treated by the methods herein. In some embodiments, the hormone dependent benign or malignant disease can be androgen dependent and estrogen dependent diseases, such as androgen or estrogen dependent cancers. In some embodiments, the sex hormone dependent benign or malignant disease can be prostate cancer or breast cancer. In some embodiments, the sex hormone dependent benign or malignant disease can be castration resistant or castration sensitive prostate cancer. In some embodiments, the sex hormone dependent benign or malignant disease can be metastatic castration resistant or metastatic castration sensitive prostate cancer. In some embodiments, the sex hormone dependent benign or malignant disease can also be ovarian cancer, bladder cancer, hepatocellular carcinoma, or lung cancer. For example, various non-neoplastic syndromes caused by androgen excess, such as endometriosis, polycystic ovary syndrome, classical or non-classical congenital adrenal hyperplasia, precocious puberty, and hirsutism, and/or syndromes caused by cortisol excess, such as Cushing's syndrome and Cushing's disease, and/or glucocorticoid excess, such as hypercortisolism, can also be treated by the method of the present specification.

The methods herein can be used in combination with one or more additional therapies for the corresponding disease or disorder. For example, the label of Zytiga® (abiraterone acetate) states that patients taking Zytiga® must also be taking a gonadotropin-releasing hormone (GnRH) analog at the same time or have already undergone a bilateral orchiectomy. Accordingly, in some embodiments of the methods of the present disclosure, the subject may be treated with a gonadotropin-releasing hormone analog and/or a bilateral orchiectomy. In some embodiments, the method also includes administering an effective amount of prednisone or prednisolone to the subject simultaneously or sequentially. However, in some embodiments, the methods herein can also achieve the desired therapeutic effect without causing adrenal insufficiency, thereby avoiding the simultaneous administration of prednisone or prednisolone. In some embodiments, the subject is not treated with a gonadotropin-releasing hormone analog and/or a bilateral orchiectomy. In some embodiments, the subject is not treated with prednisone or prednisolone.

In some embodiments, the method may include administering one or more other drugs or agents (e.g., another cancer chemotherapy drug, a hormone replacement drug, or a hormone ablation drug) to the subject , either simultaneously or sequentially, through the same or a different route of administration. In some embodiments, the other drug or agent may be a steroid, such as prednisone, prednisolone, and/or methylprednisolone. In some embodiments, the other drug or agent may be a chemotherapy drug, such as paclitaxel, mitoxantrone, and/or docetaxel. In some embodiments, the other drug or agent may be a GnRH agonist, such as leuprolide, deslorelin, goserelin, or triptorelin, e.g., leuprolide acetate (e.g., a long-acting IM injectable formulation). In some embodiments, the other drug or agent may be a glucocorticoid, including but not limited to seocalcitol, bicalutamide, flutamide, hydrocortisone, prednisone, prednisolone, or dexamethasone. The amount of other drugs or agents administered can vary and typically will be an amount effective, alone or in combination with an abiraterone prodrug or abiraterone prodrug formulation of the present disclosure, to treat the corresponding disease or disorder (e.g., prostate cancer).

Additional suitable other drugs or agents include those described herein. For example, useful other drugs or agents include, but are not limited to, anti-cancer agents, hormone ablation agents, anti-androgen agents, differentiation agents, anti-tumor agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotic agents, immunological agents, interferon-type agents, intercalating agents, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloproteinase inhibitors, gene therapy agents, and anti-androgen agents.

For example, suitable anticancer drugs include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, amsacrine, anagrelide, anastrozole, ancestim, bexarotene, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, daclizumab, dexrazoxane, dilazep, docosanol, doxifluridine, bromocriptine, carmustine, cytarabine, and diclofenac. , edelfosine, edrecolomab, eflonitine, emitefur, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, glycopin, heptaplatin, ibandronate, imiquimod, iobenguane, irinotecan, irsogladine, lanreotide, leflunomide, lenograstim, lentinan sulfate, letrozole, liarozole, lobaplatin, lonidamine, mastoprolol aztreonam, melarsoprol, metoclopramide, mifepristone, miltefosine, millimostim, mitoguazone, mitolactol, molgramostim, nafarelin, nartograstim, nedaplatin, nilutamide, noscapine, oprelvekin, osaterone, oxaliplatin, pamidronate, pegaspargase, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, porfimer sodium, raloxifene, raltitrexed, rasburicase, rituximab Suitable antiandrogens include, but are not limited to, bicalutamide, flutamide, vinorelbine ... Suitable differentiation agents include, but are not limited to, polyamine inhibitors; vitamin D and its analogs, such as calcitriol, doxercalciferol, and seocalcitol; metabolites of vitamin A, such as ATRA, retinoic acid, retinoids; short chain fatty acids; phenylbutyric acid; and nonsteroidal anti-inflammatory agents. Antitumor agents include tubulin interactors, topoisomerase inhibitors and agents, acitretin, alstonine, amonafide, amfetinil, amsacrine, anquinomycin, anti-neoplaston, aphidicolin glycinate, asparaginase, baccharin, batracillin, benflurone, benzotript, bromophosphamide, caracemide, carmethizole hydrochloride, chlorsulfaquinoxalone, clanfenur, claviridinone, crisnatol, claderm, cytarabine, cytocytin, dacarbazine, daterliptinium, dihematoporphyrin ether, dihydrolenperone, dinaline, distamycin, docetaxel, elipravine , elliptinium acetate, epothilone, ergotamine, etoposide, etretinate, fenretinide, gallium nitrate, genquadaphnine, hexadecylphosphocholine, homoharringtonine, hydroxyurea, irmofosine, isoglutamine, isotretinoin, leukoregulin, lonidamine, merbarone, merocyanine derivatives, methylanilinoacridine, minactivin, mitonafide, mitoxantrone, mopidamol, motretinide, N-(retinoyl)amino acids, N-acylated dehydroalanine, napazatrom, nocodazole derivatives, octreotide, oxanosine, paclitaxel, pancratistatin, pazeriptin, piroxantrone, polyhematoporphyrin, polyprenic acid (polyprenic acid acid), probimane, procarbazine, proglumide, razoxane, leteriptin, spatol, spirocyclopropane derivatives, spirogermanium, stripoldinone, superoxide dismutase, teniposide, thaliblastine, tocotrienol, topotecan, ukrain, vinblastine sulfate, vincristine, vindesine, binestramide, vinorelbine, vintriptol, vinzolidine, and withanolides. Kinase inhibitors include p38 inhibitors and CDK inhibitors, TNF inhibitors, metal matrix protease inhibitors (MMPs), COX-2 inhibitors (including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib), SOD mimetics, or α _v β ₃ inhibitors. Suitable antimetabolites may be selected from, but are not limited to, 5-FU-fibrinogen, acantifolic acid, aminothiadiazole, brequinar sodium, carmofur, cyclopentylcytosine, cytarabine stearate phosphate, cytarabine conjugate, desaguanine, dideoxycytidine, dideoxyguanosine, didox, doxifluridine, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2'-furanidyl)-5-fluorouracil, isopropylpyrrolidine, methobenzaprim, methotrexate, norspermidine, pentostatin, piritrexim, plicamycin, thioguanine, tiazofurin, trimetrexate, tyrosine kinase inhibitors, and uristicin. Suitable alkylating agents may be selected from, but are not limited to, aldophosphamide analogs, altretamine, anaxylon, bestravcil, budotitane, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, ciplatate, diphenylspiromustine, diplatinum cytostatic, hermustine, estramustine sodium phosphate, fotemustine, hepsulfam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, oxaliplatin, prednimustine, ranimustine, semustine, spiromustine, tauromustine, temozolomide, teroxylon, tetraplatin, and trimelamol. Suitable antibiotic agents include aclarubicin, actinomycin D, actinoplanon, adriamycin, aeroprisinin derivatives, amrubicin, anthracyclines, azinomycin A, viscaverin, bleomycin sulfate, bryostatin-1, calicheamicin, chromoximycin, dactinomycin, daunorubicin, ditrisarubicin B, dexamethasone, doxorubicin, doxorubicin-fibrinogen, elsamycin-A, epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-A1b, fostriecin, glidobactin, gregatin-A, They may be selected from, but are not limited to, corticosteroids such as glinkamycin, herbimycin, hydrocortisone, idarubicin, iludin, kazusamycin, kesarilodin, menogaril, mitomycin, neoenactin, oxalicin, oxaunomycin, peplomycin, pyratin, pirarubicin, polosuramycin, prednisone, prednisolone, pirindanaicin A, rapamycin, rhizoxin, rodorubicin, sivanomycin, siwenmycin, solangicin-A, sparsomycin, tallysomycin, terpentesin, thorazine, triclozaline A, and zorubicin. Non-limiting examples of suitable steroids include hydrocortisone, prednisone, prednisolone, or dexamethasone.

Dosage and Administration The abiraterone prodrugs and formulations disclosed herein generally can provide a long-acting release profile of abiraterone to a target user. This long-acting release profile allows a target user to administer abiraterone less frequently, for example once a week or less, thereby improving patient compliance and reducing dosage burden.

In some embodiments, the methods herein may include a once-weekly or more-than-weekly dosage regimen. Typically, the dosing frequency can range from once a week to once every few months, e.g., once a week to once every 8 weeks, or once a week to once every 3 months. In some embodiments, the dosage per dose is about 50 mg to about 2000 mg of the abiraterone prodrug (e.g., about 500 mg, about 1000 mg, about 1500 mg, or any range of values recited). In some embodiments, the dosage per dose is about 0.5 mg/kg to about 100 mg/kg of the subject 's body weight (e.g., about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any range of values recited). In some embodiments, the methods herein may include administering an abiraterone prodrug or abiraterone prodrug formulation of the present disclosure to a subject in need thereof once a week or once every few weeks, e.g., once every two weeks, once a month, where the administration results in a therapeutically effective plasma concentration of abiraterone in the subject (e.g., 0.5 ng/ml or more, 1 ng/ml or more, 8 ng/ml or more, or 8.4 ng/ml or more as described herein) for an extended period of time, such as for example, more than 1 week, more than 2 weeks, more than 3 weeks, more than 4 weeks, and up to 6 or 8 weeks or more. In some embodiments , the administration may result in a C max of a single dose of abiraterone of about 10 ng/ml to about 400 ng/ml (e.g., about 50 ng/ml to about 100 ng/ml, or about 15 ng/ml to about 160 ng/ _ml ). In some embodiments, the administration may result in a steady state C max of abiraterone of about 10 ng/ml to about 400 ng/ml (e.g., about 50 ng/ml to about 100 ng/ml, or about 15 ng/ml to about 160 ng/ml). In some embodiments, the administration may result in a single dose C _min of abiraterone of about 1 ng/ml to about 8 ng/ml, or greater than about 8 ng/ml, e.g., greater than 8.4 ng/ml, on each of days 1 to 7, 1 to 14, 1 to 21, or 1 to 28 after administration. In some embodiments, the administration may result in a steady state C _min of abiraterone of about 1 ng/ml to about 8 ng/ml, or greater than about 8 ng/ml, e.g., greater than 8.4 ng/ _ml .

であるか；あるいは、Ｒ^１は、

である。いくつかの実施形態では、アビラテロンプロドラッグは、式ＩＩの化合物であってよく、例えば、式ＩＩ中、Ｒ^２は、Ｃ_１－１６アルキル、例えば、－（ＣＨ_２）_ｎ－ＣＨ_３の式を有するアルキルであり、式中ｎは、０～１２の間の整数であるか；式ＩＩ中のＲ^２は、式－（ＣＨ_２）_ｎ－Ｃｙで表されることがあり、式中ｎは、１～６の整数であり、かつＣｙは、Ｃ_３－６シクロアルキルまたはフェニルであるが、例えば、より具体的な実施形態では、ｎは、１または２である場合があり、Ｃｙは、シクロペンチル、シクロヘキシル、またはフェニルであるか；式ＩＩ中のＲ^２は、

である。いくつかの実施形態では、アビラテロンプロドラッグはまた、酢酸アビラテロンまたは実施例２Ａ～２Ｈのいずれかであってもよい。いくつかの実施形態では、アビラテロンプロドラッグは、酢酸アビラテロン、プロピオン酸アビラテロンまたはデカン酸アビラテロンであってよい。いくつかの特定の実施形態では、アビラテロンエステルは、ペンタン酸アビラテロン、ヘキサン酸アビラテロン、ヘプタン酸アビラテロン、デカン酸アビラテロン、イソカプロン酸アビラテロン、またはシピオン酸アビラテロンであってよい。本明細書に記載の実施形態のいずれかでは、特に指定がない限り、または文脈と直接矛盾しない限り、アビラテロンプロドラッグは、デカン酸アビラテロンであり得る。 Abiraterone prodrugs suitable for use in the above once weekly or more than once weekly dosing methods include those described herein. In some embodiments, the abiraterone prodrug may be a lipophilic ester of abiraterone described herein, such as acetate, propionate, butanoate, (butyrate)pentanoate, isocaproate, bucclate, cyclohexanecarboxylate, phenylpropionate, caproate (hexanoate), enanthate (heptanoate), cypionate, octanoate, noncanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate, and hexadecanoate. In some preferred embodiments, the abiraterone prodrug may be a compound of formula I, for example, in which R ¹ is a C _7-16 alkyl, for example, an alkyl having the formula of -(CH ₂ ) _n -CH ₃ , where n is an integer between 6 and 12 (e.g., n is 6, 7, 8, 9, 10); R ¹ may be represented by the formula -(CH ₂ ) _n -Cy, where n is an integer between 1 and 6, and Cy is a C _3-6 cycloalkyl or phenyl, for example, in more specific embodiments, n may be 1 or 2, and Cy is cyclopentyl, cyclohexyl, or phenyl; R ¹ is

or R ¹ is

In some embodiments, the abiraterone prodrug may be a compound of formula II, e.g., in formula II, R ² is a C _1-16 alkyl, e.g., an alkyl having the formula -(CH ₂ ) _n -CH ₃ , where n is an integer between 0 and 12; R ² in formula II may be represented by the formula -(CH ₂ ) _n -Cy, where n is an integer between 1 and 6, and Cy is a C _3-6 cycloalkyl or phenyl, e.g., in more specific embodiments, n may be 1 or 2, and Cy is cyclopentyl, cyclohexyl, or phenyl; R ² in formula II is

In some embodiments, the abiraterone prodrug may also be abiraterone acetate or any of Examples 2A-2H. In some embodiments, the abiraterone prodrug may be abiraterone acetate, abiraterone propionate, or abiraterone decanoate. In some particular embodiments, the abiraterone ester may be abiraterone pentanoate, abiraterone hexanoate, abiraterone heptanoate, abiraterone decanoate, abiraterone isocaproate, or abiraterone cypionate. In any of the embodiments described herein, unless otherwise specified or directly contradicted by context, the abiraterone prodrug may be abiraterone decanoate.

In some embodiments, monthly or more than monthly dosing is preferred, e.g., dosing frequencies ranging from once a month to once every few months, e.g., once a month to once every two months, or once a month to once every three months. In such embodiments, the abiraterone prodrug should not only release abiraterone slowly, but also release abiraterone at sufficient plasma concentrations to be beneficial to the intended user. Monthly or more than monthly dosing is typically parenteral, such as intramuscular, intradermal, or subcutaneous. In any of the embodiments herein, unless directly contradicted, dosing may be intramuscular.

As detailed herein, it has been found that a single intramuscular dose of abiraterone acetate results in an extended release of abiraterone. However, in a dog PK study, a similar dose of abiraterone propionate did not improve upon the extended release of abiraterone acetate, and in fact, the abiraterone release observed with the propionate ester was less than that observed with the acetate ester at all time points measured. Furthermore, it was unexpectedly found that the extension of the alkyl chain to abiraterone butanoate led to a sharp decrease in solubility in various oil-based vehicles. Despite this unexpected trend, the inventors have found that certain abiraterone prodrugs or abiraterone prodrug formulations of the present disclosure, such as compounds of formula I, such as abiraterone decanoate, may be superior to acetate, propionate, or butanoate for use in monthly or monthly administration. It was also found that the PK profile, such as t _1/2 , of certain abiraterone prodrugs or abiraterone prodrug formulations of the present disclosure, e.g., compounds of Formula I, such as abiraterone decanoate, did not change significantly when different oil vehicles were used. In contrast, some variability in the PK profile was observed for abiraterone propionate depending on whether it was formulated in castor oil or corn oil, as detailed in Example 5B.

であるか；あるいは、Ｒ^１は、

である。いくつかの実施形態では、本投与により、少なくとも４週間、例えば少なくとも５週間、及び最大６または８週間以上などの期間にわたって、対象におけるアビラテロンの治療上有効な血漿中濃度がもたらされる。いくつかの実施形態では、アビラテロンの治療域血漿中濃度は、少なくとも１ｎｇ／ｍｌ、例えば、少なくとも２ｎｇ／ｍｌ、少なくとも４ｎｇ／ｍｌ、少なくとも８ｎｇ／ｍｌの濃度である場合がある。いくつかの実施形態では、アビラテロンの治療上有効な血漿中濃度はまた、約０．５ｎｇ／ｍｌ以上である場合がある。いくつかの実施形態では、本投与により、約１０ｎｇ／ｍｌ～約４００ｎｇ／ｍｌ（例えば、約５０ｎｇ／ｍｌ～約１００ｎｇ／ｍｌ、または約１５ｎｇ／ｍｌ～約１６０ｎｇ／ｍｌ）のアビラテロンの単回投与のＣ_ｍａｘがもたらされ得る。いくつかの実施形態では、本投与により、約１０ｎｇ／ｍｌ～約４００ｎｇ／ｍｌ（例えば、約５０ｎｇ／ｍｌ～約１００ｎｇ／ｍｌ、または約１５ｎｇ／ｍｌ～約１６０ｎｇ／ｍｌ）のアビラテロンの定常状態のＣ_ｍａｘがもたらされ得る。いくつかの実施形態では、本投与により、投与後２８日目に、約１ｎｇ／ｍｌ～約８ｎｇ／ｍｌ、または約８ｎｇ／ｍｌ超、例えば８．４ｎｇ／ｍｌ超のアビラテロンの単回投与のＣ_ｍｉｎがもたらされ得る。いくつかの実施形態では、本投与により、約１ｎｇ／ｍｌ～約８ｎｇ／ｍｌ、または約８ｎｇ／ｍｌ超、例えば８．４ｎｇ／ｍｌ超のアビラテロンの定常状態のＣ_ｍｉｎがもたらされ得る。いくつかの実施形態では、対象におけるアビラテロンの血漿中濃度は、例えば、投与後少なくとも１週間、例えば、１週間～３週間、実質的に一定のままであり得る。いくつかの実施形態では、投与は、対象が食事をとるかどうかに関係なく実行される。いくつかの実施形態では、本投与により、食物を伴わずに１０００ｍｇのＺｙｔｉｇａ（登録商標）を毎日１回、経口投与した場合の定常状態で観察されたアビラテロンのＣ_ｍａｘと比較して、少なくとも３０％低いアビラテロンの単回投与のＣ_ｍａｘがもらされる。いくつかの実施形態では、本投与により、食物を伴わずに１０００ｍｇのＺｙｔｉｇａ（登録商標）を毎日１回、経口投与した場合の定常状態で観察されたアビラテロンのＣ_ｍａｘと比較して、少なくとも３０％低いアビラテロンの定常状態のＣ_ｍａｘがもらされる。いくつかの実施形態では、式Ｉの化合物を含む医薬組成物は、本明細書に記載の単位製剤として製剤化され得る。このような医薬組成物向けの好適な担体、油性ビヒクル、賦形剤には、本明細書に記載されているものが含まれる。 In some specific embodiments, the disclosure provides a method of treating a sex hormone-dependent benign or malignant disease (e.g., as described herein), a syndrome resulting from androgen excess, and/or a syndrome resulting from glucocorticoid excess, such as hypercortisolism, in a subject in need thereof, the method comprising parenterally administering to the subject once a month or more than once a month a therapeutically effective amount of a compound of Formula I (e.g., as described herein), or a pharmaceutical composition comprising a compound of Formula I (e.g., as described herein). In some embodiments, the parenteral administration is intramuscular, intradermal, or subcutaneous. In some preferred embodiments, in the compound of formula I, R ¹ is a C _7-16 alkyl, for example an alkyl having the formula -(CH ₂ ) _n -CH ₃ , where n is an integer between 6 and 12 (e.g., n is 6, 7, 8, 9, or 10); R ¹ is represented by the formula -(CH ₂ ) _n -Cy, where n is an integer between 1 and 6, and Cy is a C _3-6 cycloalkyl or phenyl, but for example, in more specific embodiments, n may be 1 or 2 and Cy is cyclopentyl, cyclohexyl, or phenyl; R ¹ is

or R ¹ is

In some embodiments, the administration results in a therapeutically effective plasma concentration of abiraterone in the subject for a period of at least 4 weeks, such as at least 5 weeks, and up to 6 or 8 weeks or more. In some embodiments, the therapeutic range plasma concentration of abiraterone may be a concentration of at least 1 ng/ml, such as at least 2 ng/ml, at least 4 ng/ml, at least 8 ng/ml. In some embodiments, the therapeutically effective plasma concentration of abiraterone may also be about 0.5 ng/ml or greater. In some embodiments, the administration may result in a single dose C max of abiraterone of about 10 ng/ml to about 400 ng/ml (e.g., about 50 ng/ml to about 100 ng/ml, or about 15 ng/ml to about 160 ng/ _ml ). In some embodiments, the administration may result in a steady state C max of abiraterone of about 10 ng/ml to about 400 ng/ml (e.g., about 50 ng/ml to about 100 ng/ml, or about 15 ng/ml to about 160 ng/ml). In some embodiments, the administration may result in a single dose C _min of abiraterone of about 1 ng/ml to about 8 ng/ml, or greater than about 8 ng/ml, e.g., greater than 8.4 ng/ml, at day 28 after administration. In some embodiments, the administration may result in a steady state C _min of abiraterone of about 1 ng/ml to about 8 ng/ml, or greater than about 8 ng/ _ml , e.g., greater than 8.4 ng/ml. In some embodiments, the plasma concentration of abiraterone in the subject may remain substantially constant, e.g., for at least one week, e.g., one week to three weeks, after administration. In some embodiments, administration is performed regardless of whether the subject has eaten or not. In some embodiments, administration results in a single dose Cmax of abiraterone that is at least 30% lower than the _Cmax of abiraterone observed at steady state when 1000 mg of Zytiga® is orally administered once daily without food. In some embodiments, administration results in a steady state _Cmax of abiraterone that is at least 30% lower than the _Cmax of abiraterone observed at steady state when 1000 _mg of Zytiga® is orally administered once daily without food. In some embodiments, pharmaceutical compositions comprising a compound of formula I can be formulated as a unit dosage form as described herein. Suitable carriers, oily vehicles, excipients for such pharmaceutical compositions include those described herein.

The abiraterone prodrug and abiraterone prodrug formulations of the present disclosure can be administered to a subject in need thereof as the sole source of abiraterone. However, in some embodiments, other abiraterone drugs/formulations are not excluded. For example, in some embodiments, the administration herein can be combined with oral administration of abiraterone acetate, such as the Zytiga® formulation, simultaneously or sequentially in any order. In some embodiments, the subject can use the abiraterone prodrug and abiraterone prodrug formulation as a supplement to existing abiraterone therapy. Furthermore, the administration herein is not limited to administration of a single abiraterone prodrug or abiraterone prodrug formulation of the present disclosure. In some embodiments, two or more abiraterone prodrug and abiraterone prodrug formulations of the present disclosure can be administered to a subject .

In some embodiments, prior to the monthly or more than monthly administration, the methods herein may include an initial treatment period of more frequent dosing, such as weekly or biweekly dosing. The initial treatment period may include administering a different abiraterone drug, such as the same abiraterone prodrug or a different abiraterone prodrug. Typically, the initial treatment period may be used to achieve a plasma concentration of abiraterone of about 1 ng/ml to about 8 ng/ml or greater than about 8 ng/ml prior to the monthly or more than monthly administration described herein. However, in some embodiments, the methods herein do not include such an initial treatment period.

As discussed herein, the disclosed abiraterone prodrugs and abiraterone prodrug formulations have many advantages over the currently marketed Zytiga® product. For example, administration of the disclosed abiraterone prodrugs and abiraterone prodrug formulations to a subject typically results in a reduced _Cmax of abiraterone (e.g., at least 30% lower compared to the _Cmax of abiraterone observed at steady state when 1000 mg of Zytiga® is administered orally once daily without food).

Thus, in some embodiments, the present disclosure provides a method of treating a subject having side effects associated with high abiraterone exposure, including, for example, side effects associated with abiraterone _Cmax , comprising administering to the subject an abiraterone prodrug and abiraterone prodrug formulation of the present disclosure, which reduces side effects compared to administering 1000 mg of Zytiga® orally once daily without food. Suitable routes of administration, dosages, and frequencies include those described herein. Various side effects or adverse effects are described in the FDA-approved Zytiga® prescribing information (see, for example, the February 2018 or June 2019 version). In some embodiments, the disclosure provides methods of treating a subject whose metabolism is inhibited by abiraterone, e.g., who is also administered a substrate drug of CYP2D6 and/or CYP2C8, the methods comprising administering to the subject an abiraterone prodrug and abiraterone prodrug formulation of the disclosure, which administration reduces inhibition of metabolism of the drug compared to oral administration of 1000 mg of Zytiga® once daily without food. In some embodiments, the present disclosure provides a method of treating a subject having or likely to have hypertension, hypokalemia, or fluid retention due to mineralocorticoid excess, comprising administering to the subject an abiraterone prodrug and abiraterone prodrug formulation of the present disclosure, which reduces hypertension, hypokalemia, and fluid retention, or reduces the likelihood of having hypertension, hypokalemia, and fluid retention, as compared to administering 1000 mg of Zytiga® orally once daily without food. In some embodiments, the present disclosure provides a method of treating a subject having or likely to have adrenal cortical insufficiency, comprising administering to the subject an abiraterone prodrug and abiraterone prodrug formulation of the present disclosure, which reduces adrenal cortical insufficiency or the likelihood of having adrenal cortical insufficiency, as compared to administering 1000 mg of Zytiga® orally once daily without food. In some embodiments, the present disclosure provides a method of treating a subject with severe or fatal liver toxicity after taking Zytiga®, the method comprising administering to the subject an abiraterone prodrug and abiraterone prodrug formulation of the present disclosure, which reduces liver toxicity. Without wishing to be bound by theory, it is believed that administration of the abiraterone prodrug and abiraterone prodrug formulation of the present disclosure typically results in reduced, but effective, exposure to abiraterone, and thus is beneficial for subjects requiring lower doses of abiraterone, for example, as described above. Suitable dosage regimens and routes of administration include those described herein.

Abiraterone Decanoate Some embodiments of the present disclosure are particularly directed to abiraterone decanoate. As discussed in more detail in the Examples section, pharmacokinetic studies have shown that intramuscular injection of abiraterone decanoate formulations can result in therapeutically effective amounts of abiraterone in plasma over a long period of time in various animal models. Monkey PK studies have further shown that a single intramuscular injection of abiraterone decanoate formulations can achieve long-term CYP17A1 inhibition with sustained elevated progesterone levels and reduced cortisol and testosterone levels. Furthermore, based on the PK studies in rats, dogs, and monkeys, human PK predictions based on allometric scaling were performed. As shown in FIG. 16C, based on allometric scaling, it was predicted that C _min is expected to be 5 ng/mL at steady state after intramuscular administration of abiraterone decanoate in humans at doses of about 1000 mg once every 4 weeks. In addition, as detailed in the Examples section and Figure 14F, it has been found that abiraterone decanoate formulations containing certain combinations of oil and solvent can unexpectedly achieve significantly higher abiraterone plasma concentrations in monkeys after IM injection compared to the same dose of abiraterone decanoate formulation in 90% corn oil and 10% benzyl alcohol with substantially the same abiraterone decanoate concentration. Thus, the dose of abiraterone decanoate required to achieve a predicted C _min of 5 ng/mL at steady state can be reduced. Alternatively, the steady state C _min can be increased to levels above the predicted 5 ng/mL. These disclosures demonstrate that abiraterone can be delivered in therapeutically effective amounts to a subject (e.g., a human subject ) by injecting an abiraterone prodrug, such as an abiraterone lipophilic ester prodrug, and more particularly, by injecting abiraterone decanoate in doses less than once per week, e.g., once every two weeks, once per month, or more than once per month. Typically, the dosing frequency can range from once per week to once every several months, e.g., once per week to once every eight weeks, or once per week to once every three months, e.g., once per month, once every eight weeks, etc.

を有するデカン酸アビラテロン、または、それらの薬学的に許容される塩である化合物を提供する。いくつかの実施形態では、デカン酸アビラテロンは、その塩基性形態である場合がある。いくつかの実施形態では、デカン酸アビラテロンは、シュウ酸塩、塩酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、リン酸塩などの薬学的に許容される塩であってもよい。いくつかの実施形態では、デカン酸アビラテロンの塩は、その塩基性形態でのデカン酸アビラテロンの調製及び精製のための合成中間体として使用され得る。本明細書で論じるように、デカン酸アビラテロンは、典型的には、その塩基性形態で本明細書のアビラテロンプロドラッグ製剤中に存在する。その塩形態として特に言及されない限り、または文脈と矛盾する場合を除き、デカン酸アビラテロンは、その塩基性形態であると理解されるべきである。 In some particular embodiments, the present disclosure provides a compound of formula

or a pharmaceutically acceptable salt thereof. In some embodiments, abiraterone decanoate may be in its base form. In some embodiments, abiraterone decanoate may be a pharmaceutically acceptable salt such as oxalate, hydrochloride, benzenesulfonate, p-toluenesulfonate, phosphate, and the like. In some embodiments, a salt of abiraterone decanoate may be used as a synthetic intermediate for the preparation and purification of abiraterone decanoate in its base form. As discussed herein, abiraterone decanoate is typically present in the abiraterone prodrug formulations herein in its base form. Unless specifically referred to as its salt form or otherwise contradictory to the context, abiraterone decanoate should be understood to be in its base form.

Abiraterone decanoate or its pharma- ceutically acceptable salts can be readily prepared by one of skill in the art in light of the present disclosure. Several representative synthesis methods are described herein. In some embodiments, the present disclosure provides a method of synthesizing abiraterone decanoate, the method comprising reacting abiraterone with decanoic acid or its activated form, such as the corresponding acyl chloride, anhydride (e.g., mixed anhydride). The reaction can typically be carried out in the presence of a coupling agent, such as a carbodiimide. As shown in the Examples section, the coupling of abiraterone with decanoic acid can be carried out in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, a base, such as triethylamine, and a catalytic amount of DMAP. Salts of abiraterone decanoate can typically be prepared by reacting abiraterone decanoate with a suitable acid, such as oxalic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, or phosphoric acid, in an organic solvent, such as isopropyl acetate, ethyl acetate, etc.

In some embodiments, abiraterone decanoate may exist in a solid form, such as a crystalline form, an amorphous form, or a combination thereof. For example, in some embodiments, the present disclosure provides abiraterone decanoate in a crystalline form. In some embodiments, the crystalline form may be characterized by an X-ray powder diffraction (XRPD) spectrum having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) of the following peaks at 2Θ (±0.2°) of 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6, and 20.8 degrees; a differential scanning calorimetry (DSC) pattern having an endothermic peak with an onset temperature of about 69.0° C.; or a combination thereof. In some embodiments, the crystalline form may be characterized by an XRPD spectrum substantially similar to that shown in FIG. 12A, e.g., an XRPD spectrum showing peaks at each diffraction angle (angle 2Θ, ±0.2°) corresponding to the peaks shown in FIG. 12A, regardless of their relative intensities. In some embodiments, the crystalline form may be characterized by a DSC spectrum substantially similar to that shown in FIG. 12B.

In some embodiments, the disclosure also provides a method for preparing a crystalline form of abiraterone decanoate. In some embodiments, the method may include recrystallizing abiraterone decanoate in a suitable solvent, such as acetone and water. In a typical method, abiraterone decanoate is first dissolved in a first solvent, such as acetone, at room temperature or under heat (e.g., about 40° C.) to form a solution; the solution can then be cooled to form a suspension, which can optionally be subsequently diluted with a second solvent, such as water (typically a poor solvent in which abiraterone decanoate has low solubility), and stirred for a period of time (e.g., about 12 hours) to form the crystalline form. The amount, concentration, etc. of the solvent can be adjusted by one of skill in the art in view of the present disclosure. An exemplary procedure is also provided in Example 6A.

Abiraterone decanoate is typically prepared in a form of high purity suitable for, e.g., pharmaceutical use. In some embodiments, the present disclosure provides abiraterone decanoate in a substantially pure form, e.g., having a purity of greater than 80%, preferably greater than 90% (e.g., greater than 95%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%), e.g., by weight, HPLC area ratio, or both. In some embodiments, abiraterone decanoate may be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any range of values specified by weight and/or HPLC area ratio. For example, in some embodiments, abiraterone decanoate may be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any range of values specified by weight. Exemplary procedures for preparing substantially pure abiraterone decanoate are provided in the Examples section. Suitable HPLC methods for measuring the purity of abiraterone decanoate are also described in the Examples section. Substantially pure abiraterone decanoate may be in solid form (e.g., crystalline form, amorphous form, or combinations thereof as described herein), or in solution, suspension, or other form. For the avoidance of doubt, an abiraterone prodrug formulation comprising substantially pure abiraterone decanoate and one or more other components herein should be understood to be a mixture of substantially pure abiraterone decanoate herein and one or more other components, e.g., such a formulation may be obtained directly or indirectly by mixing (e.g., dissolving, suspending, or otherwise forming a mixture) substantially pure abiraterone decanoate with one or more other components, such as a pharma- ceutically acceptable oil, solvent, etc.

を有するデカン酸アビラテロン、またはそれらの薬学的に許容される塩、及び薬学的に許容される担体を含む医薬組成物を提供する。デカン酸アビラテロンは、典型的には、その塩基性形態で医薬組成物中に存在し、文脈に反することが明白でない限り、そのように理解されるべきである。いくつかの実施形態では、デカン酸アビラテロンは、本明細書に記載の実質的に純粋な形態である場合がある。例えば、医薬組成物は、実質的に純粋なデカン酸アビラテロンを薬学的に許容される担体及び任意の他の成分と混合することによって調製することができる。いくつかの特定の実施形態では、実質的に純粋なデカン酸アビラテロンは、本明細書に記載の結晶形であり、かつ該医薬組成物は、その結晶形を薬学的に許容される担体及び任意の他の成分と混合すること（例えば、溶解させること、懸濁すること、または別の方法で混合物を形成すること）によって調製することができる。 In some particular embodiments, the present disclosure provides a compound of formula

The present invention provides a pharmaceutical composition comprising abiraterone decanoate having the formula: or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. Abiraterone decanoate is typically present in the pharmaceutical composition in its basic form, and should be so understood unless the context clearly indicates otherwise. In some embodiments, the abiraterone decanoate may be in a substantially pure form as described herein. For example, the pharmaceutical composition can be prepared by mixing substantially pure abiraterone decanoate with a pharma- ceutically acceptable carrier and any other ingredients. In some particular embodiments, the substantially pure abiraterone decanoate is in a crystalline form as described herein, and the pharmaceutical composition can be prepared by mixing (e.g., dissolving, suspending, or otherwise forming a mixture) the crystalline form with a pharma- ceutically acceptable carrier and any other ingredients.

Typically, the pharmaceutical composition is formulated for parenteral administration. For example, in some embodiments, the pharmaceutical composition may be formulated for intramuscular, intradermal, or subcutaneous injection.

The pharmaceutical compositions are generally non-aqueous formulations, e.g., oil-based formulations, and include a non-aqueous pharma- tically acceptable carrier (e.g., as described herein). For example, in some embodiments, the pharma- tically acceptable carrier includes a pharma- tically acceptable oil, e.g., an injectable pharma- tically acceptable oil, including a vegetable-derived oil or a synthetic mono- or diglyceride of a fatty acid. In some embodiments, the pharma- tically acceptable oil may be a natural oil, a synthetic oil, or a semi-synthetic oil, such as fractionated coconut oil and a medium-chain triglyceride, such as that sold under the trademark Miglyol. In some embodiments, the pharma- tically acceptable carrier includes a triglyceride derived from a fatty acid. In some embodiments, the pharma- tically acceptable carrier includes a triglyceride derived from long- and/or medium-chain fatty acids, which may be independently polyunsaturated, monounsaturated, or saturated. As will be appreciated by those skilled in the art, medium chain fatty acids contain 6-12 carbons, such as caproic acid, caprylic acid, capric acid, lauric acid, etc., and short chain fatty acids typically have fewer than 6 carbons, while long chain fatty acids typically contain 13-21 carbons. In some embodiments, the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil, which may be selected from vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil. In some particular embodiments, the pharmaceutically acceptable carrier may comprise corn oil, which contains triglycerides whose fatty acid components are primarily linoleic acid, oleic acid, palmitic acid, and stearic acid.

In some embodiments, in addition to the pharma- ceutically acceptable oil, the pharma- ceutically acceptable carrier can further include a pharma- ceutically acceptable solvent (or co-solvent, if the oil is considered a solvent), such as an alcohol, ester, or acid. In some embodiments, the pharma- ceutically acceptable solvent can include benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid, and/or ethyl acetate. In some embodiments, the pharma- ceutically acceptable solvent can be benzyl alcohol and/or benzyl benzoate. In some embodiments, the pharma- ceutically acceptable solvent can be benzyl alcohol. In some embodiments, the pharma- ceutically acceptable solvent can be a combination of benzyl alcohol and benzyl benzoate. As discussed herein, the combination of benzyl alcohol and benzyl benzoate can greatly increase the solubility of abiraterone decanoate in the pharma- ceutically acceptable oil.

In some specific embodiments, the disclosure provides a pharmaceutical composition comprising abiraterone decanoate, a pharma- ceutically acceptable oil (e.g., as described herein), benzyl alcohol, and benzyl benzoate. In some embodiments, the pharma-ceutically acceptable oil is corn oil. In some embodiments, benzyl alcohol is present in an amount of about 5-10% by volume, benzyl benzoate is present in an amount of about 10-20% by volume, and corn oil is present in an amount of about 70-85% by volume, with the sum of benzyl alcohol, benzyl benzoate, and corn oil being 100%.

The pharmaceutical composition typically contains abiraterone decanoate at a concentration of about 25 mg/ml to about 500 mg/ml. In some embodiments, abiraterone decanoate may be present at a concentration of about 50 mg/ml, about 100 mg/ml, about 150 mg/ml, about 200 mg/ml, about 250 mg/ml, about 300 mg/ml, about 350 mg/ml, about 400 mg/ml, about 500 mg/ml, or any range of values recited. In some embodiments, abiraterone decanoate may be present at a concentration of about 100 mg/ml to about 300 mg/ml, such as about 150 mg/ml to about 250 mg/ml, about 200 mg/ml to about 300 mg/ml, etc.

Abiraterone decanoate is typically included in the pharmaceutical composition in an amount therapeutically effective to treat a disease or disorder described herein, such as prostate cancer. In some embodiments, abiraterone decanoate may be present in the pharmaceutical composition in an amount sufficient to provide a therapeutically effective plasma concentration of abiraterone for a period of at least 1 week, e.g., at least 2 weeks, at least 4 weeks, and up to 6 or 8 weeks or more, following a single administration to a subject having a sex hormone dependent benign or malignant disease, syndrome due to androgen excess, and/or syndrome due to glucocorticoid excess, such as hypercortisolism. In some embodiments, abiraterone decanoate may be present in the pharmaceutical composition in an amount sufficient to provide a therapeutically effective plasma concentration of abiraterone of about 1 ng/ml or more, e.g., about 2 ng/ml or more, about 4 ng/ml or more, about 5 ng/ml or more, about 8 ng/ml or more, for a period of at least 1 week, e.g., at least 2 weeks, at least 4 weeks, and up to 6 or 8 weeks or more, after a single administration to a subject having a sex hormone-dependent benign or malignant disease, syndrome due to androgen excess, and/or syndrome due to glucocorticoid excess, such as hypercortisolism. In some embodiments, abiraterone decanoate may be present in the pharmaceutical composition in an amount sufficient to provide a therapeutically effective plasma concentration of abiraterone of about 0.5 ng/ml or more, for a period of at least 4 weeks, e.g., at least 6 weeks, and up to 8 weeks or more, after a single administration to a subject having a sex hormone-dependent benign or malignant disease, syndrome due to androgen excess, and/or syndrome due to glucocorticoid excess, such as hypercortisolism.

を有する治療上有効な量のデカン酸アビラテロン、薬学的に許容される油、及び薬学的に許容される溶媒を含む例えば単位製剤である医薬組成物を提供し、ここで、該デカン酸アビラテロンは、約２５ｍｇ／ｍｌ～約５００ｍｇ／ｍｌ、例えば約５０ｍｇ／ｍｌ、約１００ｍｇ／ｍｌ、約１５０ｍｇ／ｍｌ、約２００ｍｇ／ｍｌ、約２５０ｍｇ／ｍｌ、約３００ｍｇ／ｍｌ、約３５０ｍｇ／ｍｌ、約４００ｍｇ／ｍｌ、約５００ｍｇ／ｍｌまたは記載する値の任意の範囲の濃度で存在するその塩基性形態であり、例えば単位製剤である該医薬組成物は、筋肉内注射、皮内注射、または皮下注射などの非経口注射用に製剤化され、例えば単位製剤である該医薬組成物は、約５０ｍｇ～約２，０００ｍｇ、例えば約１００ｍｇ、約３５０ｍｇ、約５００ｍｇ、約１０００ｍｇ、約１５００ｍｇ、約２０００ｍｇ、または記載する値の任意の範囲の量のデカン酸アビラテロンを含む。いくつかの実施形態では、医薬組成物は、単位製剤であってよい。典型的には、投与量に応じて、単位製剤の１つ以上（例えば、１つ）が、それを必要とする対象へ投与されてよい。例えば単位製剤である医薬組成物中��薬学的に許容される油は、本明細書に記載のもののいずれかであってよい。例えば、いくつかの実施形態では、薬学的に許容される油は、植物由来の油または脂肪酸の合成モノグリセリドまたはジグリセリドを含む、注射用の薬学的に許容される油である。いくつかの実施形態では、薬学的に許容される油は、天然油、合成油、または分溜ココナッツ油などの準合成油及び商標Ｍｉｇｌｙｏｌで販売されているような中鎖トリグリセリドであってよい。いくつかの実施形態では、薬学的に許容される油は、脂肪酸に由来するトリグリセリドを含むことができる。いくつかの実施形態では、薬学的に許容される油は、独立してポリ不飽和、モノ不飽和、または飽和であることがある、長鎖及び／または中鎖脂肪酸に由来するトリグリセリドを含むことができる。いくつかの実施形態では、薬学的に許容される油は、植物油、ヒマシ油、コーン油、ゴマ油、綿実油、ピーナッツ油（落花生油）、ケシ種子油、茶種子油、及び大豆油から選択することができる。いくつか���特定の実施形態では、薬学的に許容される油は、脂肪酸成分が主にリノール酸、オレイン酸、パルミチン酸及びステアリン酸であるトリグリセリドを含む、コーン油を含むことができる。また、例えば単位製剤である医薬組成物中の薬学的に許容される溶媒には、本明細書に記載のもののいずれかが含まれる。いくつかの実施形態では、薬学的に許容される溶媒（または油が溶媒として見なされる場合、共溶媒）は、アルコール、エステル、酸などである。いくつかの実施形態では、薬学的に許容される溶媒は、ベンジルアルコール、安息香酸ベンジル、エタノール、グリセロール、ポリエチレングリコール、ポリソルベート８０、酢酸、及び／または酢酸エチルを含むことができる。いくつかの実施形態では、薬学的に許容される溶媒は、ベンジルアルコール及び／または安息香酸ベンジルであってよい。いくつかの実施形態では、例えば単位製剤である医薬組成物は、デカン酸アビラテロン、（例えば、本明細書に記載されるような）薬学的に許容される油、ベンジルアルコール及び安息香酸ベンジルを含む。いくつかの実施形態では、薬学的に許容される油はコーン油である。いくつかの実施形態では、ベンジルアルコール、安息香酸ベンジル、及びコーン油の合計量が１００％となる状態で、ベンジルアルコールが、約５～１０体積％の量で存在し、安息香酸ベンジルが、約１０～２０体積％の量で存在し、かつコーン油が、約７０～８５体積％の量で存在する。 In some particular embodiments, the present disclosure provides a compound of formula

and a pharma- ceutical composition, e.g., a unit dosage form, comprising a therapeutically effective amount of abiraterone decanoate having a formula of about 25 mg/ml to about 500 mg/ml, e.g., about 50 mg/ml, about 100 mg/ml, about 150 mg/ml, about 200 mg/ml, about 250 mg/ml, about 300 mg/ml, about 350 mg/ml, about 400 mg/ml, about 500 mg/ml, or any range of values recited, the pharmaceutical composition, e.g., a unit formulation, is formulated for parenteral injection, such as intramuscular, intradermal, or subcutaneous injection, e.g., the unit formulation, comprises abiraterone decanoate in an amount of about 50 mg to about 2,000 mg, e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, about 2000 mg, or any range of values recited. In some embodiments, the pharmaceutical composition may be a unit formulation. Typically, one or more (e.g., one) of the unit formulations may be administered to a subject in need thereof, depending on the dosage. The pharma- ceutically acceptable oil in the pharmaceutical composition, e.g., a unit formulation, may be any of those described herein. For example, in some embodiments, the pharma-ceutically acceptable oil is an injectable pharma-ceutically acceptable oil, including oils of vegetable origin or synthetic mono- or diglycerides of fatty acids. In some embodiments, the pharma- ceutically acceptable oil may be a natural oil, a synthetic oil, or a semi-synthetic oil, such as fractionated coconut oil, and a medium-chain triglyceride, such as that sold under the trademark Miglyol. In some embodiments, the pharma-ceutically acceptable oil may include a triglyceride derived from a fatty acid. In some embodiments, the pharma-ceutically acceptable oil may include a triglyceride derived from a long-chain and/or medium-chain fatty acid, which may be independently polyunsaturated, monounsaturated, or saturated. In some embodiments, the pharma-ceutically acceptable oil may be selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil. In some particular embodiments, the pharma-ceutically acceptable oil may include corn oil, which includes triglycerides whose fatty acid components are primarily linoleic acid, oleic acid, palmitic acid, and stearic acid. Additionally, the pharma-ceutically acceptable solvent in the pharmaceutical composition, e.g., a unit dosage form, may include any of those described herein. In some embodiments, the pharma- ceutically acceptable solvent (or co-solvent, if oil is considered the solvent) is an alcohol, ester, acid, etc. In some embodiments, the pharma- ceutically acceptable solvent can include benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid, and/or ethyl acetate. In some embodiments, the pharma- ceutical composition can be benzyl alcohol and/or benzyl benzoate. In some embodiments, the pharmaceutical composition, e.g., a unit dosage form, comprises abiraterone decanoate, a pharma- ceutical acceptable oil (e.g., as described herein), benzyl alcohol, and benzyl benzoate. In some embodiments, the pharma- ceutical acceptable oil is corn oil. In some embodiments, benzyl alcohol is present in an amount of about 5-10% by volume, benzyl benzoate is present in an amount of about 10-20% by volume, and corn oil is present in an amount of about 70-85% by volume, with the sum of the benzyl alcohol, benzyl benzoate, and corn oil being 100%.

In some embodiments, the disclosure provides exemplary abiraterone decanoate formulations as shown in Table C. All numerical values in the table should be understood as preceded by the term "about." The concentration of abiraterone decanoate is expressed in mg of abiraterone decanoate per ml of final formulation, which may be a solution or suspension. The amount of oil (primary solvent) and co-solvent (benzyl alcohol and/or benzyl benzoate) in the table is expressed as a volume percent of the solvent, including both the oil and the co-solvent. Suitable oils include any of the pharma- ceutically acceptable oils as described herein, such as corn oil. Optional additional ingredients are not shown in Table C. Examples 3F-3H herein provide procedures for preparing representative abiraterone decanoate formulations of Table C.
TABLE C: Exemplary Abiraterone Decanoate Formulations

を有するデカン酸アビラテロンを、混合し（例えば、溶解させまたは懸濁し）、混合物（例えば、溶液または懸濁液）を形成することを含む。いくつかの実施形態では、方法は、混合物（例えば、溶液または懸濁液）を滅菌することをさらに含む。いくつかの実施形態では、溶解させることまたは懸濁することは、薬学的に許容される担体中で本明細書に記載のデカン酸アビラテロンの結晶形を混合すること（例えば、溶解させることまたは懸濁すること）を含んでもよい。いくつかの実施形態では、混合すること（例えば、溶解させることまたは懸濁すること）は、薬学的に許容される担体中で本明細書に記載の実質的に純粋なデカン酸アビラテロンを混合すること（例えば、溶解させることまたは懸濁すること）を含んでもよい。好適な薬学的に許容される担体及び量、デカン酸アビラテロンの量、デカン酸アビラテロンの濃度には、本明細書に記載のもののいずれかが含まれる。例えば、いくつかの実施形態では、薬学的に許容される担体は、薬学的に許容される油及び薬学的に許容される溶媒を含み、該薬学的に許容される油は、植物油、ヒマシ油、コーン油、ゴマ油、綿実油、ピーナッツ油、ケシ種子油、茶種子油、または大豆油を含み、該薬学的に許容される溶媒は、ベンジルアルコール及び／または安息香酸ベンジルを含み、該デカン酸アビラテロンは、約５０ｍｇ／ｍＬ～約３００ｍｇ／ｍＬ、例えば約１００ｍｇ／ｍＬ～約３００ｍｇ／ｍＬの濃度で存在する。 The pharmaceutical compositions or unit dosage forms herein can be prepared by one of skill in the art in view of the methods disclosed herein. In some embodiments, the present disclosure provides a method for preparing an abiraterone decanoate formulation suitable for parenteral administration to a subject having a sex hormone-dependent benign or malignant disease, syndrome due to androgen excess, and/or syndrome due to glucocorticoid excess, such as hypercortisolism. In some embodiments, the method comprises:

and mixing (e.g., dissolving or suspending) abiraterone decanoate having a crystalline form of abiraterone decanoate described herein in a pharma- ceutically acceptable carrier to form a mixture (e.g., a solution or suspension). In some embodiments, the method further comprises sterilizing the mixture (e.g., a solution or suspension). In some embodiments, the dissolving or suspending may comprise mixing (e.g., dissolving or suspending) a crystalline form of abiraterone decanoate described herein in a pharma-ceutically acceptable carrier. In some embodiments, the mixing (e.g., dissolving or suspending) may comprise mixing (e.g., dissolving or suspending) a substantially pure abiraterone decanoate described herein in a pharma-ceutically acceptable carrier. Suitable pharma-ceutically acceptable carriers and amounts, amounts of abiraterone decanoate, and concentrations of abiraterone decanoate include any of those described herein. For example, in some embodiments, the pharma- ceutically acceptable carrier comprises a pharma- ceutically acceptable oil and a pharma- ceutically acceptable solvent, the pharma- ceutically acceptable oil comprises vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil, the pharma- ceutically acceptable solvent comprises benzyl alcohol and/or benzyl benzoate, and the abiraterone decanoate is present at a concentration of about 50 mg/mL to about 300 mg/mL, e.g., about 100 mg/mL to about 300 mg/mL.

In some specific embodiments, the present disclosure also provides a method for treating sex hormone-dependent benign or malignant diseases, syndromes due to androgen excess, and/or syndromes due to glucocorticoid excess, such as hypercortisolism, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition (e.g., a unit dosage form described herein) comprising abiraterone decanoate as described herein. Administration is not limited to any particular route. However, abiraterone decanoate is typically administered parenterally, for example, via intramuscular, intradermal, or subcutaneous injection. In some embodiments, administration is by intramuscular injection. Unlike oral administration of abiraterone acetate, a pharmaceutical composition (e.g., a unit dosage form described herein) comprising abiraterone decanoate as described herein can be administered to a subject in need thereof with or without food.

Sex hormone-dependent benign or malignant diseases that can be treated by the method include any of those described herein. In some embodiments, the sex hormone-dependent benign or malignant disease may be selected from androgen-dependent and estrogen-dependent diseases, such as androgen-dependent or estrogen-dependent cancer. In some embodiments, the sex hormone-dependent benign or malignant disease may be selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, and lung cancer, and the like. In some embodiments, the sex hormone-dependent benign or malignant disease may be prostate cancer or breast cancer. In some embodiments, the sex hormone-dependent benign or malignant disease may be castration-resistant or castration-sensitive prostate cancer. In some embodiments, the sex hormone-dependent benign or malignant disease may be metastatic castration-resistant or metastatic castration-sensitive prostate cancer. Syndromes resulting from androgen excess and/or glucocorticoid excess, such as hypercortisolism, that can be treated by the method include any of those described herein. In some embodiments, the methods herein can be methods for treating a non-neoplastic syndrome in a subject resulting from androgen excess, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), precocious puberty, hirsutism, etc. In some embodiments, the methods herein can be methods for treating a non-neoplastic syndrome resulting from glucocorticoid (e.g., cortisol) excess, such as Cushing's syndrome or Cushing's disease.

The methods herein can be used in combination with one or more additional therapies for the corresponding disease or disorder. For example, the methods may include administering one or more other drugs or agents (such as another cancer chemotherapy drug, a hormone replacement drug, or a hormone ablation drug, as described herein, etc.) to the subject , either simultaneously or sequentially, through the same or different routes of administration. In some embodiments, the subject can also be treated with a gonadotropin releasing hormone analog and/or a bilateral orchiectomy.

As discussed herein, abiraterone is a 17α-hydroxylase/C17,20-lyase (CYP17) inhibitor that may result in reduced biosynthesis of androgens (e.g., testosterone), reduced glucocorticoids (e.g., cortisol), and mineralocorticoid excess (e.g., increased progesterone). Adrenal insufficiency is also known to be associated with abiraterone therapy, such as Zytiga®. Intramuscular administration of pharmaceutical compositions comprising abiraterone decanoate herein has been shown to provide effective plasma levels of abiraterone and long-term inhibition of CYP17A1 in vivo, along with increased progesterone levels and reduced cortisol levels.

In some embodiments, the methods herein (e.g., treating prostate cancer or treating classical or non-classical congenital adrenal hyperplasia) can include administering to the subject an agent that counteracts the reduction in glucocorticoid(s) associated with administration of abiraterone decanoate as described herein. In some embodiments, the methods can include administering to the subject in need thereof an agent effective in treating one or more symptoms associated with adrenal insufficiency, such as acute stress, fatigue, etc. In some particular embodiments, the methods can include administering to the subject a steroid, such as a corticosteroid. In some embodiments, the methods can include administering to the subject a glucocorticoid. In some particular embodiments, the methods can also include administering to the subject prednisone, prednisolone, and/or methylprednisolone. In some embodiments, the methods can also include administering to the subject an agent effective in treating cortisol deficiency, such as hydrocortisone, prednisone, prednisolone, methylprednisolone, and/or dexamethasone. In any such embodiment, the agents may be administered to a subject simultaneously or sequentially, in any order, via the same route of administration or different routes of administration.

In some embodiments, the methods herein may be characterized by a dosing frequency of once a week or less frequently. Typically, the dosing frequency can range from once a week to once every few months, e.g., once a week to once every three months, or once a week to once every eight weeks, e.g., once a month. In some embodiments, the methods include administering to the subject a pharmaceutical composition comprising abiraterone decanoate (e.g., a unit dosage form described herein) once a week, once every two weeks, once every three weeks, once a month, or more than once a month. In some embodiments, the methods include administering to the subject a pharmaceutical composition comprising abiraterone decanoate (e.g., a unit dosage form described herein) once every two weeks, once a month, or more than once a month. In some embodiments, the dosage amount of abiraterone decanoate per dose is about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of values recited). In some embodiments, the dosage amount of abiraterone decanoate per dose is about 0.5 mg/kg to about 100 mg/kg of the subject 's body weight (e.g., about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any range of values recited). In some embodiments, administration is via intramuscular injection. In some embodiments, the administration provides a therapeutically effective plasma concentration of abiraterone for a period of at least 1 week, such as at least 2 weeks, such as at least 3 weeks, at least 4 weeks, and up to 6 or 8 weeks or more. In some embodiments, the administration results in a plasma concentration of abiraterone of greater than 1.0 ng/ml (e.g., from about 1 ng/ml to about 8 ng/ml, or about 2 ng/ml or more, about 4 ng/ml or more, about 5 ng/ml or more, or about 8 ng/ml or more) over a period of at least 1 week, e.g., at least 2 weeks, e.g., at least 3 weeks, at least 4 weeks, and up to 6 or 8 weeks or more. In some embodiments, the administration results in a steady state C min of abiraterone of greater than 1.0 ng/ml (e.g., from about 1 ng/ml to about 8 ng/ml, about 2 ng/ml or more, about 4 ng/ml or more, about 5 ng/ml or more, or about 8 ng/ _ml or more). In some embodiments, the administration results in a single dose or steady state Cmax of abiraterone of about 10 ng/ml to about 400 ng/ml, e.g., about 10 ng/ml, about 15 ng/ml, about 20 ng/ml, about 30 ng/ml, about 50 ng/ml, about 60 ng/ml, about 100 ng/ml, about 150 ng/ml, about 160 ng/ml, or any range of values recited, e.g., about 10-30 ng/ml, about 20-60 ng/ml, about 15-160 ng/ _ml , or about 50-100 ng/ml. In some embodiments, the abiraterone decanoate formulation can be administered to a subject in need thereof as the sole source of abiraterone. However, in some embodiments, the abiraterone decanoate formulation can also be administered to a subject in need thereof as a supplement to another abiraterone therapy.

In some specific examples, the disclosure provides a method of treating prostate cancer, the method comprising administering abiraterone decanoate to a subject in need thereof via intramuscular, intradermal, or subcutaneous injection once a week or more than once a week, such as once a month or more than once a month, with each dose of abiraterone decanoate being about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of values recited). In some embodiments, the abiraterone decanoate is administered via intramuscular injection. In some embodiments, the prostate cancer is castration-resistant prostate cancer or castration-sensitive prostate cancer. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer.

In some specific examples, the disclosure provides a method of treating prostate cancer, the method comprising administering to a subject a 50 mg to about 2000 mg dose of abiraterone decanoate (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of values recited), or a 50 mg to about 100 mg dose of abiraterone decanoate (e.g., about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, or any range of values recited), of the subject 's body weight. The present invention includes administering a pharmaceutical composition comprising abiraterone decanoate described herein (e.g., a unit dosage form described herein) to a subject in need thereof via intramuscular, intradermal, or subcutaneous injection at about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any range of values recited), once a week or more than once a week, for example once a month or more than once a month. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the prostate cancer is castration-resistant prostate cancer or castration-sensitive prostate cancer. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer.

In some specific examples, the disclosure provides a method of treating prostate cancer comprising administering a unit formulation described herein to a subject in need thereof via intramuscular, intradermal, or subcutaneous injection once a week or more than once a week, for example once a month or more than once a month, with each dose of abiraterone decanoate being about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of values recited), or with each dose of abiraterone decanoate being about 0.5 mg/kg to about 100 mg/kg of the subject's body weight (e.g., about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any range of values recited). In some embodiments, the unit dosage form is administered via intramuscular injection. In some embodiments, the prostate cancer is castration-resistant prostate cancer or castration-sensitive prostate cancer. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer.

In some specific embodiments, the disclosure also provides methods of delivering abiraterone to a subject in need thereof, the methods comprising administering abiraterone decanoate at a dose of about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of values recited), or at a dose of about 0.5 mg/kg to about 100 mg/kg (e.g., about 0.5 mg/kg) of the subject 's body weight. The present invention includes administering to a subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) via intramuscular, intradermal, or subcutaneous injection at a dose of about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/ kg , or any range of values recited) once a week or more than once a week, for example once a month or more than once a month. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the subject suffers from a hormone-dependent benign or malignant disease, a syndrome resulting from androgen excess, and/or a syndrome resulting from glucocorticoid excess, such as hypercortisolism, e.g., as described herein.

In some specific embodiments, the disclosure also provides a method of inhibiting CYP17A1 activity in a subject in need thereof, the method comprising administering to a subject a dose of abiraterone decanoate of about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of values recited), or to a subject a dose of abiraterone decanoate of about 0.5 mg/kg to about 100 mg/kg (e.g., about 0.5 mg The present invention includes administering to a subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) via intramuscular, intradermal, or subcutaneous injection once a week or more than once a week, for example once a month or more than once a month, at about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any range of values recited). In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the subject suffers from a sex hormone-dependent benign or malignant disease, e.g., as described herein. In some embodiments, the subject suffers from a syndrome resulting from androgen excess and/or a syndrome resulting from glucocorticoid excess, such as hypercortisolism, e.g., as described herein.

In some specific embodiments, the disclosure also provides a method of reducing glucocorticoid (e.g., cortisol) levels in a subject in need thereof, the method comprising administering to a subject a dose of abiraterone decanoate of about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of values recited), or to a subject a dose of abiraterone decanoate of about 0.5 mg/kg to about 100 mg/kg (e.g., about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, or any range of values recited), or to a subject a dose of abiraterone decanoate of about 0.5 mg/kg to about 100 mg/kg (e.g., about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 1000 mg, or any range of values recited ), The method includes administering to the subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) via intramuscular, intradermal, or subcutaneous injection once a week or more than once a week, for example once a month or more than once a month, at a dose of about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any range of values recited). In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the subject is suffering from hypercortisolism as described herein, such as Cushing's syndrome or Cushing's disease.

In some specific embodiments, the present disclosure also provides a method of reducing androgen (e.g., testosterone and/or dihydrotestosterone) and/or estrogen levels in a subject in need thereof, the method comprising administering to a subject a dose of abiraterone decanoate of about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of values recited), or wherein each dose of abiraterone decanoate is about 0.5 mg/kg of the subject 's body weight. The method includes administering to a subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) via intramuscular, intradermal, or subcutaneous injection at a dose of about 0.5 mg/kg to about 100 mg/kg (e.g., about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any range of values recited), once a week or more than once a week, for example once a month or more than once a month. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the subject suffers from a syndrome resulting from androgen excess, such as congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), endometriosis, polycystic ovary syndrome, precocious puberty, or hirsutism. In some embodiments, the subject has an androgen- and/or estrogen-related cancer, such as prostate cancer or breast cancer.

Other Abiraterone Prodrugs While the present disclosure describes embodiments relating to abiraterone decanoate in more detail, those skilled in the art will understand that similar embodiments are also applicable to other abiraterone prodrugs of the present disclosure in light of the present specification. For example, like abiraterone decanoate, pharmacokinetic studies have shown that intramuscular injection of abiraterone isocaproate formulations can result in therapeutically effective amounts of abiraterone in plasma for extended periods of time. Thus, the embodiments described herein, particularly for abiraterone decanoate formulations and methods of treatment, are equally applicable to abiraterone isocaproate, with abiraterone decanoate substituted for abiraterone isocaproate.

For example, in some embodiments, the present disclosure also provides a method of treating a sex hormone-dependent benign or malignant disease, a syndrome resulting from androgen excess, and/or a syndrome resulting from glucocorticoid excess, such as hypercortisolism, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising abiraterone isocaproate as described herein (e.g., a unit dosage form as described herein). In some embodiments, a pharmaceutical composition comprising abiraterone isocaproate as described herein (e.g., a unit dosage form as described herein) can be administered to a subject in need thereof with or without food. Suitable sex hormone-dependent benign or malignant diseases, syndrome resulting from androgen excess, syndrome resulting from glucocorticoid excess, such as hypercortisolism, dosage regimens, combination treatments, etc. include those described herein, for example, with respect to abiraterone decanoate.

In some specific examples, the disclosure provides a method of treating prostate cancer, the method comprising administering abiraterone isocaproate at a dose of about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of values recited), or at a dose of about 0.5 mg/kg to about 100 mg/kg (e.g., about 0.5 mg/kg, about The present invention includes administering a pharmaceutical composition comprising abiraterone isocaproate as described herein to a subject in need thereof via intramuscular, intradermal, or subcutaneous injection at a dose of about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any range of values recited) once a week or more than once a week, for example once a month or more than once a month. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the prostate cancer is castration-resistant prostate cancer or castration-sensitive prostate cancer. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer.

In some specific examples, the disclosure provides a method of treating prostate cancer, the method comprising administering abiraterone isocaproate at a dose of about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of values recited), or at a dose of about 0.5 mg/kg to about 100 mg/kg (e.g., about 0.5 mg/kg, about The present invention includes administering a unit formulation comprising abiraterone isocaproate as described herein to a subject in need thereof via intramuscular, intradermal, or subcutaneous injection at a dose of about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any range of values recited) once a week or more than once a week, for example once a month or more than once a month. In some embodiments, the unit formulation is administered via intramuscular injection. In some embodiments, the prostate cancer is castration-resistant prostate cancer or castration-sensitive prostate cancer. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer.

In some specific embodiments, the disclosure also provides methods of delivering abiraterone to a subject in need thereof, the methods comprising administering abiraterone isocaproate at a dose of about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of values recited), or at a dose of about 0.5 mg/kg to about 100 mg/kg (e.g., about 0.5 mg/kg) of the subject 's body weight. The present invention includes administering to a subject a pharmaceutical composition comprising abiraterone isocaproate as described herein (e.g., a unit dosage form as described herein) via intramuscular, intradermal, or subcutaneous injection once a week or more than once a week, for example once a month or more than once a month, at about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any range of values recited). In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the subject suffers from a hormone-dependent benign or malignant disease, a syndrome resulting from androgen excess, and/or a syndrome resulting from glucocorticoid excess, such as hypercortisolism, e.g., as described herein.

In some specific embodiments, the disclosure also provides a method of inhibiting CYP17A1 activity in a subject in need thereof, the method comprising administering abiraterone isocaproate at a dose of about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of values recited), or at a dose of about 0.5 mg/kg to about 100 mg/kg (e.g., about 0.5 mg/kg to about 100 mg/kg) of the subject 's body weight. The present invention includes administering to a subject a pharmaceutical composition comprising abiraterone isocaproate as described herein (e.g., a unit dosage form as described herein) via intramuscular, intradermal, or subcutaneous injection once a week or more than once a week, for example once a month or more than once a month, at about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any range of values recited). In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the subject suffers from a sex hormone-dependent benign or malignant disease, e.g., as described herein. In some embodiments, the subject suffers from a syndrome resulting from androgen excess and/or a syndrome resulting from glucocorticoid excess, such as hypercortisolism, e.g., as described herein.

In some specific embodiments, the disclosure also provides a method of reducing glucocorticoid (e.g., cortisol) levels in a subject in need thereof, the method comprising administering abiraterone isocaproate at a dose of about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of values recited), or at a dose of about 0.5 mg/kg to about 100 mg/kg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, or any range of values recited), or at a dose of about 0.5 mg/kg to about 100 mg/kg (e.g., about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 1000 mg, or any range of values recited), of the subject 's body weight. The method includes administering to the subject a pharmaceutical composition comprising abiraterone isocaproate as described herein (e.g., a unit dosage form as described herein) via intramuscular, intradermal, or subcutaneous injection once a week or more than once a week, for example once a month or more than once a month, at about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/ kg , about 100 mg/kg, or any range of values recited). In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the subject suffers from hypercortisolism as described herein, such as Cushing's syndrome or Cushing's disease.

In some specific embodiments, the present disclosure also provides a method of reducing androgen (e.g., testosterone and/or dihydrotestosterone) and/or estrogen levels in a subject in need thereof, the method comprising administering abiraterone isocaproate at a dose of about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of values recited), or at a dose of about 0.5 mg/kg of the subject 's body weight. The present invention includes administering to a subject a pharmaceutical composition comprising abiraterone isocaproate as described herein (e.g., a unit dosage form as described herein) via intramuscular, intradermal, or subcutaneous injection at a dose of about 0.5 mg/kg to about 100 mg/kg (e.g., about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any range of values recited), once a week or more than once a week, for example once a month or more than once a month. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the subject suffers from a syndrome resulting from androgen excess, such as congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), endometriosis, polycystic ovary syndrome, precocious puberty, or hirsutism. In some embodiments, the subject has an androgen- and/or estrogen-related cancer, such as prostate cancer or breast cancer.

Non-Limiting Exemplary Embodiments In some embodiments, the present disclosure also provides non-limiting exemplary embodiments 1-66, as set forth below.

Embodiment 1. An abiraterone prodrug formulation suitable for parenteral administration to a subject with a hormone-dependent benign or malignant disease, comprising:
(a) one or more lipophilic ester forms of abiraterone; and (b) one or more pharma- ceutically acceptable carriers, diluents, or excipients;
The abiraterone prodrug formulation, upon said administration to the subject , achieves a therapeutic plasma concentration of abiraterone.

Embodiment 2. The abiraterone prodrug formulation of embodiment 1, wherein the therapeutic plasma concentration of abiraterone is at least 1.0 ng/ml.

Embodiment 3. The abiraterone prodrug formulation of embodiment 1, wherein the therapeutic plasma concentration of abiraterone is at least 8 ng/ml.

Embodiment 4. The abiraterone prodrug formulation of embodiment 1, wherein the therapeutic plasma concentration of abiraterone is sustained for at least 2 weeks.

Embodiment 5. The abiraterone prodrug formulation of embodiment 1, wherein the parenteral administration is selected from the group consisting of intramuscular injection, intradermal injection, and subcutaneous injection.

Embodiment 6. The abiraterone prodrug formulation of embodiment 1, wherein the lipophilic ester form is selected from the group consisting of acetate, propionate, butanoate, valerate, caproate, enanthate, cypionate, isocaproate, bucclate, cyclohexanecarboxylate, phenylpropionate, decanoate, and undecanoate.

Embodiment 7. The abiraterone prodrug formulation of embodiment 1, wherein the hormone-dependent benign or malignant disease is selected from the group consisting of androgen-dependent diseases and estrogen-dependent diseases.

Embodiment 8. The abiraterone prodrug formulation of embodiment 1, wherein the hormone-dependent benign or malignant disease is selected from the group consisting of prostate cancer and breast cancer.

Embodiment 9. The abiraterone prodrug formulation of embodiment 8, wherein the prostate cancer is selected from the group consisting of castration-resistant prostate cancer and castration-sensitive prostate cancer.

Embodiment 10. A method of treating a hormone-dependent benign or malignant disease comprising parenterally administering to a subject in need of such treatment an effective dose of at least one abiraterone prodrug formulation, said abiraterone prodrug formulation comprising:
(a) one or more lipophilic ester forms of abiraterone; and (b) one or more pharma- ceutically acceptable carriers, diluents, or excipients;
Upon said administration, the at least one abiraterone prodrug formulation achieves a therapeutic plasma concentration of abiraterone.

Embodiment 11. The method of embodiment 10, wherein the therapeutic plasma concentration of abiraterone is at least 1.0 ng/ml.

Embodiment 12. The method of embodiment 10, wherein the therapeutic plasma concentration of abiraterone is at least 8.0 ng/ml.

Embodiment 13. The method of embodiment 10, wherein the therapeutic plasma concentration of abiraterone is sustained for at least two weeks.

Embodiment 14. The method of embodiment 10, wherein the parenteral administration is selected from the group consisting of intramuscular injection, intradermal injection, and subcutaneous injection.

Embodiment 15. The method of embodiment 10, wherein the lipophilic ester form is selected from the group consisting of acetate, propionate, butanoate, valerate, caproate, enanthate, cypionate, isocaproate, bucclate, cyclohexanecarboxylate, phenylpropionate, decanoate, and undecanoate.

Embodiment 16. The method of embodiment 10, wherein the hormone-dependent benign or malignant disease is selected from the group consisting of androgen-dependent diseases and estrogen-dependent diseases.

Embodiment 17. The method of embodiment 10, wherein the hormone-dependent benign or malignant disease is selected from the group consisting of prostate cancer and breast cancer.

Embodiment 18. The method of embodiment 17, wherein the prostate cancer is selected from the group consisting of castration-resistant prostate cancer and castration-sensitive prostate cancer.

Embodiment 19. The method of embodiment 10, wherein the method further comprises monthly administration of the at least one abiraterone prodrug formulation.

Embodiment 20. The method of embodiment 10, wherein the at least one abiraterone prodrug formulation is administered in divided doses.

Embodiment 21. The method of embodiment 10, wherein the at least one abiraterone prodrug formulation is administered simultaneously with at least one other drug or agent.

Embodiment 22. The method of embodiment 10, wherein the at least one abiraterone prodrug formulation is administered prior to at least one other drug or agent.

Embodiment 23. The method of embodiment 10, wherein the at least one abiraterone prodrug formulation is administered after at least one other drug or agent.

Embodiment 24. A kit for treating a hormone-dependent benign or malignant disease as described in embodiment 10, comprising at least one abiraterone prodrug formulation.

Embodiment 25. A method of preparing an abiraterone decanoate formulation suitable for parenteral administration to a subject having a hormone-dependent benign or malignant disease, comprising:
(a) preparing and purifying abiraterone decanoate;
(b) preparing a mixture of oil and a co-solvent;
(c) combining the prepared and purified abiraterone decanoate with one of the oil and alcohol mixtures from step (b);
(d) sterilizing the mixture formed in step (c);
(e) optionally combining the mixture sterilized in step (d) with one or more pharma- ceutically acceptable carriers, diluents, or excipients.

Embodiment 26. The prepared and purified abiraterone decanoate has the following properties: LCMS m/z 504.4 (M+H); ¹ H NMR (CDCl ₃ , 200 MHz): δH 0.877 (3H, t, J = 7 Hz), 1.043 (3H, s), 1.082 (3H, s), 1.268 (16H, m), 1.643 (15H, m), 1.842 (3H, m), 2.065 (3H, m), 2.290 (5H, m), 4.602 (1H, m), 5.404 (1H, d, J = 5 Hz), 5.998 (1H, q, J 26. The method of embodiment 25, wherein the compound has chemical properties of 7.215 (1H, ddd, J = 1,5,8 Hz), 7.643 (1H, dt, J = 2,8 Hz), 8.455 (1H, dd, J = 2,5 Hz), 8.617 (1H, dd, J = 1,2 Hz).

Embodiment 27. The method of embodiment 25, wherein the mixture of oil and co-solvent is selected from the group consisting of 90% castor oil/10% benzyl alcohol and 90% corn oil/10% benzyl alcohol.

式中、Ｒ^１は、Ｒ^１０、Ｏ－Ｒ^１０、またはＮＨＲ^１０であり、
前記Ｒ^１０は、
Ｃ_７－３０アルキル；Ｃ_７－３０アルケニル；Ｃ_７－３０アルキニル；総炭素数が５～１６の、シクロアルキルで置換されたアルキル；総炭素数が７～１６の、フェニルで置換されたアルキル；総炭素数が５～１６の、１つ以上のアルキルで任意的に置換されたシクロアルキル；及び

から選択される、前記化合物またはそれらの薬学的に許容される塩��� Embodiment 28. A compound of formula I, or a pharma- ceutically acceptable salt thereof,

In the formula, R ¹ is R ¹⁰ , O—R ¹⁰ , or NHR ¹⁰ ;
The R ¹⁰ is
C _7-30 alkyl; C _7-30 alkenyl; C _7-30 alkynyl; alkyl substituted with cycloalkyl having a total of 5 to 16 carbon atoms; alkyl substituted with phenyl having a total of 7 to 16 carbon atoms; cycloalkyl optionally substituted with one or more alkyl having a total of 5 to 16 carbon atoms; and

or a pharma- ceutically acceptable salt thereof.

Embodiment 29. The compound according to embodiment 28, or a pharma- ceutically acceptable salt thereof, wherein ^R10 is _C7-16 alkyl.

Embodiment 30. The compound of embodiment 28, or a pharma- ceutically acceptable salt thereof, wherein ^R10 is alkyl substituted with _C3-6 cycloalkyl having a total of 6 to 12 carbon atoms.

Embodiment 31. The compound of embodiment 28, or a pharma- ceutically acceptable salt thereof, wherein ^R1 is _C7-16 alkyl.

Embodiment 32. The compound according to embodiment 28, wherein R ¹ is alkyl having the formula --(CH ₂ ) _n --CH ₃ , where n is an integer from 6 to 12, for example, 6, 7, 8, 9, 10, 11, or 12, or a pharma- ceutically acceptable salt thereof.

Embodiment 33. The compound according to embodiment 28, wherein R ¹ is represented by the formula --(CH ₂ ) _n -Cy, wherein n is an integer from 1 to 6, and Cy is C _3-6 cycloalkyl or phenyl, or a pharma- ceutically acceptable salt thereof.

Embodiment 34. The compound of embodiment 33, or a pharma- ceutically acceptable salt thereof, wherein n is 1 or 2 and Cy is cyclopentyl, cyclohexyl, or phenyl.

である、実施形態２８に記載の化合物またはそれらの薬学的に許容される塩。 Embodiment 35. R ¹ is

or a pharma- ceutically acceptable salt thereof.

である、実施形態２８に記載の化合物またはそれらの薬学的に許容される塩。 Embodiment 36. R ¹ is

or a pharma- ceutically acceptable salt thereof.

Embodiment 37. A pharmaceutical composition comprising a compound according to any one of embodiments 28 to 36 or a pharma- ceutical acceptable salt thereof.

Embodiment 38. The pharmaceutical composition of embodiment 37, formulated for parenteral administration.

Embodiment 39. The pharmaceutical composition of embodiment 38, formulated for intramuscular, intradermal, or subcutaneous injection.

Embodiment 40. The pharmaceutical composition of embodiment 37, further comprising a pharma- ceutical acceptable carrier.

Embodiment 41. The pharmaceutical composition of embodiment 40, wherein the pharma- ceutically acceptable carrier comprises a pharma- ceutically acceptable oil, e.g., an oil suitable as a vehicle for injection, e.g., an oil of plant origin, such as vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil, or a synthetic monoglyceride or diglyceride of a fatty acid.

Embodiment 42. The pharmaceutical composition of embodiment 40 or 41, further comprising a pharma- ceutically acceptable solvent, e.g., benzyl alcohol.

Embodiment 43. The pharmaceutical composition of any one of embodiments 37 to 42, which is a non-aqueous solution or suspension.

式中、Ｒ^２は、Ｒ^２０、Ｏ－Ｒ^２０、またはＮＨＲ^２０であり、
前記Ｒ^２０は、
Ｃ_１－３０アルキル；Ｃ_２－３０アルケニル；Ｃ_２－３０アルキニル；総炭素数が４～３０の、シクロアルキルで置換されたアルキル；総炭素数が７～３０の、フェニルで置換されたアルキル；総炭素数が３～３０の、１つ以上のアルキルで任意的に置換されたシクロアルキルから選択され、
前記医薬組成物は、筋肉内注射、皮内注射、または皮下注射用に製剤化され、前記式ＩＩの化合物またはそれらの薬学的に許容される塩は、約２５ｍｇ／ｍｌ～約５００ｍｇ／ｍｌの濃度で医薬組成物中に存在する、前記医薬組成物。 Embodiment 44. A pharmaceutical composition comprising a compound of formula II or a pharma- ceutically acceptable salt thereof,

In the formula, R ² is R ²⁰ , O—R ²⁰ , or NHR ²⁰ ;
The ^R20 is
_C1-30 alkyl; _C2-30 alkenyl; _C2-30 alkynyl; alkyl substituted with cycloalkyl having a total of 4 to 30 carbon atoms; alkyl substituted with phenyl having a total of 7 to 30 carbon atoms; cycloalkyl optionally substituted with one or more alkyl having a total of 3 to 30 carbon atoms;
The pharmaceutical composition is formulated for intramuscular, intradermal, or subcutaneous injection, and the compound of formula II or a pharma- ceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 25 mg/ml to about 500 mg/ml.

Embodiment 45. The pharmaceutical composition of embodiment 44, wherein R ² in formula II is selected from C _1-16 alkyl; alkyl substituted with cycloalkyl having a total of 5 to 16 carbon atoms; alkyl substituted with phenyl having a total of 7 to 16 carbon atoms; cycloalkyl optionally substituted with one or more alkyl having a total of 5 to 16 carbon atoms.

Embodiment 46. The pharmaceutical composition of embodiment 44, wherein R ² in said Formula II is alkyl having the formula --(CH ₂ ) _n --CH ₃ , where n is an integer from 0 to 12.

Embodiment 47. The pharmaceutical composition according to embodiment 44, wherein R ² in said formula II is represented by the formula --(CH ₂ ) _n -Cy, wherein n is an integer from 1 to 6, and Cy is C _3-6 cycloalkyl or phenyl.

である、実施形態４４に記載の医薬組成物。 Embodiment 48. ^R2 in formula II is

The pharmaceutical composition of embodiment 44, wherein

Embodiment 49. The pharmaceutical composition of any one of embodiments 44 to 48, which is a non-aqueous solution or suspension.

Embodiment 50. The pharmaceutical composition according to any one of embodiments 44 to 49, wherein the compound of formula II or a pharma- ceutically acceptable salt thereof is dissolved or suspended in a pharma- ceutical acceptable oil, e.g., an oil suitable as a vehicle for injection, e.g., an oil of plant origin, such as vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil, or a synthetic mono- or diglyceride of a fatty acid.

Embodiment 51. The pharmaceutical composition of any one of embodiments 44 to 50, further comprising a pharma- ceutically acceptable solvent, e.g., benzyl alcohol.

Embodiment 52. The pharmaceutical composition of any one of embodiments 44-51, comprising a sufficient amount of the compound of formula II or a pharma- ceutically acceptable salt thereof to provide a therapeutically effective plasma concentration of abiraterone for a period of at least two weeks after a single administration to a subject having a hormone-dependent benign or malignant disease (e.g., metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer).

Embodiment 53. The pharmaceutical composition of embodiment 52, wherein the therapeutically effective plasma concentration of abiraterone is greater than or equal to about 1 ng/ml.

Embodiment 54. The pharmaceutical composition of embodiment 53, wherein the therapeutically effective plasma concentration of abiraterone is greater than or equal to about 8 ng/ml.

Embodiment 55. A method of treating a hormone-dependent benign or malignant disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 28-36 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 37-54.

Embodiment 56. The method of embodiment 55, wherein the administration is by intramuscular, intradermal, or subcutaneous injection.

Embodiment 57 The method of embodiment 55 or 56, wherein the administration is carried out regardless of whether the subject is fed, i.e., the compound or pharmaceutical composition is administered with or without food.

Embodiment 58. The method of any one of embodiments 55 to 57, wherein the hormone-dependent benign or malignant disease is prostate cancer or breast cancer.

Embodiment 59. The method of any one of embodiments 55 to 57, wherein the hormone-dependent benign or malignant disease is castration-resistant or castration-sensitive prostate cancer.

Embodiment 60. The method of any one of embodiments 55 to 57, wherein the hormone-dependent benign or malignant disease is metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer.

Embodiment 61. The method of any one of embodiments 55-60, wherein the subject is treated with a gonadotropin releasing hormone analog and/or bilateral orchiectomy.

Embodiment 62. The method of any one of embodiments 55-61, further comprising administering to the subject an effective amount of prednisone or prednisolone.

Embodiment 63. The method of any one of embodiments 55-62, wherein the pharmaceutical composition is administered to the subject once a week or more than once a week, for example, at an administration frequency ranging from once a week to once every several months, for example, from once a week to once every 8 weeks or from once a week to once every 3 months.

Embodiment 64. The method of any one of embodiments 55-63, wherein the administration provides a plasma concentration of abiraterone greater than 1.0 ng/ml for a period of at least 2 weeks.

Embodiment 65. The method of any one of embodiments 55-63, wherein the administration provides a plasma concentration of abiraterone greater than 8.4 ng/ml for a period of at least 2 weeks.

Embodiment 66. The method of any one of embodiments 55-65, wherein said administering provides a single dose or steady state Cmax of abiraterone of about 10 ng/ml to about 400 ng/ml (e.g., about 50 ng/ml to about 100 ng/ _ml , or about 15 ng/ml to about 160 ng/ml).

Formulations, methods and kits are provided herein for treating a subject having a sex hormone dependent benign or malignant disease, such as prostate cancer. Methods for preparing formulations useful for treating a subject having a sex hormone dependent benign or malignant disease, such as prostate cancer, syndromes resulting from androgen excess and/or syndromes resulting from glucocorticoid excess, such as hypercortisolism, are also provided. Reference numbers are given to details of representative embodiments, examples of which are illustrated in the accompanying drawings.

The term " subject ", as used herein, refers to, but is not limited to, an animal or human who needs to undergo or can undergo chemotherapy for a sex hormone-dependent benign or malignant disease, such as androgen-dependent or estrogen-dependent disease (including prostate and breast cancer), or who needs to undergo or can undergo treatment for a non-neoplastic syndrome resulting from androgen excess, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), precocious puberty, hirsutism, and/or a non-neoplastic syndrome resulting from glucocorticoid excess, such as hypercortisolism, such as Cushing's syndrome or Cushing's disease. In a preferred embodiment, the subject is a human subject .

The term "other drug or agent" as used herein means at least one other compound, formulation, molecule, biological agent, etc. that can enhance the efficacy of the formulation(s), reduce the undesirable side effect(s) of the formulation(s), or improve the treatment of a particular disease (e.g., when at least one other drug or agent is administered before, simultaneously with, and after at least one abiraterone prodrug formulation). Any suitable route of administration of such "other drug or agent" can be used, e.g., oral administration, parenteral administration, etc. Those skilled in the art of treating subjects with sex hormone-dependent benign or malignant diseases (e.g., androgen-dependent or estrogen-dependent diseases), syndromes resulting from androgen excess syndromes and/or syndromes resulting from glucocorticoid excess, such as hypercortisolism, will recognize and understand how to select and use such "other drug or agent" for the intended purpose(s).

The formulation may optionally be administered via an improved sustained release device or method. The term "improved sustained release" as used herein should be understood to include delayed release, extended or prolonged release, sustained release, or targeted release, and the like. For example, in some embodiments, the improved sustained release device or method can further extend the release of the abiraterone of the prodrugs and formulations of the present disclosure. In some embodiments, the improved sustained release device or method may also include any device or method that can release a drug or product (e.g., a drug or biological agent) at a time later than immediately after its administration (and may include, for example, injection). Various improved sustained release devices have been described previously (Stubbe et al., Pharm. Res. 21:1732, 2004), and such devices may be applicable to the representative embodiments. Improved sustained release devices and methods can be recognized and utilized by those skilled in the art without undue experimentation after considering all criteria and exercising their best judgment on behalf of the subject .

The formulations and medicaments of the embodiments are administered in pharmacologically or physiologically acceptable and effective amounts, for example, to reduce or eliminate the presence of prostate tumor tissue and abnormal or malignant prostate cells in a subject exhibiting prostate cancer. Similarly, the formulations and medicaments of the embodiments are administered in prophylactically or therapeutically effective amounts, either alone or in combination with other therapeutic agents or treatments (e.g., radiation therapy and surgery), with such amounts being understood as amounts that meet the intended prophylactic or therapeutic purpose and provide the benefit obtained from the administration of such formulations and medicaments.

The terms "effective amount", "effective dose", and "therapeutic range plasma concentration" as used herein refer to, but are not limited to, an amount, dose, or concentration that can treat, delay, slow, inhibit, or eliminate the onset, presence, or progression of a disease, disorder, or condition. For example, an "effective amount", "effective dose", or "therapeutic range plasma concentration" is an amount, dose, or concentration that can reduce or eliminate the presence of prostate tumor tissue and abnormal or malignant prostate cells in a subject exhibiting prostate cancer, and thus cure (partially or completely) the disease, or prevent the onset or further spread of a disease, disorder, or condition. As a further example, an effective amount of a formulation refers to an amount that is administered alone or in combination with other therapeutic agents or treatments (e.g., radiation therapy and surgery) to clinically significantly reduce tumor burden. Those skilled in the art will understand when a clinically significant reduction in tumor burden (or improvement of a sex hormone-dependent benign or malignant disease or another disease or syndrome described herein) occurs after administration of the formulation. An "effective amount,""effectivedose," or "therapeutic plasma concentration" is an amount, dose, or concentration that does not cause significant harm to the subject , and in any case it is understood that any adverse side effects outweigh the benefits. By way of example only, an effective amount or dose of an abiraterone prodrug formulation means an amount that can achieve a plasma concentration of at least 1 ng/ml of abiraterone in a subject following parenteral administration of the prodrug formulation, e.g., at least 1 ng/ml, at least 2 ng/ml, at least 4 ng/ml, or at least 8 ng/ml, and an effective plasma concentration is one that is achieved for at least one week, e.g., at least two weeks (e.g., 4, 6, 8 weeks or more) following administration.

In general, the dosage range of the administration of the formulation according to the present disclosure is that which produces the desired effect(s). The useful dosage varies according to the age, weight and health condition of the subject to be treated, the mode, route and schedule of administration, the response of the individual subject , and the type or stage of prostate cancer (or the severity of sex hormone-dependent benign or malignant disease or other syndrome or disease described herein) for which treatment with the formulation is sought. The dosage also varies according to the nature or severity of the primary tumor and other underlying pathologies, epidemiological pathologies, the combination with other active compounds, and the route of administration. In addition, the dosage is determined by the presence of adverse side effects, such as local hypersensitivity, systemic adverse effects, and immune resistance.

The effective dosage of the formulation (and other drug(s)) can be determined without the need for experimentation (e.g., pharmacokinetic studies) by those skilled in the art after considering all criteria and exercising their best judgment on behalf of the patient (and will in most cases be determined by the particular formulation utilized). The dosage will vary depending on the particular case, but in any event will be an amount sufficient to produce a clinical effect or improvement in sex hormone-dependent benign or malignant diseases (e.g., prostate cancer), syndromes due to androgen excess, and/or syndromes due to glucocorticoid excess, such as hypercortisolism.

The formulations and medicaments of the embodiments may optionally be administered in combination with (or include) one or more pharma- ceutically acceptable carriers, diluents, or excipients. Formulations, administration techniques, pharmaceutical compositions, methods of preparing pharmaceutical compositions, and pharma- ceutically acceptable carriers, diluents, and excipients are known in the art and are described, for example, in "Remington: The Science and Practice of Pharmacy" (formerly "Remington's Pharmaceutical Sciences," University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia, Pa. (2005)), the disclosure of which is incorporated herein by reference. Those skilled in the art can use known injectable physiologically acceptable sterile solutions. To prepare a ready-to-use solution for parenteral injection or infusion, isotonic aqueous solutions are readily available, e.g., saline, phosphate-buffered saline (PBS) or corresponding plasma protein solutions. The formulations can be present as lyophilized or dried preparations, e.g., as a kit of parts, and can be dissolved in a known injection solution immediately prior to use under sterile conditions. In addition, the formulations can include one or more acceptable carriers, such as solvents, dispersions, coatings, adjuvants, stabilizers, diluents, preservatives, antibacterial and antifungal agents, isotonicity agents, absorption modifiers, and the like. "Diluents" can include water, saline, phosphate-buffered saline (PBS), dextrose, ethanol, glycerol, and the like. Isotonicity agents can include sodium chloride, dextrose, mannitol, sorbitol, and lactose, and the like. Stabilizers include albumin and alkali salts of ethylenediaminetetraacetic acid, and the like.

Any suitable route of administration may be used to provide an effective amount/dose of the formulation and agent to a subject in accordance with exemplary embodiments. Suitable routes of administration can be readily determined without undue experimentation by those skilled in the art of pharmacology, immunology, medicine, oncology, and the like. However, it is expected that the formulations will be primarily suitable for parenteral administration, such as by IM, intradermal, or subcutaneous injection.

The abbreviations used herein have their conventional meaning within the chemical and biological arts.

It should also be understood that a particular embodiment that is a variable part of this specification may be the same as or different from another particular embodiment that uses the same identifier.

Definitions of certain functional groups and chemical terms are described in more detail below: Chemical elements are identified by the Periodic Table of the Elements, CAS version, inside cover of the Handbook of Chemistry and Physics, ^75th Ed, and certain functional groups are generally defined as described herein. Additionally, for general principles of organic chemistry, as well as specific functional moieties and reactivity, see Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, ^5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc. , New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, ^3rd Edition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any manner by the exemplary list of substituents set forth herein.

As used herein, the term "alkyl," used by itself or as part of another group, refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon. In some embodiments, an alkyl group contains 1 to 30 carbon atoms (i.e., represented as a C _1-30 alkyl, alternatively as a C ₁ -C ₃₀ alkyl), or can contain a specified number of carbon atoms (i.e., a C ₁ alkyl, such as methyl, a C ₂ alkyl, such as ethyl, a C ₃ alkyl, such as propyl or isopropyl, etc.). In one embodiment, an alkyl group is a straight-chain C _1-16 alkyl group. In another embodiment, an alkyl group is a branched-chain C _3-16 alkyl group.

As used herein, the term "cycloalkyl," used by itself or as part of another group, refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic aliphatic hydrocarbons having from 3 to 12 carbon atoms (i.e., C _3-12 cycloalkyl), or containing one to three rings having the specified number of carbon atoms. In one embodiment, a cycloalkyl group has two rings. In one embodiment, a cycloalkyl group has one ring. In another embodiment, a cycloalkyl group is a C _3-8 cycloalkyl group. In another embodiment, a cycloalkyl group is a C _3-6 cycloalkyl group. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring is fused to one or more aryl or heteroaryl groups, as described above, where the point of attachment is on the cycloalkyl ring, and in such instances the number of carbons continues to refer to the number of carbons in the cycloalkyl ring system. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl.

As used herein, the term "alkenyl" used by itself or as part of another group means a straight or branched chain aliphatic hydrocarbon containing one or more (e.g., 1, 2 or 3) carbon-to-carbon double bonds. In one embodiment, an alkenyl group is a _C2-16 alkenyl group.

As used herein, the term "alkynyl" used by itself or as part of another group means a straight or branched chain aliphatic hydrocarbon containing one or more (e.g., 1, 2 or 3) carbon-to-carbon triple bonds. In one embodiment, an alkynyl has one carbon-carbon triple bond. In one embodiment, an alkynyl group is a C _2-16 alkynyl group.

As used herein, the term "abiraterone prodrug(s) of the present disclosure" refers to any of the compounds described herein of Formula I or II, lipophilic esters of abiraterone prodrugs, or Example Nos. 2A-2H, its isotopically labeled compound(s) (e.g., deuterium-enriched compounds), its possible stereoisomers (diastereoisomers, enantiomers, and racemic mixtures), its tautomers, its conformers, and/or pharma- ceutically acceptable salts thereof (e.g., acid addition salts such as HCl salts). Hydrates and solvates of the prodrugs of the present disclosure are considered compositions of the present disclosure, where the prodrug(s) are associated with water or solvent, respectively. Some of the prodrugs of the present disclosure may also exist in various polymorphic or amorphous forms. Prodrugs described herein include compounds that readily undergo chemical changes under physiological conditions to provide active abiraterone. Additionally, the prodrugs may be converted by chemical or biochemical methods in an ex vivo environment. As used herein, the term "abiraterone prodrug formulation(s) of the present disclosure" refers to any pharmaceutical composition or formulation comprising any one or more of the abiraterone prodrugs of the present disclosure, e.g., any of the formulations prepared in Examples 3A-3J. In any of the embodiments described herein, unless directly contradicted by context, the abiraterone prodrug of the present disclosure may be abiraterone decanoate. In any of the embodiments described herein, unless directly contradicted by context, the abiraterone prodrug formulation of the present disclosure may be any of the pharmaceutical compositions comprising abiraterone decanoate as described herein. In any of the embodiments described herein, unless directly contradicted by context, the abiraterone prodrug of the present disclosure may also be abiraterone isocaproate. In any of the embodiments described herein, unless directly contradicted by context, the abiraterone prodrug formulation of the present disclosure may also be any of the pharmaceutical compositions comprising abiraterone isocaproate as described herein.

The abiraterone prodrugs of the present disclosure may exist in isotopically labeled or isotopically enriched forms containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. The isotopes may be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, oxygen, and nitrogen include, but are not limited to, ^2H , ^3H , ^13C , ^14C , ^15N , and ^18O . Compounds containing other isotopes of these and/or other atoms are within the scope of the present disclosure.

The solid and dashed wedge bonds denote stereochemistry conventional in the art.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claimed subject matter.

Example 1. Long-Acting Injectable Formulations of Abiraterone Prodrugs Formulations include long-acting injectable oil-based formulations of lipophilic abiraterone prodrugs such as (1) abiraterone 3β-alkanoates and (2) C-2 to C-16 carbon straight-chain, branched-chain, cyclic, and aromatic alkanoates (i.e., aliphatic and aromatic esters of 2 to 16 carbon atoms). Abiraterone esters can include, for example, acetate, propionate, butanoate, (butate)pentanoate, isocaproate, bucclate, cyclohexanecarboxylate, phenylpropionate, caproate (hexanoate), enanthate (heptanoate), cypionate, octanoate, noncanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate, and hexadecanoate. In an exemplary embodiment, the abiraterone esters are abiraterone acetate, abiraterone propionate, and abiraterone decanoate.

The formulation may include a solution or suspension of the abiraterone prodrug in a pharma- ceutically acceptable oil, such as an injectable pharma- ceutically acceptable oil, including vegetable-derived oils or synthetic mono- or diglycerides of fatty acids. In some embodiments, the pharma-ceutically acceptable oil may include triglycerides of fatty acids (polyunsaturated, monounsaturated, and saturated), such as vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil. The vegetable oils were selected based on the prodrug solubility in the oil. It was determined that abiraterone acetate was most soluble in castor oil, which contains triglycerides whose fatty acid component is primarily rich in oleic acid (a hydroxylated monounsaturated fatty acid). Conversely, the more lipophilic prodrugs (abiraterone propionate and abiraterone decanoate) were found to be more soluble in corn oil, which contains triglycerides whose fatty acid components are primarily linoleic acid (non-hydroxylated polyunsaturated fatty acid), oleic acid (non-hydroxylated unsaturated fatty acid), palmitic acid (non-hydroxylated saturated fatty acid), and stearic acid (non-hydroxylated saturated fatty acid). Surprisingly, abiraterone butanoate was found to be less soluble in both castor oil and corn oil than the acetate, propionate, or decanoate ester prodrugs. It was also noted that there was an inverse correlation between the melting point and solubility of the prodrugs in the vegetable oils. The melting points of the various abiraterone prodrugs shown in Table 1 were measured by differential scanning calorimetry.

Table 1. Melting points of abiraterone prodrugs

The formulations may contain pharma- ceutically acceptable excipients, such as co-solvents (i.e., solubilizers), such as benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid, and ethyl acetate. It has been found that the additives/co-solvents benzyl alcohol and benzyl benzoate not only increase the solubility of the prodrug, but also reduce the viscosity and glide force of the solution (see Figures 13A-13E and Tables 2A-2D), thereby resulting in a more concentrated solution that is easier to inject through gauge needles acceptable for IM injection (e.g., 20-27 gauge, e.g., 22-25 gauge). In practice, the co-solvent is selected based on its ability to reduce the viscosity of the vehicle to allow injection through an appropriate needle or cannula. Benzyl alcohol as an additive for IM or subcutaneous injections has the advantage that it can act as a local anesthetic at the injection site (Wilson et al. Ann. Emer. Med. 33(5), 495, 1999).

The solubility of the abiraterone ester may be affected by the addition of a co-solvent to the vegetable oil vehicle. Thus, in some embodiments, the abiraterone ester is completely dissolved within the composition, while in other embodiments, the abiraterone ester is partially dispersed within the composition. In one embodiment, the abiraterone ester is completely dissolved in the vehicle.

The formulations may also contain pharma- ceutically acceptable preservatives, polymers, antioxidants, antimicrobials, chelating agents, and other excipients, including but not limited to citric acid, dextrose, ascorbic acid, benzalkonium chloride, benzoic acid, betadex sodium sulfobutylether, calcium chloride, sodium carbomethoxycellulose, chlorobutanol, creatine, croscarmellose, potassium dibasic phosphate, docusate sodium, disodium edetate, glycerin, sodium hyaluronate, hydroxypropyl betadex, lactic acid, lactose, lecithin, maleic acid, mannitol, meglumine, methylcellulose, methylparaben, microcrystalline cellulose, miripitium chloride, and the like. chloride), monothioglycerol, phenol, poloxamer 188, polyglactin, polysorbate 20, polysorbate 40, polysorbate 80, propylparaben, sodium acetate, sodium benzoate, sodium citrate, sorbitan monolaurate, sorbitol, sucrose, tartaric acid, trisodium citrate, tromantadine, tromethamine, and urea.

The formulation may be sterilized by methods known to those skilled in the art (e.g., gamma irradiation, micron filtration and autoclaving).

Abiraterone prodrug formulations can be prepared in a variety of concentrations, for example, from 25 mg/ml to 500 mg/ml. In an exemplary embodiment, the concentration is from 50 mg/ml to 300 mg/ml.

The formulation releases an effective amount of abiraterone for at least one week and up to two, three, four or more weeks following IM or subcutaneous injection. Therapeutic plasma levels of abiraterone achieved following administration of an abiraterone prodrug formulation can be, for example, 6-15 ng/ml for 14-28 days following parenteral administration. In an exemplary embodiment, the therapeutic level is 8-12 ng/ml for 14-28 days following parenteral administration. It has previously been demonstrated that a C _min of greater than 8.4 ng/ml of abiraterone is associated with a favorable prostate specific antigen response and may be a highly significant predictor of progression-free survival in patients with castration-resistant prostate cancer (Carton et al., Eur. J. Cancer, 72:54, 2017).

Example 2. Synthesis of Abiraterone Prodrugs Abiraterone Acetate Abiraterone acetate was obtained from Hetero Labs Limited, India.

Other abiraterone esters can generally be synthesized by reacting abiraterone with a suitable activated form thereof, such as ^R2COOH or ^R2COCl . The reaction is typically carried out in an aprotic vehicle, such as _CHCl3 , with a suitable base, such as triethylamine. Examples of the preparation of abiraterone propionate, abiraterone butanoate, abiraterone pentanoate, abiraterone hexanoate, abiraterone heptanoate, abiraterone isocaproate, abiraterone cypionate, and abiraterone decanoate are provided below.

Example 2A. Preparation of Abiraterone Propionate Abiraterone propionate was prepared as follows.

15.0 g (42.9 mmol) of abiraterone was added to a 500 ml round bottom flask followed by 450 ml of chloroform and 11.96 ml (85.8 mmol, 2.0 equiv.) of triethylamine. The flask was purged with nitrogen and the mixture was cooled to 0° C. in an ice bath. The mixture was stirred for 15 minutes, after which 4.12 ml (47.2 mmol, 1.1 equiv.) of propanoyl chloride was added dropwise, followed by an additional 6.57 ml (47.2 mmol, 1.1 equiv.) of triethylamine. The ice bath was removed and the solution was stirred for an additional 2 hours. The reaction was once again cooled to 0° C. and an additional 4.12 ml of propanoyl chloride and 6.57 mL of triethylamine were slowly added. The ice bath was again removed and the reaction was stirred for an additional 16 hours. The solution was then washed twice with 300 ml of water and once with 300 ml of brine. The organic phase was dried over sodium sulfate, concentrated under vacuum, and loaded onto silica. The crude compound was purified by flash chromatography using an ethyl acetate/hexane solvent system. The desired compound was eluted at approximately 30% ethyl acetate. Pure fractions were combined and concentrated under vacuum to give 8.2 g of abiraterone propionate as a yellow solid, which was 97.8% pure by HPLC analysis. Other chemical properties are: LCMS m/z 406.3 (M+H); ^1H NMR (CDCl, ₂₀₀ MHz): δH 1.096 (11H, m), 1.625 (11H, m), 1.846 (3H, m), 2.067 (3H, m), 2.323 (5H, m), 4.627 (1H, m), 5.415 (1H, d, J = 5 Hz), 5.992 (1H, q, J = 5 Hz), 7.215 (1H, ddd, J = 1,5,8 Hz), 7.677 (1H, dt, J = 2,8 Hz), 8.456 (1H, dd, J = 2.5 Hz), 8.619 (1H, dd, J = 1.2 Hz); melting point (DSC) 101 °C.

Example 2B. Preparation of Abiraterone Butanoate Abiraterone butanoate was prepared as follows.

7.0 g (20.0 mmol) of abiraterone was added to a 500 ml round bottom flask followed by 210 ml of chloroform and 5.58 ml (40.0 mmol, 2.0 equiv.) of triethylamine. The flask was purged with nitrogen and the mixture was cooled to 0° C. in an ice bath. The mixture was stirred for 15 minutes, after which 2.28 ml (22.0 mmol, 1.1 equiv.) of butanoyl chloride was added dropwise, followed by an additional 3.07 ml (22.0 mmol, 1.1 equiv.) of triethylamine. The ice bath was removed and the solution was stirred for an additional 2 hours. The reaction was once again cooled to 0° C. and an additional 2.28 ml of butanoyl chloride and 3.07 mL of triethylamine were slowly added. The ice bath was again removed and the reaction was stirred for an additional 16 hours. During the course of the reaction, the color changed rapidly from a white mixture to a yellow solution and then slowly to a red solution. After TLC and LCMS showed the reaction was complete, the solution was washed twice with 150 ml water and once with 150 ml brine. The organic phase was dried over sodium sulfate, concentrated under vacuum, and loaded onto silica. The crude compound was purified by flash chromatography using an ethyl acetate/hexane solvent system. The desired compound was eluted with about 25% ethyl acetate. Pure fractions were combined and concentrated under vacuum to give 5.5 g of abiraterone butanoate as a yellow solid. Chemical properties: LCMS m/z 420.4 (M+H); ¹ H NMR (CDCl ₃ , 200 MHz): δH 0.948 (3H, t, J = 7 Hz), 1.043 (3H, s), 1.090 (3H, s), 1.633 (15H, m), 1.842 (3H, m), 2.065 (3H, m), 2.297 (5H, m), 4.608 (1H, m), 5.413 (1H, d, J = 5 Hz), 5.990 (1H, q, J = 5 Hz), 7.215 (1H, ddd, J = 1.5.8 Hz), 7.643 (1H, dt, J = 2.8 Hz), 8.455 (1H, dd, J = 2.5 Hz), 8.615 (1H, dd, J = 1.2 Hz); melting point (DSC) 147 °C.

デカン酸アビラテロンを以下のように調製した。 Example 2C. Preparation of Abiraterone Decanoate

Abiraterone decanoate was prepared as follows.

10.0 g (28.6 mmol) of abiraterone was added to a 500 ml round bottom flask followed by 300 ml of chloroform and 7.97 ml (57.2 mmol, 2.0 equiv.) of triethylamine. The flask was purged with nitrogen and the mixture was cooled to 0° C. in an ice bath. The mixture was stirred for 15 minutes, after which 6.53 ml (31.5 mmol, 1.1 equiv.) of decanoyl chloride was added dropwise, followed by an additional 4.39 ml (31.5 mmol, 1.1 equiv.) of triethylamine. The ice bath was removed and the solution was stirred for an additional 2 hours. The reaction was once again cooled to 0° C. and an additional 6.53 ml of decanoyl chloride and 4.39 mL of triethylamine were slowly added. The ice bath was again removed and the reaction was stirred for an additional 16 hours. During the course of the reaction, the color changed rapidly from a white mixture to a yellow solution and then slowly to a red solution. After TLC and LCMS showed the reaction was complete, the solution was washed twice with 200 ml water and once with 200 ml brine. The organic phase was dried over sodium sulfate, concentrated under vacuum, and loaded onto silica. The crude compound was purified by flash chromatography using an ethyl acetate/hexane solvent system. The desired compound was eluted with approximately 20% ethyl acetate. Pure fractions were combined and concentrated under vacuum to give 8.0 g of abiraterone decanoate as a yellow solid. Chemical properties: LCMS m/z 504.4 (M+H); ¹ H NMR (CDCl ₃ , 200 MHz): δH 0.877 (3H, t, J = 7 Hz), 1.043 (3H, s), 1.082 (3H, s), 1.268 (16H, m), 1.643 (15H, m), 1.842 (3H, m), 2.065 (3H, m), 2.290 (5H, m), 4.602 (1H, m), 5.404 (1H, d, J = 5 Hz), 5.998 (1H, q, J = 5 Hz), 7.215 (1H, ddd, J = 1.5.8 Hz), 7.643 (1H, dt, J = 2.8 Hz), 8.455 (1H, dd, J = 2.5 Hz), 8.617 (1H, dd, J = 1.2 Hz); melting point (DSC) 38 °C.

ペンタン酸アビラテロンを、デカン酸アビラテロンを調製する手順（実施例２Ｃ）と類似の手順を使用して調製したが、塩化デカノイルの代わりに塩化バレロイルを使用した。ＬＣＭＳ ｍ／ｚ ４３４．３ （Ｍ＋Ｈ）；^１Ｈ ＮＭＲ （ＣＤＣｌ_３， ２００ＭＨｚ）： δ_Ｈ ０．９－２．２ （３２Ｈ， ｍ）， ４．６１ （１Ｈ， ｍ）， ５．４１ （１Ｈ， ｄ， Ｊ ＝ ５ Ｈｚ）， ５．９９ （１Ｈ， ｑ， Ｊ ＝ ５ Ｈｚ）， ７．２２ （１Ｈ， ｄｄｄ， Ｊ ＝ １，５，８ Ｈｚ）， ７．６３ （１Ｈ， ｄｔ， Ｊ ＝ ２，８ Ｈｚ）， ８．４５ （１Ｈ， ｄｄ， Ｊ ＝ ２，５ Ｈｚ）， ８．６２ （１Ｈ， ｄｄ， Ｊ ＝ １，２ Ｈｚ）。 Example 2D. Preparation of Abiraterone Pentanoate

Abiraterone pentanoate was prepared using a procedure similar to that for preparing abiraterone decanoate (Example 2C), except that valeroyl chloride was used instead of decanoyl chloride. LCMS m/z 434.3 (M+H); ¹ H NMR (CDCl ₃ , 200 MHz): δ _H 0.9-2.2 (32 H, m), 4.61 (1 H, m), 5.41 (1 H, d, J = 5 Hz), 5.99 (1H, q, J = 5 Hz), 7.22 (1H, ddd, J = 1,5,8 Hz), 7.63 (1H, dt, J = 2,8 Hz), 8.45 (1H, dd, J = 2,5 Hz), 8.62 (1H, dd, J = 1,2 Hz).

ヘキサン酸アビラテロンを、デカン酸アビラテロンを調製する手順（実施例２Ｃ）と類似の手順を使用して調製したが、塩化デカノイルの代わりに塩化ヘキサノイルを使用した。ＬＣＭＳ ｍ／ｚ ４４８．４ （Ｍ＋Ｈ）；^１Ｈ ＮＭＲ （ＣＤＣｌ_３， ２００ＭＨｚ）： δ_Ｈ ０．９－２．２ （３４Ｈ， ｍ）， ４．６０ （１Ｈ， ｍ）， ５．４０ （１Ｈ， ｄ， Ｊ ＝ ５ Ｈｚ）， ５．９８ （１Ｈ， ｑ， Ｊ ＝ ５ Ｈｚ）， ７．２１ （１Ｈ， ｄｄｄ， Ｊ ＝ １，５，８ Ｈｚ）， ７．６２ （１Ｈ， ｄｔ， Ｊ ＝ ２，８ Ｈｚ）， ８．４３ （１Ｈ， ｄｄ， Ｊ ＝ ２，５ Ｈｚ）， ８．６０ （１Ｈ， ｄｄ， Ｊ ＝ １，２ Ｈｚ）。 Example 2E. Preparation of Abiraterone Hexanoate

Abiraterone hexanoate was prepared using a procedure similar to that for preparing abiraterone decanoate (Example 2C), except that hexanoyl chloride was used instead of decanoyl chloride. LCMS m/z 448.4 (M+H); ¹ H NMR (CDCl ₃ , 200 MHz): δ _H 0.9-2.2 (34 H, m), 4.60 (1 H, m), 5.40 (1 H, d, J = 5 Hz), 5.98 (1H, q, J = 5 Hz), 7.21 (1H, ddd, J = 1,5,8 Hz), 7.62 (1H, dt, J = 2,8 Hz), 8.43 (1H, dd, J = 2,5 Hz), 8.60 (1H, dd, J = 1,2 Hz).

ヘプタン酸アビラテロンを、デカン酸アビラテロンを調製する手順（実施例２Ｃ）と類似の手順を使用して調製したが、塩化デカノイルの代わりに塩化ヘプタノイルを使用した。ＬＣＭＳ ｍ／ｚ ４６２．４ （Ｍ＋Ｈ）；^１Ｈ ＮＭＲ （ＣＤＣｌ_３， ２００ＭＨｚ）： δ_Ｈ ０．９－２．２ （３６Ｈ， ｍ）， ４．６１ （１Ｈ， ｍ）， ５．４０ （１Ｈ， ｄ， Ｊ ＝ ５ Ｈｚ）， ６．００ （１Ｈ， ｑ， Ｊ ＝ ５ Ｈｚ）， ７．２１ （１Ｈ， ｄｄｄ， Ｊ ＝ １，５，８ Ｈｚ）， ７．６４ （１Ｈ， ｄｔ， Ｊ ＝ ２，８ Ｈｚ）， ８．４５ （１Ｈ， ｄｄ， Ｊ ＝ ２，５ Ｈｚ）， ８．６１ （１Ｈ， ｄｄ， Ｊ ＝ １，２ Ｈｚ）。 Example 2F. Preparation of Abiraterone Heptanoate

Abiraterone heptanoate was prepared using a procedure similar to that for preparing abiraterone decanoate (Example 2C), except that heptanoyl chloride was used instead of decanoyl chloride. LCMS m/z 462.4 (M+H); ¹ H NMR (CDCl ₃ , 200 MHz): δ _H 0.9-2.2 (36 H, m), 4.61 (1 H, m), 5.40 (1 H, d, J = 5 Hz), 6.00 (1H, q, J = 5 Hz), 7.21 (1H, ddd, J = 1,5,8 Hz), 7.64 (1H, dt, J = 2,8 Hz), 8.45 (1H, dd, J = 2,5 Hz), 8.61 (1H, dd, J = 1,2 Hz).

イソカプロン酸アビラテロンを、デカン酸アビラテロンを調製する手順（実施例２Ｃ）と類似の手順を使用して調製したが、塩化デカノイルの代わりに４－メチルバレリル塩化物を使用した。ＬＣＭＳ ｍ／ｚ ４４８．４ （Ｍ＋Ｈ）；^１Ｈ ＮＭＲ （ＣＤＣｌ_３， ２００ＭＨｚ）： δ_Ｈ ０．９－２．２ （３４Ｈ， ｍ）， ４．６１ （１Ｈ， ｍ）， ５．４０ （１Ｈ， ｄ， Ｊ ＝ ５ Ｈｚ）， ６．００ （１Ｈ， ｑ， Ｊ ＝ ５ Ｈｚ）， ７．２２ （１Ｈ， ｄｄｄ， Ｊ ＝ １，５，８ Ｈｚ）， ７．６４ （１Ｈ， ｄｔ， Ｊ ＝ ２，８ Ｈｚ）， ８．４５ （１Ｈ， ｄｄ， Ｊ ＝ ２，５ Ｈｚ）， ８．６２ （１Ｈ， ｄｄ， Ｊ ＝ １，２ Ｈｚ）。 Example 2G. Preparation of Abiraterone Isocaproate

Abiraterone isocaproate was prepared using a procedure similar to that for preparing abiraterone decanoate (Example 2C), except that 4-methylvaleryl chloride was used in place of decanoyl chloride. LCMS m/z 448.4 (M+H); ¹ H NMR (CDCl ₃ , 200 MHz): δ _H 0.9-2.2 (34 H, m), 4.61 (1 H, m), 5.40 (1 H, d, J = 5 Hz), 6.00 (1H, q, J = 5 Hz), 7.22 (1H, ddd, J = 1,5,8 Hz), 7.64 (1H, dt, J = 2,8 Hz), 8.45 (1H, dd, J = 2,5 Hz), 8.62 (1H, dd, J = 1,2 Hz).

シピオン酸アビラテロンを、デカン酸アビラテロンを調製する手順（実施例２Ｃ）と類似の手順を使用して調製したが、塩化デカノイルの代わりに３－シクロペンチルプロパノイル塩化物を使用した。ＬＣＭＳ ｍ／ｚ ４７４．４ （Ｍ＋Ｈ）；^１Ｈ ＮＭＲ （ＣＤＣｌ_３， ２００ＭＨｚ）： δ_Ｈ ^１Ｈ ＮＭＲ （ＣＤＣｌ_３， ２００ＭＨｚ）： δ_Ｈ ０．９－２．３ （３６Ｈ， ｍ）， ４．６２ （１Ｈ， ｍ）， ５．４１ （１Ｈ， ｄ， Ｊ ＝ ５ Ｈｚ）， ６．００ （１Ｈ， ｑ， Ｊ ＝ ５ Ｈｚ）， ７．２２ （１Ｈ， ｄｄｄ， Ｊ ＝ １，５，８ Ｈｚ）， ７．６３ （１Ｈ， ｄｔ， Ｊ ＝ ２，８ Ｈｚ）， ８．４５ （１Ｈ， ｄｄ， Ｊ ＝ ２，５ Ｈｚ）， ８．６２ （１Ｈ， ｄｄ， Ｊ ＝ １，２ Ｈｚ）。 Example 2H. Preparation of Abiraterone Cypionate

Abiraterone cypionate was prepared using a procedure similar to that for preparing abiraterone decanoate (Example 2C), except that 3-cyclopentylpropanoyl chloride was used in place of decanoyl chloride. LCMS m/z 474.4 (M+H); ¹ H NMR (CDCl ₃ , 200 MHz): δ _H ¹ H NMR (CDCl ₃ , 200 MHz): δ _H 0.9-2.3 (36 H, m), 4.62 (1 H, m), 5.41 (1H, d, J = 5 Hz), 6.00 (1H, q, J = 5 Hz), 7.22 (1H, ddd, J = 1,5,8 Hz), 7.63 (1H, dt, J = 2,8 Hz), 8.45 (1H, dd, J = 2,5 Hz), 8.62 (1H, dd, J = 1,2 Hz).

Example 3 Preparation of Abiraterone Prodrug Formulations Example 3A Preparation of Abiraterone Acetate Castor Oil Solution Abiraterone acetate injectable (IM depot) castor oil solution was prepared as follows.

490 mg of abiraterone acetate was weighed into a 10 mL serum vial with a crimp stopper. 8 mL of castor oil was placed into another 10 mL serum vial with a crimp stopper. The two vials were then wrapped in aluminum foil and sterilized in an autoclave using a 30 minute liquid cycle. After sterilization, the vial was transferred to a laminar flow hood. 7 mL of sterile castor oil was then removed and added to the sterile abiraterone acetate, and the vial was restoppered and crimp sealed. The abiraterone acetate was then dissolved by sonication, vortexing, and rotating the vial. The final concentration of the sterile abiraterone acetate solution was 70 mg/ml.

Example 3B. Preparation of Abiraterone Acetate 90% Castor Oil, 10% Benzyl Alcohol Solution Abiraterone acetate injectable (IM depot) 90% castor oil, 10% benzyl alcohol solution was prepared as follows.

700 mg of abiraterone acetate was weighed into a 10 mL serum vial with a crimp stopper. 8 mL of a 90% castor oil/10% benzyl alcohol mixture was placed into another 10 mL serum vial with a crimp stopper. The two vials were then wrapped in aluminum foil and sterilized in an autoclave using a 30 minute liquid cycle. After sterilization, the vial was transferred to a laminar flow hood. 7 mL of the sterile 90% castor oil/10% benzyl alcohol solution was then removed and added to the sterile abiraterone acetate, and the vial was restoppered and crimp sealed. The abiraterone acetate was then dissolved by sonication, vortexing, and rotating the vial. The final concentration of the sterile abiraterone acetate solution was 91 mg/mL.

Example 3C. Preparation of Abiraterone Acetate 50% Castor Oil, 50% Benzyl Benzoate Solution Abiraterone acetate injectable (IM depot) 50% castor oil, 50% benzyl benzoate solution was prepared as follows.

980 mg of abiraterone acetate was weighed into a 10 mL serum vial with a crimp stopper. 8 mL of the 50% castor oil/50% benzyl benzoate mixture was placed into another 10 mL serum vial with a crimp stopper. The two vials were then wrapped in aluminum foil and sterilized in an autoclave using a 30 minute liquid cycle. After sterilization, the vial was transferred to a laminar flow hood. 7 mL of the sterile 50% castor oil/50% benzyl benzoate mixture solution was then removed and added to the sterile abiraterone acetate, and the vial was restoppered and crimp sealed. The abiraterone acetate was then dissolved by sonication, vortexing, and rotating the vial. The final concentration of the sterile abiraterone acetate solution was 124 mg/mL.

Example 3D. Preparation of Abiraterone Propionate 90% Castor Oil, 10% Benzyl Alcohol Solution Abiraterone propionate injectable (IM depot), 90% castor oil, 10% benzyl alcohol solution was prepared as follows.

1,050 mg of abiraterone propionate was weighed into a 10 mL serum vial with a crimp stopper. 8 mL of the 90% castor oil/10% benzyl alcohol mixture was placed into another 10 mL serum vial with a crimp stopper. The vehicle vial was then wrapped in aluminum foil and sterilized in an autoclave using a 30 minute liquid cycle. After sterilization, the vial was transferred to a laminar flow hood. 8 mL of the sterile 90% castor oil/10% benzyl alcohol solution was then removed and added to the abiraterone propionate, and the vial was restoppered and crimp sealed. The abiraterone propionate was then dissolved by sonication, vortexing, and rotating the vial. The final concentration of the sterile abiraterone propionate solution was 197 mg/mL.

Example 3E. Preparation of Abiraterone Propionate, 90% Corn Oil, 10% Benzyl Alcohol Solution Abiraterone propionate for injection (IM depot), 90% corn oil, 10% benzyl alcohol solution was prepared as follows.

1,050 mg of abiraterone propionate was weighed into a 10 mL serum vial with a crimp stopper. 8 mL of the 90% corn oil/10% benzyl alcohol mixture was placed into another 10 mL serum vial with a crimp stopper. The vehicle vial was then wrapped in aluminum foil and sterilized in an autoclave using a 30 minute liquid cycle. After sterilization, the vial was transferred to a laminar flow hood. 8 mL of the sterile 90% corn oil/10% benzyl alcohol solution was then removed and added to the abiraterone propionate, and the vial was recapped and crimp sealed. The abiraterone propionate was then dissolved by sonication, vortexing, and rotating the vial. The final concentration of the sterile abiraterone propionate solution was 168 mg/mL.

Example 3F. Preparation of Abiraterone Decanoate 90% Castor Oil, 10% Benzyl Alcohol Solution Abiraterone decanoate injectable (IM depot) 90% castor oil, 10% benzyl alcohol solution was prepared as follows.

1,260 mg of abiraterone decanoate was weighed into a 10 mL serum vial with a crimp stopper. 8 mL of a 90% castor oil/10% benzyl alcohol mixture was placed into another 10 mL serum vial with a crimp stopper. The vehicle vial was then wrapped in aluminum foil and sterilized in an autoclave using a 30 minute liquid cycle. After sterilization, the vial was transferred to a laminar flow hood. 8 mL of the sterile 90% castor oil/10% benzyl alcohol solution was then removed and added to the abiraterone decanoate, and the vial was recapped and crimp sealed. The abiraterone decanoate was then dissolved by sonication, vortexing, and placing the vial on a rotator. The final concentration of the sterile abiraterone decanoate solution was 160 mg/mL.

Example 3G. Preparation of Abiraterone Decanoate, 90% Corn Oil, 10% Benzyl Alcohol Solution Abiraterone decanoate for injection (IM depot), 90% corn oil, 10% benzyl alcohol solution was prepared as follows.

1,260 mg of abiraterone decanoate was weighed into a 10 mL serum vial with a crimp stopper. 8 mL of the 90% corn oil/10% benzyl alcohol mixture was placed into another 10 mL serum vial with a crimp stopper. The vehicle vial was then wrapped in aluminum foil and sterilized in an autoclave using a 30 minute liquid cycle. After sterilization, the vial was transferred to a laminar flow hood. 8 mL of the sterile 90% corn oil/10% benzyl alcohol solution was then removed and added to the abiraterone decanoate, and the vial was recapped and crimp sealed. The abiraterone decanoate was then dissolved by sonication, vortexing, and rotating the vial. The final concentration of the sterile abiraterone decanoate solution was 170 mg/mL.

Example 3H. Preparation of Abiraterone Decanoate (-200 mg/ml) in 70% Corn Oil, 10% Benzyl Alcohol, 20% Benzyl Benzoate Solution Abiraterone decanoate injection (IM depot, -200 mg/ml) in 70% corn oil, 10% benzyl alcohol, 20% benzyl benzoate solution was prepared as follows.

2,500 mg of abiraterone decanoate was weighed into a 20 mL serum vial with a crimp stopper. 60 mL of the 70% corn oil/10% benzyl alcohol/20% benzyl benzoate mixture was placed into another 100 mL serum vial with a crimp stopper. The vehicle vial was then wrapped in aluminum foil and sterilized in an autoclave using a 30 minute liquid cycle. After sterilization, the vial was transferred to a laminar flow hood. 10 mL of the sterile 70% corn oil/10% benzyl alcohol/20% benzyl benzoate solution was then removed and added to the abiraterone decanoate, and the vial was recapped and crimp sealed. The abiraterone decanoate was then dissolved by sonication, vortexing, and rotating the vial. The final concentration of the sterile abiraterone decanoate solution was 209 mg/mL.

Example 3I. Preparation of Abiraterone Decanoate (-240 mg/ml) in 70% Corn Oil, 10% Benzyl Alcohol, 20% Benzyl Benzoate Solution Abiraterone decanoate injection (IM depot, -240 mg/ml) in 70% corn oil, 10% benzyl alcohol, 20% benzyl benzoate solution was prepared as follows.

3,125 mg of abiraterone decanoate was weighed into a 20 mL serum vial with a crimp stopper. 60 mL of the 70% corn oil/10% benzyl alcohol/20% benzyl benzoate mixture was placed into another 100 mL serum vial with a crimp stopper. The vehicle vial was then wrapped in aluminum foil and sterilized in an autoclave using a 30 minute liquid cycle. After sterilization, the vial was transferred to a laminar flow hood. 10 mL of the sterile 70% corn oil/10% benzyl alcohol/20% benzyl benzoate solution was then removed and added to the abiraterone decanoate, and the vial was recapped and crimp sealed. The abiraterone decanoate was then dissolved by sonication, vortexing, and rotating the vial. The final concentration of the sterile abiraterone decanoate solution was 242 mg/mL.

Example 3J. Preparation of Abiraterone Isocaproate 90% Corn Oil, 10% Benzyl Alcohol Solution Abiraterone isocaproate for injection (IM depot), 90% corn oil, 10% benzyl alcohol solution was prepared as follows.

1190 mg of abiraterone isocaproate was weighed into a 10 mL serum vial with a crimp stopper. 8 mL of the 90% corn oil/10% benzyl alcohol mixture was placed into another 10 mL serum vial with a crimp stopper. The vehicle vial was then wrapped in aluminum foil and sterilized in an autoclave using a 30 minute liquid cycle. After sterilization, the vial was transferred to a laminar flow hood. 6.4 mL of the sterile 90% corn oil/10% benzyl alcohol solution was then removed and added to the abiraterone isocaproate, and the vial was recapped and crimp sealed. The abiraterone isocaproate was then dissolved by sonication, vortexing, and rotating the vial. The final concentration of the sterile abiraterone isocaproate solution was 158 mg/mL.

Example 4A. Solubility Testing of Abiraterone Prodrugs The solubility of various abiraterone prodrugs was tested as follows, and the results are shown in Table 2.

For each solvent studied, a sufficient amount of prodrug was weighed into a separate glass vial and 1-2 ml of solvent was added. The resulting suspension was sonicated and vortexed. If the prodrug was completely dissolved, additional prodrug was added until excess material was observed. Additional diluent may be added if there is a large excess of undissolved prodrug. The total mass and volume used was recorded. Each of the vials was tightly capped and wrapped in foil to protect from light if necessary. The vials were placed on a laboratory rotator in an incubator at 25°C (or any other temperature required). Samples were allowed to equilibrate for a minimum of one day before evaluating solubility. The solubility of each of the prodrugs was then checked again, typically after about one week.

At the appropriate time points, the vials were removed from the incubator. A small amount of the supernatant from each of the vials was transferred to a microcentrifuge tube containing a 0.22 or 0.45 um filter. The tubes were centrifuged at 10,000 rpm until all of the liquid had passed through the filter and reached the bottom of the tube. Alternatively, samples were filtered using 0.22 or 0.45 μm syringe filters. The filtered liquids were evaluated using HPLC. Samples were diluted as necessary and sample concentrations were classified as similar relative to the standards.

Table 2. Solubility of Abiraterone Prodrugs

Table 2: Solubility of Abiraterone Prodrugs (continued)

Parenteral formulations must be sterilized prior to administration. This can be accomplished by a variety of techniques, including heat sterilization (e.g., dry or moist heat), radiation sterilization (e.g., gamma radiation sterilization), filtration sterilization (e.g., 0.22 micrometer membrane filters), or gas sterilization (e.g., formaldehyde or ethylene oxide gas).

Example 4B. Solubility, Viscosity, and Glide Force Testing of Abiraterone Decanoate Formulations or Oil Vehicles In this example, the properties of various abiraterone decanoate formulations and oil vehicles are tested.

First, further solubility studies demonstrate the solubility advantage of the abiraterone decanoate formulation: 70% corn oil, 10% benzyl alcohol, 20% benzyl benzoate. See Table 2A below. The abiraterone decanoate used in the studies in Table 2 was obtained from Example 6A.
Table 2A. Solubility studies of abiraterone decanoate in different vehicles

As can be seen from this study, the combination of benzyl alcohol and benzyl benzoate can significantly increase the solubility of abiraterone decanoate in corn oil. See also Figures 13A and 13B.

Additional experiments also demonstrated that the inclusion of benzyl benzoate reduced the viscosity and glide force of the oil vehicle. Such oil vehicles may be advantageously used, if desired, in formulating the abiraterone prodrugs herein and are expected to provide abiraterone prodrug formulations with low viscosity and low glide force.

Glide force testing was performed using a tension and compression testing machine (e.g., Lloyd press or equivalent), NEXYGEN Plus materials testing software, or equivalent load cell 250N, 5mL Luer lock syringe (e.g., Becton, Dickinson and Company/BD, P/N 309646), or equivalent 23 gauge, 1.5 inch long, thin wall, precision glide needle (e.g., Becton, Dickinson and Company/BD, P/N 305194), or equivalent 27 gauge, 1.5 inch long, standard wall, precision glide needle (e.g., Becton, Dickinson and Company/BD, P/N 301629), or equivalent.

Table 2B shows the viscosity of an oil vehicle containing no additive, 10% benzyl alcohol, 20% benzyl benzoate, or a combination of 10% benzyl alcohol and 20% benzyl benzoate. See also Figure 13C.
Table 2B: Viscosity (Pa ^* s) of various oils containing additives

（表２Ｄ）添加剤を含む種々の油のグライド力（Ｎ）、２７ゲージ針

Tables 2C and 2D show the glide force (N) for an oil vehicle with no additive, an oil vehicle containing 10% benzyl alcohol, an oil vehicle containing 20% benzyl benzoate, or an oil vehicle containing a combination of 10% benzyl alcohol and 20% benzyl benzoate, using a 23 gauge needle or a 27 gauge needle, respectively. See also Figures 13D and 13E.
Table 2C: Glide force (N) of various oils containing additives, 23 gauge needle

Table 2D: Glide force (N) of various oils containing additives, 27 gauge needle

Example 5
Abiraterone Plasma Pharmacokinetics in Rats and Dogs after Administration of Abiraterone Prodrug Formulations Example 5A. PK Study of Abiraterone and Abiraterone Acetate in Rats and Dogs In the initial rat study, several formulations were investigated. These formulations were composed of abiraterone acetate as a solution in castor oil or as a suspension in sodium phosphate buffer, 0.1% Tween, and abiraterone suspension in castor oil or as an aqueous mixture of sodium phosphate buffer, 0.1% Tween. The manufacture of these long-acting IM formulations follows a common process of placing the drug in one vial, the solubilization solution in another, and sterilizing each vial. Once the components are sterilized, they are mixed together under sterile conditions to produce the final product. If the drug is in solution, sterilization is performed separately because the drug may degrade during the sterilization process. In addition, this sterilization process was chosen over sterilization by filtration due to the viscosity of the oil or the suspension nature of the two formulations.

Another study was conducted using dogs instead of rats as the animal model. Four formulations were included in the study. These formulations were a solution of abiraterone acetate in an aqueous system (specific IV), and a solution of abiraterone acetate in castor oil, a solution of abiraterone acetate in 90% castor oil and 10% benzyl alcohol, or a solution of abiraterone acetate in 50% castor oil and 50% benzyl benzoate.

The above formulations were administered as IV or IM injections into the hind leg(s) of each rat or dog animal. Plasma samples were collected over the study period and analyzed for both the prodrug and abiraterone. The results of the rat study are presented in Table 3 and Figure 1.

グループ１：酢酸アビラテロンのヒマシ油溶液（７０ｍｇ／ｍｌ）；グループ２：酢酸アビラテロンのリン酸ナトリウム緩衝液、０．１％Ｔｗｅｅｎ懸濁液（７０ｍｇ／ｍｌ）；グループ３：アビラテロンのヒマシ油懸濁液（６２．５ｍｇ／ｍｌ）；グループ４：アビラテロンのリン酸ナトリウム緩衝液、０．１％Ｔｗｅｅｎ懸濁液（６２．５ｍｇ／ｍｌ） Table 3. Mean plasma pharmacokinetic parameters of abiraterone by group after IM injection of various formulations of abiraterone or abiraterone acetate in rats.

Group 1: abiraterone acetate in castor oil (70 mg/ml); Group 2: abiraterone acetate in sodium phosphate buffer, 0.1% Tween suspension (70 mg/ml); Group 3: abiraterone in castor oil (62.5 mg/ml); Group 4: abiraterone in sodium phosphate buffer, 0.1% Tween suspension (62.5 mg/ml).

Data from rat studies showed that formulations containing abiraterone acetate performed significantly better than formulations containing abiraterone acetate. Additionally, Group 1 formulations containing abiraterone acetate as a solution performed better than Group 2 formulations containing abiraterone acetate as a suspension rather than a solution.

Figure 1 shows the mean plasma concentration of abiraterone in rats over time following IM injection of abiraterone acetate formulations into the thigh muscle of five male rats at a dose of 35 mg/kg. Blood samples to assess systemic exposure following administration of abiraterone acetate IM depot were collected 1, 2, 4, 8, 24, 48, 72, and 168 hours after administration and analyzed for abiraterone and abiraterone acetate. In this study, the abiraterone acetate castor oil solution formulation was compared to the abiraterone acetate aqueous suspension formulation, as well as abiraterone aqueous solution and castor oil suspension.

First, we attempted to administer abiraterone intramuscularly to rats as a suspension containing vegetable oil and an aqueous solution. Surprisingly, abiraterone by itself resulted in very low plasma levels (see Figure 1). Also surprising was the use of abiraterone acetate in an aqueous suspension, which resulted in low plasma levels (see Figure 1). Conversely, the vegetable oil solution of abiraterone acetate not only resulted in the highest plasma levels in rats after intramuscular injection, but also in the longest plasma concentrations of abiraterone (see Figure 1).

The abiraterone acetate castor oil IM depot solution formulation demonstrated superior plasma concentrations of abiraterone over 168 hours compared to abiraterone and abiraterone acetate aqueous solutions and castor oil suspensions.

グループ１：酢酸アビラテロン溶液（３３％ＨＰ－β－シクロデキストリン水溶液）を１０ｍｇ／ｋｇの投与量でＩＶ投与；グループ２：酢酸アビラテロンのヒマシ油溶液（６６ｍｇ／ｍｌ）を２１ｍｇ／ｋｇの投与量でＩＭ投与；グループ３：酢酸アビラテロンの１０％ベンジルアルコールを含むヒマシ油溶液（９１ｍｇ／ｍｌ）を３０ｍｇ／ｋｇの投与量でＩＭ投与；グループ４：酢酸アビラテロンの５０％安息香酸ベンジルを含むヒマシ油溶液（１２４ｍｇ／ｍｌ）を４２ｍｇ／ｋｇの投与量でＩＭ投与。 The results of the dog study are presented in Table 4 and FIG.
Table 4. Mean plasma pharmacokinetic parameters of abiraterone acetate by group following IV and IM injections in dogs.

Group 1: abiraterone acetate solution (33% HP-β-cyclodextrin in water) administered IV at a dose of 10 mg/kg; Group 2: abiraterone acetate solution in castor oil (66 mg/ml) administered IM at a dose of 21 mg/kg; Group 3: abiraterone acetate solution in 10% benzyl alcohol in castor oil (91 mg/ml) administered IM at a dose of 30 mg/kg; Group 4: abiraterone acetate solution in 50% benzyl benzoate in castor oil (124 mg/ml) administered IM at a dose of 42 mg/kg.

Data from a dog study showed that abiraterone acetate given as a solution in castor oil (with or without benzyl alcohol) produced measurable blood levels for up to 504 hours. Additionally, formulations containing benzyl benzoate produced measurable levels of abiraterone acetate, but the formulations were found to be irritating to dogs at the injection site, with one or two dogs licking or biting the injection site, resulting in open sores. This significantly reduced the percentage of prodrug absorbed by these animals, resulting in a significantly reduced average percentage of prodrug absorbed in this dose group (61.7%). Absolute bioavailability results for these formulations ranged from 61.7 to 86.2%.

Figure 2 shows the mean plasma concentration of abiraterone in dogs over time following IM injection of various abiraterone acetate formulations into the thigh muscle of male dogs (three dogs for each formulation) at doses of 19, 27, and 38 mg/kg. Blood samples to assess systemic exposure following administration of abiraterone acetate IM depot were collected at 0.5, 1, 2, 3, 4, 5, 8, 24, 48, 60, 120, 168, 336, and 504 hours post-dose and analyzed for abiraterone and abiraterone acetate.

The castor oil, castor oil/benzyl alcohol, and castor oil/benzyl benzoate IM depot solution formulations of abiraterone acetate demonstrated prolonged plasma concentrations of abiraterone of 504 hours.

To measure the bioavailability of the IM depot formulation, IV administration of abiraterone acetate (10 mg/kg dose) was included in the study. Bioavailability was found to be 86.2%, 85.7%, and 61.7%.

Computer modeling was used to predict the human pharmacokinetic profile of an abiraterone prodrug administered IM to humans based on data obtained from IM rat and dog studies. The modeling predicted that administration of 600 mg to 2,000 mg IM doses of abiraterone acetate every 2-4 weeks to a human subject would result in a desirable plasma pharmacokinetic profile in the human subject (i.e., greater than 80% bioavailability over at least 2 weeks, a C min value of abiraterone of greater than 1.0 ng/ml to 8.4 ng/ml, e.g., greater than 1 ng/ml, greater than 2 ng/ml, greater than 4 ng/ _ml , or greater than 8.4 ng/ml, and a C _max value of abiraterone of approximately 10 ng/ml to 400 ng/ml). A projected 600 mg IM dose of abiraterone acetate administered every 2 weeks should be compared to the current oral dose of 1,000 mg/day (14,000 mg over a 2-week dosing period) of Zytiga®. The higher bioavailability of IM delivery, with elimination of food effects, should result in lower patient variability, which, along with higher and less frequent plasma trough levels, should lead to better efficacy (cf. C _min >8.4 ng/ml for improved prostate-specific antigen response and improved progression-free survival in castration-resistant prostate cancer patients) (Carton et al., Eur. J. Can. 72:54, 2017).

Example 5B. PK Study of Abiraterone Propionate and Decanoate in Dogs This is a single-dose bioavailability study of several abiraterone prodrugs (propionate and decanoate esters) administered intramuscularly (IM) and intravenously to beagle dogs.

The formulations and doses used in this study are shown below.
1) Intramuscularly (IM); abiraterone propionate in 10% benzyl alcohol/90% castor oil (197 mg/mL) administered at a dose of 41 mg/kg. 2) Intramuscularly (IM); abiraterone propionate in 10% benzyl alcohol/90% corn oil (168 mg/mL) administered at a dose of 41 mg/kg. 3) Intramuscularly (IM); abiraterone decanoate in 10% benzyl alcohol/90% castor oil (160 mg/mL) administered at a dose of 50 mg/kg. 4) Intramuscularly (IM); abiraterone decanoate in 10% benzyl alcohol/90% corn oil (170 mg/mL) administered at a dose of 50 mg/kg. 5) Intravenous (IV); abiraterone propionate in 40% HP-b-CD/25 mM sodium phosphate (pH 7.4) (0.57 mg/mL) was administered at a dose of 1 mg/kg. 6) Intravenous (IV); abiraterone decanoate in 40% HP-b-CD/25 mM sodium phosphate (pH 7.4) (0.37 mg/mL) was administered at a dose of 1.2 mg/kg.

A summary of the study design is shown in Table 5 below.
Table 5: Experimental study design

All animals were dosed via IV administration. After a 72 hour washout period, all dogs were dosed via the IM route. Doses were based on an assumed body weight of 10 kg. After IV administration, blood was collected at 0.083, 0.1667, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, and 24 hours post-dose. After IM administration, blood was collected (drawn close to the time of dosing) at 0.5, 1, 2, 3, 4, 5, 8, and 12 hours post-dose, and at 1, 2, 3, 5, 7, 14, 21, 28, 35, 42, 49, 56 (decanoate only), and 63 (decanoate only) days post-dose. Blood was processed to plasma and the resulting plasma samples were analyzed for prodrug and abiraterone.

After IV administration of abiraterone propionate, animals had only one or two quantifiable plasma concentrations, making it impossible to assess reliable pharmacokinetic parameters.

Pharmacokinetic analysis was performed on plasma concentration versus time data using Phoenix WinNonlin (v8.1) noncompartmental analysis function (linear trapezoidal method for AUC calculation). Nominal dose values and sampling times were used in the calculations. For the purposes of PK calculations, all concentrations reported as "BLQ" were set to zero.

_Cmax and corresponding _Tmax values were determined by direct evaluation of the concentration versus time data. All AUC calculations were performed using the linear trapezoidal method.

Wherever data permitted, terminal elimination rate constants (lambda z, λz) were calculated. Values of λz were determined by the slope of the regression line of natural log-transformed concentration versus time with the following constraints:
Data points must be randomly distributed around a line;
- Regression must use at least 3 data points after _Cmax ;
The correlation coefficient (R ² ) of the regression must be greater than 0.80;

To optimize the reliability of the observed terminal phase (λz), the data points used to define λz were manually selected when possible. Lambda z profiles that did not meet the above guidelines had the AUC _INF , t _1/2 , CL/F, and Vz/F parameters of that animal's profile excluded, as marked with an asterisk, and the results were removed from the summary descriptive statistics.

AUC _INF values were calculated as follows: AUC _last + (C _last /λz). CL/F was calculated as: Dose per dosing interval/(AUC _INF ). Vz/F was calculated as: Dose per dosing interval/(AUC _INF ^* λz). Terminal t _1/2 was calculated as: ln(2)/λz. If the lambda z interval did not exceed the calculated half-life by at least 2-fold, the half-life value was flagged with an asterisk as unreliable and excluded from the descriptive statistics.

Mean plasma concentration versus time data are presented with standard deviation (SD) and percent coefficient of variation (CV%) and are reported to three significant figures. PK parameter values are presented as mean, SD, and CV%. Individual _Tmax values were reported to two significant figures, while all other values and descriptive statistics were reported to three significant figures.

Individual animal and group mean PK parameters for the prodrug and abiraterone after IV administration are presented in Tables 6 and 7. Individual animal and group mean PK parameters for the prodrug and abiraterone after IM administration are presented in Tables 8 and 9. Group mean plasma concentrations over time after administration to dogs are plotted in Figures 5 to 10.

Results of IV Administration: Following IV administration of abiraterone decanoate (prodrug), the mean CL value of the prodrug was calculated to be 8.88 mL/min/kg, which is considered to have low clearance. Using a dose value of 0.84 mg/kg (assuming 100% conversion of the prodrug to abiraterone), the mean CL/F value of abiraterone was 97.8 mL/min/kg. The mean Vz value of the prodrug was 0.659 L/kg and the mean Vz/F value of abiraterone was 13.0 L/kg. The mean t1 _/2 values were 0.86 hours for the prodrug and 1.5 hours for abiraterone, respectively.

Abiraterone propionate exposure was observed only at the first two time points post-dose, so reliable PK parameters could not be calculated. After IV administration of abiraterone propionate (prodrug), the mean CL/F value of abiraterone was 114 mL/min/kg and the mean Vz/F value was 20.8 L/kg. The mean t1 _/2 value of abiraterone was 2.1 hours.

After IV administration of abiraterone propionate, the Cmax values of abiraterone were nearly 4-fold higher, but the AUC values were equivalent (within 2-fold difference), indicating that the differences between the prodrugs are only minor.

Results of IM Administration: Following IM administration of the two decanoate formulations, the mean _Tmax values for abiraterone were 5.0 days for both formulations, with the mean _Tmax values for the decanoate ranging from 0.11 to 0.26 days between the formulations. The mean exposures of the prodrug and abiraterone (as evidenced by _Cmax and AUC values) were within 2-fold between the two formulations. The terminal elimination phase of the prodrug did not achieve a stable negative slope after the 7 day time point, so additional kinetic parameters could not be assessed. The mean t1 _/2 values for abiraterone (terminal t1 _/2 ) were 23 and 24 days after administration for the two vehicles. Estimates of absolute bioavailability of abiraterone were calculated using mean AUC _INF values after IV (145h ^* ng/mL) and IM administration (corrected for dose and time units = 104h ^* ng/mL for Group 5 and 134h ^* ng/mL for Group 6). Bioavailability was 72% and 92% for Group 5 and Group 6, respectively.

Following IM administration of the two propionate ester formulations, mean _Tmax values for abiraterone ranged between formulations at 0.56 or 0.61 days, and mean _Tmax values for the propionate ester ranged from 0.11 to 0.26 days (2.3 to 6.2 hours). Mean exposures of the prodrug and abiraterone (as evidenced by _Cmax and AUC values) were within a two-fold difference between the two formulations. With the exception of the 7 day time point (no values beyond day 7), mean t1/2 values for the prodrug ranged from 0.98 to 1.7 days after administration for the two different vehicles. Mean t1 _/2 values for abiraterone were 1.8 and 4.5 days after administration for the two vehicles. Estimates of absolute bioavailability of abiraterone were calculated using the mean AUC _INF values after IV (127 h ^* ng/mL) and IM administration (corrected for dose and time units = 105 h ^* ng/mL for Group 3 and 94.1 h ^* ng/mL for Group 4). Bioavailability was 83% for Group 3 and 74% for Group 4, respectively.

Tables 6-9 and Figures 5-10 provide a summary of the PK studies for this example.

（表７）１ｍｇ／ｋｇのプロピオン酸アビラテロンをイヌ（Ｎ＝６）にＩＶ投与した後のグループ別アビラテロンまたはプロピオン酸アビラテロンの平均血漿ＰＫパラメータ

（表８）４１ｍｇ／ｋｇのデカン酸アビラテロンをイヌにＩＭ投与した後の個々の動物及びグループ別アビラテロンまたはデカン酸アビラテロンの平均血漿ＰＫパラメータ

（表９）５０ｍｇ／ｋｇのプロピオン酸アビラテロンをイヌ（Ｎ＝３）にＩＭ投与した後の個々の動物及びグループ別アビラテロンまたはプロピオン酸アビラテロンの平均血漿ＰＫパラメータ

Computer modeling was used to predict the human pharmacokinetic profile of abiraterone decanoate administered IM to humans based on data obtained from rat and dog studies. Pharmacokinetic (PK) modeling and simulations were performed using the fully-validated version of WinNonlin Phoenix (8.1). A linear PK (exponential) model was fitted to the time course of abiraterone plasma concentrations following IV administration of abiraterone (acetate or decanoate formulations) to rats and dogs. The derived PK parameters of clearance (CL) and volume of distribution (Vss) were predicted in humans by allometric scaling. The rate (K01) and fractional utilization (F) of abiraterone bioavailability following IM administration to dogs were estimated by deconvolution, with the values of K01 and F assumed to be equivalent in humans. The predicted PK parameters (CL, Vss, K01, and F) were used to simulate the time course of plasma concentrations in humans following IM administration of various defined dose regimens (assuming linear kinetics of abiraterone). Modeling predicted that IM administration of abiraterone decanoate at doses as low as 120 mg every two weeks could achieve therapeutically effective abiraterone plasma concentrations in humans, with steady-state _Cmin values of abiraterone greater than about 8 ng/ml and steady-state _Cmax values of abiraterone of about 14 ng/ml. Modeling also predicted that IM administration of abiraterone decanoate would be suitable for monthly or greater than monthly human dose regimens, resulting in therapeutically effective abiraterone plasma concentrations. For example, about 350 mg of abiraterone decanoate administered IM once every 4 weeks is sufficient to provide a steady-state C _min value of abiraterone of greater than about 8 ng/ml. The steady-state C _max value of abiraterone is proportional to the dose. See also Figures 11A, 11B, 11C, and 11D. In light of the present disclosure, in some cases, the dosage regimen may include an initial dosing period with a greater dosing frequency or a different abiraterone drug to achieve some exposure of abiraterone in the treated subject , followed by a monthly (or more than monthly) dosage regimen as described herein. For example, in some cases, the dosage regimen may include an initial IM administration of abiraterone decanoate once every 2 weeks, e.g., about 2-3 times, followed by monthly administration of abiraterone decanoate. Computer modeling predicted that such a dosing regimen would achieve a steady-state C _min value of abiraterone of greater than about 8 ng/ml during the treatment period.
Table 6. Mean plasma PK parameters of abiraterone or abiraterone decanoate by group following IV administration of 1.2 mg/kg abiraterone decanoate to dogs (N=6).

Table 7. Mean plasma PK parameters of abiraterone or abiraterone propionate by group following IV administration of 1 mg/kg abiraterone propionate to dogs (N=6).

Table 8. Mean plasma PK parameters of abiraterone or abiraterone decanoate by individual animal and group following IM administration of 41 mg/kg abiraterone decanoate to dogs.

Table 9. Mean plasma PK parameters of abiraterone or abiraterone propionate by individual animal and group following IM administration of 50 mg/kg abiraterone propionate to dogs (N=3).

ジクロロメタン（３５００ｍＬ）中のアビラテロン（３８１．９ｇ、１．０９ｍｏｌ）の懸濁液にトリエチルアミン（１６５ｇ、１．６４ｍｏｌ）及び触媒量のＤＭＡＰ（１３．３５ｇ、０．１０９ｍｏｌ）を加えた。ジクロロメタン（５００ｍＬ）の溶液としてのデカン酸（２２５ｇ、１．３１ｍｏｌ）、続いてＥＤＣＩ（２９３ｇ、１．５３ｍｏｌ）を懸濁液に加え、次に反応物を２０～２５℃で１９時間撹拌した。 Example 6A. Large-Scale Preparation of Abiraterone Decanoate from Decanoic Acid

To a suspension of abiraterone (381.9 g, 1.09 mol) in dichloromethane (3500 mL) was added triethylamine (165 g, 1.64 mol) and a catalytic amount of DMAP (13.35 g, 0.109 mol). Decanoic acid (225 g, 1.31 mol) as a solution in dichloromethane (500 mL) was added to the suspension followed by EDCI (293 g, 1.53 mol) and the reaction was then stirred at 20-25° C. for 19 hours.

Subsequently, 10 wt% aqueous _NaH2PO4 (4000 _mL ) was added and the reaction was stirred for 20 minutes. The organic layer was separated and extracted with 10 wt% _{aqueous NaH2PO4} (2000 mL) and brine (2000 mL). The organic layer was solvent exchanged with acetonitrile (4750 mL) and concentrated to 3100 g while maintaining the bath temperature below 40° C. The suspension was diluted with acetonitrile (900 g). The solids were isolated by filtration to give 510 g of crude abiraterone decanoate.

510 g of crude abiraterone decanoate was dissolved in acetone (4000 mL) at 40° C. The solution was filtered through filter paper. The filtrate was transferred to a 12 L 3-neck flask, diluted to 5100 g, and reheated to 40° C. to form a solution. The solution was slowly cooled to 20° C. to form a suspension. This was diluted with water (1020 mL) and stirred at room temperature overnight. The solids were filtered, the flask rinsed with the filtrate, and transferred to a filter funnel. The wet cake was transferred to a drying tray and dried overnight in a vacuum oven at 40-45° C. to give 457.1 g (90% yield) as a white solid. ^1H NMR ( _CDCl3 , 400 MHz): _dH 8.62 (d, 1H, J=1.9 Hz), 8.31 (dd, 1H, J=4.9, 1.6 Hz), 7.64 (dt, 1H, J= 7.9, 1.9 Hz), 7.21 (ddd, 1H, J = 8.0, 4.9, 0.8 Hz), 6.01-5.97 (m, 1H), 5.44-5.40 (m, 1H), 4.68-4.58 (m, 1H), 2.39-2.23 (m, 3H), 2.27 (t, 2H, J = 7.6 Hz), 2.12-2.00 (m, 3H), 1.91-1.54 (m, 10H), 1.49 (dt, 1H, J = 11.9, 5.1 Hz), 1.35-1.23 (m, 12H), 1.20-1.07 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H), 0.88 (t, 3H, J = 6.8 Hz). Elemental analysis, theoretical (corrected for 0.055% moisture level): C, 81.0%, H, 9.8%, N, 2.8%; found: C, 81.1%, H, 10.2%, N, 2.8%.

Using HPLC, the abiraterone decanoate obtained in this example was found to have a purity of 99.7% by weight. For HPLC analysis, abiraterone decanoate samples were prepared in methanol at a concentration of 0.05 mg/mL (for assay analysis) or 5 mg/mL (for impurity analysis). HPLC conditions were as follows: HPLC column: Halo C8 (2.7 um, 100x3.0 mm); Injection volume: 5 uL; Column temperature: 40°C; Sample temperature: ambient temperature; Detection: 210 nm; Mobile phase: 25 mM ammonium acetate, pH 8.0 (MPA) and 95/5 acetonitrile/tetrahydrofuran (MPB); Flow rate: 0.6 ml/min; Gradient: Started with 65/35 MPA/MPB, reached 100% MPB in 35 min, maintained at 100% MPB until 40 min, returned to 65/35 MPA/MPB at 40.10 min, and maintained at 65/35 MPA/MPB until the end of 45 min.

The white solid obtained in this example was also characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). XRPD was performed on a Bruker D8 Discover X-ray diffractometer equipped with a Θ-Θ vertical goniometer using a Vantec-500 as detector. Standard conditions: voltage 40 kV, current 40 mA, radiation: Cu, temperature: ambient, X-ray source exit slit size: 0.5 mm pinhole, snout collimator: 0.5 mm, sample holder: polished quartz plate. Operating conditions: detector distance: 30 cm, chi integral range: 2Θ from 4 to 40 degrees, counting time: 120 seconds/frame, frame number: 3, Θ1 position: 4 degrees, Θ2 position: 4 degrees, frame width: 12, scan axis: interlocking. The software used was GADD software, General Area Detector Diffraction System, version 4.1.50; and DIFFRAC. EVA, version 4.0. DSC was performed using a TA Instruments Q2000 (Thermal Advantage V 5.0.0-qualified) with a sample size of 2-10 mg, a heating range of 25°C to 250°C, and a heating rate of 10°C/min. Representative XRPD and DSC spectra are shown in Figures 12A-12B. Thermogravimetric analysis (TGA) was also performed on this sample. TGA was performed on a TA Instruments TGA Q500 (Thermal Advantage V5.2.5-qualified) with a sample size of 5-20 mg, a heating range of 25°C to 150°C, and a heating rate of 10°C/min. A representative TGA trace is shown in Figure 12C.

Example 6B. Preparation of Abiraterone Decanoate Salts Preparation of Abiraterone Decanoate Oxalate A 5200 g solution of abiraterone decanoate (374 g, 744 mmol) dissolved in isopropyl acetate was placed in a 12 L reactor. Oxalic acid (18.0 g) was charged and stirred for 2 hours. The suspension was warmed to 72° C. and stirred for 2 hours. After cooling to 60° C., oxalic acid (20 g) and isopropyl acetate (1000 g) were charged. Heating was continued at 60° C. for 30 minutes. Additional oxalic acid (20 g) and isopropyl acetate (600 g) were charged and heating was continued at 60° C. After 30 minutes, additional oxalic acid (15.7 g) and isopropyl acetate (600 g) were charged. The reaction temperature was increased to 72° C. and heating was maintained for 18 hours.

The reaction was then cooled to room temperature and further cooled to 5-10°C and the slurry was stirred at the same temperature for 2 hours. The solids were filtered and rinsed with cold isopropyl acetate (520 mL). The wet cake was transferred to a drying tray and dried in a vacuum oven at 45-50°C to a constant weight of 410 g (92.8% yield). HPLC of abiraterone decanoate oxalate showed a purity of 99.62 A%. ^1H NMR ( _CDCl3 , 400 MHz): _dH 12.62 (brs, 2H), 8.84 (d, 1H, J = 1.8 Hz), 8.69 (d, 1H, J = 5.5, 1.1 Hz), 8.24 (dt, 1H, J = 8.3, 1.7 Hz), 7.75 (dt, 1H, J = 8.2, 5.5), 6.32-6.29 (m, 1H), 5.44-5.39 (m, 1H), 4.68-4.58 (m, 1H), 2.42-2.31 (m, 3H), 2.28 (t, 2H, J = 7.5 Hz), 2.20-2.00 (m, 3H), 1.93-1.47 (m, 11H), 1.38-1.11 (m, 14H), 1.10 (s, 6H), 0.88 (t, 3H, J = 6.9 Hz).

Preparation of Abiraterone Decanoate HCl Salt A solution of abiraterone decanoate (20 mmol) in EtOAc (140 mL) was treated with 2M HCl/ether (12 mL; 24 mmol; 1.2 equiv.). The suspension was heated at 50° C. overnight and then cooled to 0-5° C. for 2 h. The solid was filtered reasonably quickly and rinsed with EtOAc to give 7.97 g of abiraterone decanoate HCl salt (14.76 mmol; 74% yield) as a white solid. ^1H NMR (CDCl ₃ , 400 MHz): _dH 8.70 (d, 1H, J = 1.6 Hz), 8.58 (dd, 1H, J = 1.6, 5.6 Hz), 8.34 (dt, 1H, J = 8.3, 1.6 Hz), 7.84 (dd, 1H, J = 8.3, 5.6 Hz), 6.37-6.33 (m, 1H), 5.44-5.39 (m, 1H), 4.68-4.58 (m, 1H), 4.43-2.31 (m, 3H), 2.27 (t, 2H, J = 7.5 Hz), 2.20-2.00 (m, 3H), 1.92-1.45 (m, 13H), 1.36-1.23 (m, 13H), 1.21-1.10 (m, 2H), 1.09 (s, 3H), 1.08 (s, 3H), 0.88 (t, 3H, J = 6.9 Hz).

Preparation of Abiraterone Decanoate Benzenesulfonate A solution of abiraterone decanoate (0.57 mmol) in ethyl acetate (10 ml) was treated with benzenesulfonic acid (0.72 mmol). The resulting solid abiraterone decanoate benzensulfonate (0.72 mmol) was isolated by filtration (yield 74%). ^1H NMR ( _CDCl3 , 400 MHz): _dH 8.87 (d, 1H, J = 1.7 Hz), 8.81 (brd, 1H, J = 5.6 Hz), 8.32 (dt, 1H, J = 8.1, 1.4 Hz), 7.97-7.92 (m, 2H), 7.86 (dd, 1H, J = 8.1, 5.6 Hz), 7.41-7.36 (m, 3H), 6.36-6.32 (m, 1H), 5.44-5.38 (m, 1H), 4.68-4.56 (m, 1H), 2.59-2.30 (m, 3H), 2.27 (t, 2H, J = 7.5 Hz), 2.17-2.00 (m, 4H), 1.91-1.54 (m, 10H), 1.47 (dt, 1H, J = 12.1, 4.7 Hz), 1.35-1.22 (m, 15H), 1.20-1.10 (m, 1H), 1.08 (s, 3H), 1.06 (s, 3H), 0.88 (t, 3H, J = 7.2 Hz).

Preparation of Abiraterone decanoate p-toluenesulfonate: A solution of abiraterone decanoate (0.57 mmol) in ethyl acetate (10 ml) was treated with p-toluenesulfonic acid (0.72 mmol). The resulting solid abiraterone decanoate p-toluenesulfonate was isolated by filtration (yield 64%). ^1H NMR ( _CDCl3 , 400 MHz): _dH 8.85 (d, 1H, J = 1.7 Hz), 8.81 (brd, 1H, J = 5.6 Hz), 8.31 (dt, 1H, J = 8.4, 1.6 Hz), 7.85 (dd, 1H, J = 8.3, 5.8 Hz), 7.82 (dt, 1H, J = 8.3, 1.6 Hz), 7.18 (d, 2H, J = 8.0 Hz), 6.36-6.31 (m, 1H), 5.45-5.39 (m, 1H), 4.69-4.57 (m, 1H), 2.57-2.30 (m, 6H), 2.28 (t, 2H, J = 7.5 Hz), 2.19-2.00 (m, 4H), 1.93-1.54 (m, 10H), 1.46 (dt, 1H, J = 4.8, 1.20 Hz), 1.36-1.10 (m, 16H), 1.08 (s, 3H), 1.06 (s, 3H), 0.88 (t, 3H, J = 6.9 Hz).

Preparation of Abiraterone Decanoate Phosphate A solution of abiraterone decanoate (1.0 mmol) in isopropyl acetate (10 ml) was treated with phosphoric acid (69.6 mg, 0.61 mmol). The resulting solid abiraterone decanoate phosphate was isolated by filtration (0.39 g, 65% yield). 1H NMR ( _CDCl3 , 400 MHz): _dH 9.75 (brs, 4H), 8.60 (brs, 2H), 8.00 (brd, 1H, J = 7.7), 7.65 (brs, 1H), 6.17 (brs, 1H), 5.37 (brs, 1H), 4.59 (brs, 1H), 2.45-2.16 (m, 6H), 2.09-1.78 (m, 5H), 1.73-1.44 (m, 9H), 1.35-1.21 (m, 16H), 1.03 (s, 3H), 0.95 (s, 3H), 0.88 (t, 3H, J = 6.9 Hz).

Example 7. Abiraterone Decanoate Studies in Rats and Monkeys and Allometric Scaling and Prediction of Plasma Profiles in Humans Example 7A. Abiraterone Decanoate Studies in Monkeys In monkey PK studies, a 90 mg/kg abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 192 mg/ml abiraterone decanoate) was administered intramuscularly to male cynomolgus monkeys (n=3).

As a comparison, abiraterone decanoate in 40% HP-β-cyclodextrin 25 mM sodium phosphate buffer (pH 7.4) (0.4 mg/ml) was administered IV at a dose of 1.2 mg/kg (mean n=3). For IV administration, blood samples were taken at 0, 0.083, 0.17, 0.25, 0.5, 0.75, 1, 2, 4, 8, and 24 hours. The results are shown in Table 10A and FIG. 14A.
Table 10A. Monkey IV and PK parameters (arithmetic mean)

A single dose PK study was performed by intramuscularly injecting a 90 mg/kg abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 192 mg/ml abiraterone decanoate) into male cynomolgus monkeys (n=3). The abiraterone decanoate formulation was injected intramuscularly into the thigh of each hind leg in two separate injections using a 27 gauge needle. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 5, 8, 24, 48, 72, 120, 168, 336, 504, 672, 840, 1008, 1176, and 1344 hours. Plasma concentrations of abiraterone decanoate and abiraterone were measured. The results are shown in Table 10B and FIG. 14B.
Table 10B. Single-dose PK parameters in monkeys (geometric mean; median Tmax)

Progesterone, cortisol and testosterone levels were also analyzed in this single-dose PK study. As shown in Figure 14C, long-term CYP17A1 inhibition was achieved after a single IM injection, as evidenced by sustained elevated progesterone levels and reduced cortisol and testosterone levels. Because the monkeys in this study were not castrated, the reduction in testosterone levels was minimal.

A repeat-dose PK study was also performed. In this study, the abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 192 mg/ml abiraterone decanoate) was administered intramuscularly to male cynomolgus monkeys (n=3) on days 0, 7, and 35 (each dose 90 mg/kg). Each dose of the abiraterone decanoate formulation was administered intramuscularly in two separate injections into the thigh of each hind leg using a 27-gauge needle. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 5, 8, 24, 48, 72, 120, 168, 192, 216, 240, 288, 336, 504, 672, 840, 864, 888, 912, 960, 1008, 1176, 1344, 1512, and 1680 hours. Plasma concentrations of abiraterone decanoate and abiraterone were measured. Results are shown in FIG. 14E.

Example 7B. Study of the Effect of Benzyl Benzoate on Abiraterone Exposure in Monkeys This example compares the pharmacokinetic behavior of IM injections of two different abiraterone decanoate formulations.
Formulation 1 - Abiraterone decanoate in 90% corn oil, 10% benzyl alcohol with a concentration of abiraterone decanoate of 207 mg/ml. Formulation 2 - Abiraterone decanoate in 70% corn oil, 10% benzyl alcohol, 20% benzyl benzoate with a concentration of abiraterone decanoate of 209 mg/ml.

100 mg/kg of Formulations 1 and 2 were administered intramuscularly to male cynomolgus monkeys (n=1). Injections were given on days 0, 7, and 14. Blood samples were collected at 0, 1, 2.5, 5, 7.5, 10, 24, 48, 72, 120, and 168 hours after each injection. Plasma abiraterone concentrations are shown in Figure 14F.

As shown in Figure 14F, IM injection of Formulation 2 unexpectedly resulted in significantly higher abiraterone plasma concentrations in monkeys compared to IM injection of the same dose of Formulation 1. This trend was also confirmed by parallel studies at different dose levels.

Example 7C. Abiraterone Decanoate Study in Rats In a rat PK study, a 90 mg/kg abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 172 mg/ml abiraterone decanoate) was administered intramuscularly to male rats (n=5).

As a comparison, abiraterone decanoate in 40% HP-β-cyclodextrin 25 mM sodium phosphate buffer (pH 7.4) (0.4 mg/ml) was administered IV at a dose of 1.2 mg/kg (mean n=5). For IV administration, blood samples were taken at 0, 0.083, 0.17, 0.25, 0.5, 0.75, 1, 2, 4, 8, and 24 hours. The results are shown in Table 11A and FIG. 15A.
Table 11A: Rat IV and PK parameters

A single dose PK study was performed by intramuscularly injecting male rats (n=5) with a 90 mg/kg abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 172 mg/ml abiraterone decanoate). The abiraterone decanoate formulation was injected intramuscularly into the hind thigh using a 27 gauge needle. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 5, 8, 24, 48, 72, 120, 168, 336, 504, 672, 840, 1008, 1176, and 1344 hours. Plasma concentrations of abiraterone decanoate and abiraterone were measured. The results are shown in Table 11B and FIG. 15B.
Table 11B. Rat single IM dose PK parameters

A repeat-dose PK study was also performed. In this study, the abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 172 mg/ml abiraterone decanoate) was administered intramuscularly to male rats (n=5) on days 0, 7, and 35 (each dose 90 mg/kg). Each dose of the abiraterone decanoate formulation was injected intramuscularly into the hind thigh using a 27-gauge needle. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 5, 8, 24, 48, 72, 120, 168, 192, 216, 240, 288, 336, 504, 672, 840, 864, 888, 912, 960, 1008, 1176, 1344, 1512, and 1680 hours. Plasma concentrations of abiraterone decanoate and abiraterone were measured. Results are shown in FIG. 15C.

Example 7D. Allometric Scaling and Prediction of the Plasma Profile of Abiraterone in Humans This pharmacokinetic (PK) analysis involves modeling the plasma concentration of abiraterone after single intravenous (IV) and intramuscular (IM) administration of abiraterone to rats, dogs, and monkeys. After IV and IM administration to rats, dogs, and monkeys, PK parameters were derived from the PK model and the plasma profile of abiraterone in humans after IM administration of abiraterone decanoate was predicted by deconvolution and allometric scaling.

Abiraterone decanoate was administered IV (1.2 mg/kg) and IM (90 mg/kg) to rats and monkeys. Animals received IV and IM dosing, respectively. Abiraterone decanoate was administered IV (1.2 mg/kg) and IM (50 mg/kg) to dogs, and IM (87 mg/kg) to dogs. Plasma samples were collected for 24 hours after a single IV dose to rats, dogs, and monkeys, and a single intramuscular dose to dogs. Plasma samples were collected up to 1344 hours after a single IM dose to rats, dogs, and monkeys. PK results are reported herein.

Pharmacokinetic Modeling: Pharmacokinetic models (1- and 2-compartment with zero-order input) were fitted (with or without predicted 1/C weighting) to individual animal abiraterone plasma concentration profiles following a single intravenous dose of abiraterone to rats, dogs, and monkeys using WinNonlin Phoenix Version 8.2. Modeling was based on the assumptions of linear (dose-proportional) and time-independent kinetics, and complete conversion of abiraterone decanoate prodrug to abiraterone. The function (representing 1-compartment kinetics with zero-order absorption) was WinNonlin Model 2, and the function (representing 2-compartment kinetics with zero-order absorption) was WinNonlin Model 10. Weighting was included depending on the pattern of residuals (residual Y vs. predicted concentration or time) and the precision of the estimated parameters. Appropriate models were selected based on (i) visual inspection of the model fit to the data, (ii) the lowest Akaike Information Criterion (AIC), and (iii) the precision (CV) of the estimated parameters. Total body clearance (CL) and apparent volume of distribution ( _Vss ) were derived from exponential functions.

Deconvolution: The rate and extent of input from intramuscular administration was simulated by deconvolution using WinNonlin Phoenix Version 8.2. Deconvolution is based on linear systems analysis and is defined by the convolution integral: G(t)=R(t) ^* H(t). G(t) is the measured plasma concentration profile after intramuscular administration, H(t) is the exponential function described in Section 3.2, and R(t), the input rate from the IM depot over time, is derived by deconvolution as described above. The slope of the input rate versus time generates the input rate constant ( _K01 ). The integral of the input rate versus time generates the cumulative input function and an estimate of absolute bioavailability.

Allometric Scaling to Humans: Plasma concentration profiles in humans after intramuscular administration were simulated based on predictions of CL and Vss (which describe the kinetics of abiraterone) and the rate and extent of input (absorption) into the systemic circulation (bioavailability). The kinetics of abiraterone in animals were characterized by PK parameters (CL and _Vss ) derived from an exponential model. CL and _Vss in humans were predicted from CL and _Vss in animals by an allometric approach: _Vss = a· ^Wx , where a is the intercept, W is the body weight, and x is the allometric index, so log _Vss = x·log W+log a (derived from a log-log plot of the log of body weight vs. _Vss for the three species). CL in humans was derived by the data-driven method of Tang ^[5] , i.e., CL human/kg = 0.407·CL monkey/kg. The rate and extent of input was derived by deconvolution.

Results: A biexponential function was deemed to best describe the time course of plasma concentrations of abiraterone following a single intravenous dose in rats, dogs, and monkeys. The plasma clearance (CL) of abiraterone was 11,414, 6,469, and 2,578 mL/h/kg in rats, dogs, and monkeys, respectively. The apparent distribution volumes at steady state ( _Vss ) of abiraterone were 22,313, 14,205, and 5,732 mL/kg in rats, dogs, and monkeys, respectively. See Table 12A below.
Table 12A. Summary of PK parameters of abiraterone in rats, dogs, and monkeys following intravenous and intramuscular administration of abiraterone decanoate.

The allometrically scaled predicted CL (from monkeys only, where CL was very high among rats and dogs) and _Vss (from rats, dogs, and monkeys) in humans were 73 L/h and 437 L, respectively. The predicted _Vss in humans was significantly greater than total body water (42 L), indicating widespread tissue distribution. The predicted CL in humans was not significantly different from hepatic blood flow (80 L/h).

Deconvolution of the IM and IV profiles provided estimates of the rate and extent of abiraterone bioavailability. IM bioavailability in rats, dogs, and monkeys was 19, 56, and 14%, respectively. Input (release from the IM depot) half-lives following IM administration to rats, dogs, and monkeys were 325, 319, and 325 hours, respectively.

＊ヒトにおける１次吸収モデル及び線形反応速度を含む１－コンパートメント動態を仮定した予測 Therefore, the parameters CL (73 L/h), V _ss (437 L), K01 (0.00213 ^{h −1} ) and F (56%) were used to simulate the plasma profile in humans, see Table 12B, Figures 16A and 16B.
Table 12B. Predictive parameters of abiraterone in humans following intramuscular administration of abiraterone decanoate ^*

*Predictions assuming one-compartment disposition with first-order absorption model and linear kinetics in humans

The predicted steady-state C _min value after monthly intramuscular administration of 1000 mg abiraterone to humans (i.e., every 4 weeks) was 5 ng/mL. See FIG. 16C. We believe that monthly intramuscular human bioavailability at this dose level may be greater than the 56% used in the predictions in FIG. 16C, approaching perfect bioavailability. If we assume perfect bioavailability, we believe that the predicted steady-state C _min value after monthly intramuscular administration of 1000 mg abiraterone to humans would be 9.3 ng/mL. See FIG. 16D.

Conclusions: The volume of distribution ( _Vss ) in humans (437 L) was predicted by allometric growth with good correlation between rats, dogs, and monkeys. _Vss indicates extensive tissue distribution in humans. Total body clearance (CL) in humans (73 L/h) was predicted by monkey allometric growth. CL in humans was not significantly different from hepatic blood flow. Absorption rate (absorption half-life of 325 hours) and bioavailability (F of 56%) were predicted from deconvolution of intramuscular and intravenous data. The predicted steady-state _Cmin following intramuscular administration of 1000 mg abiraterone decanoate once every 4 weeks in humans was 5 ng/mL.

Example 8. Study of Abiraterone Isocaproate and Abiraterone Decanoate in Dogs The objective of this study was to compare the pharmacokinetics (PK) of two different esters of abiraterone (isocaproate and decanoate) following a single dose administration to beagle dogs using an intramuscular (IM) formulation, as well as a single intravenous (IV) formulation of abiraterone isocaproate to allow calculation of the absolute bioavailability of the isocaproate ester.

Untreated male beagle dogs were obtained for use in this study from Marshall Bioresources, North Rose, NY. Animals were 6-7 months old and weighed 7.0-7.9 kilograms at the time of first dosing.

^＊プロドラッグの濃度 Two groups of three male dogs/group underwent standard evaluations including weight, clinical observations, and blood sampling for PK. One group of three dogs received abiraterone isocaproate via IV on day 1 (Test Article #1, abiraterone isocaproate in 40% HP-β-cyclodextrin). After a minimum of 72 hours washout, all six dogs were administered via IM. Three dogs receiving abiraterone isocaproate IV were given an abiraterone isocaproate IM preparation (Test Article #2, abiraterone isocaproate in 90% corn oil/10% benzyl alcohol) and the remaining three dogs were given an abiraterone decanoate IM preparation (Test Article #3, abiraterone decanoate in 90% corn oil/10% benzyl alcohol). Doses were based on an assumed body weight of 10 kg, which may affect the calculated CL (or CL/F), Vz (or Vz/F) values, and bioavailability assessments. The study design is summarized in the table below.

^* Prodrug concentration

Blood was collected pre-dose, after IV dosing, and at 0.083, 0.1667, 0.25, 0.5, 0.75, 1, 2, 4, and 24 hours post-dose. Blood was collected immediately prior to dosing, and after IM dosing, and at 0.5, 1, 2, 3, 4, 5, 8, and 24 hours post-dose, and at 2, 3, 5, 7, 14, 21, 28, 35, and 49 days post-dose (collected close to the time of dosing). Blood was processed to plasma and the resulting plasma samples were analyzed for the prodrug and abiraterone.

Pharmacokinetic analysis was performed on plasma concentration versus time data using Phoenix WinNonlin (v8.1) noncompartmental analysis function (linear trapezoidal method for AUC calculation). See, e.g., Example 5B.

Results: Single-dose pharmacokinetics of abiraterone and abiraterone isocaproate following IV administration of 1 mg/kg abiraterone isocaproate: Evidence of systemic exposure of abiraterone and abiraterone isocaproate was observed in all treated dogs following IV administration (Table 13A and FIG. 17A). Following IV administration of abiraterone isocaproate (prodrug), the mean CL value of the prodrug was calculated to be 62.8 mL/min/kg, which was considered high clearance. Using a dose value of 0.78 mg/kg (assuming 100% conversion of the prodrug to abiraterone), the mean CL/F value of abiraterone was 63.3 mL/min/kg. The mean Vz value of the prodrug was 1.91 L/kg and the mean Vz/F value of abiraterone was 4.22 L/kg. The mean t _1/2 values were 0.350 and 0.773 hours for the prodrug and abiraterone, respectively.

Single-dose pharmacokinetics of abiraterone and abiraterone isocaproate following IM administration of abiraterone isocaproate: Following IM administration, evidence of systemic exposure of abiraterone and abiraterone isocaproate was observed in all treated dogs (Table 13B and FIG. 17B), although it should be noted that there was a wide variability in the CV% values for exposure parameters ( _Cmax and AUC values) ranging from 60-70%. Following IM administration, the mean _Tmax values were 1.7 days for abiraterone and 0.19 days for the isocaproate prodrug, respectively. The mean _Cmax values were 20.2 ng/mL for abiraterone and 106 ng/mL for the isocaproate prodrug, respectively. The mean AUC _last values were 266 days ^* ng/mL for abiraterone and 281 days ^* ng/mL for the isocaproate prodrug, respectively. The mean t _1/2 values were 9.3 days for abiraterone and 7.4 days for the isocaproate prodrug, respectively.

Estimates of absolute bioavailability of abiraterone were calculated using the mean AUC _INF values following IV administration of 0.78 mg/kg abiraterone isocaproate (206 h ^* ng/mL, or 131 h ^* ng/mL when corrected for dose) and IM administration of 60 mg/kg abiraterone isocaproate (corrected for dose and time units=114 h ^* ng/mL). Estimated abiraterone bioavailability from the isocaproate was calculated to be 87%, however these data should be interpreted with caution as they are based on an assumed body weight of 10 kg.

（表１３Ｂ）イヌにＩＭ投与後のアビラテロンまたはアビラテロンプロドラッグの血漿ＰＫパラメータの概要

Single-dose pharmacokinetics of abiraterone and abiraterone decanoate following IM administration of abiraterone decanoate: Following IM administration, evidence of systemic exposure of abiraterone and abiraterone decanoate was observed in all treated dogs (Table 13B and FIG. 17C). Abiraterone exposure parameters ( _Cmax and AUC values) varied from 60-70%, while decanoate exposure parameters were less variable with CV% values less than 27%. Following IM administration, mean _Tmax values were 5.7 days for abiraterone and 0.71 days for the decanoate ester prodrug, respectively. Mean _Cmax values were 7.82 ng/mL for abiraterone and 45.0 ng/mL for the decanoate ester prodrug, respectively. The mean AUC _last values were 176 days ^* ng/mL for abiraterone and 298 days ^* ng/mL for the decanoate prodrug, respectively. The mean T _1/2 values were 14 days for abiraterone and 6.7 days for the decanoate prodrug, respectively. Estimates of absolute bioavailability of abiraterone were calculated using the mean AUC _INF values after 0.86 mg/kg abiraterone decanoate IV administration (145 h ^* ng/mL, or 169 h ^* ng/mL when corrected for dose) and 60 mg/kg IM administration (corrected for dose and time units=70.4 h ^* ng/mL). The estimated abiraterone bioavailability was calculated to be 42%, however these data should be interpreted with caution as they are based on an assumed body weight of 10 kg. A comparison of the mean plasma concentration profiles of abiraterone following IM administration of abiraterone isocaproate or abiraterone decanoate is shown in FIG. 17D.
Table 13A. Summary of plasma PK parameters of abiraterone or abiraterone isocaproate following IV administration to dogs.

Table 13B. Summary of plasma PK parameters of abiraterone or abiraterone prodrugs following IM administration to dogs.

Conclusion of Example 8: After administration, evidence of systemic exposure of abiraterone was observed in all treated dogs. Comparing the mean _Tmax and _Cmax values, the isocaproate ester prodrug had shorter _Tmax values and higher _Cmax values, suggesting that it is absorbed more rapidly than the decanoate ester prodrug. The mean AUC values of abiraterone after IM administration of the isocaproate ester prodrug were seen to be less than two-fold higher compared to the decanoate ester prodrug. Longer half-life values were observed after IM administration compared to those observed after IV administration, suggesting that the prodrug has a slower release/absorption profile when administered via the IM route. There was some evidence that the half-life of abiraterone appeared to be longer after decanoate administration, which may be due to the slower absorption of the decanoate ester prodrug.

Each of the references mentioned within this disclosure is incorporated herein by reference in their respective entireties.

As used herein, the term "about" modifies quantities related to the present disclosure and refers to variations in numerical quantities, but such variations may occur, for example, through routine testing and processing, through unintentional errors in such testing and processing, through differences in manufacturing, supply, or purity of the components/materials used in the present disclosure. As used herein, a particular value with "about" includes the particular value, for example, about 10%, including 10%. Whether or not modified by the term "about," the claims include the equivalent of the recited quantity. In one embodiment, the term "about" means within 20% of the reported numerical value.

With respect to aspects of the disclosure described as a genus, all individual species are considered separate and independent aspects of the disclosure. When aspects of the disclosure are described as "comprising" an element, embodiments "consisting of" or "consisting essentially of" that element are also contemplated.

Any of the various aspects, embodiments, and options described herein may be combined in any and all variations.

Although several embodiments of the present invention have been described herein, it should be apparent to those skilled in the art that the foregoing are merely illustrative and not limiting, presented by way of example only. Numerous modifications and other embodiments are within the scope of those skilled in the art and are contemplated to be within the scope of the present invention and its equivalents. Variations of the present invention will be readily apparent to those skilled in the art, and it will be understood that the present invention is intended to include those alternatives. Since many further modifications may occur to those skilled in the art, it is not desired to limit the present invention to the exact construction and operation, and therefore, the operations illustrated and described, all suitable modifications and equivalents may be used as falling within the scope of the present invention.

Claims (38)

The structure:

or a pharma- ceutically acceptable salt thereof. A pharmaceutical composition comprising the abiraterone decanoate of claim 1, or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable carrier. A pharmaceutical composition comprising the abiraterone decanoate of claim 1 and a pharma- ceutical acceptable carrier. The pharmaceutical composition according to claim 2 or 3, which is formulated for intramuscular, intradermal, or subcutaneous injection. The pharmaceutical composition according to claim 2 or 3, wherein the pharma- ceutically acceptable carrier comprises a pharma- ceutically acceptable oil and, optionally, a further pharma- ceutically acceptable solvent. The pharmaceutical composition of claim 5, wherein the pharma- ceutically acceptable oil comprises a triglyceride and the further pharma- ceutically acceptable solvent, if present, comprises an alcohol, an ester and/or an acidic solvent. The pharmaceutical composition of claim 6, wherein the pharma- ceutically acceptable oil is selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil, and the further pharma-ceutically acceptable solvent, if present, comprises benzyl alcohol, benzyl benzoate, or a combination thereof. The pharmaceutical composition according to claim 2 or 3, comprising a sufficient amount of abiraterone decanoate or a pharma- ceutical acceptable salt thereof to provide a therapeutically effective plasma concentration of abiraterone or a plasma concentration of abiraterone of 1 ng/ml or more for a period of at least two weeks after a single administration to a subject having one or more diseases selected from sex hormone-dependent benign or malignant diseases, syndromes due to androgen excess, and syndromes due to glucocorticoid excess. The pharmaceutical composition according to any one of claims 2 to 8, for use in a method for treating one or more diseases selected from sex hormone-dependent benign or malignant diseases, syndromes caused by androgen excess, and syndromes caused by glucocorticoid excess, the method comprising administering a therapeutically effective amount of the pharmaceutical composition to a subject in need thereof. The pharmaceutical composition of claim 9, wherein the administration is by intramuscular, intradermal, or subcutaneous injection, and optionally the pharmaceutical composition is administered to the subject with or without food. The pharmaceutical composition according to claim 9 or 10, wherein the one or more diseases are selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, lung cancer, endometriosis, polycystic ovary syndrome, Cushing's syndrome, Cushing's disease, classic or non-classical congenital adrenal hyperplasia, precocious puberty, hirsutism, and combinations thereof. The pharmaceutical composition according to claim 9 or 10, wherein the one or more diseases are sex hormone-dependent benign or malignant diseases selected from castration-resistant prostate cancer and castration-sensitive prostate cancer. The pharmaceutical composition according to claim 9 or 10, wherein the one or more diseases are sex hormone-dependent benign or malignant diseases selected from metastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer. The pharmaceutical composition according to any one of claims 9 to 13, wherein the subject is treated with a gonadotropin releasing hormone analogue and/or bilateral orchiectomy. The pharmaceutical composition of any one of claims 9 to 14, wherein the method further comprises administering a corticosteroid to the subject. The pharmaceutical composition of any one of claims 9 to 15, wherein the method further comprises administering to the subject hydrocortisone, prednisone, prednisolone, methylprednisolone, and/or dexamethasone. The pharmaceutical composition according to any one of claims 9 to 16, which is administered to the subject once a week or more than once a week. The administration,
(a) a plasma concentration of abiraterone greater than 1.0 ng/ml for a period of at least two weeks;
18. The pharmaceutical composition of any one of claims 9 to 17, which provides: (b) a single dose or steady state C _max of abiraterone of 10 ng/ml to 400 ng/ml; or (c) both (a) and (b). 13. A pharmaceutical composition comprising the abiraterone decanoate of claim 1, a pharma- ceutically acceptable oil, and a pharma-ceutically acceptable solvent,
the abiraterone decanoate is in its base form and is present in a concentration of 25 mg/ml to 500 mg/ml;
The pharmaceutical composition is formulated for intramuscular, intradermal, or subcutaneous injection;
The pharmaceutical composition comprises the abiraterone decanoate in an amount between 50 mg and 2,000 mg. 20. The pharmaceutical composition of claim 19, wherein the pharma- ceutically acceptable oil comprises a triglyceride and the pharma- ceutically acceptable solvent comprises an alcohol, an ester and/or an acidic solvent. 21. The pharmaceutical composition of claim 20, wherein the pharma- ceutical acceptable oil comprises vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil, the pharma-ceutical acceptable solvent comprises benzyl alcohol and/or benzyl benzoate, and the abiraterone decanoate is present at a concentration of 50 mg/mL to 300 mg/mL. The pharmaceutical composition according to any one of claims 19 to 21 for treating prostate cancer, wherein the pharmaceutical composition is administered to a subject in need thereof once a month or more than once a month via intramuscular, intradermal, or subcutaneous injection. The pharmaceutical composition of claim 22, which is administered via intramuscular injection. 24. The pharmaceutical composition of claim 22 or 23, wherein the pharmaceutical composition is administered to the subject at a dosing frequency ranging from once a month to once every three months. abiraterone decanoate according to claim 1, which is in a crystalline form characterized by an X-ray powder diffraction (XRPD) spectrum having one or more peaks at 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6, and 20.8 degrees 2Θ (±0.2°); a differential scanning calorimetry (DSC) pattern having an endothermic peak at an onset temperature of 69.0° C. (including variations in said temperature that may occur through routine DSC testing and processing); or a combination thereof. 1. A method for preparing an abiraterone decanoate formulation suitable for parenteral administration to a subject having a sex hormone dependent benign or malignant disease, syndrome due to androgen excess, or syndrome due to glucocorticoid excess, comprising:
a) reacting in a pharma- ceutically acceptable carrier with a compound of the formula:

to form a mixture; and optionally b) sterilizing the mixture formed in a). 27. The method of claim 26, wherein the mixing comprises mixing a crystalline form of abiraterone decanoate in the pharma- ceutically acceptable carrier, and the crystalline form is characterized by an X-ray powder diffraction (XRPD) spectrum having one or more peaks at 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6, and 20.8 degrees 2Θ (±0.2°); a differential scanning calorimetry (DSC) pattern having an endothermic peak at an onset temperature of 69.0° C. (including variations in said temperature that may occur through routine DSC testing and processing); or a combination thereof. 28. The method of claim 26 or 27, wherein the pharma- ceutically acceptable carrier comprises a pharma- ceutically acceptable oil and a pharma- ceutically acceptable solvent, the pharma- ceutically acceptable oil comprises vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil, the pharma- ceutically acceptable solvent comprises benzyl alcohol or benzyl benzoate, and the abiraterone decanoate is present at a concentration of 50 mg/mL to 300 mg/mL. 1) Abiraterone decanoate according to claim 1,
2) a pharma- ceutically acceptable oil; and 3) benzyl alcohol and/or benzyl benzoate,
The pharmaceutical composition, wherein the abiraterone decanoate is in its base form, and optionally characterized by one or more of the following:
(i) the pharma- ceutically acceptable oil is corn oil;
(ii) the pharmaceutical composition comprises benzyl alcohol and benzyl benzoate, wherein the benzyl alcohol is present in an amount of 5-10% by volume, the benzyl benzoate is present in an amount of 10-20% by volume, and corn oil is present in an amount of 70-85% by volume, the total amount of benzyl alcohol, benzyl benzoate, and corn oil being 100%; and
(iii) the abiraterone decanoate is present in a concentration from 100 mg/ml to 300 mg/ml. 1) 50 mg to 2000 mg of abiraterone decanoate according to claim 1;
2) a pharma- ceutically acceptable oil; and 3) a pharma-ceutically acceptable solvent,
1. A unit dosage form, wherein the abiraterone decanoate is in its basic form and is present in a concentration of 25 mg/ml to 500 mg/ml, and optionally characterized by one or more of the following:
(i) the pharma- ceutically acceptable oil is corn oil;
(ii) the pharma- ceutically acceptable solvent comprises benzyl alcohol and benzyl benzoate;
(iii) the unit dosage form comprises benzyl alcohol in an amount of 5-10% by volume, benzyl benzoate in an amount of 10-20% by volume, and corn oil in an amount of 70-85% by volume, the sum of the amounts of benzyl alcohol, benzyl benzoate, and corn oil being 100%; and
(iv) the abiraterone decanoate is present in a concentration from 100 mg/ml to 300 mg/ml. The pharmaceutical composition of claim 29 or the unit dosage form of claim 30 for the treatment of prostate cancer, optionally administered by intramuscular injection once a month or more than once a month to a subject in need thereof. 31. The pharmaceutical composition of claim 29 or the unit dosage form of claim 30, wherein the pharmaceutical composition or the unit dosage form is administered to a subject in need thereof via intramuscular injection once a month to once every three months. The pharmaceutical composition or unit dosage form of claim 31 or 32, wherein the subject is further treated with hydrocortisone, prednisone, prednisolone, methylprednisolone, and/or dexamethasone. The pharma- ceutically acceptable salt of abiraterone decanoate according to claim 1, wherein the pharma-ceutically acceptable salt is an oxalate, a hydrochloride, a benzenesulfonate, a p-toluenesulfonate, or a phosphate. 1. A pharmaceutical composition comprising a compound of formula II or a pharma- ceutical acceptable salt thereof,

In the formula,
^R2 is selected from : _C7-16 alkyl; and alkyl substituted with cycloalkyl having a total of 4 to 30 carbon atoms;
the pharmaceutical composition is formulated for intramuscular, intradermal, or subcutaneous injection, and the compound of formula II or a pharma- ceutically acceptable salt thereof is present in the pharmaceutical composition in a concentration of 25 mg/ml to 500 mg/ml;
Optionally, the pharmaceutical composition is characterized by one or more of the following:
(i) the pharmaceutical composition is a non-aqueous solution or suspension; and
(ii) The compound of formula II or a pharma- ceutically acceptable salt thereof is dissolved or suspended in a pharma- ceutically acceptable oil, optionally wherein said pharma- ceutically acceptable oil is vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil. The pharmaceutical composition of claim 35, further comprising benzyl alcohol, benzyl benzoate, or a combination thereof. The pharmaceutical composition according to claim 35 or 36, for the treatment of one or more diseases selected from sex hormone-dependent benign or malignant diseases, syndromes caused by androgen excess, and syndromes caused by glucocorticoid excess. A compound of formula I, or a pharma- ceutically acceptable salt thereof,

wherein R ¹ is an alkyl having the formula -(CH ₂ ) _n -CH ₃ , where n is an integer selected from 6, 7, 8, 9, 10, 11, or 12.

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