Abiraterone Prodrug

Abstract

Sustained-release abiraterone prodrug formulations, methods, and kits for parenteral administration to patients with sex hormone-dependent benign or malignant diseases such as prostate cancer, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess such as hypercortisolism.

Description

[Technical field]

[0001] 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 contents of each of which are incorporated by reference in their entirety.

[0002] 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 the overproduction of androgens (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 the overproduction of glucocorticoids, typically cortisol. [Background technology]

[0003] Abiraterone ((3β)-17-(pyridin-3-yl)androsta-5,16-dien-3-ol; CAS number 154229-19-3); Chemical formula: C 24 H 31NO; 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).

[0004] Abiraterone itself is poorly absorbed, but can be administered orally as an abiraterone acetate prodrug. Abiraterone acetate is also poorly absorbed, but can be converted to abiraterone in the intestine, which makes it less absorbed 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.

[0005] It is known that oral abiraterone acetate is not absorbed in the gastrointestinal tract (and is 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).

[0006] Abiraterone prevents the normal physiological production of steroids by the adrenal gland, so its prodrug formulations are generally prescribed at low doses of steroids to prevent adrenal insufficiency.In fact, 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.The 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.

[0007] Because administration of abiraterone acetate with food increases its absorption (and therefore potentially increases and significantly variability in exposure, which in some cases could lead to various 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.

[0008] The prescribing information states that when administered orally daily at 1,000 mg Zytiga® to patients with metastatic castration-resistant prostate cancer, the steady-state C max The values ​​were 226 ± 178 ng / mL (mean ± SD), and the area under the curve (AUC) value was 1173 ± 690 ng·hr / mL (mean ± SD). subject A single-dose (1,000 mg) crossover study of Zytiga® in rats confirmed that systemic exposure of abiraterone was increased when Zytiga® was administered with food. max The ACE and AUC values ​​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).

[0009] 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 dosing burden on patients (4 × 250 mg tablets taken once daily). In addition, the combination of low bioavailability and high food effect results in high variability in blood levels in patients. Furthermore, abiraterone is rapidly excreted, and the approved dosing regimen is limited to 100 mg / day C min of abiraterone, which is believed to be associated with loss of therapeutic benefit in patients with metastatic castration-resistant prostate cancer.

[0010] Parenteral modes of administration (e.g., parenteral routes) have been explored for other classes of drugs, but to date, no sustained release injectable prodrug formulations of abiraterone exist. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Stappaerts et al.,Eur.J.Pharmaceutics Biopharmaceutics 90:1, 2015 Summary of the Invention

[0012] In various embodiments, the disclosure provides novel abiraterone prodrugs, long-acting abiraterone prodrug formulations, and methods for treating, for example, sex hormone-dependent benign or malignant diseases and / or syndromes resulting from androgen and / or glucocorticoid excess. subject and methods of using the agents in the treatment of chronic obstructive pulmonary disease. Typically, the novel abiraterone prodrugs herein can be fatty acid esters of abiraterone, which 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 provide improved bioavailability, elimination of food effects, reduced dosage burden, reduced dosing frequency, and sustained effective plasma levels of abiraterone, e.g., daily C 100 / mL or more than those observed with oral administration of abiraterone acetate. min The present invention is groundbreaking in that it provides continuous plasma exposure above levels, e.g., for at least one week, typically at least two weeks, following administration of the abiraterone prodrug formulation. Additionally, pharmacokinetic and pharmacodynamic studies of representative abiraterone prodrugs herein, such as abiraterone decanoate or abiraterone isocaproate, have demonstrated that abiraterone prodrugs are effective in treating patients with sex hormone-dependent benign or malignant diseases, syndromes due to androgen excess, and / or syndromes due to glucocorticoid excess, as described herein. subject The novel abiraterone prodrugs and formulations disclosed herein for treating ADHD demonstrate suitability for weekly, monthly, or even less frequent dosing, which 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 taken daily).

[0013] 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: TIFF0007644713000001.tif42128 R in the formula 1 is defined herein.

[0014] In one exemplary embodiment, the subject is a patient with a sex hormone-dependent benign or malignant disease, syndrome resulting from androgen excess, and / or syndrome resulting from glucocorticoid (e.g., cortisol) excess. subject Abiraterone prodrug formulations for parenteral administration to a subject are provided. 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 cosolvents and excipients). In certain exemplary embodiments, the lipophilic ester form of abiraterone can be an 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: TIFF0007644713000002.tif42128 R in the formula 2 is 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.

[0015] 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 treating 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 and castration-sensitive prostate cancer. In some embodiments, the 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.

[0016] Parenteral formulations fill a long-standing unmet need by providing an alternative to oral formulations that suffer from: (1) poor 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 requirement 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.

[0017] One object of the present disclosure is to provide an effective dose of at least one abiraterone prodrug formulation to a patient in need thereof. subject In some embodiments, the present invention provides a method for inhibiting CYP17A1 activity, such as inhibiting 17α-hydroxylase activity and 17,20-lyase activity by parenteral administration to subject The patient 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.

[0018] One object of the present disclosure is to provide an effective dose of at least one abiraterone prodrug formulation to a patient in need thereof. subject In some embodiments, the present invention provides a method for reducing glucocorticoid (e.g., cortisol) levels by parenteral administration to subject The patient is suffering from a syndrome resulting from glucocorticoid excess, such as resulting from hypercortisolism as described herein. subject suffers from Cushing's syndrome or Cushing's disease.

[0019] One object of the present disclosure is to provide an effective dose of at least one abiraterone prodrug formulation to a patient in need thereof. subjectThe present invention provides a method for reducing androgen (e.g., testosterone and / or dihydrotestosterone) and / or estrogen levels by parenteral administration to a subject. In some embodiments, subject The subject suffers from a syndrome resulting from androgen excess, such as classic or non-classic congenital adrenal hyperplasia, endometriosis, polycystic ovary syndrome (PCOS), precocious puberty, or hirsutism. subject suffers from androgen and / or estrogen related cancer, such as prostate cancer or breast cancer.

[0020] Another object is to provide an effective dose of at least one abiraterone prodrug formulation to a patient in need of such treatment. subject The present invention 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, by parenteral administration of a compound of the present invention to a human subject. In one exemplary embodiment, the method is for treating a sex hormone-dependent benign or malignant disease, such as an androgen-dependent disease or an estrogen-dependent disease, such as an androgen-dependent cancer or an estrogen-dependent cancer. 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.

[0021] 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. subjectUpon administration of the formulation to the patient, 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 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, a hormone replacement drug, or a hormone ablation drug). In certain aspects, 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 among, for example, acetate, propionate, butanoate, valerate, caproate, enanthate, cypionate, isocaproate, bucyclate, cyclohexanecarboxylate, phenylpropionate, decanoate, or undecanoate.

[0022] Another object is to treat patients with 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. subjectThe present invention provides a kit for treating . In an exemplary embodiment, the kit includes a container, such as a vial, ampoule, or pre-loaded syringe, containing one or more formulations. In another exemplary embodiment, the kit includes a container, such as a vial, ampoule, or 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, ampoule, or 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.

[0023] Another object is to treat patients with sex hormone-dependent benign or malignant diseases, syndromes due to androgen excess, and / or syndromes due to glucocorticoid excess, such as hypercortisolism. subject The present invention provides a method for preparing an abiraterone decanoate formulation suitable for parenteral administration to humans.

[0024] These and other objects may be achieved in certain embodiments.

[0025] In some embodiments, the present disclosure provides:

[0026] [1] A compound of formula I or a pharma- ceutically acceptable salt thereof, TIFF0007644713000003.tif42128In formula, R 1 is R 10 , OR 10 , or NHR 10 and R 10 teeth, 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 TIFF0007644713000004.tif10128, or a pharma- ceutically acceptable salt thereof.

[0027] [2] R 1 is C 7-16 The compound according to [1], or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

[0028] [3] R 1 is the formula -(CH2) n The compound according to [1] or [2], or a pharma- ceutically acceptable salt thereof, wherein n is an alkyl having -CH3, and n is an integer selected from 6, 7, 8, 9, 10, 11, or 12.

[0029] [4] R 1 is an alkyl having the formula -(CH2)8-CH3, or The compound according to [1], or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of TIFF0007644713000005.tif10128.

[0030] [5] A pharmaceutical composition comprising the compound according to any one of [1] to [4] or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0031] [6] Below formula A pharmaceutical composition comprising abiraterone decanoate having TIFF0007644713000006.tif35128, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0032] [7] The pharmaceutical composition according to [5] or [6], formulated for intramuscular, intradermal, or subcutaneous injection.

[0033] [8] The pharmaceutical composition described in 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.

[0034] [9] The pharmaceutical composition of [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.

[0035]

[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.

[0036]

[11] Have one or more of the following disorders: sex hormone-dependent benign or malignant disorders, syndromes caused by androgen excess, and syndromes caused by glucocorticoid excess such as hypercortisolism subject The pharmaceutical composition according to any one of [6] to

[10] , comprising an amount of abiraterone decanoate or a pharma- ceutical acceptable salt thereof sufficient to provide a therapeutically effective plasma concentration of abiraterone, i.e., a plasma concentration of abiraterone of about 1 ng / ml or greater, 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 patient.

[0037]

[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, comprising administering to a patient in need thereof 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, subject The method comprises administering a therapeutically effective amount of the pharmaceutical composition according to any one of [5] to

[11] .

[0038]

[13] The method according to

[12] , wherein the administration is by intramuscular injection, intradermal injection, or subcutaneous injection.

[0039]

[14] The pharmaceutical composition may be administered with or without food. subject The method according to any one of

[12] to

[13] , wherein the method is administered to

[0040]

[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.

[0041]

[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.

[0042]

[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.

[0043]

[18] Ibid. subject The method according to any one of

[12] to

[17] , wherein the patient is treated with a gonadotropin releasing hormone analogue and / or bilateral orchiectomy.

[0044]

[19] Corticosteroids subjectThe method according to any one of

[12] to

[18] , further comprising administering to a subject.

[0045]

[20] Prednisone, prednisolone, and / or methylprednisolone subject The method according to any one of

[12] to

[19] , further comprising administering to a subject.

[0046]

[21] The pharmaceutical composition is administered at a frequency ranging from once a week or more than once a week, for example, 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. subject The method according to any one of

[12] to

[20] , wherein the method is administered to

[0047]

[22] The administration results in: (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 of abiraterone of about 10 ng / ml to about 400 ng / ml. max or (c) both (a) and (b).

[0048]

[23] A pharmaceutical composition, for example a unit dosage form, comprising the following formula: A pharmaceutical composition comprising a therapeutically effective amount of abiraterone decanoate having a concentration of about 25 mg / ml to about 500 mg / ml, a pharma- ceutical acceptable oil, and a pharma- ceutical acceptable solvent, wherein the abiraterone decanoate is in its basic form present in a concentration of about 25 mg / ml to about 500 mg / ml, and wherein the pharmaceutical composition, e.g., a unit dosage form, is formulated for intramuscular, intradermal, or subcutaneous injection, and wherein the pharmaceutical composition, e.g., a unit dosage form, comprises the abiraterone decanoate in an amount of about 50 mg to about 2,000 mg.

[0049]

[24] The pharmaceutical composition, e.g., a unit dosage form, described in

[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.

[0050]

[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.

[0051]

[26] A method for treating prostate cancer, comprising administering to a subject in need thereof subject the method comprising administering a pharmaceutical composition, e.g., a unit formulation according to any one of

[23] to

[25] , via intramuscular, intradermal, or subcutaneous injection, to the patient once a month or more than once a month, for example, once a month to once every several months, for example, once a month to once every two months, or once a month to once every three months.

[0052]

[27] The method of

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

[0053]

[28] Have, for example, a sex hormone-dependent benign or malignant disorder, syndromes due to androgen excess, and / or syndromes due to glucocorticoid excess, such as hypercortisolism subject 1. A method for preparing an abiraterone decanoate formulation suitable for parenteral administration to a subject, comprising: a) in a pharma- ceutically acceptable carrier, TIFF0007644713000008.tif35128 to form a mixture; b) optionally sterilizing the mixture formed in a); The method comprising:

[0054]

[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 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 with an onset temperature of about 69.0°C; or a combination thereof.

[0055]

[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.

[0056] Embodiments of the present disclosure may fill 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 fill 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. Embodiments of the present disclosure provide long-acting sustained release depot-based parenteral formulations of abiraterone prodrugs, methods of making same, methods of treatment using same, and methods of treatment for various diseases, including prostate cancer. subject The major drawbacks and deficiencies of prior art formulations of abiraterone acetate (including the commercially available oral formulation) can be overcome by providing a kit for convenient administration of the formulation to a subject.

[0057] The features have been outlined more broadly 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. It will be appreciated that 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.

[0058] 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 used herein is for the purpose of description and should not be regarded as limiting.

[0059] Thus, those skilled in the art will appreciate that the concepts underlying the present disclosure may be readily utilized as a basis for the design of other formulations, methods, systems, kits, and compositions for carrying out the several purposes of the present disclosure, and it is therefore important that equivalent structures within the scope of the present disclosure are included in the present disclosure.

[0060] 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. [Brief description of the drawings]

[0061] [Figure 1]

[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 suspension in castor oil (62.5 mg / ml), and abiraterone in sodium phosphate buffer, 0.1% Tween suspension (62.5 mg / ml). [Diagram 2] 2 shows the mean plasma concentrations (ng / ml) of abiraterone in dogs at different time periods (hours) after IM or intravenous (IV) administration of various abiraterone acetate formulations. Figure 2 shows the profile obtained after IV administration of abiraterone acetate solution (33% HP-β-cyclodextrin in water) at a dose of 10 mg / kg, IM administration of abiraterone acetate in castor oil (66 mg / ml) at a dose of 21 mg / kg, IM administration of abiraterone acetate in 10% benzyl alcohol in castor oil (91 mg / ml) at a dose of 30 mg / kg, and IM administration of abiraterone acetate in 50% benzyl benzoate in castor oil (124 mg / ml) at a dose of 42 mg / kg. [Diagram 3] 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) after IV administration of abiraterone acetate (administered at 10.3 mg / ml as a solution in 33% HP-β-cyclodextrin in water). [Figure 4] 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) after IM administration of abiraterone acetate in 10% benzyl alcohol in castor oil (91 mg / ml) at a dose of 30 mg / kg. [Diagram 5]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. Error bars represent standard deviation. [Figure 6] FIG. 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. Error bars represent standard deviation. [Figure 7] FIG. 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. [Figure 8] FIG. 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. [Figure 9] FIG. 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. [Figure 10] Figure 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. [Figure 11A] 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 Cmin value of approximately 8 ng / ml of abiraterone. [Figure 11B]1 shows exemplary predicted human abiraterone plasma concentrations following intramuscular administration of abiraterone decanoate according to computer modeling of 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 Cmin value of approximately 8 ng / ml of abiraterone. [Figure 11C] 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 Cmin value of approximately 8 ng / ml for abiraterone. [Figure 11D] 1 shows exemplary predicted human abiraterone plasma concentrations following intramuscular administration of abiraterone decanoate according to computer modeling of 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 Cmin value of approximately 8 ng / ml of abiraterone. [Figure 12A] 1 shows a representative X-ray powder diffraction (XRPD) spectrum of the abiraterone decanoate solid form prepared in Example 6A. [Figure 12B] FIG. 1 shows a differential scanning calorimetry (DSC) spectrum of the abiraterone decanoate solid form prepared in Example 6A. [Figure 12C] 1 shows a thermogravimetric analysis (TGA) of the abiraterone decanoate solid form prepared in Example 6A. [Figure 13A] 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. [Figure 13B] 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. [Figure 13C]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. [Figure 13D] Shown is the glide force (N) of an oil vehicle with no additives, 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. [Figure 13E] Shown is the glide force (N) of an oil vehicle with no additives, 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. [Figure 14A] FIG. 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 cynomolgus monkeys (n=3). [Figure 14B] Figure 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone decanoate following a single IM administration of abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 192 mg / ml abiraterone decanoate) at a dose of 90 mg / kg abiraterone decanoate to male cynomolgus monkeys (n=3). [Figure 14C] The observed time course data for steroid levels (progesterone, cortisol, and testosterone levels) following this single IM administration are shown in Figure 14C. As shown in Figure 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. [Figure 14D]14D 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. [Figure 14E] Figure 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. [Figure 14F] Figure 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 was 100 mg / kg. [Figure 15A] Figure 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). [Figure 15B]Figure 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone decanoate following a single IM administration of abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 172 mg / ml abiraterone decanoate) at a dose of 90 mg / kg of abiraterone decanoate to male rats (n=5). [Figure 15C] Figure 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, 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. [Figure 16A] Allometric scaling of the volume of distribution (Vss) of abiraterone in rats, dogs, and monkeys, and predicted in humans, is shown. [Figure 16B] 1 shows the predicted plasma profile of abiraterone in humans following a single intramuscular dose of 1 mg abiraterone based on 56% bioavailability. [Figure 16C] 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%. [Figure 16D] 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. [Figure 17A] 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. Error bars represent standard deviation. [Figure 17B] 1 shows time course data for mean plasma concentrations of abiraterone and abiraterone isocaproate following IM administration of abiraterone isocaproate to dogs. Error bars represent standard deviation. [Figure 17C]1 shows time course data for mean plasma concentrations of abiraterone and abiraterone decanoate following IM administration of abiraterone decanoate to dogs. Error bars represent standard deviation. [Figure 17D] FIG. 1 shows time course data for mean abiraterone plasma concentrations following IM administration of abiraterone isocaproate or abiraterone decanoate to dogs. Error bars represent standard deviation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0062] Detailed Description This disclosure is intended to subject The present invention relates to compounds and compositions that deliver therapeutic plasma levels of the potent abiraterone to patients with rheumatoid arthritis. Initial studies 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 extended periods of time when administered parenterally (e.g., intramuscularly).

[0063] 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, including improved bioavailability, elimination of the food effect associated with oral abiraterone acetate formulations, reduced dosing burden, improved patient compliance, reduced dosing frequency, maintenance of stable blood levels of potent drugs, and reduced associated side effects. max In some embodiments, methods of using the novel abiraterone prodrugs and formulations for treating, 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.

[0064] 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 pharma- ceutically acceptable salts thereof. TIFF0007644713000009.tif42128

[0065] Various groups are represented by R in formula I. 1 In some embodiments, R 1 may 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 , OR 10 or NHR 10 where R 10 is 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 Branched chain C5 or C6 alkyl such as TIFF0007644713000010.tif10128.

[0066] In some preferred embodiments, R 10 is C 7-30 As used herein, unless expressly stated to be substituted, alkyl is to be understood to be unsubstituted. However, alkyl may be either straight or branched. In some embodiments, R 10 is a linear C 7-30 In some embodiments, R 10 is a branched chain C 7-30 In some embodiments, R 10 is a linear C 7-16 alkyl, e.g., R10 is the formula -(CH2) n In some embodiments, R 10 is a branched chain C 7-16 It may be alkyl.

[0067] In some embodiments, R 10 may also be alkyl substituted with cycloalkyl. Typically, in such embodiments, R 10 has 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. Cycloalkyls are typically unsubstituted. However, in some embodiments, cycloalkyls can have, for example, one or two lower alkyls (e.g., C 1-4 In some embodiments, R 10 Typically, C 3-6 In some embodiments, R is an alkyl substituted with cycloalkyl. 10 is C 3-6 A linear alkyl substituted with a cycloalkyl, e.g., R 10 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, R 10 is the formula -(CH2) n -Cy, where n is 1 or 2, and Cy is cyclopentyl or cyclohexyl. 10 Also, C 3-6 Branched alkyl substituted with cycloalkyl (e.g., branched C 2-6 As used herein, a branched C2 alkyl group is to be understood as a 1,1-disubstituted ethyl group, e.g., CH(CH3)-Cy.

[0068] In some embodiments, R 10 may also be alkyl substituted with phenyl. Typically, in such embodiments, R 10 has a total of 7 to 16 carbons, in other words, the total number of carbons in the alkyl and phenyl portions is 5 to 16. In some embodiments, R 10 is a straight chain alkyl substituted with phenyl, e.g., R 10 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) and Cy is phenyl. 10 is the formula -(CH2) n -Cy, where n is 1 or 2 and Cy is phenyl. In some embodiments, R 10 Also includes branched alkyl substituted with phenyl (e.g., branched C 2-6 ). Phenyl is typically unsubstituted. However, in some embodiments, phenyl may be substituted with, for example, one or two lower alkyls (e.g., C 1-4 alkyl).

[0069] In some embodiments, R 10 may be cycloalkyl optionally substituted with one or more alkyl. In such embodiments, R 10 Typically, R 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 is unsubstituted or C 1-4 Alkyl-substituted C 3-6 In some particular embodiments, R 10 teeth, It may be TIFF0007644713000011.tif17128.

[0070] In some embodiments, R 10may be a branched C5 or C6 alkyl. In some embodiments, R 10 teeth, TIFF0007644713000012.tif10128. Other branched chain C5 or C6 alkyls are also suitable.

[0071] In some embodiments, R 10 is C 7-30 Alkenyl or C 7-30 It may be an unsaturated aliphatic group such as alkynyl.

[0072] In some preferred embodiments, the compound of formula I is an ester of abiraterone, e.g., R 1 is R 10 and R 10 is defined herein. In some embodiments, R in formula I 1 is C 7-16 For example, alkyl may be -(CH2) n -CH3, where n is an integer between 6 and 12 (e.g., 6, 7, 8, 9, 10, 11, or 12). 1 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6, and Cy is C 3-6 For example, in more specific embodiments, n can be 1 or 2, and Cy is cyclopentyl, cyclohexyl, or phenyl. 1 teeth In some particular embodiments, R in formula I may be 1 teeth It may be TIFF0007644713000014.tif17128. R 1 Other suitable groups of R are as defined herein. 10 Includes any of the following.

[0073] In some embodiments, R in formula I1 Also, OR 10 or NHR 10 R may be 10 is defined herein.

[0074] 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 mentioned as such a 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.

[0075] Compounds of formula I can be easily synthesized by those skilled in the art in view of the present disclosure. Exemplary syntheses of representative compounds are described in the Examples section. For example, typically, esters of formula I can be prepared by reacting abiraterone with the corresponding carboxylic acid, or with the corresponding activated form thereof, such as acyl chloride, anhydride, etc. Exemplary reaction conditions using activated forms, such as acyl chloride, are provided in the Examples section.

[0076] Abiraterone Prodrug Formulations The abiraterone prodrugs herein, including the compounds of formula I, require subject , for example, having a sex hormone-dependent benign or malignant disease as defined herein, a syndrome resulting from androgen excess, and / or a syndrome resulting from glucocorticoid excess, such as hypercortisolism. subject 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 extended periods of time, such as 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.

[0077] 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, for example, 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 in FDA-Approved Drugs Database of the Center for Drug Evaluation and Research of the U.S. Food and Drug Administration. In some embodiments, the pharmaceutically acceptable carrier may 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, as described in the United States Pharmacopeia. In some embodiments, the pharmaceutically acceptable carrier may be a pharmaceutically acceptable oil, e.g., 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), e.g., one that meets the criteria as described in the corresponding monographs of the United States Pharmacopeia. In some embodiments, the pharmaceutically 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 mono- or diglyceride of fatty acids, e.g., 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 long and / or medium chain fatty acids, which may be independently polyunsaturated, monounsaturated, or saturated. In some embodiments, two or more different pharma-ceutically 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-ceutically 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 recited ranges of values).

[0078] 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. TIFF0007644713000015.tif42128R in the formula 2is 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.

[0079] Various groups are represented by R in formula II. 2 In some embodiments, R 2 may be selected such that the compound of formula II is an ester, carbamate, or carbonate of abiraterone. 2 is R 20 , OR 20 or NHR 20 And R 20 is C 1-30 Alkyl;C 2-30 Alkenyl; C 2-30 is selected from 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.

[0080] In some preferred embodiments, R 20 is C 1-16 In some embodiments, R20 is a linear C 1-16 In some embodiments, R 20 is a branched chain C 3-16 In some embodiments, R 20 may be a branched C5 or C6 alkyl. In some embodiments, R 20 teeth, TIFF0007644713000016.tif10128. In some embodiments, R 20 is the formula -(CH2) n -CH3, 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).

[0081] In some embodiments, R 20 may also be alkyl substituted with cycloalkyl. Typically, in such embodiments, R 20 has a total of 4 to 30, e.g., 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). Cycloalkyls are typically unsubstituted. However, in some embodiments, cycloalkyls can have, for example, one or two lower alkyls (e.g., C 1-4 In some embodiments, R 20 Typically, C 3-6 In some embodiments, R is an alkyl substituted with cycloalkyl. 20 is C 3-6 A linear alkyl substituted with a cycloalkyl, e.g., R 20 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, R 20 is the formula -(CH2) n-Cy, where n is 1 or 2, and Cy is cyclopentyl or cyclohexyl. 20 Also, C 3-6 Branched alkyl substituted with cycloalkyl (e.g., branched C 2-6 ) may be.

[0082] In some embodiments, R 20 may also be alkyl substituted with phenyl. Typically, in such embodiments, R 20 has a total of 7 to 30 carbons, for example 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). 20 is a straight chain alkyl substituted with phenyl, e.g., R 20 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) and Cy is phenyl. 20 is the formula -(CH2) n -Cy, where n is 1 or 2 and Cy is phenyl. In some embodiments, R 20 Also includes branched alkyl substituted with phenyl (e.g., branched C 2-6 ). Phenyl is typically unsubstituted. However, in some embodiments, phenyl may be substituted with, for example, one or two lower alkyls (e.g., C 1-4 alkyl).

[0083] In some embodiments, R 20 may be cycloalkyl optionally substituted with one or more alkyl. In such embodiments, R 20 Typically, R has a total of 3 to 30 carbons, 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). 20 is unsubstituted or C 1-4 Alkyl-substituted C 3-6In some particular embodiments, R 20 teeth, It may be TIFF0007644713000017.tif17128.

[0084] In some embodiments, R 20 is C 2-30 Alkenyl or C 2-30 It may be an unsaturated aliphatic group such as alkynyl.

[0085] In some preferred embodiments, the compound of formula II is an abiraterone ester, e.g., R 2 is R 20 and R 20 is defined herein. In some embodiments, R in formula II 2 is C 1-16 For example, alkyl may be -(CH2) n -CH3, where n is an integer from 0 to 12. In some embodiments, R in Formula II 2 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6, and Cy is C 3-6 For example, in more specific embodiments, n can be 1 or 2, and Cy is cyclopentyl, cyclohexyl, or phenyl. 2 teeth, It may be TIFF0007644713000018.tif18128. R 2 Other suitable groups of R are as defined herein. 20In 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.

[0086] In some embodiments, R in formula II 2 Also, OR 20 or NHR 20 R may be 20 is defined herein.

[0087] 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 otherwise contradictory to the context, the compound of formula II may be in its basic form in the abiraterone prodrug formulations described herein.

[0088] Compounds of formula II can be easily synthesized by those skilled in the art in view of the present disclosure. Exemplary syntheses of representative compounds are described in the Examples section. For example, typically, esters of formula II can be prepared by reacting abiraterone with the corresponding carboxylic acid or with its own activated form, such as the corresponding acyl chloride, anhydride, etc. Exemplary reaction conditions using activated forms, such as acyl chloride, are provided in the Examples section.

[0089] 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 (not the aqueous suspension) of abiraterone acetate prodrugs 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, as 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, e.g., 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 long-chain and / or medium-chain fatty acids, 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, such as those listed in the FDA 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.

[0090] 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% of the solvent).

[0091] 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. Furthermore, 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.

[0092] 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.

[0093] 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.

[0094] Abiraterone prodrug formulations may also contain pharma- ceutically acceptable preservatives, polymers, antioxidants, antimicrobial agents, 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, dibasic potassium phosphate, docusate sodium, sodium edetate, glycerin, sodium hyaluronate, hydroxypropyl betadex, lactic acid, lactose, lecithin, maleic acid, mannitol, meglumine, methylcellulose, methylparaben, microcrystalline cellulose, miripitium chloride ... 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.

[0095] Abiraterone prodrug formulations may be sterilized by methods known to those of skill in the art (e.g., gamma irradiation, micron filtration, and autoclaving).

[0096] 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 used to treat patients in need thereof, such as those having, for example, sex hormone-dependent benign or malignant diseases, syndromes due to androgen excess, and / or syndromes due to glucocorticoid excess, such as hypercortisolism. subjectIn some embodiments, the abiraterone prodrugs and abiraterone prodrug formulations disclosed herein (e.g., formulations containing a compound of Formula I or II as described herein) are used to treat patients with hormone-dependent benign or malignant diseases, syndromes due to androgen excess, and / or syndromes due to glucocorticoid excess, such as hypercortisolism. subject The therapeutic range plasma levels of abiraterone 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 the patient. 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 can be about 0.5 ng / ml or greater.

[0097] 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 Figure 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 indicates that abiraterone acetate could be administered as a single injection over an extended period of time. subject This is meant to first demonstrate that it is possible to deliver abiraterone to a patient in need of treatment with a schizophrenia patient, thus allowing for administration less frequently, such as once per week to once more than once per week, for example, 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.

[0098] 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 the case 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 takes into account the appropriate 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).

[0099] Unit preparation 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 forms include: subject, For example, those with sex hormone-dependent benign or malignant diseases (e.g., metastatic castration-resistant or metastatic castration-sensitive prostate cancer), syndromes due to androgen excess, and / or syndromes due to glucocorticoid excess, such as hypercortisolism. subjectAfter a single administration (e.g., intramuscular injection) to the subject, the unit formulation is administered for a period of at least 2 weeks, such as at least 3 weeks, at least 4 weeks, at least 5 weeks, and up to 6 or 8 weeks or more. subject The therapeutic range plasma concentration of abiraterone may include a sufficient amount of the corresponding prodrug to provide a therapeutically effective plasma concentration of abiraterone at 1 ng / ml. 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 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 includes 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 dosage form can further comprise a pharma- ceutically acceptable solvent, e.g., an alcohol, an ester, and / or an acid, such as benzyl alcohol, benzyl benzoate, or combinations thereof. Other ingredients suitable for unit dosage forms include those described herein.

[0100] 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 administration 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, for example 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.

[0101] In some embodiments, the unit dosage form can be formulated to obtain a certain pharmacokinetic (PK) profile, for example a PK profile in which the curve is substantially flat after an initial period of increase. Typically, the unit dosage form is subject for the first few hours to several weeks (e.g., 5 days or 1 week) after administration. subject In some embodiments, after this initial period of increase, plasma concentrations of abiraterone in subject The plasma concentration of abiraterone in the patient may plateau and remain substantially constant for an extended period of time, for example, at least several days (eg, 2, 3, 4, 5, or 6 days) or at least one week, at least two weeks.

[0102] In some embodiments, the unit dosage form is suitable for and requires administration once a month (or more than once a month). subject After a single administration (e.g., intramuscularly) to a subject, 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 PK profile that is consistent for at least 4 weeks; subject (b) providing a therapeutically effective plasma concentration of abiraterone in a single dose 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); max (c) no food effect; (d) C of abiraterone observed at steady state when administered orally at 1000 mg Zytiga® once daily without food. max At least 30% lower C of a single dose of abiraterone compared to max (e) a C of a single dose of abiraterone of about 1 ng / ml to about 8 ng / ml, or greater than about 8 ng / ml, 28 days after administration. min (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 can 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 lack of food effect generally refers to the administration of the unit dosage form with or without food. subject It should be understood that no significant differences in PK are observed when administered in the fed or fasted state, e.g., in some embodiments, the lack of food effect refers to subject Between them, C of abiraterone max and AUC are substantially the same (e.g., 80% to 125%). max is untreated subject (Generally, patients should have not taken any abiraterone medication for at least 3 days, e.g., at least 1 week, prior to dosing and should have no observable abiraterone in their plasma prior to dosing. subject C achieved after a single dose to maxAs used herein, the C min That is, untreated subject By "minimum concentration" is meant the minimum concentration observed on a given day, e.g., 28 days after administration, following a single dose to the subject.

[0103] In some embodiments, the unit dosage form is suitable for and requires administration once a month (or more than once a month). subject After administration (e.g., intramuscularly) of the unit formulation once a month to a patient, the unit formulation achieves the following (a) to (g): (a) a steady-state C 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); max (b) no food effect; (c) C of abiraterone observed at steady state when administered orally at 1000 mg Zytiga® once daily without food. max At least 30% lower steady-state C of abiraterone compared to max (d) a steady-state C of abiraterone of about 1 ng / ml to about 8 ng / ml, or greater than about 8 ng / ml; min (g) the plasma concentration of abiraterone remains substantially constant after each administration, e.g., for at least one week, e.g., for one to three weeks. As used herein, steady-state C max or C min Typically, subject C observed after reaching a steady state after several doses to max or C min It should be understood that.

[0104] 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 is 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.

[0105] Specific prescription examples In some embodiments, the present disclosure also provides some specific abiraterone prodrug formulations, which in some embodiments may be unit formulations or multiple unit formulations. 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, the co-solvent is not included in the formulation. In some embodiments, the co-solvent does not include benzyl benzoate. Other optional ingredients are also described herein. (Table A) Prescription examples TIFF0007644713000019.tif129158

[0106] 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 TIFF0007644713000020.tif123158

[0107] 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); 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); 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); 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; etc. 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.

[0108] Treatment methods Some embodiments of the present disclosure require subject In various embodiments, the disclosure also provides methods of treating or preventing a disease or disorder in which administration of abiraterone is beneficial.

[0109] In some embodiments, the present disclosure requires subject The present invention provides a method for delivering abiraterone to a subject, the method comprising administering either an abiraterone prodrug or an abiraterone prodrug formulation of the present disclosure to a subject. subject In some embodiments, administering to subject The subject suffers from a sex hormone dependent benign or malignant disease, e.g., an androgen dependent or estrogen dependent disease, as described herein. In some embodiments, subject suffers from androgen excess syndrome and / or glucocorticoid excess syndrome, such as hypercortisolism, e.g., as described herein. In any of the embodiments described herein, unless directly contradicted, subject is human subject The subject may be, for example, a human patient having a hormone-dependent benign or malignant disease as described herein, a syndrome due to androgen excess, and / or a syndrome due to glucocorticoid excess, such as hypercortisolism. As used herein, a hormone-dependent benign or malignant disease, whether preceded by the term "sex", is to be understood as a sex hormone-dependent benign or malignant disease, such as an androgen-dependent or estrogen-dependent disease.

[0110] 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 Figure 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 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 resulting from high sex hormone levels, such as androgen and estrogen levels.

[0111] In some embodiments, the disclosure provides a method of inhibiting CYP17A1 activity, such as inhibiting 17α-hydroxylase activity and 17,20-lyase activity, the method comprising administering to a subject a subject an abiraterone prodrug or abiraterone prodrug formulation of the disclosure. subject In some embodiments, administering to subject The subject suffers from a sex hormone dependent benign or malignant disease, e.g., as described herein. In some embodiments, subject The patient suffers from, for example, androgen excess syndrome and / or glucocorticoid excess syndrome, such as hypercortisolism, as described herein.

[0112] In some embodiments, the present disclosure requires subjectand a method of reducing glucocorticoid (e.g., cortisol) levels comprising administering to a subject a therapeutically effective amount of an abiraterone prodrug or abiraterone prodrug formulation of the present disclosure. subject In some embodiments, administering to subject The patient suffers from a syndrome resulting from glucocorticoid excess, such as hypercortisolism, as described herein, such as Cushing's syndrome or Cushing's disease.

[0113] In some embodiments, the present disclosure requires subject and / or estrogen levels in a subject, the method comprising administering to the subject an abiraterone prodrug or abiraterone prodrug formulation of the present disclosure. subject In some embodiments, administering to subject 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. subject suffers from androgen and / or estrogen related cancer, such as prostate cancer or breast cancer.

[0114] 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 involve administering a therapeutically effective amount of any of the disclosed abiraterone prodrugs or abiraterone prodrug formulations to a subject in need thereof. subject In any of the embodiments described herein, unless directly contradicted, subject is human subject The subject may be, for example, a human patient having a 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.

[0115] Administration in the methods herein is not limited to any particular route. However, in some preferred embodiments, administration may be parenteral, such as intramuscular, intradermal, or subcutaneous injection. Parenteral administration may be advantageous in some embodiments. For example, in some embodiments, administration may be by: subject In some cases, the administration is parenteral, such as by intramuscular injection, which can be performed with or without food. subject It does not matter whether the dose is taken after a meal or on an empty stomach. This eliminates the restriction on the currently marketed Zytiga® formulation, which states that the drug "must be taken on an empty stomach, with water, at least one hour before a meal or two hours after a meal." Thus, among other benefits, the methods herein can also improve patient compliance.

[0116] Various 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 cancer. 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 resulting from androgen excess and / or glucocorticoid excess, such as hypercortisolism, including syndromes resulting from androgen excess, such as endometriosis, polycystic ovary syndrome, classical or non-classical congenital adrenal hyperplasia, precocious puberty, hirsutism, and / or syndromes resulting from cortisol excess, such as Cushing's syndrome and Cushing's disease, can also be treated by the methods herein.

[0117] The methods herein can be used in combination with one or more additional therapies for the corresponding disease or disorder. For example, the label for Zytiga® (abiraterone acetate) states that patients taking Zytiga® should 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, subject may be treated with gonadotropin releasing hormone analogs and / or bilateral orchiectomy. In some embodiments, the method also includes administering an effective amount of prednisone or prednisolone simultaneously or sequentially. subjectHowever, in some embodiments, the methods herein can also achieve the desired therapeutic effect without causing adrenal insufficiency, thereby avoiding the need to administer prednisone or prednisolone at the same time. subject is not treated with gonadotropin releasing hormone analogs and / or bilateral orchiectomy. subject is not treated with prednisone or prednisolone.

[0118] In some embodiments, the method includes administering one or more other drugs or agents (e.g., another cancer chemotherapy drug, a hormone replacement drug, or a hormone ablation drug) simultaneously or sequentially, through the same or different routes of administration. subject 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., 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).

[0119] 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.

[0120] 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, benfluron, benzotript, bromophosphamide, caracemide, carmethizole hydrochloride, chlorsulfaquinoxalone, clanfenur, claviridinone, crisnatol, claderm, cytarabine, cytocytin, dacarbazine, dateriptinium, dihematoporphyrin ether, dihydrolenperone, dinaline, distamycin, docetaxel, eliprabin , elliptinium acetate, epothilone, ergotamine, etoposide, etretinate, fenretinide, gallium nitrate, genquadaphnine, hexadecylphosphocholine, homoharringtonine, hydroxyurea, irmofosine, isoglutamine, isotretinoin, leukoregulin, lonidamine, mervalone, 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 alpha. vSuitable antimetabolites may be selected from, but are not limited to, 5-FU-fibrinogen, acantifolic acid, aminothiadiazole, brequinar sodium, carmofur, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine complex, 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 uricitin. 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, ermustine, 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, ditricarubicin B, dexamethasone, doxorubicin, doxorubicin-fibrinogen, elsamycin-A, epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-A1b, fostriecin, glidobactin, gregatin-A, The steroids 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.

[0121] Usage / Dosage The abiraterone prodrugs and formulations disclosed herein can generally provide a long-acting release profile of abiraterone to a target user, which can allow the target user to administer abiraterone less frequently, for example once a week or less, thereby improving patient compliance and reducing dosage burden.

[0122] In some embodiments, the methods herein may include weekly or more than weekly dosing. Typically, the dosing frequency can range from once a week to once every several months, e.g., once a week to once every 8 weeks, or once a week to once every 3 months. In some embodiments, the dose per dose is about 50 mg to about 2000 mg of abiraterone prodrug (e.g., about 500 mg, about 1000 mg, about 1500 mg, or any range of values ​​recited). ... subject In some embodiments, the method herein involves administering an abiraterone prodrug or abiraterone prodrug formulation of the present disclosure to a patient once a week or once every few weeks, e.g., once every two weeks, once a month, or once a month, of the patient's body weight in need thereof. subject wherein the administration results in a sustained period of time, such as for 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. subject In some embodiments, the administration results in a therapeutically effective plasma concentration of abiraterone in the blood (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). In some embodiments, the administration results in a C 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). max In some embodiments, the administration can result in a steady-state C 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). maxIn some embodiments, the administration can result in a C of a single dose 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 days 1-7, 1-14, 1-21, or 1-28 after administration. min In some embodiments, the administration can result in a steady-state C 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. min may result.

[0123] Suitable abiraterone prodrugs for use in the above once-weekly or more-than-weekly dosing regimen 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, such as a compound of formula I, in which R 1 is C 7-16 Alkyl, e.g., -(CH2) n -alkyl having the formula -CH3, where n is an integer between 6 and 12 (e.g., n is 6, 7, 8, 9, 10); 1 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6, and Cy is 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; R1 teeth, TIFF0007644713000021.tif10128; or R 1 teeth, In some embodiments, the abiraterone prodrug can be a compound of formula II, e.g., in formula II, R 2 is C 1-16 Alkyl, e.g., -(CH2) n -CH3, where n is an integer between 0 and 12; or R 2 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6, and Cy is C 3-6 cycloalkyl or phenyl, but for example, in more specific embodiments, n can be 1 or 2 and Cy is cyclopentyl, cyclohexyl, or phenyl; R 2 teeth, TIFF0007644713000023.tif18128. 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 specific 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.

[0124] In some embodiments, a dosing frequency of once a month or more than once a month is preferred, for example, once a month to once every few months, for example, once a month to once every two months, or once a month to once every three months. In such embodiments, the abiraterone prodrug must not only release abiraterone slowly, but also release abiraterone at sufficient plasma concentrations to be beneficial to the intended user. The once a month or more than once a month dosing is typically parenteral, such as intramuscular, intradermal, or subcutaneous. In any of the embodiments herein, unless directly contradicted, the dosing may be intramuscular.

[0125] 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 PK study in dogs, 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.Moreover, it was unexpectedly found that the extension of the alkyl chain to abiraterone butanoate leads 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. Certain abiraterone prodrugs or abiraterone prodrug formulations of the present disclosure, e.g., t 1 / 2 It was also found that the PK profiles of such drugs did not change significantly when different oil vehicles were used. In contrast, as detailed in Example 5B, some variability in the PK profile was observed for abiraterone propionate depending on whether it was formulated in castor oil or corn oil.

[0126] In some specific embodiments, the present disclosure requires subject The present invention provides a method for 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, the method comprising administering to the subject 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), once a month or more than once a month. subject In some preferred embodiments, parenteral administration is intramuscular, intradermal, or subcutaneous. In some preferred embodiments, in the compound of formula I, R 1 is C 7-16 Alkyl, e.g., -(CH2) n -alkyl having the formula -CH3, where n is an integer between 6 and 12 (e.g., n is 6, 7, 8, 9, or 10); 1 is the formula -(CH2) n -Cy, where n is an integer of 1 to 6, and Cy is 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 teeth, TIFF0007644713000024.tif10128; or R 1 teeth, In some embodiments, the administration provides a therapeutic effect for a period of at least 4 weeks, such as at least 5 weeks, and up to 6 or 8 weeks or more. subjectIn 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 therapeutically effective plasma concentration of abiraterone may also be about 0.5 ng / ml or greater. In some embodiments, the administration results in a single dose C 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). max In some embodiments, the administration can result in a steady-state C 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). max In some embodiments, the administration can result in a C of a single dose 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, 28 days after administration. min In some embodiments, the administration can result in a steady-state C 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. min In some embodiments, subject The plasma concentration of abiraterone in the subject can remain substantially constant, for example, for at least one week, e.g., one to three weeks, after administration. subject is performed with or without food. In some embodiments, the administration reduces the C of abiraterone observed at steady state when 1000 mg of Zytiga® is administered orally once daily without food. max At least 30% lower C of a single dose of abiraterone compared to max In some embodiments, the administration reduces the C of abiraterone observed at steady state when 1000 mg of Zytiga® is administered orally once daily without food. maxAt least 30% lower steady-state C of abiraterone compared to max In some embodiments, the pharmaceutical composition comprising the 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.

[0127] The abiraterone prodrugs and abiraterone prodrug formulations disclosed herein are intended to be used as a sole source of abiraterone and are therefore not intended to be used as a sole source of abiraterone. subject However, in some embodiments, other abiraterone drugs / formulations are not excluded. For example, in some embodiments, administration herein can be combined with oral administration of abiraterone acetate, such as the Zytiga® formulation, either simultaneously or sequentially in any order. In some embodiments, subject can use abiraterone prodrugs and abiraterone prodrug formulations as a supplement to existing abiraterone therapy. Furthermore, 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 prodrugs and abiraterone prodrug formulations of the present disclosure are administered in combination. subject It can be administered to

[0128] 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.

[0129] As discussed herein, the abiraterone prodrug and abiraterone prodrug formulations of the present disclosure have many advantages over the currently marketed Zytiga® product. For example, the abiraterone prodrug and abiraterone prodrug formulations of the present disclosure subject Administration of abiraterone to max (e.g., C of abiraterone observed at steady state when administered orally at 1000 mg Zytiga® once daily without food) max (at least 30% lower compared to

[0130] Thus, in some embodiments, the present disclosure provides, for example, the C max Side effects associated with high abiraterone exposure, including side effects associated with subject The present invention provides a method for treating an inflammatory bowel disorder, the method comprising administering the abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure to an inflammatory bowel disorder. subject to the rectum, which results in reduced side effects compared to oral administration of 1000 mg of Zytiga® 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, e.g., February 2018 or June 2019 editions). In some embodiments, the present disclosure relates to a method of administering abiraterone to a patient in need of treatment with abiraterone, where a substrate drug for CYP2D6 and / or CYP2C8, whose metabolism is inhibited by abiraterone, is also administered. subject The present invention provides a method for treating an inflammatory bowel disorder, the method comprising administering the abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure to an inflammatory bowel disorder. subject to a patient with, or at risk of having, fluid retention due to hypertension, hypokalemia, or mineralocorticoid excess, which results in less inhibition of drug metabolism compared to oral administration of 1000 mg of Zytiga® once daily without food. subjectThe present invention provides a method for treating an inflammatory bowel disorder, the method comprising administering the abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure to an inflammatory bowel disorder. subject to reduce hypertension, hypokalemia, and fluid retention, or reduce 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 for treating adrenal insufficiency in a subject who has or is likely to have adrenal insufficiency. subject The present invention provides a method for treating an inflammatory bowel disorder, the method comprising administering the abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure to an inflammatory bowel disorder. subject to reduce the likelihood of having adrenal insufficiency or adrenal insufficiency compared to administering 1000 mg of Zytiga® orally once daily without food. In some embodiments, the present disclosure provides a method for treating or preventing severe or fatal liver toxicity after taking Zytiga®. subject The present invention provides a method for treating an inflammatory bowel disorder, the method comprising administering the abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure to an inflammatory bowel disorder. subject Without wishing to be bound by theory, administration of the abiraterone prodrugs and abiraterone prodrug formulations disclosed herein typically results in reduced, yet effective, exposure to abiraterone, thus reducing the need for lower doses of abiraterone, for example as described above. subject Suitable dosage regimens and routes of administration include those described herein.

[0131] Abiraterone Decanoate Some embodiments of the present disclosure are specifically 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 prolonged period 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, after intramuscular administration of abiraterone decanoate in humans once every 4 weeks at doses of about 1000 mg, C min was predicted to be expected to be 5 ng / mL at steady state. In addition, as detailed in the Examples section and FIG. 14F, it was 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, which has substantially the same abiraterone decanoate concentration. Thus, the predicted C of 5 ng / mL at steady state was expected to be expected to be 5 ng / mL at steady state. In addition, as detailed in the Examples section and FIG. 14F, it was 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, which has substantially the same abiraterone decanoate concentration. min It is possible to reduce the dose of abiraterone decanoate required to achieve a steady-state C min to a predicted level of greater than 5 ng / mL. These disclosures suggest that abiraterone can be administered by injecting an abiraterone prodrug, such as an abiraterone lipophilic ester prodrug, and more particularly, by injecting abiraterone decanoate in doses less than weekly, e.g., once every two weeks, once a month, or more than once a month. subject (e.g., human subjectTypically, the frequency of administration can range from once a week to once every several months, e.g., once a week to once every 8 weeks, or once a week to once every 3 months, e.g., once a month, once every 8 weeks, etc.

[0132] In some particular embodiments, the present disclosure provides a compound of formula The present invention provides a compound that is abiraterone decanoate or a pharma- ceutically acceptable salt thereof, having a TIFF0007644713000026.tif35128. In some embodiments, abiraterone decanoate may be in its base form. In some embodiments, abiraterone decanoate may be in a pharma- ceutically 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 inconsistent with the context, abiraterone decanoate should be understood to be in its base form.

[0133] Abiraterone decanoate or its pharma- ceutically acceptable salts can be readily prepared by those skilled in the art in light of the present disclosure. Some representative synthesis methods are described herein. In some embodiments, the present disclosure provides a method for synthesizing abiraterone decanoate, which comprises 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.

[0134] 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) 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 at 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 the same as that shown in Figure 12A, e.g., an XRPD spectrum showing peaks at each diffraction angle (angle 2Θ, ±0.2°) corresponding to the peaks shown in Figure 12A, regardless of their relative intensities. In some embodiments, the crystalline form may be characterized by a DSC spectrum substantially the same as that shown in Figure 12B.

[0135] In some embodiments, the present 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 heating (e.g., about 40° C.) to form a solution; the solution can then be cooled to form a suspension, which can optionally be followed by diluting the suspension with a second solvent, such as water (typically a poor solvent in which abiraterone decanoate has low solubility), and stirring for a period of time (e.g., about 12 hours) to form a crystalline form. The amount, concentration, etc. of the solvent can be adjusted by those skilled in the art in view of the present disclosure. An exemplary procedure is also shown in Example 6A.

[0136] Abiraterone decanoate is typically prepared in a form of high purity suitable for, for example, pharmaceutical use. In some embodiments, the present disclosure provides a substantially pure form of abiraterone decanoate, 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 can be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, by weight and / or by HPLC area ratio, or any range of values ​​specified. For example, in some embodiments, abiraterone decanoate can be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, by weight, or any range of values ​​specified. 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, the abiraterone prodrug formulations comprising substantially pure abiraterone decanoate and one or more other components herein should be understood to be mixtures of substantially pure abiraterone decanoate herein with one or more other components, e.g., such formulations can 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 pharma- ceutically acceptable oils, solvents, etc.

[0137] In some particular embodiments, the present disclosure provides a compound of formula The present invention provides a pharmaceutical composition comprising abiraterone decanoate having a TIFF0007644713000027.tif35128, 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.

[0138] 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.

[0139] The pharmaceutical composition is generally a non-aqueous formulation, e.g., an oil-based formulation, and includes a non-aqueous pharma- ceutically acceptable carrier (e.g., as described herein). For example, in some embodiments, the pharma-ceutically acceptable carrier includes a pharma-ceutically acceptable oil, e.g., an injectable pharma-ceutically acceptable oil, including a plant-derived oil or a synthetic mono- or diglyceride of a fatty acid. 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 includes a triglyceride derived from a fatty acid. In some embodiments, the pharma-ceutically acceptable carrier includes a triglyceride derived from a long-chain and / or medium-chain fatty acid, 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.

[0140] 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, an ester, or an 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- ceutical acceptable oil.

[0141] 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, the benzyl alcohol is present in an amount of about 5-10% by volume, the benzyl benzoate is present in an amount of about 10-20% by volume, and the 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%.

[0142] 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.

[0143] 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 is used to treat a disease or disorder characterized by a sex hormone-dependent benign or malignant disorder, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolism. subject Abiraterone 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. subject The abiraterone 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, 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. subjectThe abiraterone may be present in the pharmaceutical composition in an amount sufficient to provide a therapeutically effective plasma concentration of about 0.5 ng / ml or greater for a period of at least 4 weeks, e.g., at least 6 weeks and up to 8 weeks or more, following a single administration to the subject.

[0144] In some particular embodiments, the present disclosure provides a compound of formula The present invention provides a pharmaceutical composition, e.g., a unit dosage form, comprising a therapeutically effective amount of abiraterone decanoate having a TIFF0007644713000028.tif35128, a pharma- ceutically acceptable oil, and a pharma-ceutically acceptable solvent, wherein the abiraterone decanoate is at a concentration 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, about 600 mg / ml, about 700 mg / ml, about 800 mg / ml, about 900 mg / ml, about 1000 mg / ml, about 150 mg / ml, about 2 ...250 mg / ml, about 300 mg / ml, about 400 mg / ml, about 500 mg / ml, about 600 mg / ml, about 700 mg / ml, about 800 mg / ml, about 900 mg / ml, about 1000 mg / ml, about 150 mg / ml, about 200 mg / ml, about 350 mg / ml, about 400 mg / ml, about 500 mg / ml, about 600 mg / ml, about 1000 mg / ml, about 15 The pharmaceutical composition, e.g., a unit dosage form, is formulated for parenteral injection, such as intramuscular, intradermal, or subcutaneous injection, and the pharmaceutical composition, e.g., a unit dosage form, contains 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 dosage form. Typically, one or more (e.g., one) of the unit dosage forms may be administered in a single dose, depending on the dosage required. subjectThe pharma- ceutical composition, e.g., a unit dosage form, may be administered to the patient. The pharma- ceutical acceptable oil in the pharmaceutical composition may be any of those described herein. For example, in some embodiments, the pharma- ceutical acceptable oil is an injectable pharma- ceutical acceptable oil, including vegetable-derived oils or synthetic mono- or diglycerides of fatty acids. In some embodiments, the pharma-ceutical 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-ceutical acceptable oil may include triglycerides derived from fatty acids. In some embodiments, the pharma-ceutical acceptable oil may include triglycerides derived from long- and / or medium-chain fatty acids, which may be independently polyunsaturated, monounsaturated, or saturated. In some embodiments, the pharma-ceutical acceptable oil may be selected from vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil (groundnut oil), poppy seed oil, tea seed oil, and soybean oil. In some particular embodiments, the pharma- ceutically acceptable oil can include corn oil, which contains triglycerides whose fatty acid components are primarily linoleic, oleic, palmitic, and stearic acids. Also, the pharma- ceutical composition, e.g., a unit dosage form, can include any of those described herein. In some embodiments, the pharma- ceutical acceptable solvent (or co-solvent, if oil is considered a solvent) is an alcohol, ester, acid, or the like. In some embodiments, the pharma- ceutical 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, can include abiraterone decanoate, a pharma- ceutical acceptable oil (e.g., as described herein), benzyl alcohol, and benzyl benzoate. In some embodiments, the pharma- ceutical composition 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 total amounts of benzyl alcohol, benzyl benzoate, and corn oil being 100%.

[0145] 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 DECANATE FORMULATIONS TIFF0007644713000029.tif117163

[0146] The pharmaceutical compositions or unit dosage forms herein can be prepared by those skilled in the art in view of the methods disclosed herein. In some embodiments, the present disclosure relates to a method for treating or preventing a patient having a sex hormone-dependent benign or malignant disease, syndrome due to androgen excess, and / or syndrome due to glucocorticoid excess, such as hypercortisolism. subject In some embodiments, the method includes preparing an abiraterone decanoate formulation suitable for parenteral administration to a subject. and mixing (e.g., dissolving or suspending) abiraterone decanoate with TIFF0007644713000030.tif35128 to form a mixture (e.g., a solution or suspension). In some embodiments, the method further includes sterilizing the mixture (e.g., a solution or suspension). In some embodiments, the dissolving or suspending may include 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 include 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.

[0147] In some specific 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, which method involves administering a therapeutically effective amount of a pharmaceutical composition (e.g., a unit dosage form as described herein) comprising abiraterone decanoate as described herein. subjectAdministration 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, pharmaceutical compositions comprising abiraterone decanoate described herein (e.g., unit dosage forms described herein) can be administered with or without food. subject It can be administered to

[0148] 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 are directed to treating conditions resulting from androgen excess, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), precocious puberty, and hirsutism. subject 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.

[0149] The methods herein can be used in combination with one or more additional therapies for the corresponding disease or disorder. For example, the methods can be used in combination with one or more other drugs or agents (e.g., another cancer chemotherapy drug, a hormone replacement drug, or a hormone ablation drug, etc., as described herein), either simultaneously or sequentially, through the same or different routes of administration. subject In some embodiments, administering to subject It may also be treated with gonadotropin releasing hormone analogs and / or bilateral orchiectomy.

[0150] 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.

[0151] In some embodiments, the methods herein (e.g., treating prostate cancer or treating classical or non-classical congenital adrenal hyperplasia) include administering an agent that counteracts the reduction in glucocorticoid(s) associated with administration of abiraterone decanoate as described herein. subject In some embodiments, the method includes administering to a patient in need thereof an agent effective to treat one or more symptoms associated with adrenal insufficiency, such as acute stress, fatigue, etc. subject In some particular embodiments, the methods include administering a steroid, such as a corticosteroid, to subjectIn some embodiments, the method includes administering a glucocorticoid to subject In some particular embodiments, the method also includes administering prednisone, prednisolone, and / or methylprednisolone to subject In some embodiments, the method also includes administering to the subject a drug effective for treating cortisol deficiency, such as hydrocortisone, prednisone, prednisolone, methylprednisolone, and / or dexamethasone. subject In any such embodiment, the agents can be administered simultaneously or sequentially, in any order, via the same route of administration or different routes of administration. subject It can be administered to

[0152] 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 several 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 involve administering a pharmaceutical composition comprising abiraterone decanoate (e.g., a unit dosage form as described herein) once a week, once every two weeks, once every three weeks, once a month, or more than once a month. subject In some embodiments, the method includes administering a pharmaceutical composition (e.g., a unit dosage form described herein) comprising abiraterone decanoate to a patient once every two weeks, once a month, or more than once a month. subject In some embodiments, the dose 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 dose of abiraterone decanoate per dose is subjectThe dose is from about 0.5 mg / kg to about 100 mg / kg of 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 results in a therapeutically effective plasma concentration of abiraterone for 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 plasma concentration of abiraterone of greater than 1.0 ng / ml (e.g., 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) for 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 of abiraterone of greater than 1.0 ng / ml (e.g., 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). min In some embodiments, the administration results in a single dose or steady state C 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. max In some embodiments, the abiraterone decanoate formulation provides a therapeutically effective amount of abiraterone that is sufficient to meet the needs of patients with abiraterone-deficient individuals. subject However, in some embodiments, the abiraterone decanoate formulation may also be administered as a supplement to another abiraterone therapy, if required. subject It can be administered to

[0153] In some specific examples, the disclosure provides methods of treating prostate cancer, which involve administering abiraterone decanoate 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). subject In some embodiments, abiraterone decanoate is administered via intramuscular injection. In some embodiments, the prostate cancer is castration-resistant or castration-sensitive prostate cancer. In some embodiments, the prostate cancer is metastatic castration-resistant or metastatic castration-sensitive prostate cancer.

[0154] In some specific examples, the disclosure provides a method of treating prostate cancer, the method comprising administering to a patient 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 patient receiving 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), subject and administering to a subject in need thereof 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, e.g., once a month or more than once a month, at 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) of body weight of the subject in need thereof. subject In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the prostate cancer is castration-resistant or castration-sensitive prostate cancer. In some embodiments, the prostate cancer is metastatic castration-resistant or metastatic castration-sensitive prostate cancer.

[0155] In some specific examples, the disclosure provides a method of treating prostate cancer, the method comprising administering to a patient 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 patient receiving 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), subject and administering to a subject in need thereof a unit formulation described herein via intramuscular, intradermal, or subcutaneous injection at 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) of body weight of the subject in need thereof once a week or more than once a week, e.g., once a month or more than once a month. subject 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.

[0156] In some specific embodiments, the present disclosure also requires subject Also provided are methods of delivering abiraterone to a patient, the methods comprising administering abiraterone decanoate to a patient in a dose range 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 in a dose range of about 10 ... subject and administering to a subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) at about 0.5 mg / kg to about 100 mg / kg of 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) once a week or more than once a week, e.g., once a month or more than once a month, via intramuscular, intradermal, or subcutaneous injection. subjectIn some embodiments, the pharmaceutical composition is administered via intramuscular injection. subject The patient suffers from, for example, a hormone-dependent benign or malignant disease, a syndrome resulting from androgen excess, and / or a syndrome resulting from glucocorticoid excess, such as hypercortisolism, as described herein.

[0157] In some specific embodiments, the present disclosure also requires subject Also provided is a method of inhibiting CYP17A1 activity in a subject, 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 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), subject and administering to a subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) at about 0.5 mg / kg to about 100 mg / kg of 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) once a week or more than once a week, e.g., once a month or more than once a month, via intramuscular, intradermal, or subcutaneous injection. subject In some embodiments, the pharmaceutical composition is administered via intramuscular injection. subject The subject suffers from a sex hormone dependent benign or malignant disease, e.g., as described herein. In some embodiments, subject The patient suffers from, for example, androgen excess syndrome and / or glucocorticoid excess syndrome, such as hypercortisolism, as described herein.

[0158] In some specific embodiments, the present disclosure also requires subjectAlso provided is a method for reducing glucocorticoid (e.g., cortisol) levels in a patient, the method comprising administering to a patient 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 a dose of abiraterone decanoate of about 100 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), subject and administering to a subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) at about 0.5 mg / kg to about 100 mg / kg of 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) once a week or more than once a week, e.g., once a month or more than once a month, via intramuscular, intradermal, or subcutaneous injection. subject In some embodiments, the pharmaceutical composition is administered via intramuscular injection. subject The subject suffers from hypercortisolism as described herein, such as Cushing's syndrome or Cushing's disease.

[0159] In some specific embodiments, the present disclosure also requires subject Also provided is a method for reducing androgen (e.g., testosterone and / or dihydrotestosterone) and / or estrogen levels in a subject, 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 100 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), subjectand administering to a subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) at about 0.5 mg / kg to about 100 mg / kg of 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) once a week or more than once a week, e.g., once a month or more than once a month, via intramuscular, intradermal, or subcutaneous injection. subject In some embodiments, the pharmaceutical composition is administered via intramuscular injection. subject 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. subject suffers from androgen and / or estrogen related cancer, such as prostate cancer or breast cancer.

[0160] Other abiraterone prodrugs Although 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.

[0161] 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, which method involves administering a therapeutically effective amount of a pharmaceutical composition (e.g., a unit dosage form as described herein) comprising abiraterone isocaproate as described herein. subject In some embodiments, the pharmaceutical compositions comprising abiraterone isocaproate described herein (e.g., unit dosage forms described herein) can be administered with or without food. subject Suitable sex hormone dependent benign or malignant disorders, syndromes resulting from androgen excess, syndromes resulting from glucocorticoid excess such as hypercortisolism, dosage regimens, co-treatments, etc. include those described herein relating to, for example, abiraterone decanoate.

[0162] In some specific examples, the disclosure provides a method of treating prostate cancer, the method comprising administering to a patient a dose of abiraterone isocaproate in an amount 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 in which each dose of abiraterone isocaproate is about 100 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), subject and administering to a subject in need thereof a pharmaceutical composition comprising abiraterone isocaproate as described herein via intramuscular, intradermal, or subcutaneous injection at 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) of body weight of a subject in need thereof once a week or more than once a week, for example once a month or more than once a month. subject In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the prostate cancer is castration-resistant or castration-sensitive prostate cancer. In some embodiments, the prostate cancer is metastatic castration-resistant or metastatic castration-sensitive prostate cancer.

[0163] In some specific examples, the disclosure provides a method of treating prostate cancer, the method comprising administering to a patient a dose of abiraterone isocaproate in an amount 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 in which each dose of abiraterone isocaproate is about 100 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), subject and administering to a subject in need thereof a unit formulation comprising abiraterone isocaproate as described herein via intramuscular, intradermal, or subcutaneous injection at 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) of body weight once a week or more than once a week, for example once a month or more than once a month. subject 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.

[0164] In some specific embodiments, the present disclosure also requires subject Also provided are methods of delivering abiraterone to a patient, the methods comprising administering abiraterone isocaproate in 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 in a dose of abiraterone isocaproate in a dose of about 100 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), subjectand administering to a subject a pharmaceutical composition comprising abiraterone isocaproate as described herein (e.g., a unit dosage form as described herein) at about 0.5 mg / kg to about 100 mg / kg of 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) once a week or more than once a week, e.g., once a month or more than once a month, via intramuscular, intradermal, or subcutaneous injection. subject In some embodiments, the pharmaceutical composition is administered via intramuscular injection. subject The patient suffers from, for example, a hormone-dependent benign or malignant disease, a syndrome resulting from androgen excess, and / or a syndrome resulting from glucocorticoid excess, such as hypercortisolism, as described herein.

[0165] In some specific embodiments, the present disclosure also requires subject Also provided is a method of inhibiting CYP17A1 activity in a subject, the method comprising administering to a subject a dose of abiraterone isocaproate 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 isocaproate 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), subject and administering to a subject a pharmaceutical composition comprising abiraterone isocaproate as described herein (e.g., a unit dosage form as described herein) at about 0.5 mg / kg to about 100 mg / kg of 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) once a week or more than once a week, e.g., once a month or more than once a month, via intramuscular, intradermal, or subcutaneous injection. subject In some embodiments, the pharmaceutical composition is administered via intramuscular injection. subjectThe subject suffers from a sex hormone dependent benign or malignant disease, e.g., as described herein. In some embodiments, subject The patient suffers from, for example, androgen excess syndrome and / or glucocorticoid excess syndrome, such as hypercortisolism, as described herein.

[0166] In some specific embodiments, the present disclosure also requires subject Also provided is a method for reducing glucocorticoid (e.g., cortisol) levels in a patient, the method comprising administering to a patient a dose of abiraterone isocaproate 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 a dose of abiraterone isocaproate 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), subject and administering to a subject a pharmaceutical composition comprising abiraterone isocaproate as described herein (e.g., a unit dosage form as described herein) at about 0.5 mg / kg to about 100 mg / kg of 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) once a week or more than once a week, e.g., once a month or more than once a month, via intramuscular, intradermal, or subcutaneous injection. subject In some embodiments, the pharmaceutical composition is administered via intramuscular injection. subject The subject suffers from hypercortisolism as described herein, such as Cushing's syndrome or Cushing's disease.

[0167] In some specific embodiments, the present disclosure also requires subjectAlso provided is a method for reducing androgen (e.g., testosterone and / or dihydrotestosterone) and / or estrogen levels in a subject, the method comprising administering to a subject a dose of abiraterone isocaproate 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 isocaproate is about 100 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), subject and administering to a subject a pharmaceutical composition comprising abiraterone isocaproate as described herein (e.g., a unit dosage form as described herein) at about 0.5 mg / kg to about 100 mg / kg of 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) once a week or more than once a week, e.g., once a month or more than once a month, via intramuscular, intradermal, or subcutaneous injection. subject In some embodiments, the pharmaceutical composition is administered via intramuscular injection. subject 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. subject suffers from androgen and / or estrogen related cancer, such as prostate cancer or breast cancer.

[0168] Non-Limiting Exemplary Embodiments In some embodiments, the present disclosure also provides non-limiting exemplary embodiments 1-66, as set forth below.

[0169] Embodiment 1. Having a hormone-dependent benign or malignant disease subject 1. An abiraterone prodrug formulation suitable for parenteral administration to (a) one or more lipophilic ester forms of abiraterone, and (b) containing one or more pharma- ceutically acceptable carriers, diluents, or excipients; The above subject wherein, upon said administration to a subject, the abiraterone prodrug formulation achieves a therapeutic plasma concentration of abiraterone.

[0170] Embodiment 2. The abiraterone prodrug formulation of embodiment 1, wherein the therapeutic plasma concentration of abiraterone is at least 1.0 ng / ml.

[0171] Embodiment 3. The abiraterone prodrug formulation of embodiment 1, wherein the therapeutic plasma concentration of abiraterone is at least 8 ng / ml.

[0172] Embodiment 4. The abiraterone prodrug formulation of embodiment 1, wherein the therapeutic plasma concentration of abiraterone is sustained for at least two weeks.

[0173] Embodiment 5. The abiraterone prodrug formulation of embodiment 1, wherein said parenteral administration is selected from the group consisting of intramuscular injection, intradermal injection, and subcutaneous injection.

[0174] 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, bucyclate, cyclohexanecarboxylate, phenylpropionate, decanoate, and undecanoate.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] Embodiment 10. A method of treating a hormone-dependent benign or malignant disease, comprising administering an effective dose of at least one abiraterone prodrug formulation to a patient in need of such treatment. subject and parenterally administering the abiraterone prodrug formulation to (a) one or more lipophilic ester forms of abiraterone, and (b) containing 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.

[0179] Embodiment 11. The method of embodiment 10, wherein the therapeutic plasma concentration of abiraterone is at least 1.0 ng / ml.

[0180] Embodiment 12. The method of embodiment 10, wherein the therapeutic plasma concentration of abiraterone is at least 8.0 ng / ml.

[0181] Embodiment 13. The method of embodiment 10, wherein the therapeutic plasma concentration of abiraterone is sustained for at least 2 weeks.

[0182] 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.

[0183] 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, bucyclate, cyclohexanecarboxylate, phenylpropionate, decanoate and undecanoate.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] Embodiment 19. The method of embodiment 10, wherein the method further comprises monthly administration of the at least one abiraterone prodrug formulation.

[0188] Embodiment 20. The method of embodiment 10, wherein the at least one abiraterone prodrug formulation is administered in divided doses.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] Embodiment 24. A kit for treating a hormone-dependent benign or malignant disease according to embodiment 10, comprising at least one abiraterone prodrug formulation.

[0193] Embodiment 25. Having a hormone-dependent benign or malignant disease subject 1. A method for preparing an abiraterone decanoate formulation suitable for parenteral administration to a subject, 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; The method comprising:

[0194] Embodiment 26. The prepared and purified abiraterone decanoate has LCMS m / z 504.4 (M+H); 1H NMR (CDCl3, 200MHz): 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 26. The method of embodiment 25, wherein the compound has the chemical properties of: 8.617 (1H, dd, J = 1,2 Hz), 8.617 (1H, dd, J = 1,2 Hz).

[0195] 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.

[0196] Embodiment 28. A compound of formula I, or a pharma- ceutically acceptable salt thereof, TIFF0007644713000031.tif42128In formula, R 1 is R 10 , OR 10 , or NHR 10 and R 10 teeth, 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 TIFF0007644713000032.tif10128, or a pharma- ceutically acceptable salt thereof.

[0197] Embodiment 29. The R 10 is C 7-16 The compound according to embodiment 28, or a pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0198] Embodiment 30. The R 10 is a compound with a total of 6 to 12 carbon atoms, 3-6 29. The compound according to embodiment 28, wherein the alkyl is substituted with cycloalkyl; or a pharma- ceutically acceptable salt thereof.

[0199] Embodiment 31. The R 1 is C 7-16 The compound according to embodiment 28, or a pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0200] Embodiment 32. The R 1 is the formula -(CH2) n Compounds according to embodiment 28, wherein n is an alkyl having -CH3, wherein n is an integer from 6 to 12, for example 6, 7, 8, 9, 10, 11, or 12; and pharma- ceutically acceptable salts thereof.

[0201] Embodiment 33. The R 1 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6, and Cy is C 3-6 The compound according to embodiment 28, wherein R is cycloalkyl or phenyl; or a pharma- ceutically acceptable salt thereof.

[0202] Embodiment 34. The compound according to embodiment 33, wherein n is 1 or 2 and Cy is cyclopentyl, cyclohexyl, or phenyl. Or a pharma- ceutically acceptable salt thereof.

[0203] Embodiment 35. The R 1 teeth, TIFF0007644713000033.tif10128 or a pharma- ceutically acceptable salt thereof.

[0204] Embodiment 36. The R 1 teeth, TIFF0007644713000034.tif17128 or a pharma- ceutically acceptable salt thereof.

[0205] Embodiment 37. A pharmaceutical composition comprising a compound according to any one of embodiments 28 to 36 or a pharma- ceutically acceptable salt thereof.

[0206] Embodiment 38. The pharmaceutical composition of embodiment 37, which is formulated for parenteral administration.

[0207] Embodiment 39. The pharmaceutical composition of embodiment 38, which is formulated for intramuscular, intradermal, or subcutaneous injection.

[0208] Embodiment 40. The pharmaceutical composition of embodiment 37, further comprising a pharma- ceutically acceptable carrier.

[0209] 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 mono- or diglyceride of a fatty acid.

[0210] Embodiment 42. The pharmaceutical composition of embodiment 40 or 41, further comprising a pharma- ceutically acceptable solvent, for example, benzyl alcohol.

[0211] Embodiment 43. A pharmaceutical composition according to any one of embodiments 37 to 42, which is a non-aqueous solution or suspension.

[0212] Embodiment 44. A pharmaceutical composition comprising a compound of formula II or a pharma- ceutically acceptable salt thereof, TIFF0007644713000035.tif42128In formula, R 2 is R 20 , OR 20 , or NHR 20 and R 20 teeth, C 1-30 Alkyl;C 2-30 Alkenyl; C 2-30 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 in a concentration of about 25 mg / ml to about 500 mg / ml.

[0213] Embodiment 45. R in Formula II 2 is C 1-16 The pharmaceutical composition of embodiment 44, wherein the alkyl group is selected from the group consisting of 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; and cycloalkyl optionally substituted with one or more alkyl having a total of 5 to 16 carbon atoms.

[0214] Embodiment 46. R in Formula II 2 is the formula -(CH2) n The pharmaceutical composition according to embodiment 44, wherein n is an alkyl having —CH3, wherein n is an integer from 0 to 12.

[0215] Embodiment 47. R in Formula II 2 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6, and Cy is C 3-6 The pharmaceutical composition according to embodiment 44, wherein R is cycloalkyl or phenyl.

[0216] Embodiment 48. R in Formula II 2 teeth, The pharmaceutical composition of embodiment 44, wherein the pharmaceutical composition is TIFF0007644713000036.tif18128.

[0217] Embodiment 49. The pharmaceutical composition of any one of embodiments 44 to 48, which is a non-aqueous solution or suspension.

[0218] 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- ceutically acceptable oil, e.g. an oil suitable as a vehicle for injection, e.g. an oil of vegetable 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 fatty acid.

[0219] Embodiment 51. The pharmaceutical composition of any one of embodiments 44 to 50, further comprising a pharma- ceutically acceptable solvent, for example, benzyl alcohol.

[0220] Embodiment 52. Patients with hormone-dependent benign or malignant disease (e.g., metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer) subject 52. The pharmaceutical composition according to any one of embodiments 44-51, comprising a sufficient amount of the compound of formula II or a pharma- ceutical acceptable salt thereof to provide a therapeutically effective plasma concentration of abiraterone for a period of at least two weeks following a single administration to a subject.

[0221] Embodiment 53. The pharmaceutical composition of embodiment 52, wherein the therapeutically effective plasma concentration of abiraterone is about 1 ng / ml or greater.

[0222] 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.

[0223] Embodiment 55. A method for treating a hormone-dependent benign or malignant disease, comprising administering to a subject in need thereof subject The method comprises administering to said patient a therapeutically effective amount of a compound according to any one of embodiments 28-36 or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 37-54,

[0224] Embodiment 56. The method of embodiment 55, wherein the administration is an intramuscular, intradermal, or subcutaneous injection.

[0225] Embodiment 57. The administration comprises administering subject 57. The method of embodiment 55 or 56, wherein said administering is carried out without regard to food, i.e., said compound or pharmaceutical composition is administered with or without food.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 61. The above subject The method of any one of embodiments 55-60, wherein the ovarian hyperplasia is treated with a gonadotropin releasing hormone analog and / or a bilateral orchiectomy.

[0230] Embodiment 62. An effective amount of prednisone or prednisolone is administered to subject The method of any one of embodiments 55-61, further comprising administering to

[0231] Embodiment 63. The pharmaceutical composition is administered once a week or more than once a week, for example, once a week to once every few months, for example, once a week to once every 8 weeks or once a week to once every 3 months. subject The method of any one of embodiments 55-62, wherein the patient is administered

[0232] Embodiment 64. The method of any one of embodiments 55-63, wherein said administration provides a plasma concentration of abiraterone greater than 1.0 ng / ml for a period of at least 2 weeks.

[0233] Embodiment 65. The method of any one of embodiments 55-63, wherein said administration provides a plasma concentration of abiraterone greater than 8.4 ng / ml for a period of at least 2 weeks.

[0234] Embodiment 66. The administration is a single dose or steady-state C 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) of abiraterone. max The method of any one of embodiments 55 to 65, wherein the method comprises:

[0235] Having sex hormone-dependent benign or malignant diseases such as prostate cancer subject Provided herein are formulations, methods and kits for treating a patient having a sex hormone dependent benign or malignant disease (e.g., prostate cancer), syndromes due to androgen excess and / or syndromes due to glucocorticoid excess, such as hypercortisolism. subject Also provided is a method for preparing a formulation useful for treating. Reference is made to details of representative embodiments, examples of which are illustrated in the accompanying drawings.

[0236] term" subject" as used herein means, but is not limited to, an animal or human who needs to 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 an animal or human who needs to 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, subject is human subject It is.

[0237] 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. Patients with benign or malignant sex hormone-dependent diseases (e.g., androgen-dependent diseases or estrogen-dependent diseases), syndromes due to androgen excess syndromes and / or syndromes due to glucocorticoid excess, such as hypercortisolism. subject Those skilled in the art of treating rheumatoid arthritis will recognize and understand how to select and use such "other drugs or agents" for the intended purpose(s).

[0238] 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, an improved sustained release device or method can further extend the release of the abiraterone prodrugs and formulations of the present disclosure. In some embodiments, an improved sustained release device or method may also include any device or method that can release an agent or product (e.g., a drug or biologic) 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 consider all criteria, subject These techniques can be recognized and utilized by those of ordinary skill in the art without undue experimentation, after exercising their best judgment on behalf of others.

[0239] The formulations and medicaments of the embodiments are indicated, for example, for prostate cancer. subject The formulations and agents of the embodiments are administered in a pharmacologically or physiologically acceptable and effective amount to reduce or eliminate the presence of prostate tumor tissue and abnormal or malignant prostate cells in the prostate. Similarly, the formulations and agents of the embodiments are administered in a prophylactically or therapeutically effective amount, alone or in combination with other therapeutic agents or treatments (e.g., radiation therapy and surgery), where such an amount should be understood as an amount that meets the intended prophylactic or therapeutic purpose and provides the benefit obtained from the administration of such formulations and agents.

[0240] The terms "effective amount," "effective dose," and "therapeutic 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 plasma concentration" is indicative of prostate cancer. subject The amount, dose or concentration of the agent capable of reducing or eliminating the presence of prostate tumor tissue and abnormal or malignant prostate cells in the prostate, i.e., curing the disease (partially or completely) or preventing the onset or further spread of a disease, disorder or condition. By way of further example, an effective amount of the formulation means the amount administered alone or in combination with other therapeutic agents or treatments (e.g., radiation therapy and surgery) to produce a clinically significant reduction in tumor burden. One of skill in the art will understand when a clinically significant reduction in tumor burden (or amelioration of a sex hormone-dependent benign or malignant disease or another disease or syndrome as described herein) has occurred following administration of the formulation. An "effective amount", "effective dose", or "therapeutic plasma concentration" refers to: subject It is understood that an effective amount or dose of an abiraterone prodrug formulation is an amount, dosage or concentration that does not significantly harm the patient, and in any event, any adverse side effects are outweighed by the benefits. By way of example only, an effective amount or dose of an abiraterone prodrug formulation is subject By effective plasma concentration is meant an amount capable of achieving a plasma concentration of 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 of abiraterone in a dose-dependent manner, and an effective plasma concentration is one that is achieved for at least 1 week, e.g., at least 2 weeks (e.g., 4, 6, 8 weeks or more) after administration.

[0241] Generally, the dosage ranges for administration of the formulations according to the present disclosure are those that produce the desired effect(s). subject Age, weight and health condition of the individual, mode, route and schedule of administration subjectThe dosage will vary depending on the response to the drug, as well as 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 will also vary depending on the nature or severity of the primary tumor and other underlying pathologies, epidemiological pathology, co-administration with other active compounds, and route of administration. In addition, the dosage will be determined by the presence of adverse side effects, such as local hypersensitivity, systemic adverse effects, and immune resistance.

[0242] 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.

[0243] The formulations and medicaments of the embodiments can be administered in combination with (or can include) one or more pharma- ceutically acceptable carriers, diluents, or excipients, if desired. Formulations, administration techniques, pharmaceutical compositions, methods for 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 physiologically acceptable sterile solutions for injection. To prepare a ready-to-use solution for parenteral injection or infusion, isotonic aqueous solutions, such as saline, phosphate buffered saline (PBS), or corresponding plasma protein solutions, are readily available. The formulation can be present as a lyophilized or dried preparation, for example as a kit of parts, and can be dissolved in a known injection solution immediately before use under sterile conditions. In addition, the formulation can include one or more acceptable carriers, such as solvents, dispersions, coatings, adjuvants, stabilizers, diluents, preservatives, antibacterial and antifungal agents, isotonicity agents, absorption modifiers, etc. "Diluents" can include water, saline, phosphate-buffered saline (PBS), dextrose, ethanol, glycerol, etc. Isotonicity agents can include sodium chloride, dextrose, mannitol, sorbitol, and lactose, etc. Stabilizers include albumin and alkali salts of ethylenediaminetetraacetic acid, etc.

[0244] Any suitable route of administration may be used to administer effective amounts / doses of formulations and agents according to exemplary embodiments. subjectThe formulations may be used to provide a therapeutic agent to a patient in need thereof. 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 primarily be suitable for parenteral administration, such as by IM, intradermal, or subcutaneous injection.

[0245] The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0246] It is also to 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.

[0247] Definitions of specific functional groups and chemical terms are explained in more detail below. For chemical elements, see the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th In addition, general principles of organic chemistry and specific functional moieties and reactivities are described in detail in the following references: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Ed., 1999; th 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, 3 rdEdition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any manner by the exemplary list of substituents depicted herein.

[0248] As used herein, the term "alkyl," used by itself or as part of another group, refers to a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, an alkyl contains 1 to 30 carbon atoms (i.e., C 1-30 Alkyl, or C1-C 30 In one embodiment, the alkyl group may be represented as a straight chain C alkyl, or may contain a specified number of carbon atoms (i.e., a C alkyl such as methyl, a C alkyl such as ethyl, a C alkyl such as propyl or isopropyl, etc.). 1-16 In another embodiment, the alkyl group is a branched chain C 3-16 It is an alkyl group.

[0249] As used herein, the term "cycloalkyl" used by itself or as part of another group refers to cycloalkyl having 3 to 12 carbon atoms (i.e., C 3-12 Cycloalkyl refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic aliphatic hydrocarbons 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 has C 3-8 In another embodiment, the cycloalkyl group is 3-6Cycloalkyl groups. "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.

[0250] As used herein, the term "alkenyl" by itself or as part of another group refers to 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 2-16 It is an alkenyl group.

[0251] 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 It is an alkynyl group.

[0252] 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, any of the 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, in which 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, 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, for example, 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.

[0253] The abiraterone prodrugs of the present disclosure may exist in isotopically labeled or isotopically enriched forms that contain 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: 2 H, 3 H, 13 C. 14 C. 15 N, and 18 Compounds containing other isotopes of these and / or other atoms are within the scope of the disclosure.

[0254] The solid and dashed wedge bonds represent the stereochemistry conventional in the art. EXAMPLES

[0255] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claimed subject matter.

[0256] Example 1. Long-acting injectable formulation of abiraterone prodrug The 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 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, (butyrate) pentanoate, isocaproate, bucclate, cyclohexanecarboxylate, phenylpropionate, caproate (hexanoate), enanthate (heptanoate), cypionate, octanoate, noncanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate, and hexadecanoate. In exemplary embodiments, the abiraterone esters are abiraterone acetate, abiraterone propionate, and abiraterone decanoate.

[0257] The formulation can include a solution or suspension of the abiraterone prodrug in a pharma- ceutically acceptable oil, such as 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 can include triglycerides of fatty acids (polyunsaturated, monounsaturated, and saturated), such as vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil. The vegetable oil was selected based on the prodrug solubility in the oil. It was determined that abiraterone acetate is 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.

[0258] Table 1. Melting points of abiraterone prodrugs TIFF0007644713000037.tif31128

[0259] 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 acceptable gauge needles 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 injection 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).

[0260] 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.

[0261] The formulations may also contain pharma- ceutically acceptable preservatives, polymers, antioxidants, antimicrobial agents, 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, dibasic potassium phosphate, docusate sodium, disodium edetate, glycerin, sodium hyaluronate, hydroxypropyl betadex, lactic acid, lactose, lecithin, maleic acid, mannitol, meglumine, methylcellulose, methylparaben, microcrystalline cellulose, miripitium chloride, glycerin ... 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.

[0262] The formulations may be sterilized by methods known to those skilled in the art (eg, gamma irradiation, micron filtration and autoclaving).

[0263] 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.

[0264] 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 the abiraterone prodrug formulation can be, for example, 6-15 ng / ml for 14-28 days following parenteral administration. In an exemplary embodiment, the therapeutic levels are 8-12 ng / ml for 14-28 days following parenteral administration. A C of greater than 8.4 ng / ml of abiraterone is minIt has previously been demonstrated that it 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).

[0265] Example 2. Synthesis of Abiraterone Prodrugs Abiraterone acetate Abiraterone acetate was obtained from Hetero Labs Limited, India.

[0266] Other abiraterone esters are generally 2 COOH or R 2 Abiraterone can be synthesized by reacting it with a suitable activated form thereof, such as COCl. 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 shown below. TIFF0007644713000038.tif26128

[0267] Example 2A. Preparation of Abiraterone Propionate Abiraterone propionate was prepared as follows.

[0268] 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 characteristics were LCMS m / z 406.3 (M+H); 1 H NMR (CDCl3, 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.

[0269] Example 2B. Preparation of Abiraterone Butanoate Abiraterone butanoate was prepared as follows.

[0270] 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 rapidly changed from a white mixture to a yellow solution and then slowly changed to a red solution. After TLC and LCMS showed the reaction was complete, the solution was washed with 150 ml water twice and 150 ml brine once. 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 25% ethyl acetate. Pure fractions were combined and concentrated under vacuum to give 5.5 g of abiraterone butanoate as a yellow solid. Chemical characteristics were LCMS m / z 420.4 (M+H); 1 H NMR (CDCl3, 200MHz): 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.

[0271] Example 2C. Preparation of Abiraterone Decanoate TIFF0007644713000039.tif29139Abiraterone decanoate was prepared as follows.

[0272] 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 rapidly changed from a white mixture to a yellow solution and then slowly changed 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 characteristics were LCMS m / z 504.4 (M+H); 1H NMR (CDCl3, 200MHz): 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.

[0273] Example 2D. Preparation of Abiraterone Pentanoate TIFF0007644713000040.tif29139Abiraterone 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 (CDCl3, 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).

[0274] Example 2E. Preparation of Abiraterone Hexanoate TIFF0007644713000041.tif29139Abiraterone 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 (CDCl3, 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).

[0275] Example 2F. Preparation of Abiraterone Heptanoate TIFF0007644713000042.tif29139Abiraterone 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 (CDCl3, 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).

[0276] Example 2G. Preparation of Abiraterone Isocaproate TIFF0007644713000043.tif29128Abiraterone isocaproate was prepared using a procedure similar to that for preparing abiraterone decanoate (Example 2C), except that 4-methylvaleryl chloride was used instead of decanoyl chloride. LCMS m / z 448.4 (M+H); 1 H NMR (CDCl3, 200MHz): δ H0.9-2.2 (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).

[0277] Example 2H. Preparation of Abiraterone Cypionate TIFF0007644713000044.tif29128Abiraterone cypionate was prepared using a procedure similar to that for preparing abiraterone decanoate (Example 2C), except that 3-cyclopentylpropanoyl chloride was used instead of decanoyl chloride. LCMS m / z 474.4 (M+H); 1 H NMR (CDCl3, 200MHz): δ H 1 H NMR (CDCl3, 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).

[0278] 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.

[0279] 490 mg of abiraterone acetate was weighed and placed 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 recapped 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.

[0280] Example 3B. Preparation of Abiraterone Acetate-90% Castor Oil, 10% Benzyl Alcohol Solution Abiraterone acetate injection (IM depot) 90% castor oil, 10% benzyl alcohol solution was prepared as follows:

[0281] 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.

[0282] Example 3C. Preparation of Abiraterone Acetate-50% Castor Oil-50% Benzyl Benzoate Solution Abiraterone acetate injection (IM depot) 50% castor oil, 50% benzyl benzoate solution was prepared as follows:

[0283] 980 mg of abiraterone acetate was weighed and placed 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 recapped 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.

[0284] Example 3D. Preparation of Abiraterone Propionate 90% Castor Oil, 10% Benzyl Alcohol Solution Abiraterone propionate injection (IM depot) 90% castor oil, 10% benzyl alcohol solution was prepared as follows:

[0285] 1,050 mg of abiraterone propionate 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 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 197 mg / mL.

[0286] Example 3E. Preparation of Abiraterone Propionate-90% Corn Oil, 10% Benzyl Alcohol Solution Abiraterone propionate injection (IM depot) 90% corn oil, 10% benzyl alcohol solution was prepared as follows:

[0287] 1,050 mg of abiraterone propionate was weighed and placed into a 10 mL serum vial with a crimp stopper. 8 mL of a 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.

[0288] Example 3F. Preparation of Abiraterone Decanoate 90% Castor Oil, 10% Benzyl Alcohol Solution Abiraterone decanoate injection (IM depot) 90% castor oil, 10% benzyl alcohol solution was prepared as follows:

[0289] 1,260 mg of abiraterone decanoate was weighed and placed 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 rotating the vial. The final concentration of the sterile abiraterone decanoate solution was 160 mg / ml.

[0290] Example 3G. Preparation of Abiraterone Decanoate-90% Corn Oil, 10% Benzyl Alcohol Solution Abiraterone decanoate injection (IM depot) 90% corn oil, 10% benzyl alcohol solution was prepared as follows:

[0291] 1,260 mg of abiraterone decanoate was weighed and placed into a 10 mL serum vial with a crimp stopper. 8 mL of a 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.

[0292] Example 3H. Preparation of Abiraterone Decanoate (~200mg / ml)·70% Corn Oil, 10% Benzyl Alcohol, 20% Benzyl Benzoate Solution Abiraterone decanoate injection (IM depot, ~200 mg / ml) 70% corn oil, 10% benzyl alcohol, 20% benzyl benzoate solution was prepared as follows:

[0293] 2,500 mg of abiraterone decanoate was weighed and placed 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.

[0294] Example 3I. Preparation of Abiraterone Decanoate (~240mg / ml) - 70% Corn Oil, 10% Benzyl Alcohol, 20% Benzyl Benzoate Solution Abiraterone decanoate injection (IM depot, ~240 mg / ml) 70% corn oil, 10% benzyl alcohol, 20% benzyl benzoate solution was prepared as follows:

[0295] 3,125 mg of abiraterone decanoate was weighed and placed 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.

[0296] Example 3J. Preparation of Abiraterone Isocaproate in 90% Corn Oil and 10% Benzyl Alcohol Abiraterone isocaproate for injection (IM depot) 90% corn oil, 10% benzyl alcohol solution was prepared as follows:

[0297] 1190 mg of abiraterone isocaproate was weighed and placed into a 10 mL serum vial with a crimp stopper. 8 mL of a 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 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.

[0298] 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.

[0299] 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. If there was a large excess of undissolved prodrug, additional diluent may be added. 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.

[0300] 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.

[0301] Table 2. Solubility of abiraterone prodrugs TIFF0007644713000045.tif89164

[0302] Table 2: Solubility of Abiraterone Prodrugs (continued) TIFF0007644713000046.tif65164

[0303] Parenteral formulations must be sterilized prior to administration, which can be accomplished by a variety of techniques, including heat sterilization (e.g., dry heat or moist heat), radiation sterilization (e.g., gamma sterilization), sterile filtration (e.g., 0.22 micrometer membrane filters), or gas sterilization (e.g., formaldehyde or ethylene oxide gas).

[0304] Example 4B. Solubility, Viscosity, and Glide Force Studies of Abiraterone Decanoate Formulations or Oil Vehicles In this example, the properties of various abiraterone decanoate formulations and oil vehicles are examined.

[0305] 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 TIFF0007644713000047.tif66153

[0306] 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.

[0307] 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.

[0308] Glide force testing was performed using a tension and compression testing machine (e.g., a Lloyd press or equivalent), NEXYGEN Plus materials testing software, or equivalent load cell 250N, a 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.

[0309] Table 2B shows the viscosity of an oil vehicle without additives, 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. See also Figure 13C. (Table 2B) Viscosity (Pa) of various oils containing additives * s) TIFF0007644713000048.tif65158

[0310] 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 TIFF0007644713000049.tif71158 (Table 2D) Glide force (N) for various oils containing additives, 27 gauge needle TIFF0007644713000050.tif71158

[0311] Example 5 Abiraterone plasma pharmacokinetics in rats and dogs after administration of an abiraterone prodrug formulation Example 5A. PK Studies of Abiraterone and Abiraterone Acetate in Rats and Dogs In the initial rat study, several formulations were examined. These formulations consisted 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, as there is a possibility that 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 suspending nature of the two formulations.

[0312] 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, abiraterone acetate in 90% castor oil and 10% benzyl alcohol, or abiraterone acetate in 50% castor oil and 50% benzyl benzoate.

[0313] 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.

[0314] Table 3. Group-specific mean plasma pharmacokinetic parameters of abiraterone following IM injection of various formulations of abiraterone or abiraterone acetate in rats. TIFF0007644713000051.tif117160 Group 1: Abiraterone acetate in castor oil (70mg / ml); Group 2: Abiraterone acetate in sodium phosphate buffer, 0.1% Tween suspension (70mg / ml); Group 3: Abiraterone in castor oil (62.5mg / ml); Group 4: Abiraterone in sodium phosphate buffer, 0.1% Tween suspension (62.5mg / ml)

[0315] 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.

[0316] 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 an abiraterone acetate aqueous suspension formulation, as well as abiraterone aqueous solution and castor oil suspension.

[0317] 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 FIG. 1). Also surprising was the use of abiraterone acetate in an aqueous suspension, which resulted in low plasma levels (see FIG. 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 FIG. 1).

[0318] 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 suspension.

[0319] The results of the dog study are presented in Table 4 and FIG. Table 4. Group-specific mean plasma pharmacokinetic parameters of abiraterone acetate following IV and IM injections in dogs. TIFF0007644713000052.tif231110Group 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.

[0320] 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 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 wounds. 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%.

[0321] Figure 2 shows the mean plasma concentrations 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 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.

[0322] 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.

[0323] To measure the bioavailability of the IM depot formulation, IV administration of abiraterone acetate (at a dose of 10 mg / kg) was included in the study. Bioavailability was found to be 86.2%, 85.7%, and 61.7%.

[0324] 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. Modeling included human pharmacokinetic profiles of abiraterone acetate administered IM at doses of 600 mg to 2,000 mg every 2 to 4 weeks. subject When administered to humans, subject Desired plasma pharmacokinetic profile in the blood (i.e., greater than 80% bioavailability, C of abiraterone between 1.0 ng / ml and greater than 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, for at least 2 weeks) min value, and C of abiraterone of approximately 10 ng / ml to 400 ng / ml. maxThe predicted IM dose of 600 mg 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, together with higher and less frequent plasma trough levels, should result in better efficacy (see Clin Pharmacology, 2018, for improved prostate-specific antigen response and improved progression-free survival in patients with castration-resistant prostate cancer). min is greater than 8.4 ng / ml) (Carton et al., Eur. J. Can. 72:54, 2017).

[0325] Example 5B. PK Study of Abiraterone Propionate and Abiraterone Decanoate in Dogs This was a single-dose bioavailability study of several abiraterone prodrugs (propionate and decanoate esters) administered intramuscularly (IM) and intravenously to beagle dogs.

[0326] The formulations and doses used in this study are shown below. 1) Intramuscular (IM); Abiraterone propionate in 10% benzyl alcohol / 90% castor oil (197 mg / mL) at a dose of 41 mg / kg 2) Intramuscular (IM); Abiraterone propionate in 10% benzyl alcohol / 90% corn oil (168 mg / mL) at a dose of 41 mg / kg 3) Intramuscular (IM); Abiraterone decanoate in 10% benzyl alcohol / 90% castor oil (160 mg / mL) at a dose of 50 mg / kg 4) Intramuscular (IM); Abiraterone decanoate in 10% benzyl alcohol / 90% corn oil (170 mg / mL) at a dose of 50 mg / kg 5) Intravenous (IV); Abiraterone propionate (0.57 mg / mL) in 40% HP-b-CD / 25 mM sodium phosphate (pH 7.4) at a dose of 1 mg / kg 6) Intravenous (IV); Abiraterone decanoate (0.37 mg / mL) in 40% HP-b-CD / 25 mM sodium phosphate (pH 7.4) at a dose of 1.2 mg / kg

[0327] A summary of the study design is shown in Table 5 below. Table 5. Experimental study design TIFF0007644713000053.tif150152

[0328] All animals were dosed via IV administration. After a 72 hour washout period, all dogs were dosed via the IM route. Dose was 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.

[0329] After IV administration of abiraterone propionate, animals had only one or two quantifiable plasma concentrations, so reliable pharmacokinetic parameters could not be assessed.

[0330] Pharmacokinetic analysis was performed on plasma concentration versus time data using Phoenix WinNonlin (v8.1) noncompartmental analysis function (linear trapezoidal method for calculating AUC). Nominal dose values ​​and sampling times were used for calculations. For the purposes of PK calculations, all concentrations reported as "BLQ" were set to zero.

[0331] C max and the corresponding T max Values ​​were determined by direct evaluation of the concentration versus time data. All AUC calculations were performed using the linear trapezoidal method.

[0332] 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; In regression, C max At least three data points after must be used; Regression correlation coefficient (R 2 ) must be greater than 0.80;

[0333] To optimize the reliability of the identified terminal phase (λz), when possible, the data points used to define λz were manually selected. Lambda z profiles that did not meet the above guidelines are marked with an asterisk (AUC) of that animal's profile. INF , t 1 / 2 , CL / F, and Vz / F parameters were excluded and their results were removed from the summary descriptive statistics.

[0334] AUC INF Values ​​were calculated as follows: AUC last +(C last / λz). CL / F was calculated as: Dose per dosing interval / (AUC INF ) and Vz / F was calculated as follows: Dose per dosing interval / (AUC INF * λz). Termination t 1 / 2 was calculated as follows: ln(2) / λz. If the lambda z interval did not exceed the calculated half-life by at least two times, the half-life value was flagged with an asterisk as unreliable and excluded from the descriptive statistics.

[0335] 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 T maxValues ​​were recorded to two significant figures, whereas all other values ​​and descriptive statistics were recorded to three significant figures.

[0336] The mean PK parameters of the prodrug and abiraterone by individual animal and group after IV administration are presented in Tables 6 and 7. The mean PK parameters of the prodrug and abiraterone by individual animal and group after IM administration are presented in Tables 8 and 9. The mean plasma concentrations over time by group after administration to dogs are plotted in Figures 5 to 10.

[0337] 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 t 1 / 2 The values ​​were 0.86 hours for the prodrug and 1.5 hours for abiraterone, respectively.

[0338] Because exposure to abiraterone propionate was observed only at the first two time points after dosing, 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 t 1 / 2 The value was 2.1 hours.

[0339] The Cmax values ​​of abiraterone after IV administration of abiraterone propionate were nearly 4-fold higher, yet the AUC values ​​were equivalent (within a 2-fold difference), indicating only minor differences between the prodrugs.

[0340] Results of IM administration: Mean T of abiraterone after IM administration of the two decanoate formulations maxThe mean T values ​​for both formulations were 5.0 days, and the mean T values ​​for the decanoate ester were 5.0 days. max Values ​​ranged from 0.11 to 0.26 days across formulations. Mean exposure to prodrug and abiraterone (C max The mean t of abiraterone (as manifested by the AUC values) was within 2-fold difference 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. 1 / 2 Value(terminal t 1 / 2 ) were administered 23 and 24 days after dosing with the two vehicles. Estimates of the absolute bioavailability of abiraterone were calculated based on the mean AUC INF Using the values, IV administration (145 h * ng / mL) and IM (adjusted for dose and time unit = 104 h for Group 5) * ng / mL, and Group 6 at 134 h * The bioavailability was calculated after 10 min (mg / mL) administration. The bioavailability was 72% in group 5 and 92% in group 6, respectively.

[0341] Mean T of abiraterone between formulations after IM administration of the two propionate ester formulations max The values ​​ranged from 0.56 to 0.61 days, with the mean T max Values ​​ranged from 0.11 to 0.26 days (2.3 to 6.2 hours). The mean exposure of the prodrug and abiraterone (C max The mean t values ​​for abiraterone (as manifested by AUC values) were within 2-fold between the two formulations. With the exception of the 7th day time point (no values ​​were available after that), the mean t values ​​for the prodrug ranged from 0.98 to 1.7 days after administration for the two different vehicles. 1 / 2 The values ​​were 1.8 and 4.5 days after dosing for the two vehicles. Estimates of the absolute bioavailability of abiraterone were calculated as the mean AUC INF Using the values, IV administration (127 h * ng / mL) and IM (adjusted for dose and time unit = 105 h for Group 3) * ng / mL, and Group 4 was 94.1 h *The bioavailability was calculated after 10 min (mg / mL) administration. The bioavailability was 83% in group 3 and 74% in group 4, respectively.

[0342] Tables 6-9 and Figures 5-10 provide a summary of the PK studies of this example.

[0343] Computer modeling was used to predict the human pharmacokinetic profile of abiraterone decanoate administered IM based on data obtained from rat and dog studies. Pharmacokinetic (PK) modeling and simulations were performed using a fully-validated version of WinNonlin Phoenix (8.1). A linear PK (exponential) model was fitted to the time course of abiraterone plasma concentrations after 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 of bioavailability (K01) and fractional utilization (F) of abiraterone after IM administration to dogs were estimated by deconvolution, and it was assumed that the values ​​of K01 and F are 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 demonstrated that IM administration of as little as 120 mg abiraterone decanoate every 2 weeks resulted in a steady-state C of abiraterone of >8 ng / ml. min value, the steady-state C of approximately 14 ng / ml abiraterone max Modeling predicts that therapeutically effective abiraterone plasma concentrations in humans can be achieved with a steady-state C value of greater than about 8 ng / ml for abiraterone with IM administration of abiraterone decanoate. Modeling also predicts that IM administration of abiraterone decanoate is suitable for monthly or greater than monthly human dosing regimens, which can achieve therapeutically effective abiraterone plasma concentrations. For example, IM administration of approximately 350 mg of abiraterone decanoate once every 4 weeks can be sufficient to achieve a steady-state C value of greater than about 8 ng / ml for abiraterone. minIt is sufficient to provide a steady-state C value for abiraterone. max The values ​​are proportional to the dose. See also Figures 11A, 11B, 11C, and 11D. In light of this disclosure, in some cases, the dosage regimen may be subject To achieve some exposure of abiraterone in the setting of a vasopressin-resistant ketone, the dosage regimen may include an initial dosing period with a more frequent dosing frequency or a different abiraterone drug, followed by a monthly (or more than monthly) dosing regimen as described herein. For example, in some cases, the dosage regimen may include an initial IM dosing of abiraterone decanoate once every two weeks, e.g., about 2-3 times, followed by monthly dosing of abiraterone decanoate. Computer modeling has demonstrated that such a dosage regimen would result in a steady-state C of abiraterone of greater than about 8 ng / ml during the treatment period. min It was predicted that the value could be achieved. 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) TIFF0007644713000054.tif22967 (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) TIFF0007644713000055.tif21563 (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 TIFF0007644713000056.tif229109 (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) TIFF0007644713000057.tif22987

[0344] Example 6A. Large-Scale Preparation of Abiraterone Decanoate from Decanoic Acid TIFF0007644713000058.tif34134To 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), then the reaction was stirred at 20-25 °C for 19 h.

[0345] 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.

[0346] 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 was rinsed with the filtrate, and transferred to a filter funnel. The wet cake was transferred to a drying tray and dried overnight at 40-45° C. in a vacuum oven to give 457.1 g (90% yield) as a white solid. 1 H NMR (CDCl3, 400 MHz): H8.62 (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%.

[0347] Using HPLC methodology, 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). The HPLC conditions were as follows: HPLC column: Halo C8 (2.7um, 100x3.0mm); Injection volume: 5uL; Column temperature: 40°C; Sample temperature: ambient; Detection: 210nm; Mobile phase: 25mM ammonium acetate, pH 8.0 (MPA) and 95 / 5 acetonitrile / tetrahydrofuran (MPB); Flow rate: 0.6ml / min; Gradient: starting at 65 / 35 MPA / MPB, reaching 100% MPB in 35 minutes, maintaining 100% MPB until 40 minutes, returning to 65 / 35 MPA / MPB at 40.10 minutes, maintaining 65 / 35 MPA / MPB until the end of 45 minutes.

[0348] 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 temperature, 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-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 using 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-150 °C, and a heating rate of 10 °C / min. A representative TGA trace is shown in Figure 12C.

[0349] Example 6B. Preparation of Abiraterone Decanoate Salts Preparation of abiraterone oxalate decanoate A 5200 g solution of abiraterone decanoate (374 g, 744 mmol) dissolved in isopropyl acetate was charged to 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.

[0350] 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 h. The solid was 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%. 1 H NMR (CDCl3, 400 MHz): H 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).

[0351] Preparation of Abiraterone Decanoate HCl Salt A solution of abiraterone decanoate (20 mmol) dissolved 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 moderately quickly and rinsed with EtOAc to give 7.97 g of abiraterone decanoate HCl salt (14.76 mmol; 74% yield) as a white solid. 1 H NMR (CDCl3, 400 MHz): H 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).

[0352] Preparation of abiraterone benzenesulfonate decanoate 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 benzenesulfonate (0.72 mmol) was isolated by filtration (74% yield). 1 H NMR (CDCl3, 400 MHz): H8.87 (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).

[0353] Preparation of abiraterone p-toluenesulfonate decanoate 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 (64% yield). 1 H NMR (CDCl3, 400 MHz): H8.85 (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).

[0354] Preparation of abiraterone phosphate decanoate 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): d H 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).

[0355] Example 7. Study of Abiraterone Decanoate in Rats and Monkeys and Allometric Scaling and Prediction of Plasma Profiles in Humans Example 7A. Abiraterone Decanoate Study in Monkeys In a monkey PK study, 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).

[0356] 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 Figure 14A. Table 10A: Monkey IV PK parameters (arithmetic mean) TIFF0007644713000059.tif42138

[0357] A single-dose PK study was performed by intramuscularly injecting 90 mg / kgm of the 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 Figure 14B. Table 10B. Single-dose PK parameters in monkeys (geometric mean; median Tmax) TIFF0007644713000060.tif42161

[0358] 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.

[0359] A repeat-dose PK study was also performed in which an 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 using a 27-gauge needle in two separate injections into the thigh of each hind leg. 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. The results are shown in Figure 14E.

[0360] Example 7B. Study of the effect of benzyl benzoate on abiraterone exposure in monkeys This example compares the pharmacokinetic behavior of two different abiraterone decanoate formulations upon IM injection. 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

[0361] Formulations 1 and 2 were administered intramuscularly at 100 mg / kg 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.

[0362] As shown in Figure 14F, IM injection of Formulation 2 unexpectedly resulted in significantly higher abiraterone plasma concentrations in monkeys compared to the same dose of IM injection of Formulation 1. This trend was also confirmed by parallel studies at different dose levels.

[0363] 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).

[0364] As a comparison, abiraterone decanoate was administered IV at a dose of 1.2 mg / kg (mean n=5) in 40% HP-β-cyclodextrin 25 mM sodium phosphate buffer (pH 7.4) (0.4 mg / ml). 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 Figure 15A. Table 11A: Rat IV PK parameters TIFF0007644713000061.tif36138

[0365] A single dose PK study was performed by intramuscularly injecting 90 mg / kgm of abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 172 mg / ml abiraterone decanoate) into male rats (n=5). 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 Figure 15B. Table 11B. Single IM dose PK parameters in rats TIFF0007644713000062.tif42161

[0366] A repeat-dose PK study was also performed in which 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 Figure 15C.

[0367] Example 7D. Allometric Scaling and Prediction of Abiraterone Plasma Profile in Humans This pharmacokinetic (PK) analysis involves modeling the plasma concentrations of abiraterone following single intravenous (IV) and intramuscular (IM) doses of abiraterone in rats, dogs, and monkeys. PK parameters were derived from the PK model following IV and IM administration to rats, dogs, and monkeys, and the plasma profile of abiraterone in humans following IM administration of abiraterone decanoate was predicted by deconvolution and allometric scaling.

[0368] Abiraterone decanoate was administered IV (1.2 mg / kg) and IM (90 mg / kg) to rats and monkeys. Animals received IV and IM doses, 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.

[0369] 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 models that fit 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 (V ss ) was derived from the exponential function.

[0370] Deconvolution: Using WinNonlin Phoenix Version 8.2, the rate and extent of input from intramuscular administration was simulated by deconvolution. Deconvolution is based on linear system 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 represented by 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 gives the input rate constant (K 01 ) is generated. Integration of the input rate versus time generates a cumulative input function and an estimate of absolute bioavailability.

[0371] 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 entry (absorption) into the systemic circulation (bioavailability). The kinetics of abiraterone in animals were simulated using the PK parameters (CL and V ss ) in humans. ss The CL and V in animals were determined by allometric methods. ss It was predicted from V ss =a W x where a is the intercept, W is the body weight, and x is the allometric index, and therefore log V ss = x log W + log a (3 weights vs. V ss The CL in humans is calculated using the Tang [5] The input rate and extent were derived by a data-driven method, i.e., CL human / kg = 0.407 CL monkey / kg.

[0372] Results: The time course of abiraterone plasma concentrations after a single intravenous dose in rats, dogs, and monkeys was best described by a biexponential function. The plasma clearance (CL) of abiraterone was 11414, 6469, and 2578 mL / h / kg in rats, dogs, and monkeys, respectively. The steady-state apparent volume of distribution (V ss ) were 22313, 14205 and 5732 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. TIFF0007644713000063.tif36128

[0373] The allometric scaling predicted CL in humans (only from monkeys, where the CL was very high among rats and dogs) was 73 L / h and Vss (from rats, dogs and monkeys) was 437L. The predicted V ss was significantly greater than total body water (42 L) and showed widespread tissue distribution. The predicted CL in humans was not significantly different from hepatic blood flow (80 L / h).

[0374] Deconvolution of the IM and IV profiles provided an estimate 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.

[0375] Therefore, CL(73L / h), V ss (437L), K01(0.00213h -1 ) and F(56%) parameters were used to simulate plasma profiles in humans. See Table 12B, Figures 16A and 16B. Table 12B. Predictive parameters of abiraterone in humans following intramuscular administration of abiraterone decanoate * TIFF0007644713000064.tif36128*Predictions assuming one-compartment kinetics with first-order absorption model and linear kinetics in humans

[0376] Predicted steady-state C after monthly (i.e., every 4 weeks) intramuscular administration of 1000 mg abiraterone to humans min The value was 5 ng / mL. See FIG. 16C. We believe that the human bioavailability for monthly intramuscular administration at this dose level may be greater than the 56% used in the predictions in FIG. 16C and approach perfect bioavailability. Assuming perfect bioavailability, we estimate the steady-state predicted C after monthly intramuscular administration of 1000 mg abiraterone to humans. minThe value is believed to be 9.3 ng / mL. See Figure 16D.

[0377] Conclusion: Volume of distribution (V ss )(437L) was predicted by allometric growth with good correlation between rats, dogs and monkeys. ss shows extensive tissue distribution in humans. Total body clearance (CL) in humans (73 L / h) was predicted by allometric growth in monkeys. 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. Steady-state predicted C after intramuscular administration of 1000 mg abiraterone decanoate once every 4 weeks in humans min was 5ng / mL.

[0378] 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 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.

[0379] Naïve 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 kg at the time of first dosing.

[0380] 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 No. 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 No. 2, abiraterone isocaproate in 90% corn oil / 10% benzyl alcohol), and the remaining three dogs received an abiraterone decanoate IM preparation (Test Article No. 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. TIFF0007644713000065.tif32162 * Prodrug Concentration

[0381] 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.

[0382] Pharmacokinetic analysis was performed on plasma concentration versus time data using Phoenix WinNonlin (v8.1) non-compartmental analysis function (linear trapezoidal method for calculating AUC) (see, e.g., Example 5B).

[0383] Results: Single-dose pharmacokinetics of abiraterone and abiraterone isocaproate following IV administration of 1 mg / kg abiraterone isocaproate: Following IV administration, evidence of systemic exposure of abiraterone and abiraterone isocaproate was observed in all treated dogs (Table 13A and Figure 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 is 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 The values ​​were 0.350 hours and 0.773 hours for the prodrug and abiraterone, respectively.

[0384] 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 no significant differences in exposure parameters (C max It should be noted that the CV% values ​​of the mean T max The values ​​were 1.7 days for abiraterone and 0.19 days for the isocaproate prodrug, respectively. max The values ​​were 20.2 ng / mL for abiraterone and 106 ng / mL for the isocaproate prodrug, respectively. Mean AUC last The values ​​were 266 days for abiraterone and 270 days for abiraterone, respectively. * ng / mL, and 281 days for isocaproate prodrugs * ng / mL. Mean t 1 / 2 The values ​​were 9.3 days for abiraterone and 7.4 days for the isocaproate prodrug, respectively.

[0385] Estimates of the absolute bioavailability of abiraterone were calculated as the mean AUC INF Using the values, abiraterone isocaproate 0.78 mg / kg was administered IV (206 h * ng / mL, or 131 h when dose-corrected * ng / mL) and 60 mg / kg abiraterone isocaproate IM (corrected for dose and time units = 114 h * The estimated bioavailability of abiraterone from 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.

[0386] 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 Figure 17C). Abiraterone exposure parameters (C max The mean T max The values ​​were 5.7 days for abiraterone and 0.71 days for the decanoate prodrug, respectively. max The values ​​were 7.82 ng / mL for abiraterone and 45.0 ng / mL for the decanoate ester prodrug, respectively. Mean AUC last The values ​​were 176 days for abiraterone and 177 days for abiraterone, respectively. * ng / mL, and 298 days for decanoate prodrug * ng / mL. Mean T 1 / 2 The values ​​were 14 days for abiraterone and 6.7 days for the decanoate ester prodrug, respectively. Estimates of the absolute bioavailability of abiraterone were calculated as the mean AUC INF Using the values, abiraterone decanoate was administered IV at 0.86 mg / kg (145 h * ng / mL, or 169 h when adjusted for dose *ng / mL) and 60 mg / kg IM (corrected for dose and time units = 70.4 h * 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 Figure 17D. Table 13A. Summary of plasma PK parameters of abiraterone or abiraterone isocaproate following IV administration to dogs TIFF0007644713000066.tif21055 (Table 13B) Summary of plasma PK parameters of abiraterone or abiraterone prodrugs following IM administration to dogs TIFF0007644713000067.tif20992

[0387] Conclusion of Example 8: Following dosing, evidence of systemic exposure to abiraterone was observed in all treated dogs. Mean T max and C max When comparing the values, the isocaproate ester prodrug had a higher T than the decanoate ester prodrug. max The value is short, C max The mean AUC values ​​for abiraterone after IM administration of the isocaproate ester prodrug were seen to be less than 2-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 is some evidence that the half-life of abiraterone appears to be longer after decanoate administration, which may be due to slower absorption of the decanoate ester prodrug.

[0388] Each reference mentioned within this disclosure is incorporated herein by reference in its respective entirety.

[0389] As used herein, the term "about" modifies the quantities associated with the present disclosure and refers to variations in numerical quantities, which may occur, for example, through routine testing and processing, through unintentional errors during such testing and processing, and through differences in the manufacture, supply, or purity of the components / materials used in the present disclosure. As used herein, a particular value with "about" includes the particular value, such as 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.

[0390] With respect to aspects of the disclosure that are described as a genus, all individual species are considered to be 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.

[0391] Any of the various aspects, embodiments, and options described herein may be combined in any and all variations.

[0392] 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, and are 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

1. The structure: or a pharma- ceutically acceptable salt thereof.

2. 10. A pharmaceutical composition comprising the abiraterone decanoate of claim 1, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

3. 13. A pharmaceutical composition comprising the abiraterone decanoate of claim 1 and a pharma- ceutically acceptable carrier.

4. 4. The pharmaceutical composition of claim 2 or 3, formulated for intramuscular, intradermal, or subcutaneous injection.

5. 4. 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.

6. 6. 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.

7. 7. 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 additional pharma-ceutically acceptable solvent, if present, comprises benzyl alcohol, benzyl benzoate, or a combination thereof.

8. 4. The pharmaceutical composition of 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 greater, 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.

9. 9. 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 to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition.

10. 10. The pharmaceutical composition of claim 9, wherein the administration is by intramuscular, intradermal, or subcutaneous injection, optionally wherein the pharmaceutical composition is administered to the subject with or without food.

11. 11. The pharmaceutical composition of 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.

12. 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.

13. 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.

14. 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 a bilateral orchiectomy.

15. The pharmaceutical composition of any one of claims 9 to 14, wherein the method further comprises administering a corticosteroid to the subject.

16. 16. 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.

17. 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.

18. The administration, (a) a plasma concentration of abiraterone greater than 1.0 ng / ml for a period of at least two weeks; (b) Single dose or steady-state C of 10 ng / ml to 400 ng / ml of abiraterone ｍａｘ ;or (c) Both (a) and (b). The pharmaceutical composition according to any one of claims 9 to 17,

19. 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. 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. 21. The pharmaceutical composition of claim 20, 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 in a concentration from 50 mg / mL to 300 mg / mL.

22. 22. 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.

23. 23. The pharmaceutical composition of claim 22, which is administered via intramuscular injection.

24. 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.

25. 2. The abiraterone decanoate of claim 1, which is in a crystalline form characterized by an X-ray powder diffraction (XRPD) spectrum having one or more 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 69.0° C. (including variations in said temperature that may occur through routine DSC testing and processing); or a combination thereof.

26. 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: forming a mixture; and optionally b) sterilizing the mixture formed in a); and The method comprising:

27. 27. The method of claim 26, wherein said mixing comprises mixing a crystalline form of abiraterone decanoate in the pharma- ceutically acceptable carrier, and said 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. 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.

29. 1) Abiraterone decanoate according to claim 1, 2) a pharma- ceutically acceptable oil, and 3) Benzyl alcohol and / or benzyl benzoate A pharmaceutical composition comprising: 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.

30. 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 A unit dosage form comprising:

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.

31. 31. 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.

32. 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.

33. 33. 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.

34. 2. 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.

35. 1. A pharmaceutical composition comprising a compound of formula II or a pharma- ceutical acceptable salt thereof, During the ceremony, R ２ is C ７－１６ alkyl; and cycloalkyl-substituted alkyl 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.

36. 36. The pharmaceutical composition of claim 35, further comprising benzyl alcohol, benzyl benzoate, or a combination thereof.

37. 37. 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.

38. A compound of formula I, or a pharma- ceutically acceptable salt thereof, In the formula, R １ is represented by 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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