Abiraterone prodrug

Abstract

Provided are sustained-release abiraterone prodrug formulations, methods, and kits for parenteral administration to subjects suffering from sex hormone-dependent benign or malignant conditions such as prostate cancer, syndromes due to androgen excess, and / or syndromes due to glucocorticoid excess such as hypercortisolemia.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 814,568, filed on March 6, 2019, and U.S. Provisional Application No. 62 / 849,259, filed on May 17, 2019, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present disclosure generally relates to novel abiraterone prodrugs and long-acting, depot-based parenteral formulations of abiraterone prodrugs. The present disclosure is amenable to a wide range of applications, such as for intramuscular (IM) injection to patients with androgen- or estrogen-dependent benign or malignant conditions, including various cancers (such as prostate cancer, bladder cancer, hepatocellular carcinoma, lung cancer, breast cancer, and ovarian cancer, etc.), and for the treatment of non-neoplastic syndromes caused by excessive androgen production (including classic and non-classical congenital adrenal hyperplasia, endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc.) or by excessive glucocorticoid production (usually Cortisol in conditions such as Cushing's syndrome or Cushing's disease). Background Art

[0003] Abiraterone ((3β)-17-(pyridin-3-yl)androsta-5,16-dien-3-ol; CAS No.: 154229-19-3); Formula: C 24 H 31 NO; molar weight: 349.5 g / mol) is an inhibitor of CYP17A1 (CYP17A1 is a member of the cytochrome P450 enzyme superfamily that catalyzes the synthesis of cholesterol, steroids and other lipids and is involved in drug metabolism). CYP17A1 has 17α-hydroxylase activity and 17,20-lyase activity. Abiraterone effectively and selectively inhibits the CYP17A1 17α-hydroxylase and 17,20-lyase enzyme activities. The 17α-hydroxylase activity of CYP17A1 is required for the production of glucocorticoids such as cortisol. However, the hydroxylase and 17,20-lyase activities of CYP17A1 are required for the production of androgenic steroids (e.g., androstenedione, testosterone, and dihydrotestosterone) and estrogenic steroids (estrone, estradiol, estriol) by converting 17α-hydroxypregnenolone into the sex steroid precursor, dehydroepiandrosterone, see Fig.14D Thus, abiraterone interferes with the synthesis of androgens and estrogens both in the gonads (primarily in the testes and ovaries) and outside the gonads (e.g., in the adrenal glands and in the tumor itself).

[0004] Although abiraterone itself is poorly absorbed, it can be administered orally as an abiraterone acetate prodrug. Abiraterone acetate is also poorly absorbed but can be converted to abiraterone in the intestines, and after cleavage of the acetate prodrug, abiraterone is poorly absorbed into the bloodstream. Abiraterone acetate ((3β)-17-(3-pyridyl)androsten-5-acetate; CAS No. 154229-18-2) is available in the United States for The brand name is approved for the treatment of castration-resistant or castration-sensitive prostate cancer. Abiraterone acetate is also now available worldwide.

[0005] It is known that orally administered abiraterone acetate is not absorbed by the gastrointestinal tract (and is not detected in plasma). Instead, it has been demonstrated that abiraterone acetate is hydrolyzed to abiraterone in the intraluminal environment, resulting in abiraterone supersaturation, which is responsible for the strong driving force for abiraterone absorption (Stappaerts et al., Eur. J. Pharmaceutics Biopharmaceutics 90: 1, 2015).

[0006] Because abiraterone blocks the normal physiological production of steroids by the adrenal glands, its prodrug formulations are often prescribed with low-dose steroids to prevent adrenal insufficiency. Tablets (250 mg) are approved in the United States for use 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 provided recommends 1,000 mg (4 x 250 mg tablets) taken orally once daily in combination with prednisone (5 mg) taken orally twice daily for patients with castration-resistant prostate cancer or once daily for patients with castration-sensitive prostate cancer. Used in combination with prednisone or prednisolone.

[0007] Because administration of abiraterone acetate with food increases the absorption of abiraterone acetate (thus, potentially resulting in increased and highly variable exposure, which could potentially lead to a variety of side effects, including cardiovascular side effects and / or hepatotoxicity), the prodrug should be taken on an empty stomach at least one hour before or two hours after a meal. The prescribing information for states that it must be taken on an empty stomach, and food should not be consumed for at least two hours before and at least one hour after oral administration.

[0008] The prescribing information explains that for patients with metastatic castration-resistant prostate cancer, a daily oral dose of 1,000 mg Abiraterone steady state C maxThe value was 226±178 ng / mL (mean±SD) and its area under the curve (AUC) value was 1173±690 ng.hr / mL (mean±SD). A single-dose (1,000 mg) crossover study found that When administered with food, systemic exposure of abiraterone is increased. When administered with a low-fat meal (7% fat, 300 calories), the C max and AUC values ​​were approximately 7 and 5 times higher, respectively, whereas When administered with a high-fat meal (57% fat, 825 calories), the levels were approximately 17-fold and 10-fold higher, respectively.

[0009] The currently approved solid oral dosage form of the prodrug abiraterone acetate has several disadvantages. For example, it has very low bioavailability, requiring patients to take a large pill burden per day (4 x 250 mg tablets once a day). In addition, due to the combination of low bioavailability and a large food effect, it results in highly variable blood levels in patients. Furthermore, because abiraterone is rapidly cleared, this approved administration regimen results in a daily C of abiraterone. min , which is believed to be associated with loss of treatment efficacy in patients with metastatic castration-resistant prostate cancer.

[0010] Non-oral modes of administration (eg, parenteral routes) have been explored for other classes of drugs. However, to date, there are no sustained-release injectable prodrug formulations of abiraterone. Summary of the invention

[0011] In various embodiments, the present disclosure provides novel abiraterone prodrugs, long-acting abiraterone prodrug formulations, and methods of using them, for example, for treating subjects with sex hormone-dependent benign or malignant conditions and / or syndromes caused by androgen and / or glucocorticoid excess. Typically, the novel abiraterone prodrugs herein can be fatty acid esters of abiraterone, which release abiraterone and safe, degradable fatty acid components upon cleavage. As described in detail herein, the novel abiraterone prodrugs and formulations disclosed herein are a breakthrough compared to oral abiraterone acetate formulations because they provide increased bioavailability, eliminate food effects, reduce pill burden, reduce administration frequency, and sustained effective abiraterone plasma levels, such as continuous plasma exposures higher than the daily C observed with oral administration of abiraterone acetate. minLevels, for example, persist for at least one week, typically at least two weeks, after administration of the abiraterone prodrug formulation. In addition, pharmacokinetic and pharmacodynamic studies of representative abiraterone prodrugs herein (such as abiraterone decanoate or abiraterone isoleate) demonstrate that the novel abiraterone prodrugs and formulations disclosed herein are suitable for administration once a week, once a month, or even less frequently for the treatment of subjects with sex hormone-dependent benign or malignant conditions described herein, syndromes caused by androgen excess, and / or syndromes caused by glucocorticoid excess. This feature alone represents a significant difference from currently marketed This is a significant improvement over the FDA-approved tablets, which require patients to carry a large daily pill burden (4 x 250 mg tablets once daily).

[0012] Some embodiments of the present disclosure relate to novel abiraterone prodrugs. In some embodiments, the abiraterone prodrug may be a compound of formula I or a pharmaceutically acceptable salt thereof:

[0013]

[0014] Where R 1 Defined in this article.

[0015] In a representative embodiment, abiraterone prodrug formulation is provided for parenteral administration to a subject suffering from sex hormone-dependent benign or malignant diseases, syndrome caused by androgen excess and / or syndrome caused by glucocorticoid (e.g., cortisol) excess. On the one hand, the formulation includes the lipophilic ester form of abiraterone and one or more pharmaceutically acceptable carriers, diluents or excipients (so that, for example, the prodrug formulation exists as a solution or suspension in a pharmaceutically acceptable oil, the oil such as oil or synthetic oil of plant origin, including synthetic fatty acid monoglyceride or diglyceride; For example, the prodrug formulation can exist as a solution or suspension in vegetable oil and other cosolvents and excipients). In certain representative embodiments, the lipophilic ester form of abiraterone can be acetate, propionate, butyrate, valeric acid ester, caprylate, enanthate, cyclopentyl propionate, isocrylate, butanecarboxylate, cyclohexanecarboxylate, phenyl propionate, decanoate or undecanoate. In some embodiments, the abiraterone prodrug formulation may comprise a compound of Formula II or a pharmaceutically acceptable salt thereof:

[0016]

[0017] Where R 2As defined herein. In some embodiments, the abiraterone prodrug formulation can be formulated for intramuscular injection, intradermal injection, or subcutaneous injection. In some embodiments, the compound of formula II or a pharmaceutically acceptable salt thereof can be present in the formulation at a concentration of about 25 mg / ml to about 500 mg / ml.

[0018] Typically, after the formulation (e.g., abiraterone prodrug formulation herein) is administered, the therapeutic plasma concentration of abiraterone is reached and continues for at least one week, for example, at least two weeks and up to four weeks or more weeks. On the one hand, after parenteral administration of the prodrug formulation, the therapeutic plasma concentration of abiraterone is at least 1 ng / ml, for example, 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 plasma concentration of abiraterone may also be about 0.5 ng / ml or higher. Parenteral administration may be via intramuscular injection, intradermal injection or subcutaneous injection. On the one hand, the formulation is suitable for treating sex hormone-dependent benign or malignant conditions, such as androgen-dependent conditions and estrogen-dependent conditions, such as androgen-dependent cancer or estrogen-dependent cancer. Sex hormone-dependent benign or malignant conditions may include prostate cancer and breast cancer. Prostate cancer may include castration-resistant prostate cancer and castration-sensitive prostate cancer. In some embodiments, sex hormone-dependent benign or malignant conditions may include various cancers, such as ovarian cancer, bladder cancer, hepatocellular carcinoma, lung cancer, etc. It is expected that inhibition of CYP17A1 will reduce excessive production of androgens and glucocorticoids (e.g., Cortisol). The abiraterone prodrug formulations herein are not limited to treating tumor conditions described herein, but can also be used to treat non-tumor syndromes caused by excessive androgens and glucocorticoids (e.g., Cortisol). On the one hand, the formulation is suitable for treating non-tumor syndromes caused by excessive androgens, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classic or non-classical congenital adrenal hyperplasia), precocious puberty, hirsutism, etc., and / or syndromes caused by excessive glucocorticoids (e.g., Cortisol), such as Cushing's syndrome or Cushing's disease.

[0019] Parenteral formulations fill a long-standing unmet need by providing an alternative to oral formulations, which suffer from the following problems: (1) poor bioavailability, (2) interactions with ingested food, (3) delivery of highly variable blood levels of the parent drug with the potential for reduced efficacy and increased side effects, (4) requirement for daily administration and high pill burden, and (5) poor patient compliance due to the need to fast within hours of administration, high pill burden, and the need for daily supplemental administration of prednisone or prednisolone and conflicting dosing schedules when taken with food.

[0020] An object of the present disclosure is to provide a method of inhibiting CYP17A1 activity, such as inhibiting 17α-hydroxylase activity and 17,20-lyase activity, by parenterally administering an effective dose of at least one abiraterone prodrug formulation to a subject in need thereof. In some embodiments, the subject suffers from a sex hormone-dependent benign or malignant condition, a syndrome caused by androgen excess, and / or a syndrome caused by glucocorticoid excess (such as hypercortisolemia described herein).

[0021] An object of the present disclosure is to provide a method of reducing glucocorticoid (e.g., Cortisol) levels by parenterally administering an effective dose of at least one abiraterone prodrug formulation to a subject in need thereof. In some embodiments, the subject suffers from an excess of glucocorticoids, such as a syndrome caused by hypercortisolemia as described herein. In some embodiments, the subject suffers from Cushing's syndrome or Cushing's disease.

[0022] An object of the present disclosure is to provide a method of reducing the level of androgen (e.g., testosterone and / or dihydrotestosterone) and / or estrogen by parenterally administering an effective dose of at least one abiraterone prodrug formulation to a subject in need thereof. In some embodiments, the subject suffers from a syndrome caused by androgen excess, such as classic and nonclassical congenital adrenal hyperplasia, endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc. In some embodiments, the subject suffers from androgen and / or estrogen related cancers, such as prostate cancer or breast cancer.

[0023] Another object is to provide a method for treating sex hormone-dependent benign or malignant conditions, syndromes caused by androgen excess, and / or syndromes caused by glucocorticoid excess (such as hypercortisolemia) by parenteral administration of at least one abiraterone prodrug formulation to a subject in need of such treatment. In a representative embodiment, the method is used to treat sex hormone-dependent benign or malignant conditions, which are androgen-dependent conditions or estrogen-dependent conditions, such as androgen-dependent cancer or estrogen-dependent cancer. Sex hormone-dependent benign or malignant conditions may include prostate cancer or breast cancer. Prostate cancer may include castration-resistant prostate cancer and castration-sensitive prostate cancer. In some embodiments, sex hormone-dependent benign or malignant conditions may also include ovarian cancer, bladder cancer, hepatocellular carcinoma, lung cancer, etc. In a representative embodiment, the method is used to treat non-neoplastic syndromes caused by androgen excess, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classic or nonclassical congenital adrenal hyperplasia), precocious puberty, hirsutism, etc., and / or syndromes caused by excess glucocorticoids (e.g., Cortisol), such as Cushing's syndrome or Cushing's disease.

[0024] In some embodiments, the abiraterone prodrug formulation may include at least one compound of formula I or II or a pharmaceutically acceptable salt thereof. On the one hand, the formulation includes a lipophilic ester form of abiraterone and one or more pharmaceutically acceptable carriers, diluents or excipients. In certain representative embodiments, the lipophilic ester form of abiraterone may be, for example, acetate, propionate, butyrate, valeric acid ester, caprylate, enanthate, cyclopentyl propionate, isocrylate, butanecarboxylate, cyclohexanecarboxylate, phenyl propionate, decanoate or undecanoate. After the formulation is applied to a subject in need thereof, the therapeutic plasma concentration of abiraterone is reached and continued for at least one week, for example, at least two weeks and up to four weeks or more weeks. On the one hand, after parenteral administration of the prodrug formulation, the therapeutic plasma concentration of abiraterone is at least 1 ng / ml, for example, 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 plasma concentration of abiraterone may also be about 0.5 ng / ml or higher. Parenteral administration can be via intramuscular injection, intradermal injection or subcutaneous injection. In certain embodiments, the method may include administering at least one abiraterone prodrug formulation once a month. On the one hand, at least one abiraterone prodrug formulation can be administered in divided doses. In another representative embodiment, at least one abiraterone prodrug formulation can be administered simultaneously with one or more different prodrug formulations and / or at least one other drug or medicament (e.g., another cancer chemotherapy drug, hormone replacement drug or hormone ablation drug). In certain aspects, at least one abiraterone prodrug formulation can be administered before at least one other drug or medicament. Alternatively, at least one abiraterone prodrug formulation can be administered after at least one other drug or medicament. In other representative embodiments, one or more formulations can be administered more than once in the process of several days, weeks, months or years to provide initial and continuous treatment of sex hormone-dependent benign or malignant conditions (such as prostate cancer), syndromes caused by excessive androgens and / or syndromes caused by excessive glucocorticoids such as hypercortisolemia. In another representative embodiment, at least one abiraterone prodrug formulation can contain at least two different lipophilic ester forms of abiraterone and the formulation can 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 can contain at least two different lipophilic ester forms of abiraterone and the formulation can be administered before at least one other drug or agent. Alternatively, at least one abiraterone prodrug formulation can contain at least two different lipophilic ester forms of abiraterone and the formulation can be administered before at least one other drug or agent.In other representative embodiments, one or more formulations containing at least two different lipophilic ester forms of abiraterone may be administered more than once over the course of days, weeks, months, or years to provide initial and ongoing treatment of sex hormone-dependent benign or malignant conditions (such as prostate cancer), syndromes due to androgen excess, and / or syndromes due to glucocorticoid excess such as hypercortisolemia. The lipophilic ester form of abiraterone may be selected from, for example, acetate, propionate, butyrate, valeric acid ester, isocaprylate, enanthate, cypionate, isocaprylate, butyrate, cyclohexanecarboxylate, phenyl propionate, decanoate, or undecanoate.

[0025] Another object is to provide a test kit for treating a subject suffering from a sex hormone-dependent benign or malignant condition (e.g., prostate cancer), a syndrome caused by excessive androgen, and / or a syndrome caused by excessive glucocorticoids such as hypercortisolemia. In representative embodiments, the test kit includes a container, such as a bottle, an ampoule, or a pre-filled syringe, which contains one or more preparations. In another representative embodiment, the test kit includes a container, such as a bottle, an ampoule, or a pre-filled syringe, which contains one or more preparations and at least one other drug or medicament that can enhance the efficacy of the preparation or reduce the adverse side effects of the preparation. In other representative embodiments, the test kit includes a container, such as a bottle, an ampoule, or a pre-filled syringe, which contains one or more preparations and at least one other drug or medicament that can enhance the efficacy of the preparation or reduce the adverse side effects of the preparation. It should be understood that the preparation can contain a lipophilic ester form of abiraterone or two or more different lipophilic ester forms of abiraterone. Those skilled in the art will appreciate that kits and packages may be prepared that include one, all or any combination of a formulation, a diluent, a buffer, an adjuvant, a pharmaceutically acceptable carrier and at least one other drug or agent that can enhance the efficacy of the formulation or reduce an adverse side effect of the formulation.

[0026] Another object is to provide a method for preparing abiraterone decanoate formulation suitable for parenteral administration to subjects suffering from sex hormone-dependent benign or malignant disorders, syndromes due to androgen excess and / or syndromes due to glucocorticoid excess such as hypercortisolemia.

[0027] These and other objects can be achieved in certain embodiments.

[0028] In some embodiments, the present disclosure provides:

[0029] [1] A compound of formula I or a pharmaceutically acceptable salt thereof,

[0030]

[0031] Where R 1 For R 10 , OR 10 or NHR 10 ,

[0032] Where R 10 Selected from:

[0033] C 7-30 Alkyl; C 7-30 Alkenyl; C 7-30 Alkynyl: alkyl having a total of 5 to 16 carbon atoms substituted by a cycloalkyl group; alkyl having a total of 7 to 16 carbon atoms substituted by a phenyl group; cycloalkyl having a total of 5 to 16 carbon atoms optionally substituted by one or more alkyl groups; and

[0034] [2] The compound or pharmaceutically acceptable salt thereof as described in [1], wherein R 1 C 7-16 alkyl,

[0035] [3] The compound or pharmaceutically acceptable salt thereof according to [1] or [2], wherein R 1 It has the formula -(CH2) n -CH3 alkyl, wherein n is an integer selected from 6, 7, 8, 9, 10, 11 or 12.

[0036] [4] The compound or a pharmaceutically acceptable salt thereof as described in [1], wherein R 1 is -(CH2)8-CH3 or The alkyl group;

[0037] [5] A pharmaceutical composition comprising the compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier;

[0038] [6] A pharmaceutical composition comprising abiraterone decanoate having the following formula:

[0039]

[0040] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0041] [7] The pharmaceutical composition according to [5] or [6], which is formulated for intramuscular injection, intradermal injection or subcutaneous injection,

[0042] [8] The pharmaceutical composition of any one of [5] to [7], wherein the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil and optionally another pharmaceutically acceptable solvent,

[0043] [9] The pharmaceutical composition of [8], wherein the pharmaceutically acceptable oil comprises a triglyceride (e.g., a long chain and / or medium chain triglyceride), and the additional pharmaceutically acceptable solvent, if present, comprises an alcohol, an ester, and / or an acidic solvent,

[0044]

[10] The pharmaceutical composition of any one of [8]-[9], wherein the pharmaceutically acceptable oil is selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil (earthen oil), poppy seed oil, tea seed oil and soybean oil, and the additional pharmaceutically acceptable solvent, if present, comprises benzyl alcohol, benzyl benzoate or a combination thereof,

[0045]

[11] A pharmaceutical composition as described in any of [6]-

[10] , comprising abiraterone decanoate or a pharmaceutically acceptable salt thereof, wherein the amount of abiraterone decanoate or a pharmaceutically acceptable salt thereof is sufficient to provide a therapeutically effective abiraterone plasma concentration, or an abiraterone plasma concentration of about 1 ng / ml or more, for at least two weeks (e.g., at least three weeks, at least four weeks and up to six weeks or eight weeks or longer) after a single administration to a subject suffering from one or more conditions selected from sex hormone-dependent benign or malignant conditions, syndromes caused by excess androgens, and syndromes caused by excess glucocorticoids such as hypercortisolemia.

[0046]

[12] A method for treating one or more conditions selected from sex hormone-dependent benign or malignant conditions, syndromes due to androgen excess, and syndromes due to glucocorticoid excess such as hypercortisolemia, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition described in any one of [5] to

[11] ,

[0047]

[13] The method of

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

[0048]

[14] The method of any one of

[12] -

[13] , wherein the pharmaceutical composition is administered to the subject with or without food,

[0049]

[15] The method of any one of

[12] -

[14] , wherein the one or more conditions 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 congenital adrenal hyperplasia, nonclassical congenital adrenal hyperplasia, precocious puberty, hirsutism, and combinations thereof.

[0050]

[16] The method of any one of

[12] -

[14] , wherein the one or more conditions are sex hormone-dependent benign or malignant conditions selected from castration-resistant prostate cancer and castration-sensitive prostate cancer.

[0051]

[17] The method of any one of

[12] -

[14] , wherein the one or more conditions are sex hormone-dependent benign or malignant conditions selected from metastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer.

[0052]

[18] The method of any one of

[12] -

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

[0053]

[19] The method of any one of

[12] -

[18] , further comprising administering a corticosteroid to the subject,

[0054]

[20] The method of any one of

[12] to

[19] , further comprising administering prednisone, prednisolone and / or methylprednisolone to the subject,

[0055]

[21] The method of any one of

[12] to

[20] , wherein the pharmaceutical composition is administered to the subject once a week or more than once a week, for example, the administration frequency ranges from once a week to once every several months, such as once a week to once every eight weeks, or once a week to once every three months,

[0056]

[22] The method of any one of

[12] -

[21] , wherein the administration provides (a) abiraterone plasma concentrations above 1.0 ng / ml for at least two weeks; (b) a single dose of abiraterone or a steady-state C of between about 10 ng / ml and about 400 ng / ml. max or (c) both (a) and (b),

[0057]

[23] A pharmaceutical composition, such as a unit dosage form, comprising a therapeutically effective amount of abiraterone decanoate having the formula:

[0058] a pharmaceutically acceptable oil and a pharmaceutically acceptable solvent, wherein the abiraterone decanoate is present in its basic form at a concentration of about 25 mg / ml to about 500 mg / ml, wherein the pharmaceutical composition, e.g., a unit dosage form, is formulated for intramuscular injection, intradermal injection, or subcutaneous injection, wherein the pharmaceutical composition, e.g., a unit dosage form, comprises abiraterone decanoate in an amount of about 50 mg to about 2,000 mg.

[0059]

[24] The pharmaceutical composition of

[23] , e.g., in unit dosage form, wherein the pharmaceutically acceptable oil comprises a triglyceride, and the pharmaceutically acceptable solvent comprises an alcohol, an ester and / or an acid solvent,

[0060]

[25] A pharmaceutical composition as described in

[23] or

[24] , such as a unit dosage form, wherein the pharmaceutically 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 pharmaceutically acceptable solvent comprises benzyl alcohol and / or benzyl benzoate, and wherein the abiraterone decanoate is present in a concentration of about 50 mg / mL to about 300 mg / mL, such as about 100 mg / mL to about 300 mg / mL,

[0061]

[26] A method for treating prostate cancer, comprising administering the pharmaceutical composition described in any one of

[23] -

[25] , e.g., in unit dosage form, to a subject in need thereof via intramuscular injection, intradermal injection, or subcutaneous injection, once a month or more than once a month, for example, the administration frequency ranges from once a month to once every several months, such as once a month to once every two months, or once a month to once every three months, etc.

[0062]

[27] The method of

[26] , wherein the pharmaceutical composition, such as a unit dosage form, is administered via intramuscular injection,

[0063]

[28] A method for preparing abiraterone decanoate formulation suitable for parenteral administration to a subject suffering from a sex hormone-dependent benign or malignant condition, a syndrome due to androgen excess, and / or a syndrome due to glucocorticoid excess such as hypercortisolemia, comprising:

[0064] a) abiraterone decanoate having the following formula:

[0065] mixed in a pharmaceutically acceptable carrier to form a mixture; and optionally

[0066] b) sterilizing the mixture formed in a),

[0067]

[29] The method of

[28] , wherein the mixing comprises mixing a crystalline form of abiraterone decanoate in the pharmaceutically acceptable carrier, wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) peaks: 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,

[0068]

[30] The method of

[28] or

[29] , wherein the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil and a pharmaceutically acceptable solvent, wherein the pharmaceutically 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 pharmaceutically acceptable solvent comprises benzyl alcohol or benzyl benzoate, and wherein the abiraterone decanoate is present in a concentration of about 50 mg / mL to about 300 mg / mL, such as about 100 mg / mL to about 300 mg / mL.

[0069] Embodiments of the present disclosure can meet the long-term needs of sex hormone-dependent diseases and oncology fields, including chemotherapy for prostate cancer. Embodiments of the present disclosure can also meet the long-term needs of the syndrome field caused by excessive androgen syndrome and / or due to excessive glucocorticoids such as hypercortisolemia. Embodiments of the present disclosure can overcome the major shortcomings and deficiencies of the prior art formulations (including commercially available oral dosage forms) of abiraterone acetate by providing a long-acting, sustained-release reservoir-based parenteral formulation of abiraterone prodrug, a method for producing the formulation, a method for treating the formulation, and a test kit for conveniently applying the formulation to a subject of various diseases including prostate cancer who needs to treat.

[0070] Thus, features have been summarized rather broadly so that the detailed description that follows may be better understood and the contribution of the present invention to the art may be better appreciated. Of course, there are additional features that will be further described below. Indeed, it should be understood that both the foregoing summary and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the present disclosure.

[0071] In this regard, before explaining in detail at least one embodiment of the present invention, it is to be understood that the application of the present invention is not limited to the details of component construction and arrangement set forth in the following description or shown in the accompanying drawings. The present invention can have other embodiments and can be implemented and executed in various ways. In addition, it is to be understood that the terms and terminology employed herein are for descriptive purposes and should not be considered limiting.

[0072] Therefore, those skilled in the art will recognize that the concepts upon which the present disclosure is based can be easily used as the basis for designing other formulations, methods, systems, kits and compositions to achieve the several purposes of the present disclosure. Therefore, it is important that equivalent constructions that do not depart from the spirit and scope of the present disclosure are included in the present disclosure.

[0073] The accompanying drawings, which are included to provide a further understanding and are incorporated in and constitute a part of this specification, illustrate several embodiments and together with the description serve to explain principles. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] Figure 1 Shown are mean plasma concentrations of abiraterone (ng / ml) at various times (hours) following intramuscular (IM) administration of various abiraterone or abiraterone acetate formulations in rats. Figure 1 Shown are the curves obtained with abiraterone acetate solution in castor oil (70 mg / ml); the curve obtained with abiraterone acetate suspension, sodium phosphate buffer, 0.1% Tween (70 mg / ml); the curve obtained with abiraterone suspension in castor oil (62.5 mg / ml) and the curve obtained with abiraterone suspension, sodium phosphate buffer, 0.1% Tween (62.5 mg / ml).

[0076] Figure 2 Shown are mean plasma concentrations of abiraterone (ng / ml) at various times (hours) following intramuscular or intravenous (IV) administration of various abiraterone acetate formulations in dogs. Figure 2 Shown are curves obtained by intravenous administration of abiraterone acetate solution (33% HP-β-cyclodextrin in water) at a dose of 10 mg / kg; a curve obtained by intramuscular administration of abiraterone acetate solution in castor oil (66 mg / ml) at a dose of 21 mg / kg; a curve obtained by intramuscular administration of abiraterone acetate solution in castor oil containing 10% benzyl alcohol (91 mg / ml) at a dose of 30 mg / kg; and a curve obtained by intramuscular administration of abiraterone acetate solution in castor oil containing 50% benzyl benzoate (124 mg / ml) at a dose of 42 mg / kg.

[0077] Figure 3 Shown are mean plasma concentrations (ng / ml) of abiraterone (top line) and abiraterone acetate (bottom line) at various times (hours) following intravenous administration of abiraterone acetate (as a 33% HP-β-cyclodextrin aqueous solution at a dose of 10.3 mg / ml) in dogs.

[0078] Figure 4 Shown are mean plasma concentrations (ng / ml) of abiraterone (top line) and abiraterone acetate (bottom line) at various times (hours) following intramuscular administration of abiraterone acetate (91 mg / ml) in castor oil containing 10% benzyl alcohol in dogs at a dose of 30 mg / kg.

[0079] Figure 5 Data are shown plotting mean abiraterone and abiraterone decanoate plasma concentrations versus time following intravenous administration of 1.2 mg / kg abiraterone decanoate in dogs. Error bars represent standard deviations.

[0080] Figure 6Data are shown plotting mean abiraterone and abiraterone propionate plasma concentrations versus time following intravenous administration of 1 mg / kg abiraterone propionate in dogs. Error bars represent standard deviations.

[0081] Figure 7 Data are shown plotting mean abiraterone and abiraterone decanoate plasma concentrations versus time following intramuscular administration of 50 mg / kg abiraterone decanoate (90% castor oil / 10% benzyl alcohol) in dogs. Error bars represent standard deviation.

[0082] Figure 8 Data are shown plotting mean abiraterone and abiraterone decanoate plasma concentrations versus time following intramuscular administration of 50 mg / kg abiraterone decanoate (90% corn oil / 10% benzyl alcohol) in dogs. Error bars represent standard deviation.

[0083] Fig. 9 Data are shown plotting mean abiraterone and abiraterone propionate plasma concentrations versus time following intramuscular administration of 41 mg / kg abiraterone propionate (90% castor oil / 10% benzyl alcohol) in dogs. Error bars represent standard deviation.

[0084] Fig.10 Data are shown plotting mean abiraterone and abiraterone propionate plasma concentrations versus time following intramuscular administration of 41 mg / kg abiraterone propionate (90% corn oil / 10% benzyl alcohol) in dogs. Error bars represent standard deviations.

[0085] Fig.11A , Fig. 11B , Fig. 11C and Fig.11D Shown are exemplary predicted human abiraterone plasma concentrations following intramuscular administration of abiraterone decanoate obtained by computer modeling in humans using an assumed infusion half-life identical to that observed in dogs. Fig.11A Computer modeling predictions following biweekly 120 mg intramuscular doses of abiraterone decanoate are shown and Fig. 11B Computer modeling predictions following 350 mg intramuscular doses of abiraterone decanoate every four weeks are shown. Fig. 11C Computer modeling predictions following 1000 mg intramuscular doses of abiraterone decanoate every six weeks are shown. Fig.11D Computer modeling predictions following bimonthly 1700 mg intramuscular doses of abiraterone decanoate are shown. Fig.11A , Fig. 11B , Fig. 11C and Fig.11D The horizontal line in the figure represents the target C of abiraterone. min The value was about 8 ng / ml.

[0086] Fig. 12AA representative X-ray powder diffraction (XRPD) spectrum of the solid form of abiraterone decanoate prepared in Example 6A is presented.

[0087] Fig. 12B Shown is the differential scanning calorimetry (DSC) spectrum of the solid form of abiraterone decanoate prepared in Example 6A.

[0088] Fig. 12C Shown is the thermogravimetric analysis (TGA) of the solid form of abiraterone decanoate prepared in Example 6A.

[0089] Fig.13A A graph presenting the solubility of abiraterone decanoate in corn oil in the presence of varying amounts of benzyl alcohol and benzyl benzoate. Fig. 13B Contour plot showing the solubility of abiraterone decanoate in corn oil in the presence of varying amounts of benzyl alcohol and benzyl benzoate. Fig. 13C The viscosity (Pa*s) of various oil vehicles without additives or with 10% benzyl alcohol, 20% benzyl benzoate or a combination of 10% benzyl alcohol and 20% benzyl benzoate is shown. Fig.13D and Fig.13E Shown are the glide forces (N) of various oil vehicles tested with a 5 ml syringe using a 23 gauge needle or a 27 gauge needle, respectively, without additives or with 10% benzyl alcohol, 20% benzyl benzoate, or a combination of 10% benzyl alcohol and 20% benzyl benzoate.

[0090] Fig.14A Shown are mean abiraterone and abiraterone decanoate plasma concentration versus time curve data following intravenous 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) in male cynomolgus monkeys (n=3).

[0091] Fig. 14B Shown are curve data of mean abiraterone and abiraterone decanoate plasma concentrations versus time following a single intramuscular administration of an abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 192 mg / ml abiraterone decanoate) at a dose of 90 mg / kg abiraterone decanoate in male cynomolgus monkeys (n=3). Fig. 14C The data are shown as a graph of the steroid levels (progesterone, cortisol and testosterone levels) observed after this single dose intramuscular administration versus time. Fig. 14C As shown, after a single intramuscular dose, long-lasting CYP17A1 inhibition was achieved, as evidenced by a sustained increase in progesterone levels and a decrease in glucocorticoid (cortisol) and sex hormone (testosterone) levels. Fig.14DBiochemical pathways showing the effects of CYP17A1 inhibition on the synthesis of androgens, estrogens, glucocorticoids, progesterone, and mineralocorticoids are presented. Fig.14D As shown, inhibition of CYP17A1 17a-hydroxylase and C17,20-lyase activities will result in (1) increased levels of progesterone and mineralocorticoids; (2) decreased levels of glucocorticoids such as cortisol; and (3) decreased levels of sex hormones, such as androgens (such as testosterone and dihydrotestosterone) and estrogens (such as estradiol).

[0092] Fig.14E Shown are mean abiraterone and abiraterone decanoate plasma concentration versus time curve data following multiple dose intramuscular administration of an abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 192 mg / ml abiraterone decanoate) in male cynomolgus monkeys (n=3) on Days 0, 7, and 35. Each dose was 90 mg / kg abiraterone decanoate.

[0093] Fig.14F Shown are mean abiraterone plasma concentration versus time curve data in male cynomolgus monkeys (n=1) after multiple dose intramuscular administration 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) on Days 0, 7, and 14. Each dose was 100 mg / kg abiraterone decanoate.

[0094] Fig.15A Shown are mean abiraterone and abiraterone decanoate plasma concentration versus time data following intravenous 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) in male rats (n=5).

[0095] Fig. 15B Shown are curve data of mean abiraterone and abiraterone decanoate plasma concentrations versus time following a single intramuscular administration of an abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 172 mg / ml abiraterone decanoate) at a dose of 90 mg / kg abiraterone decanoate in male rats (n=5).

[0096] Fig. 15C Shown are mean abiraterone and abiraterone decanoate plasma concentration versus time curve data following multiple dose intramuscular administration of an abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 172 mg / ml abiraterone decanoate) in male rats (n=5) on days 0, 7, and 35. Each dose was 90 mg / kg abiraterone decanoate.

[0097] Fig.16A Allometric scaling of the volume of distribution (Vss) of abiraterone in rat, dog and monkey is shown, with predictions in humans.

[0098] Fig. 16B The predicted plasma profile of abiraterone following a single 1 mg intramuscular dose of abiraterone in humans based on a bioavailability of 56% is shown.

[0099] Fig. 16C The predicted plasma profile of abiraterone following repeated intramuscular doses of abiraterone decanoate at 1000 mg every 4 weeks in humans based on a bioavailability of 56% is shown.

[0100] Fig.16D The predicted plasma profile of abiraterone following repeated intramuscular doses of abiraterone decanoate at 1000 mg every 4 weeks in humans assuming complete bioavailability is shown.

[0101] Fig.17A Data are shown plotting mean abiraterone and abiraterone isocaprylate plasma concentrations versus time following intravenous administration of 1.0 mg / kg abiraterone isocaprylate in dogs. Error bars represent standard deviations.

[0102] Fig. 17B Data are shown plotting mean abiraterone and abiraterone isocaprylate plasma concentrations versus time following intramuscular administration of abiraterone isocaprylate in dogs. Error bars represent standard deviations.

[0103] Fig. 17C Data are shown plotting mean abiraterone and abiraterone decanoate plasma concentrations versus time following intramuscular administration of abiraterone decanoate in dogs. Error bars represent standard deviations.

[0104] Fig.17D Data are shown plotting mean abiraterone plasma concentration versus time following intramuscular administration of abiraterone isoleate or abiraterone decanoate in dogs. Error bars represent standard deviation. DETAILED DESCRIPTION

[0105] The present disclosure relates to compounds and compositions that deliver therapeutic plasma levels of active drug Abiraterone to subjects over an extended period of time. Preliminary experiments in rats determined that intramuscular injection of active drug Abiraterone suspension did not reach the desired therapeutic plasma levels. However, as described in detail herein, representative novel Abiraterone prodrugs and formulations were found to reach the desired therapeutic plasma levels over a long period of time when administered parenterally (e.g., intramuscularly).

[0106] Therefore, various embodiments of the present disclosure are directed to such novel abiraterone prodrugs and formulations, which may have various advantages over existing abiraterone formulations such as commercially available oral abiraterone acetate formulations. These advantages include, but are not limited to, improved bioavailability, elimination of the food effect associated with oral abiraterone acetate formulations, reduced pill burden, better patient compliance, reduced dosing frequency, sustained and stable blood levels of active drug, lower C max , thereby reducing the associated side effects. In some embodiments, methods of using the novel abiraterone prodrugs and formulations are also provided, for example, for treating sex hormone-dependent benign or malignant conditions (such as prostate cancer), syndromes caused by androgen excess, and / or syndromes caused by glucocorticoid excess such as hypercortisolemia.

[0107] Compounds of formula I:

[0108] In some embodiments, the present disclosure provides a novel abiraterone prodrug. In some embodiments, the novel abiraterone prodrug is a compound of formula I or a pharmaceutically acceptable salt thereof:

[0109]

[0110] Various groups are suitable as R in formula I 1 In some embodiments, R 1 Such that the compound of Formula I is an ester (e.g., a lipophilic ester), carbamate, or carbonate of abiraterone. 1 YesR 10 , OR 10 or NHR 10 , where R 10 Selected from: C 7-30 Alkyl; C 7-30 Alkenyl; C 7-30 Alkynyl; alkyl groups typically having a total carbon number of 5 to 16 substituted by cycloalkyl; alkyl groups typically having a total carbon number of 7 to 16 substituted by phenyl; cycloalkyl groups typically having a total carbon number of 5 to 16 optionally substituted by one or more alkyl groups; and branched C5 or C6 alkyl groups such as

[0111] In some preferred embodiments, R 10 It is C 7-30 As used herein, unless explicitly stated to be substituted, alkyl is understood to be unsubstituted. However, alkyl can be straight chain or branched. In some embodiments, R 10 Can be a straight chain C 7-30 In some embodiments, R 10 Can be branched C 7-30In some embodiments, R 10 It is a straight chain C 7-16 Alkyl groups, such as R 10 May have the formula -(CH2) n -CH3, wherein n is an integer between 6 and 15 (e.g., 6 to 12, such as 6, 7, 8, 9, 10, 11 or 12). In some embodiments, R 10 Can be branched C 7-16 alkyl.

[0112] In some embodiments, R 10 It can also be an alkyl group substituted with a cycloalkyl group. Typically, in such embodiments, R 10 The total number of carbon atoms in the cycloalkyl group is between 5 and 16, that is, the total number of carbon atoms from the alkyl and cycloalkyl groups is between 5 and 16. Cycloalkyl groups are usually unsubstituted. However, in some embodiments, the cycloalkyl group may be optionally substituted with, for example, one or two lower alkyl groups (e.g., C 1-4 In some embodiments, R 10 Can be C 3-6 The alkyl group substituted by cycloalkyl generally has a total carbon number between 6 and 12. In some embodiments, R 10 Can be C 3-6 Cycloalkyl-substituted straight-chain alkyl, for example, R 10 May have the formula -(CH2) n -Cy, wherein n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is C 3-6 In some embodiments, R 10 May have the formula -(CH2) n -Cy, wherein n is 1 or 2, and Cy is cyclopentyl or cyclohexyl. 10 It can also be C 3-6 Cycloalkyl-substituted branched chain alkyl (e.g., branched chain C 2-6 As used herein, branched C2 alkyl is understood to be a 1,1-disubstituted ethyl group, for example -CH(CH3)-Cy.

[0113] In some embodiments, R 10 It can also be an alkyl group substituted with phenyl. Typically, in such embodiments, R 10 The total number of carbon atoms in R is between 7 and 16, that is, the total number of carbon atoms from the alkyl moiety and the phenyl moiety is between 5 and 16. 10 It can be a straight chain alkyl substituted with a phenyl group, for example, R 10 May have the formula -(CH2) n-Cy, wherein n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is phenyl. 10 May have the formula -(CH2) n -Cy, wherein n is 1 or 2, and Cy is phenyl. 10 It may also be a branched alkyl group substituted with a phenyl group (e.g., a branched C 2-6 The phenyl group is typically unsubstituted. However, in some embodiments, the phenyl group may be optionally substituted with, for example, one or two lower alkyl groups (e.g., C 1-4 alkyl) substituted.

[0114] In some embodiments, R 10 can be a cycloalkyl group optionally substituted with one or more alkyl groups. In such embodiments, R 10 Typically the total number of carbon atoms is between 5 and 16, i.e., the total number of carbon atoms of the cycloalkyl group and its optional substituents is between 5 and 16. 10 Can be C 3-6 Cycloalkyl, unsubstituted or substituted with C 1-4 In some embodiments, R 10 Can be

[0115] In some embodiments, R 10 It can be a branched C5 or C6 alkyl group. In some embodiments, R 10 Can be Other branched C5 or C6 alkyl groups are also suitable.

[0116] In some embodiments, R 10 It may be an unsaturated aliphatic group, such as C 7-30 Alkenyl or C 7-30 Alkynyl.

[0117] In some preferred embodiments, the compound of formula I is an ester of abiraterone, for example, R 1 YesR 10 , where R 10 In some embodiments, R in Formula I 1 Can be C 7-16 Alkyl groups, for example, have the formula -(CH2) n -CH3 alkyl, wherein n is an integer between 6 and 12 (e.g., 6, 7, 8, 9, 10, 11 or 12). 1 Can be obtained from -(CH2) n -Cy represents, wherein n is an integer from 1 to 6, and Cy is C 3-6Cycloalkyl or phenyl, for example, in more specific embodiments, n can be 1 or 2, and Cy is cyclopentyl, cyclohexyl or phenyl. In some specific embodiments, R in Formula I 1 Can be In some specific embodiments, R in Formula I 1 Can be R 1 Other suitable groups include any of the R 10 .

[0118] In some embodiments, R in Formula I 1 It can also be OR 10 or NHR 10 , where R 10 Defined in this article.

[0119] Typically, the compound of formula I may be present in a formulation in a basic form, for example in a non-aqueous formulation. However, in some embodiments, pharmaceutically acceptable salts of the compound of formula I are also useful. Unless specifically mentioned as a salt thereof or inconsistent with the context, the compound of formula I may be present in its basic form in the abiraterone prodrug formulations described herein.

[0120] In view of the present disclosure, one skilled in the art can readily synthesize compounds of Formula I. 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 an activated form thereof, such as the corresponding acyl chloride, anhydride, etc. Exemplary reaction conditions using activated forms such as acyl chlorides are shown in the Examples section.

[0121] Abiraterone prodrug formulations

[0122] Abiraterone prodrugs herein, including compounds of formula I, can be used to deliver Abiraterone to a subject in need thereof, for example, to a subject suffering from sex hormone-dependent benign or malignant conditions, syndromes caused by androgen excess, and / or syndromes caused by glucocorticoid excess such as hypercortisolemia. Typically, Abiraterone prodrugs can be formulated into parenteral formulations, such as intramuscular, intradermal or subcutaneous formulations, and in some embodiments can be formulated into Abiraterone that delivers therapeutically effective plasma concentrations over an extended period of time, for example, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks and up to 6 weeks or 8 weeks or longer, etc.

[0123] Various abiraterone prodrugs, such as abiraterone esters, carbamates or carbonates 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 abiraterone prodrug formulations) comprising a compound of formula I (e.g., any one or more as defined herein) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition can be formulated for parenteral administration, such as intramuscular injection, intradermal injection or subcutaneous injection. The pharmaceutical composition generally includes a pharmaceutically acceptable carrier. Suitable carriers include those known in the art, such as those described in "Remington: The Science and Practice of Pharmacy" (formerly known as "Remington's Pharmaceutical Sciences," University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia, Pa. (2005)) and the FDA-approved drugs of the Center for Drug Evaluation and Research of the U.S. Food and Drug Administration. In some embodiments, a pharmaceutically acceptable carrier can be a carrier approved by the FDA for intramuscular, intradermal or subcutaneous drug products, for example, those listed in the FDA inactive ingredient database. In some embodiments, a pharmaceutically acceptable carrier can be any suitable non-aqueous vehicle for injection, such as those described in the U.S. Pharmacopoeia. In some embodiments, a pharmaceutically acceptable carrier can be a pharmaceutically acceptable oil, such as vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil or soybean oil. In some embodiments, a pharmaceutically acceptable oil can be suitable for use as an injection vehicle, such as an oil that meets the standards described in the corresponding U.S. Pharmacopoeia monograph (for example, as described herein). In some embodiments, a pharmaceutically acceptable oil can be an oil of plant origin suitable for use as an injection vehicle. In some embodiments, a pharmaceutically acceptable oil can be a synthetic oil suitable for use as an injection vehicle, such as a synthetic fatty acid monoglyceride or diglyceride, for example, when cooled to 10°C, it is liquid and remains clear and the iodine value is not more than 140. In some embodiments, pharmaceutically acceptable oil can be natural oil, synthetic oil or semi-synthetic oil, for example fractionated coconut oil and medium chain triglyceride, such as those sold with trademark Miglyol.In some embodiments, pharmaceutically acceptable carrier comprises triglyceride derived from fatty acid.In some embodiments, pharmaceutically acceptable carrier comprises triglyceride derived from long chain and / or medium chain fatty acid, can be polyunsaturated, monounsaturated or saturated triglyceride independently.In some embodiments, two or more different pharmaceutically acceptable oils can be used.In some embodiments, the pharmaceutical composition is a non-aqueous solution or a suspension. In some embodiments, the pharmaceutical composition also includes a pharmaceutically acceptable solvent, such as benzyl alcohol. In some embodiments, the compound of formula I or a pharmaceutically 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 range between the values).

[0124] In some embodiments, the present disclosure also provides pharmaceutical compositions (alternatively sometimes referred to herein as abiraterone prodrug formulations) comprising a compound of Formula II or a pharmaceutically acceptable salt thereof.

[0125]

[0126] Where R 2 As defined herein. In some embodiments, the pharmaceutical composition can be formulated for intramuscular injection, intradermal injection or subcutaneous injection. In some embodiments, the compound of formula II or its pharmaceutically acceptable salt can be present in the pharmaceutical composition at a concentration of about 25mg / ml to about 500mg / ml (e.g., about 25mg / ml, about 50mg / ml, about 100mg / ml, about 150mg / ml, about 200mg / ml, about 250mg / ml, about 300mg / ml, about 400mg / ml, about 500mg / ml or any range between the values). In some embodiments, the pharmaceutical composition is a non-aqueous solution or suspension. In some embodiments, the compound of formula II or its pharmaceutically acceptable salt is dissolved or suspended in a pharmaceutically acceptable oil (e.g., 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 also includes a pharmaceutically acceptable solvent, such as benzyl alcohol.

[0127] Various groups are suitable as R in formula II 2 In some embodiments, R 2 Such that the compound of formula II is an ester, carbamate or carbonate of abiraterone. 2 YesR 20 , OR 20 or NHR 20 , where R 20 Selected from: C 1-30 Alkyl; C 2-30 Alkenyl; C 2-30alkynyl; alkyl substituted with cycloalkyl, typically having a total carbon number between 4 and 30; alkyl substituted with phenyl, typically having a total carbon number between 7 and 30; and cycloalkyl optionally substituted with one or more alkyl, typically having a total carbon number between 3 and 30.

[0128] In some preferred embodiments, R 20 It is C 1-16 In some embodiments, R 20 Can be straight chain C 1-16 In some embodiments, R 20 Can be branched C 3-16 In some embodiments, R 20 It can be a branched C5 or C6 alkyl group. In some embodiments, R 20 Can be In some embodiments, R 20 May have the formula -(CH2) n -CH3, wherein n is an integer between 0 and 12 (eg, between 6 and 12, such as 6, 7, 8, 9, 10, 11 or 12).

[0129] In some embodiments, R 20 It can also be an alkyl group substituted with a cycloalkyl group. Typically, in such embodiments, R 20 The total number of carbon atoms in the cycloalkyl group is between 4 and 30, such as between 5 and 16 (i.e., the total number of carbon atoms from the alkyl and cycloalkyl groups is between 5 and 16). Cycloalkyl groups are typically unsubstituted. However, in some embodiments, the cycloalkyl group may be optionally substituted with, for example, one or two lower alkyl groups (e.g., C 1-4 In some embodiments, R 20 Can be C 3-6 The alkyl group substituted by cycloalkyl generally has a total carbon number between 6 and 12. In some embodiments, R 20 Can be C 3-6 Cycloalkyl-substituted straight-chain alkyl, for example, R 20 May have the formula -(CH2) n -Cy, wherein n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is C 3-6 In some embodiments, R 20 May have the formula -(CH2) n -Cy, wherein n is 1 or 2, and Cy is cyclopentyl or cyclohexyl. 20 It can also be C 3-6 Cycloalkyl-substituted branched chain alkyl (e.g., branched chain C 2-6 ).

[0130] In some embodiments, R 20 It can also be an alkyl group substituted with phenyl. Typically, in such embodiments, R 20 The total number of carbon atoms in R is between 7 and 30, such as between 7 and 16, (i.e., the total number of carbon atoms from the alkyl moiety and the phenyl moiety is between 7 and 16). 20 It can be a straight chain alkyl substituted with a phenyl group, for example, R 20 May have the formula -(CH2) n -Cy, wherein n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is phenyl. 20 May have the formula -(CH2) n -Cy, wherein n is 1 or 2, and Cy is phenyl. 20 It may also be a branched alkyl group substituted with a phenyl group (e.g., a branched C 2-6 The phenyl group is typically unsubstituted. However, in some embodiments, the phenyl group may be optionally substituted with, for example, one or two lower alkyl groups (e.g., C 1-4 alkyl) substituted.

[0131] In some embodiments, R 20 can be a cycloalkyl group optionally substituted with one or more alkyl groups. In such embodiments, R 20 Typically the total number of carbon atoms is between 3 and 30, such as between 5 and 16 (i.e. the total number of carbon atoms of the cycloalkyl group and its optional substituents is between 5 and 16). 20 Can be C 3-6 Cycloalkyl, unsubstituted or substituted with C 1-4 In some embodiments, R 20 Can be

[0132] In some embodiments, R 20 It may be an unsaturated aliphatic group, such as C 2-30 Alkenyl or C 2-30 Alkynyl.

[0133] In some preferred embodiments, the compound of formula II is an abiraterone ester, for example, R 2 YesR 20 , where R 20 In some embodiments, R in Formula II 2 Can be C 1-16 Alkyl groups, for example, have the formula -(CH2) n-CH3 alkyl, wherein n is an integer between 0 and 12. In some embodiments, R in Formula II 2 Can be obtained from -(CH2) n -Cy represents, wherein n is an integer from 1 to 6, and Cy is C 3-6 Cycloalkyl or phenyl, for example, in more specific embodiments, n can be 1 or 2, and Cy is cyclopentyl, cyclohexyl or phenyl. In some specific embodiments, R in Formula II 2 Can be R 2 Other suitable groups include any of the R 20 . In some embodiments, abiraterone ester can be acetic acid ester, propionic acid ester, butyric acid ester, (valeric acid ester) valerate, isocaprylic acid ester, butyric acid ester, cyclohexane carboxylic acid ester, phenyl propionic acid ester, caprylic acid ester (hexanoate), enanthate (enanthate), cyclopentyl propionate, octanoate, nonanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate or hexadecanoate of abiraterone. In some embodiments, abiraterone ester can be abiraterone acetate, abiraterone propionate and abiraterone decanoate. In some specific embodiments, abiraterone ester can be abiraterone valerate, abiraterone hexanoate, abiraterone enanthate, abiraterone decanoate, isocaprylic acid abiraterone or abiraterone cyclopentyl propionate.

[0134] In some embodiments, R in Formula II 2 It can also be OR 20 or NHR 20 , where R 20 Defined in this article.

[0135] Typically, the compound of formula II may be present in a formulation in a basic form, such as in a non-aqueous formulation. However, in some embodiments, a pharmaceutically acceptable salt of the compound of formula II is also useful. Unless specifically mentioned as a salt thereof or inconsistent with the context, the compound of formula II may be present in the abiraterone prodrug formulation described herein in its basic form.

[0136] In view of the present disclosure, those skilled in the art can easily synthesize compounds of formula II. An exemplary synthesis of representative compounds is described in the Examples section. For example, in general, esters of formula II can be prepared by reacting abiraterone with a corresponding carboxylic acid or an activated form thereof, such as a corresponding acyl chloride, anhydride, etc. Exemplary reaction conditions using activated forms such as acyl chlorides are shown in the Examples section.

[0137] 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 levels of abiraterone in plasma over longer durations than aqueous solutions or suspensions. For example, as described in detail herein, intramuscular injections of aqueous suspensions and vegetable oil solutions of abiraterone acetate prodrugs were evaluated in rats. Surprisingly, it was determined that vegetable oil solutions of abiraterone acetate prodrugs (rather than aqueous suspensions) produced the highest plasma levels and also produced the longest duration of exposure to the active drug abiraterone (see Figure 1 ). Therefore, in some embodiments, the abiraterone prodrug formulation herein may include the abiraterone prodrug of the present disclosure (e.g., a compound of Formula I or Formula II) dissolved or dispersed in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier may be any suitable non-aqueous vehicle for injection, such as those described in the United States Pharmacopoeia. In some embodiments, the pharmaceutically acceptable carrier may be a pharmaceutically acceptable oil, such as a vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil. In some embodiments, a pharmaceutically acceptable oil may be an oil suitable for use as an injection vehicle, such as an oil that meets the standards described in the corresponding United States Pharmacopoeia monograph (e.g., described herein). In some embodiments, a pharmaceutically acceptable oil may be an oil of plant origin suitable for use as an injection vehicle. In some embodiments, a pharmaceutically acceptable oil may be a synthetic oil suitable for use as an injection vehicle, such as a synthetic fatty acid monoglyceride or diglyceride, such as those that are liquid and remain clear when cooled to 10°C and have an iodine value of no more than 140. In some embodiments, pharmaceutically acceptable oil can be natural oil, synthetic oil or semi-synthetic oil, for example fractionated coconut oil and medium chain triglyceride, such as those sold with trademark Miglyol.In some embodiments, pharmaceutically acceptable carrier includes triglyceride derived from fatty acid.In some embodiments, pharmaceutically acceptable carrier includes triglyceride derived from long chain and / or medium chain fatty acid, which can be polyunsaturated, monounsaturated or saturated triglyceride independently.In some embodiments, pharmaceutically acceptable oil can be oil approved by FDA for intramuscular, intradermal or subcutaneous drug products, for example, any one of those listed in FDA inactive ingredient database.In some specific embodiments, pharmaceutically acceptable oil is castor oil or corn oil.In some embodiments, two or more different pharmaceutically acceptable oils can be used.

[0138] Other ingredients may also be optionally included in the abiraterone prodrug formulations herein. In some embodiments, the abiraterone prodrug formulations may also include a pharmaceutically 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 have the advantages of increasing the solubility of the prodrug and reducing the viscosity and / or slip of the solution, see e.g. Figures 13A-13E And Table 2A-2D, it provides a more concentrated solution that is easier to be injected through a needle of acceptable specifications for intramuscular injection (e.g., No. 20-27 such as No. 22-25). The cosolvent can be selected according to the ability of the cosolvent to reduce the viscosity of the vehicle to allow injection through a suitable injection needle or cannula. Benzyl alcohol as an additive in intramuscular or subcutaneous injection also has the advantage of being able to 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 also includes benzyl alcohol. In some embodiments, if present, a certain level of cosolvent (e.g., about 0-50% of the solvent, such as about 10%) can be included so that it does not cause irritation (or only very small or tolerable irritation) at the injection site.

[0139] In some embodiments, abiraterone prodrug formulations may include benzyl benzoate as a cosolvent, for example, about 0-50% of the solvent, typically 0-35% or 0-30%, or about 20%. In some embodiments, abiraterone prodrug formulations may include a combination of benzyl alcohol and benzyl benzoate as a cosolvent. In some embodiments, benzyl alcohol may be present in an amount of about 0-20% (e.g., 0-15% or 0-10%, such as about 10%) of the solvent, and benzyl benzoate may be present in an amount of about 0-50% (e.g., 0-35% or 0-30%, such as about 20%) of the solvent, wherein the balance of the solvent may be any one or more pharmaceutically acceptable oils described herein, such as corn oil, castor oil, sesame oil, peanut oil, cottonseed oil and / or Miglyol 812, etc. As discussed in more detail in the Examples section, it is found that including benzyl benzoate in various oil vehicles is advantageous in all respects. See, for example Figures 13A-13Eand Tables 2A-2D. For example, the combination of benzyl alcohol and benzyl benzoate was shown to achieve lower viscosity and glide force than using only benzyl alcohol or benzyl benzoate. In addition, it was unexpectedly found that a representative abiraterone prodrug (abiraterone decanoate) formulation comprising oil (corn oil, 70%) as well as benzyl alcohol (10%) and benzyl benzoate (20%) achieved much higher abiraterone plasma exposure in monkeys when administered in the same amount compared to a formulation with substantially the same concentration of abiraterone decanoate comprising the same oil vehicle but without benzyl benzoate (i.e. corn oil, 90% and benzyl alcohol, 10%).

[0140] Although the oil vehicles described herein are generally used for the abiraterone prodrugs of the present disclosure, it is also expected that such oil vehicles can be used to formulate other active ingredients. In some embodiments, the present disclosure also provides benzyl alcohol comprising an amount of about 0-20% (e.g., 0-15% or 0-10%, such as about 10%) of the oil vehicle, and benzyl benzoate accounting for an amount of about 0-50% (e.g., 0-35% or 0-30%, such as about 20%) of the oil vehicle, wherein the balance of the oil vehicle can be any one or more pharmaceutically acceptable oils described herein, such as corn oil, castor oil, sesame oil, peanut oil, cottonseed oil and / or Miglyol 812, etc.

[0141] The solubility of the abiraterone ester can be affected after adding a cosolvent to the vegetable oil vehicle. In some embodiments, the abiraterone ester is completely dissolved in the composition, while in other embodiments, the abiraterone ester is partially dispersed in the composition. In one embodiment, the abiraterone ester is completely dissolved in the vehicle.

[0142] Abiraterone prodrug formulations may also contain pharmaceutically acceptable preservatives, polymers, antioxidants, antimicrobial agents, chelating agents and other excipients, such as citric acid, glucose, ascorbic acid, benzalkonium chloride, benzoic acid, sodium sulfobutyl ether β-cyclodextrin, calcium chloride, sodium carboxymethylcellulose, chlorobutanol, creatine, cross-linked carboxymethylcellulose, dipotassium hydrogen phosphate, sodium docusate, sodium edetate, glycerol, sodium hyaluronate, hydroxypropyl β-cyclodextrin, lactic acid, lactose, Lecithin, maleic acid, mannitol, meglumine, methylcellulose, methylparaben, microcrystalline cellulose, mepiridium chloride, monothioglycerol, phenol, poloxamer 188, polysaccharide lactate, polysorbate 20, polysorbate 40, polysorbate 80, propylparaben, sodium acetate, sodium benzoate, sodium citrate, sorbitan monolaurate, sorbitol, sucrose, tartaric acid, trisodium citrate, tromantanamide, tromethamine, and urea.

[0143] Abiraterone prodrug formulations can be sterilized by methods known to those skilled in the art (eg, gamma irradiation, micron filtration, and autoclaving).

[0144] Abiraterone extended release

[0145] Abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure (e.g., those containing compounds of Formula I or Formula II as described herein) are generally formulated preferably as parenteral formulations, such as intramuscular, intradermal or subcutaneous formulations to provide long-acting release of abiraterone to subjects in need thereof, such as those suffering from sex hormone-dependent benign or malignant conditions, syndromes caused by androgen excess, and / or syndromes caused by glucocorticoid excess such as hypercortisolemia. In some embodiments, abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure (e.g., those containing compounds of Formula I or Formula II as described herein) can be formulated to deliver therapeutic plasma levels of abiraterone to subjects suffering from sex hormone-dependent benign or malignant conditions, syndromes caused by androgen excess, and / or syndromes caused by glucocorticoid excess such as hypercortisolemia after a single administration over an extended period 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 weeks or 8 weeks or longer, etc.). In some embodiments, the therapeutic plasma concentration of Abiraterone can be at least 1 ng / ml, such as at least 2 ng / ml, at least 4 ng / ml, at least 8 ng / ml. In some embodiments, the therapeutic plasma concentration of Abiraterone can also be about 0.5 ng / ml or higher.

[0146] As shown herein, abiraterone acetate in vegetable oil was evaluated in dogs. Solutions of abiraterone acetate in castor oil and cosolvents benzyl alcohol and benzyl benzoate were prepared in different strengths (66-124 mg / ml) and injected intramuscularly into dogs, and plasma levels of parent abiraterone drug were measured over three weeks (see Figure 2 ). Data from canine studies indicate that abiraterone acetate administered as a solution in castor oil (with or without benzyl alcohol) produces measurable blood levels up to 504 hours. The absolute bioavailability of these formulations was found to range between 61.7% and 86.2%. This represents the first demonstration that abiraterone can be delivered to subjects over a long period of time via a single injection, thus allowing less frequent dosing, such as once a week or more than once a week, for example, dosing frequencies ranging from once a week to once every several months, such as from once a week to once every eight weeks or from once a week to once every three months.

[0147] 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 because it is controlled by the rate of release of the prodrug from the oil vehicle into aqueous tissues and the bioconversion rate of the ester prodrug to the parent drug abiraterone. Unlike abiraterone acetate, which is administered orally and bioconversion occurs prior to drug absorption (and thus the prodrug is not observed in plasma), when the abiraterone prodrug is administered parenterally (intravenously or intramuscularly) in dogs, the prodrug is observed in plasma (see, e.g., Figure 3-10 ), where it is converted to the parent drug abiraterone in plasma. Thus, one aspect of the present disclosure is the selection of ester prodrugs and vegetable oil / cosolvent vehicles to allow sufficient dissolution of the ester prodrug in the vehicle to allow injection, controlled release of the ester prodrug from the oil reservoir (depending on the partition coefficient of the drug between the oil phase and the aqueous phase), and then allow bioconversion of the ester prodrug to the abiraterone parent drug. A selection of abiraterone prodrugs (acetate, propionate, butyrate, valerate, caproate, enanthate, isocaprylate, cypionate, and decanoate) were prepared and their solubility in several vegetable oils and cosolvents was determined (see Table 2).

[0148] Unit dosage form

[0149] In some embodiments, the Abiraterone prodrugs and Abiraterone prodrug formulations disclosed herein (e.g., those containing Formula I or II compounds described herein) can be formulated into unit dosage forms. In some embodiments, the unit dosage form can include a sufficient amount of the corresponding prodrug so that after a single administration (e.g., intramuscular injection) to a subject, such as a subject suffering from a sex hormone-dependent benign or malignant condition (e.g., metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer), a syndrome caused by excessive androgen and / or a syndrome caused by excessive glucocorticoids such as hypercortisolemia, the unit dosage form provides a therapeutically effective Abiraterone plasma concentration in the subject for at least two weeks, such as at least 3 weeks, at least 4 weeks, at least 5 weeks and up to 6 weeks or 8 weeks or longer, etc. In some embodiments, the therapeutic plasma concentration of Abiraterone can be at least 1 ng / ml, such as at least 2 ng / ml, at least 4 ng / ml, at least 8 ng / ml. In some embodiments, the therapeutic plasma concentration of Abiraterone can also be about 0.5 ng / ml or higher. In some embodiments, the unit dosage form is a parenteral preparation, such as an intramuscular, intradermal or subcutaneous preparation. In some embodiments, the unit dosage form is a non-aqueous solution or suspension. In some embodiments, the unit dosage form comprises abiraterone prodrugs (e.g., compounds of Formula I or Formula II) dissolved or suspended in pharmaceutically acceptable oils such as vegetable oils 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 can be used in the unit dosage form. In some embodiments, the unit dosage form may also include a pharmaceutically acceptable solvent, such as alcohol, ester and / or acid, such as benzyl alcohol, benzyl benzoate or a combination thereof. Other suitable components for unit dosage forms include those described herein.

[0150] Abiraterone prodrugs (e.g., compounds of Formula I or Formula II) are typically present in a unit dosage form 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 range between the values). The amount of abiraterone prodrug in a unit dosage form can vary, depending on various factors, such as the clearance rate of the corresponding abiraterone prodrug, the expected frequency of administration, and the required plasma level. Typically, the amount of abiraterone prodrug can be in the range of about 50 mg to about 2000 mg, and if expressed as the equivalent of abiraterone, the general range can be about 25 mg to about 1750 mg. In some embodiments, in order to achieve a lower frequency of administration, such as a monthly administration frequency, the prodrug can be included in the unit dosage form with a concentration as high as that the subject user can safely tolerate. Typically, unit dosage forms are formulated to have a viscosity suitable for parenteral injection, such as intramuscular, intradermal or subcutaneous injection.

[0151] In some embodiments, the unit dosage form can be formulated to achieve certain pharmacokinetic (PK) profiles, such as a PK profile having a substantially flat curve after an initial rising period. Typically, after the unit dosage form is administered to a subject, the plasma concentration of abiraterone in the subject can increase during the first few hours to a few days (e.g., 5 days or a week) after administration and then gradually level off, see e.g. Figure 2-4 In some embodiments, after this initial rising period, the plasma concentration of abiraterone in the subject can level off and can be substantially constant over an extended period of time, such as at least several days (e.g., 2, 3, 4, 5, or 6 days), or at least 1 week, at least 2 weeks, etc.

[0152] In some embodiments, the unit dosage form is suitable for once-monthly (or more than once-monthly) administration, and when administered once (e.g., intramuscularly) to a subject in need thereof, the unit dosage form achieves a PK profile characterized by one or more of the following: (a) the unit dosage form provides a therapeutically effective plasma concentration of abiraterone in the subject for at least 4 weeks; (b) a single dose C of abiraterone is max between about 10 ng / ml and about 400 ng / ml (e.g., between about 50 ng / ml and about 100 ng / ml, or between about 15 ng / ml and about 160 ng / ml); (c) no food effect; (d) comparable to a 1000 mg oral dose once daily without food. The C of abiraterone observed at steady state max In comparison, a single dose of abiraterone max(e) a single dose of abiraterone on day 28 after administration of C min (f) the plasma concentration of abiraterone remains substantially constant after administration, for example, for at least 1 week, for example, 1 week to 3 weeks. In some embodiments, substantially constant over a period of time may mean that the highest concentration observed on any day (i.e., 24 hours) during the period of time is no more than 4 times, for example, no more than 2 times, the lowest concentration observed on the same day. No food effect is generally understood to mean that no significant difference in PK is observed when a unit dosage form is administered to a subject who has eaten or not eaten. For example, in some embodiments, no food effect may mean that the C of abiraterone between subjects administered in a fed state or a fasted state is no more than 10%. max and AUC are substantially the same (e.g., between 80% and 125%). As used herein, a single dose of C max It should be understood that after a single administration to a naive subject (generally a subject who has not received any abiraterone drug for at least 3 days, such as at least 1 week, prior to administration and in whom no plasma abiraterone was observed prior to administration), C max The single dose C used in this paper min It refers to the minimum concentration observed on a given day following a single administration to untreated subjects, for example, on day 28 following administration.

[0153] In some embodiments, the unit dosage form is suitable for once-monthly (or more than once-monthly) administration, and when the unit dosage form is administered (e.g., intramuscularly) to a subject in need thereof once a month, the unit dosage form achieves: (a) a steady-state C of abiraterone max between about 10 ng / ml and about 400 ng / ml (e.g., between about 50 ng / ml and about 100 ng / ml, or between about 15 ng / ml and about 160 ng / ml); (b) no food effect; (c) comparable to a 1000 mg once daily oral dose without food. The C of abiraterone observed at steady state max In comparison, the steady-state C of abiraterone max (d) The steady-state C of abiraterone min Between about 1 ng / ml and about 8 ng / ml, or above about 8 ng / ml; and (g) the plasma concentration of abiraterone remains substantially constant after each administration, for example, for at least 1 week, for example, 1 week to 3 weeks. Steady state C as used herein max or C min It is understood that after steady state is reached, the C is usually observed after multiple administrations to subjects. max or C min .

[0154] In some embodiments, the unit dosage form can be packaged in a container such as a vial or an ampoule. In some embodiments, the unit dosage form may be included in a pre-filled syringe or a test kit with a syringe (such as a disposable syringe). Other packaging and / or containers are also available, which is known to those skilled in the art. In some embodiments, a test kit comprising a plurality of unit dosage forms as described herein is also provided. In some embodiments, the test kit may also include a syringe. Although in some embodiments, it is advantageous to prepare abiraterone prodrug formulations in unit dosage form, in some embodiments, the present disclosure also provides abiraterone prodrug formulations that allow multiple single uses, or abiraterone prodrug formulations that can be subdivided into a plurality of unit dosage forms.

[0155] Exemplary Specific Formulations

[0156] In some embodiments, the present disclosure also provides some specific abiraterone prodrug formulations, which can be unit dosage forms or multi-unit dosage forms in some embodiments. For example, the following table (Table A and Table B) shows some representative abiraterone ester prodrug formulations in oil vehicles. All numerical values ​​in the table should be understood as being preceded by the term "about". The concentration of abiraterone prodrug refers to the amount (mg) of abiraterone prodrug in each ml of the final formulation, and the final formulation can be a solution or a suspension. The amount of oil (main solvent) and cosolvent in the table is expressed as the volume percentage of the solvent, and the solvent includes both oil and cosolvent. Suitable oil includes any pharmaceutically acceptable oil described herein. Suitable cosolvents also include any of those described herein, such as alcohol, ester and / or acid, such as benzyl alcohol, benzyl benzoate or a combination thereof, see, for example, Table B. An example of a suitable cosolvent is benzyl alcohol. An example of a suitable cosolvent is a combination of benzyl alcohol and benzyl benzoate. In some embodiments, cosolvents are not included in the formulation. In some embodiments, cosolvents do not include benzyl benzoate. Other optional ingredients are described herein.

[0157] Table A. Exemplary Formulations

[0158]

[0159] like Figures 13A-13EAs shown in the embodiment section, benzyl alcohol and / or benzyl benzoate can improve the solubility of the abiraterone prodrug of the present disclosure in oil vehicles (such as corn oil), and can reduce the viscosity and slip of various oil vehicles, and the oil vehicles include corn oil, sesame oil, peanut oil, cottonseed oil and Miglyol 812 (medium chain triglycerides, mainly a mixture of caprylic acid / caprylic triglycerides). In some embodiments, the present disclosure provides an abiraterone prodrug formulation comprising an abiraterone prodrug and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier includes a pharmaceutically 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 isoleate. Pharmaceutically acceptable oils generally include triglycerides derived from fatty acids. In some embodiments, pharmaceutically acceptable oil can be natural oil, synthetic oil or semi-synthetic oil, for example fractionated coconut oil and medium chain triglyceride, such as those sold with trademark Miglyol.In some embodiments, pharmaceutically acceptable oil can be selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil (peanut oil), poppy seed oil, tea seed oil and soybean oil.In some embodiments, present disclosure provides some exemplary preparations shown in Table B.

[0160] Table B. Other exemplary formulations

[0161]

[0162] In some embodiments, the present invention also provides the following specific formulations: abiraterone acetate solution in castor oil, with a concentration of about 50 mg / mL to about 200 mg / mL (such as 70 mg / mL); abiraterone acetate solution in 10% benzyl alcohol / 90% castor oil, with a concentration of about 50 mg / mL to about 200 mg / mL (such as about 90 mg / mL); abiraterone acetate solution in 50% benzyl benzoate / 50% castor oil, with a concentration of about 50 mg / mL to about 200 mg / mL (such as about 100 mg / mL); abiraterone propionate solution in 10% benzyl alcohol / 90% castor oil at a concentration of about 50 mg / mL to about 300 mg / mL (such as about 200 mg / mL); abiraterone propionate solution in 10% benzyl alcohol / 90% corn oil at a concentration of about 50 mg / mL to about 300 mg / mL (such as about 168 mg / mL); abiraterone decanoate solution in castor oil at a concentration of about 100 mg / mL to about 300 mg / mL (such as 160 mg / mL); L or 170 mg / mL); abiraterone decanoate solution in corn oil at a concentration of about 100 mg / mL to about 300 mg / mL (such as 160 mg / mL or 170 mg / mL); abiraterone decanoate solution in 10% benzyl alcohol / 90% castor oil at a concentration of about 100 mg / mL to about 300 mg / mL (such as 160 mg / mL or 170 mg / mL); abiraterone decanoate solution in 10% benzyl alcohol / 90% corn oil at a concentration of about 100 mg / mL to about 3 00mg / mL (such as 160mg / mL or 170mg / mL); abiraterone decanoate solution in 70% corn oil, 10% benzyl alcohol, 20% methyl benzoate, with a concentration of about 150mg / mL to about 300mg / mL (such as about 200mg / mL or about 240mg / mL); abiraterone isoleate solution in 90% corn oil, 10% benzyl alcohol, with a concentration of about 120mg / mL to about 200mg / mL (such as about 150mg / ml or about 160mg / ml). In some embodiments, the present disclosure also provides any specific formulation prepared herein, such as prepared in Examples 3A-3J. In some embodiments, the present disclosure also provides the formulation described in Example 1 herein.

[0163] Treatment

[0164] Some embodiments of the present disclosure relate to methods of delivering abiraterone to a subject in need thereof. In various embodiments, the present disclosure also provides methods of treating or preventing a disease or condition for which administration of abiraterone is beneficial.

[0165] In some embodiments, the present disclosure provides a method for delivering abiraterone to a subject in need thereof, the method comprising administering any abiraterone prodrug or abiraterone prodrug formulation of the present disclosure to the subject. In some embodiments, the subject suffers from sex hormone-dependent benign or malignant conditions, such as androgen-dependent conditions or estrogen-dependent conditions described herein. In some embodiments, the subject suffers from a syndrome caused by excessive androgen and / or a syndrome caused by excessive glucocorticoids (such as hypercortisolemia described herein). In any embodiment described herein, unless directly contradictory, the subject can be a human subject, such as a human subject suffering from sex hormone-dependent benign or malignant conditions, a syndrome caused by excessive androgen and / or a syndrome caused by excessive glucocorticoids (such as hypercortisolemia described herein). As used herein, hormone-dependent benign or malignant conditions, whether or not there is the term "sex" in front, should be understood as sex hormone-dependent benign or malignant conditions, such as androgen-dependent conditions or estrogen-dependent conditions.

[0166] As detailed herein, in monkey PK studies, a single intramuscular injection of abiraterone decanoate, a representative abiraterone prodrug, was shown to achieve long-term CYP17A1 inhibition, sustained increases in progesterone levels, and decreases in cortisol and testosterone levels for up to 8 weeks. Fig.14D As shown, inhibition of CYP17A1 17a-hydroxylase and C17,20-lyase activity is expected to result in (1) increased levels of progesterone and mineralocorticoids; (2) decreased levels of glucocorticoids such as cortisol; (3) decreased levels of sex hormones, such as androgens (such as testosterone and dihydrotestosterone) and estrogens (such as estradiol). Therefore, the abiraterone prodrugs and prodrug formulations disclosed herein can be advantageously used to inhibit CYP17A1 activity, reduce glucocorticoid levels such as cortisol levels, reduce sex hormone levels such as androgen and / or estrogen levels, and / or treat conditions associated with high glucocorticoid levels (such as cortisol levels), and / or treat conditions caused by high sex hormone levels (such as androgen and / or estrogen levels).

[0167] In some embodiments, the present 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 any abiraterone prodrug or abiraterone prodrug formulation of the present disclosure. In some embodiments, the subject suffers from a sex hormone-dependent benign or malignant condition, for example, as described herein. In some embodiments, the subject suffers from a syndrome caused by androgen excess and / or a syndrome caused by glucocorticoid excess (such as hypercortisolemia described herein).

[0168] In some embodiments, the present disclosure provides a method of reducing the level of a glucocorticoid (e.g., Cortisol) in a subject in need thereof, the method comprising administering to the subject any abiraterone prodrug or abiraterone prodrug formulation of the present disclosure. In some embodiments, the subject suffers from a syndrome caused by an excess of glucocorticoids, such as hypercortisolemia as described herein, such as Cushing's syndrome or Cushing's disease.

[0169] In some embodiments, the present disclosure provides a method of reducing the level of androgen (e.g., testosterone and / or dihydrotestosterone) and / or estrogen in a subject in need thereof, the method comprising administering to the subject any abiraterone prodrug or abiraterone prodrug formulation of the present disclosure. In some embodiments, the subject suffers from a syndrome caused by androgen excess, such as congenital adrenal hyperplasia (e.g., classic and non-classical congenital adrenal hyperplasia), endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc. In some embodiments, the subject suffers from androgen and / or estrogen related cancers, such as prostate cancer or breast cancer.

[0170] In some embodiments, a method for treating a sex hormone-dependent benign or malignant condition, a syndrome caused by excessive androgen, and / or a syndrome caused by excessive glucocorticoids (such as hypercortisolemia) is provided. Typically, the method includes administering a therapeutically effective amount of any abiraterone prodrug or abiraterone prodrug formulation of the present disclosure to a subject in need thereof. In some embodiments, unless directly contradictory, the subject can be a human subject, such as a human subject suffering from a sex hormone-dependent benign or malignant condition, a syndrome caused by excessive androgen, and / or a syndrome caused by excessive glucocorticoids (such as hypercortisolemia described herein).

[0171] Administration in the methods herein is not limited to any particular route. However, in some preferred embodiments, administration may be parenteral administration, such as intramuscular injection, intradermal injection, or subcutaneous injection. In some embodiments, parenteral administration may be advantageous. For example, in some embodiments, administration may be parenteral administration, such as intramuscular injection, which may be performed regardless of whether the subject has eaten. In other words, the subject's fed or fasted state is not important. This removes the need for conventional methods that are currently on the market. A formulation-related restriction that states that the drug "must be taken on an empty stomach at least 1 hour before or 2 hours after a meal." Thus, among other advantages, the methods herein can improve patient compliance.

[0172] Various sex hormone-dependent benign or malignant conditions can be treated with the methods herein. In some embodiments, hormone-dependent benign or malignant conditions can be androgen-dependent conditions and estrogen-dependent conditions, such as androgen- or estrogen-dependent cancers. In some embodiments, sex hormone-dependent benign or malignant conditions can be prostate cancer or breast cancer. In some embodiments, sex hormone-dependent benign or malignant conditions are castration-resistant prostate cancer or castration-sensitive prostate cancer. In some embodiments, sex hormone-dependent benign or malignant conditions can be metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer. In some embodiments, sex hormone-dependent benign or malignant conditions can also be ovarian cancer, bladder cancer, hepatocellular carcinoma, or lung cancer. Various non-neoplastic syndromes caused by androgen excess and / or by glucocorticoid excess such as hypercortisolemia can also be treated with the methods herein, for example, syndromes caused by androgen excess such as endometriosis, polycystic ovary syndrome, classic or nonclassical congenital adrenal hyperplasia, precocious puberty, hirsutism, etc., and / or syndromes caused by glucocorticoid excess, such as Cushing's syndrome or Cushing's disease, etc.

[0173] The methods herein can be used together with one or more additional therapies for the corresponding disease or condition. For example, Label (abiraterone acetate) states that acceptance Patients should also receive gonadotropin-releasing hormone (GnRH) analogs at the same time, or bilateral orchiectomy should be performed. Therefore, in some embodiments of the method disclosed herein, the subject can also be treated with a gonadotropin-releasing hormone analog and / or bilateral orchiectomy to treat the subject. In some embodiments, the method also includes administering an effective amount of prednisone or prednisolone to the subject simultaneously or sequentially. However, in some embodiments, the method herein can also achieve the desired therapeutic effect without causing adrenal cortical insufficiency, thereby avoiding the co-administration of prednisone or prednisolone. In some embodiments, the subject is not treated with a gonadotropin-releasing hormone analog and / or bilateral orchiectomy. In some embodiments, prednisone or prednisolone is not administered to the subject.

[0174] In some embodiments, the method may include administering one or more other drugs or agents (e.g., another cancer chemotherapy drug, a hormone replacement drug, or a hormone ablation drug) to the subject simultaneously or sequentially by the same route of administration or a different route of administration. In some embodiments, the other drugs or agents may be steroids, such as prednisone, prednisolone, and / or methylprednisolone. In some embodiments, the other drugs or agents may be chemotherapy drugs, such as paclitaxel, mitoxantrone, and / or docetaxel. In some embodiments, the other agents or drugs may be GnRH agonists, such as leuprolide, deslorelin, goserelin, or triptorelin, for example leuprolide acetate (e.g., a long-acting intramuscular injection formulation). In some embodiments, other agents or drugs can be seocalcitol, bicalutamide, flutamide, glucocorticoids, including but not limited to hydrocortisone, prednisone, prednisolone or dexamethasone. The amount of other drugs or agents to be administered can vary, and can generally be an amount that is effective to treat a corresponding disease or disorder (e.g., prostate cancer) alone or in combination with abiraterone prodrugs or abiraterone prodrug formulations of the present disclosure.

[0175] Other suitable other drugs or agents include those described herein. For example, useful other drugs or agents include, but are not limited to, anticancer agents, hormone ablators, antiandrogens, differentiation agents, antitumor agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotic agents, immune agents, interferon agents, intercalating agents, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloproteinase inhibitors, gene therapy agents, and antiandrogens.

[0176] For example, suitable anticancer agents include, but are not limited to, acemannan, aclarubicin, aldesleukin, alemruzumab, alitretinoin, altretamine, amifostine, amsacrine, anagrelide, anastrozole, ancestim, bexarotene, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, daclizumab, dexrazoxane, dilazep, docosanol, doxifluridine, bromocriptine, carmustine, cytarabine, diclofenac, edelfosine, edrecolomab, eflornithine, emitefur, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate phosphate), formestane, fotemustine, gallium nitrate, gemcitabine, glycopine, heptaplatin, ibandronic acid, imiquimod, iobenguane, irinotecan, irsogladine, lanreotide, leflunomide, lenograstim, lentinan sulfatesulfate), letrozole, liarozole, lobaplatin, lonidamine, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mitoguazone, mitolactol, molgramostim, nafarelin, nartograstim, nedaplatin, nilutamide, noscapine, oprelvekin, osaterone, oxaliplatin, pamidronic acid, pegaspargase, pentosan polysulfate sodium polysulfate sodium), pentostatin, picibanil, pirambicin, porfimer sodium sodium), raloxifene, raltitrexed, rasburicase, rituximab, romurtide, sargramostim, sizofiran, sobuzoxane, sonermin, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfaalfa), topotecan, toremifene, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, ubenimex, valrubicin, verteporfin, vinorelbine. Suitable anti-androgen agents include, but are not limited to, bicalutamide, flutamide, and nilutamide. Suitable differentiation agents include, but are not limited to, polyamine inhibitors; vitamin D and its analogs, such as calcitriol, doxorcalciferol, and siocalciferol; metabolites of vitamin A, such as ATRA, retinoic acid, retinoids; short chain fatty acids; phenylbutyric acid; and nonsteroidal anti-inflammatory agents; anti-tumor agents, including, but not limited to, tubulin interacting agents, topoisomerase inhibitors and agents, acitretin, alstonine, amonafide, amphetamine, amsacrine, ankinomycin, anti-tumor substances, aphidicolin glycinate, asparaginase, baccharin, batracylin, benfluron, benzotript, bromofosfamide, caracemide, carmethizole hydrochloride, hydrochloride), chlorsulfaquinoxalone, clanfenur, claviridenone, crisnatol, curaderm, cytarabine, cytocytin, dacarbazine, datelliptinium, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, docetaxel, elliprabin, elliptiniumacetate, epothilones, ergotamine, etoposide, etretinate, fenretinide, gallium nitrate, genkwadaphnin, hexadecylphosphocholine, homoharringtonine, hydroxyurea, ilmofosine, isoglutamine, isotretinoin, leukoregulin, lonidamine, merbarone, merocyanine derivatives, methylanilinoacridine, minactivin, mitonadine, mitonafide, mitoquidone, mitoxantrone, mopidamol, motretinide, N-(retinyl) amino acids, N-acylated-dehydroalanine, nafazatrom, nocodazole derivatives, ocreotide, oquizanocinc, paclitaxel, pancratistatin, pazelliptine, piroxantrone, polyhaematoporphyrin, polypicric acid acid, probimane, procarbazine, proglumide, razoxane, retelliptine, spatol, spirocyclopropane derivatives, spirogermanium, strypoldinone, superoxide dismutase, teniposide, thaliblastine, tocotrienol, topotecan, Ukrainian anticancer drugs, vinblastine sulfatesulfate), vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, and withanolide; kinase inhibitors, including p38 inhibitors and CDK inhibitors, TNF inhibitors, matrix metalloproteinase inhibitors (MMPs), COX-2 inhibitors, including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib; SOD mimetics or α vβ3 inhibitors. Suitable antimetabolites may be selected from, but are not limited to, 5-FU-fibrinogen, acanthifolic acid, aminothiadiazoles, brequinar sodium, carmofur, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine conjugates, deazaguanine, dideoxycytidine, dideoxyguanosine, didox, doxifluridine, fazarabine, floxuridine, fludarabine phosphate phosphate), 5-fluorouracil, N-(2′-furanyl)-5-fluorouracil, isopropylpyrrolizine, methobenzaprim, methotrexate, norspermidine, pentostatin, pirituxim, plicamycin, thioguanine, tiazofurin, trimetrexate, tyrosine kinase inhibitors, and uricytin. Suitable alkylating agents may be selected from, but are not limited to, aldophosphamide analogs, hexamethylmelamine, anaxirone, bestrabucil, budotitane, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cyplatate, diphenylspiromustine, diplatinum cytostatics, elmustine, estramustine phosphate ...estramustine phosphate, estramustine phosphate, estramustine phosphate, estramustine phosphate, estramustine phosphate, estramustine phosphate, estramustine phosphate, estramustine phosphate, estramustine phosphate,sodium), fotemustine, hepsulfam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, oxaliplatin, prednimustine, ranimustine, semustine, spiromustine, tauromustine, temozolomide, teroxirone, tetraplatin, and trimelamol. Suitable antibiotic agents may be selected from, but are not limited to, aclarubicin, dactinomycin, actinoplanone, adriamycin, aeroplysinin derivatives, amrubicin, anthracycline, azino-mycin-A, bisucaberin, bleomycin sulfate, bryostatin-1, calichemycin, chromoximycin, dactinomycin, daunorubicin, ditrisarubicin B,B), dexamethasone, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-A1b, fostriecin, glidobactin, gregatin-A, grincamycin, herbimycin, corticosteroids (such as hydrocortisone), idarubicin (idarubicin), rubicin, illudins, kazusamycin, kesarirhodins, menogaril, mitomycin, neoenactin, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, prednisone, prednisolone, pyrindanycin A), rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, sorangicin-A, sparsomycin, talisomycin, terpentecin, thrazine, tricrozarin A and zorubicin. Non-limiting examples of suitable steroids include hydrocortisone, prednisone, prednisolone or dexamethasone.

[0177] Dosage regimen

[0178] Abiraterone prodrugs and formulations disclosed herein can generally provide a long-acting release of Abiraterone to a subject user. This long-acting release profile allows abiraterone to be administered to a subject user at a low dosing frequency (such as once a week or even less frequently), which can improve patient compliance and reduce pill burden.

[0179] In some embodiments, the method herein can have a dosing regimen once a week or more than once a week. Typically, the scope of dosing frequency can be from once a week to once every several months, such as from once a week to once every eight weeks, or from once a week to once every three months. In some embodiments, the dosage of each dose is about 50mg to about 2000mg (for example, about 500mg, about 1000mg, about 1500mg, or any range between the values) of abiraterone prodrug. In some embodiments, the dosage of each dose of abiraterone prodrug is about 0.5mg / kg to about 100mg / kg (for example, about 0.5mg / kg, about 1mg / kg, about 5mg / kg, about 10mg / kg, about 20mg / kg, about 30mg / kg, about 50mg / kg, about 90mg / kg, about 100mg / kg or any range between the values) subject weight. In some embodiments, the methods herein may include administering to a subject in need thereof an abiraterone prodrug or abiraterone prodrug formulation of the present disclosure once a week, or more than once a week, such as once every two weeks, once a month, wherein the administration provides a therapeutically effective abiraterone plasma concentration (e.g., as described herein, such as 0.5 ng / ml and above, 1 ng / ml and above, 8 ng / ml and above, or 8.4 ng / ml and above) for a long period of time, such as more than 1 week, more than 2 weeks, more than 3 weeks, more than 4 weeks, and up to six weeks or eight weeks or more, etc. In some embodiments, the administration may provide 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 provide 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 may provide a single dose C of abiraterone of about 1 ng / ml to about 8 ng / ml or above about 8 ng / ml, such as above 8.4 ng / ml, on each of days 1 to 7, or days 1 to 14, or days 1 to 21, or days 1 to 28 after administration. min In some embodiments, the administration may provide a steady-state C of abiraterone of about 1 ng / ml to about 8 ng / ml or above about 8 ng / ml, such as above 8.4 ng / ml. min .

[0180] Abiraterone prodrugs suitable for the above-mentioned once a week or once a week administration method include those described herein. In some embodiments, the abiraterone prodrug can be a lipophilic ester of abiraterone described herein, such as acetate, propionate, butyrate, (valeric acid ester) valerate, isocrylic acid ester, butyric acid ester, cyclohexanecarboxylate, phenylpropionic acid ester, caprylic acid ester (hexanoate), enanthate (enanthate), cyclopentyl propionate, octanoate, nonanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate and hexadecanoate. In some preferred embodiments, the abiraterone prodrug can be a compound of formula I, such as a compound of formula I, wherein R 1 It is C 7-16 Alkyl groups, for example, have the formula -(CH2) n -CH3 alkyl, wherein n is an integer between 6 and 12 (e.g., n is 6, 7, 8, 9, 10); or R 1 From the formula -(CH2) n -Cy represents, wherein 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; or R 1 yes or R 1 yes In some embodiments, the abiraterone prodrug can be a compound of Formula II, wherein R in Formula II is 2 Can be C 1-16 Alkyl groups, for example, have the formula -(CH2) n -CH3 alkyl, wherein n is an integer between 0 and 12; or R in formula II 2 It can be expressed by the formula -(CH2) n -Cy represents, wherein n is an integer from 1 to 6, and Cy is C 3-6 Cycloalkyl or phenyl, for example, in more specific embodiments, n can be 1 or 2, and Cy is cyclopentyl, cyclohexyl or phenyl; or R in Formula II 2 Can be In some embodiments, the abiraterone prodrug may also be abiraterone acetate or any one 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 valerate, abiraterone caproate, abiraterone enanthate, abiraterone decanoate, abiraterone isoleate, or abiraterone cypionate. In any embodiment described herein, unless otherwise noted or directly contradictory to the context, the abiraterone prodrug may be abiraterone decanoate.

[0181] In some embodiments, administration once a month or more than once a month is required, for example, the range of administration frequency is from once a month to once every several months, such as from once a month to once every two months, or from once a month to once every three months. In such embodiments, the abiraterone prodrug not only needs to release the abiraterone slowly, but also needs to release the abiraterone of sufficient plasma concentration so that it can be beneficial to the user being tested. Administration once a month or more than once a month is usually parenteral administration, such as intramuscular, intradermal or subcutaneous. In any embodiment herein, unless directly contradictory, administration can be intramuscular administration.

[0182] As described in detail herein, a single intramuscular administration of abiraterone acetate was found to provide extended release of abiraterone. However, canine PK studies showed that similar administration of abiraterone propionate did not improve the extended release of abiraterone acetate, and in fact, the abiraterone release observed from the propionate ester was lower than the acetate release observed at all measured time points. In addition, it was unexpectedly found that the extension of the alkyl chain to abiraterone butyrate resulted in a sharp decrease in solubility in various oil vehicles. Despite this unexpected trend, the inventors have found that certain abiraterone prodrugs or abiraterone prodrug formulations disclosed herein, such as compounds of Formula I, such as abiraterone decanoate, can be superior to acetate, propionate or butyrate in administration once a month or more. It was also found that the PK curves of certain abiraterone prodrugs or abiraterone prodrug formulations disclosed herein, such as compounds of Formula I such as abiraterone decanoate, such as t 1 / 2 , there were no significant changes when different oil vehicles were used. In contrast, as detailed in Example 5B, some changes were observed in the PK profile of abiraterone propionate, depending on whether it was formulated in castor oil or corn oil.

[0183] In some specific embodiments, the present disclosure provides a method of treating a sex hormone-dependent benign or malignant condition (e.g., as described herein), a syndrome caused by androgen excess, and / or a syndrome caused by glucocorticoid excess (such as hypercortisolemia) in a subject in need thereof, the method comprising administering to the subject parenterally 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. In some embodiments, parenteral administration is intramuscular, intradermal, or subcutaneous administration. In some preferred embodiments, in the compound of Formula I, R 1 It is C 7-16 Alkyl groups, for example, have the formula -(CH2) n -CH3 alkyl, wherein n is an integer between 6 and 12 (eg, n is 6, 7, 8, 9 or 10); or R 1 From the formula -(CH2) n-Cy represents, wherein 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; or R 1 yes or R 1 yes In some embodiments, administration provides therapeutically effective abiraterone plasma concentrations in the subject for at least 4 weeks, such as at least 5 weeks and up to 6 weeks or 8 weeks or longer, etc. In some embodiments, the therapeutic plasma concentration of abiraterone can be at least 1 ng / ml, for example, a concentration of at least 2 ng / ml, at least 4 ng / ml, at least 8 ng / ml. In some embodiments, the therapeutically effective abiraterone plasma concentration can also be about 0.5 ng / ml or higher. In some embodiments, the administration can provide 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 provide 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 may provide a single dose C of abiraterone of about 1 ng / ml to about 8 ng / ml or above about 8 ng / ml, such as above about 8.4 ng / ml, on day 28 after administration. min In some embodiments, the administration can provide a steady-state C of abiraterone of about 1 ng / ml to about 8 ng / ml or above about 8 ng / ml, such as above about 8.4 ng / ml. min In some embodiments, the plasma concentration of abiraterone in the subject can remain substantially constant, e.g., for at least 1 week, e.g., 1 week to 3 weeks after administration. In some embodiments, administration is performed regardless of whether the subject has eaten. In some embodiments, the plasma concentration of abiraterone in the subject can remain substantially constant, e.g., for at least 1 week, e.g., 1 week to 3 weeks after administration. Following a once-daily oral dose, the C of abiraterone observed at steady state max The administration provides at least a 30% reduction in the C of a single dose of abiraterone compared to max In some embodiments, compared to 1000 mg of Following a once-daily oral dose, the C of abiraterone observed at steady state max The administration provides at least a 30% decrease in the steady-state C of abiraterone compared to maxIn some embodiments, pharmaceutical compositions comprising compounds of Formula I may be formulated into unit dosage forms as described herein. Suitable carriers, oil vehicles, excipients for such pharmaceutical compositions include those described herein.

[0184] The abiraterone prodrugs and abiraterone prodrug formulations disclosed herein can be administered to a subject in need thereof as the sole source of abiraterone. However, in some embodiments, other abiraterone drugs / formulations are not excluded. For example, in some embodiments, administration herein can be combined with abiraterone acetate such as Oral administration of the formulations is combined simultaneously or sequentially in any order. In some embodiments, the subject can use abiraterone prodrugs and abiraterone prodrug formulations as a supplement to existing abiraterone therapy. Moreover, the administration herein is not limited to the 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 can be administered to the subject.

[0185] In some embodiments, the methods herein may include an initial treatment period with a higher dosing frequency, such as weekly or biweekly dosing, prior to monthly or more dosing. The initial treatment period may include administration of the same abiraterone prodrug or different abiraterone drugs such as different abiraterone prodrugs. 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 above, prior to monthly or more dosing as described herein. However, in some embodiments, the methods herein do not include such an initial treatment period.

[0186] As discussed herein, the abiraterone prodrugs and abiraterone prodrug formulations disclosed herein have many advantages over currently marketed Advantages of the product. For example, administration of the abiraterone prodrugs and abiraterone prodrug formulations disclosed herein to a subject generally results in a C max Reduced (e.g., compared to 1000 mg without food) After once-daily oral dosing, the C of abiraterone observed at steady state max At least 30% lower than the previous day).

[0187] Thus, in some embodiments, the present disclosure provides a method for treating a patient having side effects associated with high exposure to abiraterone, such as having abiraterone C max The method comprises administering to the subject an abiraterone prodrug and an abiraterone prodrug formulation of the present disclosure, wherein the abiraterone prodrug and the abiraterone prodrug formulation of the present disclosure are administered to the subject ... The administration reduces side effects compared to once daily oral dosing. Suitable routes of administration, dosage amounts, and frequencies include those described herein. Various side effects or adverse reactions are described in the prescribing information, see, for example, the February 2018 or June 2019 versions. In some embodiments, the present disclosure provides a method of treating a subject who is also administered a drug whose metabolism is inhibited by abiraterone, such as a drug that is a substrate for CYP2D6 and / or CYP2C8, the method comprising administering to the subject an abiraterone prodrug or abiraterone prodrug formulation of the present disclosure, wherein the abiraterone prodrug is administered to the subject without food. In some embodiments, the present disclosure provides a method of treating a subject suffering from or at risk of hypertension, hypokalemia, or fluid retention caused by excess mineralocorticoids, the method comprising administering to the subject an abiraterone prodrug and an abiraterone prodrug formulation of the present disclosure, wherein the abiraterone prodrug is administered to the subject at a dose of 1000 mg without food. The administration reduces hypertension, hypokalemia, and fluid retention or the risk of hypertension, hypokalemia, and fluid retention compared to administration of a once daily oral dose. In some embodiments, the present disclosure provides a method of treating a subject having or at risk of adrenal insufficiency, the method comprising administering to the subject an abiraterone prodrug and an abiraterone prodrug formulation of the present disclosure, wherein the administration reduces hypertension, hypokalemia, and fluid retention or the risk of hypertension, hypokalemia, and fluid retention compared to administration of a once daily oral dose. The administration reduces adrenal insufficiency or the risk of developing adrenal insufficiency compared to administration of a once daily oral dose. In some embodiments, the present disclosure provides a method for treating A method for treating a subject with severe or fatal hepatotoxicity after undergoing treatment, the method comprising administering to the subject an abiraterone prodrug and abiraterone prodrug formulation of the present disclosure, wherein the administration reduces the hepatotoxicity.

[0188] Without wishing to be bound by theory, it is believed that administration of the abiraterone prodrugs and abiraterone prodrug formulations disclosed herein generally results in reduced but effective abiraterone exposure, thus benefiting subjects requiring lower doses of abiraterone (e.g., as described above). Suitable dosing regimens, routes of administration include those described herein.

[0189] Abiraterone Decanoate

[0190] 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 provide therapeutically effective amounts of plasma abiraterone over extended periods of time in various animal models. In monkey PK studies, it was further shown that a single intramuscular injection of abiraterone decanoate formulation can achieve prolonged CYP17A1 inhibition, resulting in sustained increases in progesterone levels and decreases in cortisol and testosterone levels. In addition, based on PK studies in rats, dogs, and monkeys, human PK predictions were made based on allometric scaling. Fig. 16C As shown, based on allometric scaling, it is predicted that after intramuscular administration of abiraterone decanoate to humans at a dose of approximately 1000 mg once every 4 weeks, C min At steady state, it is 5 ng / mL. Fig.14F As described in detail in , it was unexpectedly found that abiraterone decanoate formulations with certain combinations of oil and solvent could achieve significantly higher abiraterone plasma concentrations in monkeys after intramuscular injection compared to the same dose of abiraterone decanoate formulation in 90% corn oil and 10% benzyl alcohol, both of which had essentially the same abiraterone decanoate concentrations. Thus, achieving a predicted C of 5 ng / mL at steady state is min The required dose of abiraterone decanoate may be reduced. Alternatively, the steady-state C min It can also be increased to a predicted level higher than 5ng / mL. These disclosures demonstrate that abiraterone prodrugs, such as abiraterone lipophilic ester prodrugs, more particularly abiraterone decanoate, can be injected with a frequency lower than once a week, such as once every two weeks, once a month, or once more than a month, to deliver a therapeutically effective amount of abiraterone to a subject (e.g., a human subject). Typically, the frequency of administration can range from once a week to once every several months, such as from once a week to once every eight weeks, or from once a week to once every three months, such as once a month, once every eight weeks, etc.

[0191] In some specific embodiments, the present disclosure provides a compound which is abiraterone decanoate having the formula:

[0192]

[0193] Or its pharmaceutically acceptable salt. In some embodiments, abiraterone decanoate can be in its alkaline form. In some embodiments, abiraterone decanoate can also be in its pharmaceutically acceptable salt, such as oxalate, hydrochloride, benzenesulfonate, p-toluenesulfonate, phosphate, etc. In some embodiments, the salt of abiraterone decanoate can be used as a synthetic intermediate for preparing and purifying abiraterone decanoate in its alkaline form. As discussed herein, abiraterone decanoate is usually present in the abiraterone prodrug formulation herein in its alkaline form. Unless specifically mentioned in its salt form or otherwise contradictory to the context, abiraterone decanoate should be understood to be in its alkaline form.

[0194] In view of the present disclosure, those skilled in the art can easily prepare abiraterone decanoate or its pharmaceutically acceptable salt. Some exemplary synthesis methods are described herein. In some embodiments, the present disclosure provides a method for synthesizing abiraterone decanoate, which includes reacting abiraterone with decanoic acid or its activated form, such as corresponding acyl chloride, anhydride (e.g., mixed anhydride), etc. The reaction can usually be carried out in the presence of a coupling agent such as carbodiimide. As shown in the example section, the coupling of abiraterone and 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. The salt of abiraterone decanoate can be prepared by reacting abiraterone decanoate with a suitable acid such as oxalic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid or phosphoric acid, usually in an organic solvent such as isopropyl acetate, ethyl acetate, etc.

[0195] 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 is 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: 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6, and 20.8, 2θ degrees, ±0.2°; a differential scanning calorimetry (DSC) graph having an endothermic peak with an onset temperature of about 69.0°C; or a combination thereof. In some embodiments, the crystalline form may be characterized by having a crystalline form with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) peaks. Fig. 12A The XRPD spectra are substantially the same as those shown in FIG. Fig. 12A The peaks are shown at various diffraction angles (2θ degrees, ± 0.2°) regardless of their relative intensities. In some embodiments, the crystalline form may be characterized as being substantially similar to Fig. 12B The same DSC spectra are shown.

[0196] 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 may be first dissolved in a first solvent, such as acetone, at room temperature or under heating (such as about 40 ° C) conditions to form a solution; the solution may then be cooled to form a suspension; and optionally, the suspension may then be diluted with a second solvent (usually an anti-solvent in which Abiraterone decanoate has a low solubility) such as water, and stirred for a period of time (such as about 12 hours) to form a crystalline form. Those skilled in the art may adjust the amount, concentration, etc. of the solvent according to the present disclosure. An exemplary procedure is also shown in Example 6A.

[0197] Abiraterone decanoate is usually prepared in a high purity form, for example, suitable for pharmaceutical use. In some embodiments, the disclosure provides abiraterone decanoate in a substantially pure form, such as by weight, by HPLC area or both, with a purity higher than 80%, preferably higher than 90% (e.g., higher than 95%, higher than 97%, higher than 98%, higher than 99%, higher than 99.5%). In some embodiments, abiraterone decanoate may be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9% or any range between specified values ​​by weight and / or by HPLC area. For example, in some embodiments, abiraterone decanoate may be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9% or any range between specified values ​​by weight. Exemplary procedures for preparing substantially pure abiraterone decanoate are shown in the Examples section. The HPLC method suitable for measuring the purity of Abiraterone decanoate is also described in the Examples section. Substantially pure Abiraterone decanoate can be in solid form (e.g., crystalline form, amorphous form, or a combination thereof as described herein) or in solution, suspension, or another form. For the avoidance of doubt, the Abiraterone prodrug formulation comprising substantially pure Abiraterone decanoate and one or more other ingredients herein should be understood as a mixture of substantially pure Abiraterone decanoate and one or more other ingredients herein, for example, such formulations can be obtained directly or indirectly by mixing substantially pure Abiraterone decanoate with one or more other ingredients such as pharmaceutically acceptable oils, solvents, etc. (e.g., dissolving, suspending, or otherwise forming a mixture).

[0198] In some specific embodiments, the present disclosure provides a pharmaceutical composition comprising abiraterone decanoate having the formula:

[0199]

[0200] Or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier. Decanoic acid abiraterone is usually present in the pharmaceutical composition in its alkaline form, and unless the context is obviously contrary, it should be understood as such. In some embodiments, decanoic acid abiraterone can also be in a substantially pure form as described herein. For example, a pharmaceutical composition can be prepared by mixing substantially pure decanoic acid abiraterone with a pharmaceutically acceptable carrier and optional other ingredients. In some specific embodiments, substantially pure decanoic acid abiraterone is in a crystalline form as described herein, and a pharmaceutical composition can be prepared by mixing a crystalline form with a pharmaceutically acceptable carrier and optional other ingredients (e.g., dissolving, suspending or otherwise forming a mixture).

[0201] Typically, the pharmaceutical composition is formulated for parenteral administration. For example, in some embodiments, the pharmaceutical composition can be formulated for intramuscular injection, intradermal injection, or subcutaneous injection.

[0202] Pharmaceutical compositions are typically non-aqueous formulations, such as oil-based formulations, and include non-aqueous pharmaceutically acceptable carriers (e.g., described herein). For example, in some embodiments, pharmaceutically acceptable carriers include pharmaceutically acceptable oils, such as pharmaceutically acceptable injection oils, including oils of plant origin or synthetic fatty acid monoglycerides or diglycerides. In some embodiments, pharmaceutically acceptable oils can be natural oils, synthetic oils, or semi-synthetic oils, such as fractionated coconut oil and medium-chain triglycerides, such as those sold under the trademark Miglyol. In some embodiments, pharmaceutically acceptable carriers include triglycerides derived from fatty acids. In some embodiments, pharmaceutically acceptable carriers include triglycerides derived from long-chain and / or medium-chain fatty acids, which can be independently polyunsaturated, monounsaturated, or saturated triglycerides. As understood by those skilled in the art, medium-chain fatty acids generally include 6-12 carbons, such as caproic acid, caprylic acid, capric acid, lauric acid, etc.; short-chain fatty acids are generally less than 6 carbons; and long-chain fatty acids generally include 13-21 carbon atoms. In some embodiments, the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil, which can be selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil (peanut oil), poppy seed oil, tea seed oil and soybean oil. In some specific embodiments, the pharmaceutically acceptable carrier can include corn oil, which includes triglycerides, wherein the fatty acid constituents are mainly linoleic acid, oleic acid, palmitic acid and stearic acid.

[0203] In some embodiments, in addition to pharmaceutically acceptable oil, the pharmaceutically acceptable carrier may also include a pharmaceutically acceptable solvent (or co-solvent, if oil is counted as a solvent), such as alcohol, ester, acid, etc. In some embodiments, a pharmaceutically acceptable solvent may include benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid and / or ethyl acetate. In some embodiments, a pharmaceutically acceptable solvent may be benzyl alcohol and / or benzyl benzoate. In some embodiments, a pharmaceutically acceptable solvent may be benzyl alcohol. In some embodiments, a pharmaceutically acceptable solvent may be a combination of benzyl alcohol and benzyl benzoate. As discussed herein, the combination of benzyl alcohol and benzyl benzoate can significantly improve the solubility of abiraterone decanoate in a pharmaceutically acceptable oil.

[0204] In some specific embodiments, the present disclosure provides a pharmaceutical composition comprising abiraterone decanoate, a pharmaceutically acceptable oil (e.g., as described herein), benzyl alcohol and benzyl benzoate. In some embodiments, the pharmaceutically acceptable oil is corn oil. In some embodiments, benzyl alcohol is present in an amount of about 5-10% by volume, benzyl benzoate is present in an amount of about 10-20% by volume, and corn oil is present in an amount of about 70-85% by volume, wherein the combined volume of benzyl alcohol, benzyl benzoate and corn oil is 100%.

[0205] Pharmaceutical composition generally includes the decanoic acid abiraterone of about 25mg / ml to about 500mg / ml in concentration. In some embodiments, decanoic acid abiraterone can exist with the concentration of any scope between about 50mg / ml, about 100mg / ml, about 150mg / ml, about 200mg / ml, about 250mg / ml, about 300mg / ml, about 350mg / ml, about 400mg / ml, about 500mg / ml or described value. In some embodiments, decanoic acid abiraterone can exist with the concentration of about 100mg / ml to about 300mg / ml, such as about 150mg / ml to about 250mg / ml, about 200mg / ml to about 300mg / ml etc.

[0206] Abiraterone decanoate in the pharmaceutical composition is generally included in a therapeutically effective amount for treating a disease or condition described herein, such as prostate cancer. In some embodiments, abiraterone decanoate may be present in the pharmaceutical composition in an amount sufficient to provide a therapeutically effective abiraterone plasma concentration for at least one week, e.g., at least two weeks, at least four weeks, and up to six weeks or eight weeks or more, after a single administration to a subject suffering from a sex hormone-dependent benign or malignant condition, a syndrome caused by androgen excess, and / or a syndrome caused by glucocorticoid excess, such as hypercortisolemia. In some embodiments, abiraterone decanoate may be present in a pharmaceutical composition in an amount sufficient to provide a therapeutically effective abiraterone plasma concentration of about 1 ng / ml or more, such as about 2 ng / ml or more, about 4 ng / ml or more, about 5 ng / ml or more, about 8 ng / ml or more, etc., after a single administration to a subject suffering from a sex hormone-dependent benign or malignant condition, a syndrome caused by excess androgen, and / or a syndrome caused by excess glucocorticoids such as hypercortisolemia, for at least one week, for example, at least two weeks, at least four weeks, and up to six weeks or eight weeks or more. In some embodiments, abiraterone decanoate may be present in a pharmaceutical composition in an amount sufficient to provide a therapeutically effective abiraterone plasma concentration of about 0.5 ng / ml or more after a single administration to a subject suffering from a sex hormone-dependent benign or malignant condition, a syndrome caused by excess androgen, and / or a syndrome caused by excess glucocorticoids such as hypercortisolemia, for at least four weeks, for example, at least six weeks, and up to eight weeks or more.

[0207] In some specific embodiments, the present disclosure provides a pharmaceutical composition, such as a unit dosage form, comprising a therapeutically effective amount of abiraterone decanoate having the formula:

[0208] Pharmaceutically acceptable oil and pharmaceutically acceptable solvent, wherein decanoic acid abiraterone is in its alkaline form, it exists with following concentration: about 25mg / ml to about 500mg / ml, such as about 50mg / ml, about 100mg / ml, about 150mg / ml, about 200mg / ml, about 250mg / ml, about 300mg / ml, about 350mg / ml, about 400mg / ml, about 500mg / ml, or any scope between described values, wherein said pharmaceutical composition, such as unit dosage form, is formulated for parenteral injection, such as intramuscular injection, intradermal injection or subcutaneous injection, wherein said pharmaceutical composition, such as unit dosage form, comprises decanoic acid abiraterone, and its amount is about 50mg to about 2,000mg, such as about 100mg, about 350mg, about 500mg, about 1000mg, about 1500mg, about 2000mg, or any scope between described values.In some embodiments, said pharmaceutical composition can be in unit dosage form. Typically, according to the dosage, one or more (e.g., 1) unit dosage forms can be administered to a subject in need thereof. The pharmaceutically acceptable oil in a pharmaceutical composition (e.g., unit dosage form) can be any oil described herein. For example, in some embodiments, the pharmaceutically acceptable oil for injection of a pharmaceutically acceptable oil includes oil from a plant source or a synthetic fatty acid monoglyceride or diglyceride. In some embodiments, a pharmaceutically acceptable oil can 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, a pharmaceutically acceptable oil can include triglycerides derived from fatty acids. In some embodiments, a pharmaceutically acceptable oil can include triglycerides derived from long-chain and / or medium-chain fatty acids, which can be independently polyunsaturated, monounsaturated, or saturated triglycerides. In some embodiments, a pharmaceutically acceptable oil can be selected from vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil (peanut oil), poppy seed oil, tea seed oil, and soybean oil. In some specific embodiments, pharmaceutically acceptable oil can include corn oil, which includes triglycerides, wherein the fatty acid constituents are mainly linoleic acid, oleic acid, palmitic acid and stearic acid. The pharmaceutically acceptable solvent in the pharmaceutical composition (e.g., unit dosage form) also includes any solvent described herein. In some embodiments, a pharmaceutically acceptable solvent (or co-solvent, if oil is counted as a solvent), such as alcohol, ester, acid, etc. In some embodiments, a pharmaceutically acceptable solvent can include benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid and / or ethyl acetate. In some embodiments, a pharmaceutically acceptable solvent can be benzyl alcohol and / or benzyl benzoate. In some embodiments, a pharmaceutical composition, such as a unit dosage form, comprises abiraterone decanoate, pharmaceutically acceptable oil (e.g., described herein), benzyl alcohol and benzyl benzoate.In some embodiments, the pharmaceutically acceptable oil is corn oil. In some embodiments, benzyl alcohol is present in an amount of about 5-10% by volume, benzyl benzoate is present in an amount of about 10-20% by volume, and corn oil is present in an amount of about 70-85% by volume, wherein the combined volume of benzyl alcohol, benzyl benzoate, and corn oil is 100%.

[0209] In some embodiments, the present disclosure provides exemplary abiraterone decanoate formulations as shown in Table C. All numerical values ​​in the table are understood to be preceded by the term "about". The concentration of abiraterone decanoate refers to the amount (mg) of abiraterone in each ml of the final formulation, and the final formulation can be a solution or a suspension. The amount of oil (primary solvent) and co-solvent (benzyl alcohol and / or benzyl benzoate) in the table is expressed as a volume percentage of the solvent, and the solvent includes both oil and co-solvent. Suitable oils include any pharmaceutically acceptable oil described herein, such as corn oil. Optional additional ingredients are not shown in Table C. Examples 3F-3H herein show procedures for preparing representative abiraterone decanoate formulations of Table C.

[0210] Table C. Exemplary Abiraterone Decanoate Formulations

[0211]

[0212] Those skilled in the art can prepare the pharmaceutical composition or unit dosage form of the present invention according to the methods disclosed herein. In some embodiments, the present disclosure provides a method for preparing abiraterone decanoate formulation suitable for parenteral administration to subjects suffering from sex hormone-dependent benign or malignant conditions, syndromes caused by excessive androgens, and / or syndromes caused by excessive glucocorticoids such as hypercortisolemia. In some embodiments, the method comprises abiraterone decanoate having the following formula:

[0213] Mixing (such as dissolving or suspending) forms a mixture (such as a solution or suspension) in a pharmaceutically acceptable carrier. In some embodiments, the method further includes sterilizing the mixture (e.g., a solution or suspension). In some embodiments, dissolving or suspending may include mixing (e.g., dissolving or suspending) the crystalline form of Abiraterone Decanoate described herein in a pharmaceutically acceptable carrier. In some embodiments, mixing (such as dissolving or suspending) may include mixing (e.g., dissolving or suspending) substantially pure Abiraterone Decanoate described herein in a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers and amounts, the amount of Abiraterone Decanoate, the concentration of Abiraterone Decanoate, include any of those described herein. For example, in some embodiments, the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil and a pharmaceutically acceptable solvent, wherein the pharmaceutically 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 pharmaceutically acceptable solvent comprises benzyl alcohol and / or benzyl benzoate, and wherein the abiraterone decanoate is present at a concentration of about 50 mg / mL to about 300 mg / mL, such as about 100 mg / mL to about 300 mg / mL.

[0214] In some specific embodiments, the present disclosure also provides a method for treating a sex hormone-dependent benign or malignant condition, a syndrome caused by excessive androgen and / or a syndrome caused by excessive glucocorticoids such as hypercortisolemia, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) to a subject in need thereof. Administration is not limited to any particular route. However, abiraterone decanoate is usually administered parenterally, for example, via intramuscular injection, intradermal injection or subcutaneous injection. In some embodiments, administration is by intramuscular injection. Different from the oral administration of abiraterone acetate, a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) can be administered to a subject in need thereof with or without food.

[0215] The sex hormone-dependent benign or malignant conditions that can be treated with the method include any of those described herein. In some embodiments, sex hormone-dependent benign or malignant conditions can be selected from androgen-dependent conditions and estrogen-dependent conditions, such as androgen-dependent or estrogen-dependent cancers. In some embodiments, sex hormone-dependent benign or malignant conditions can be selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma and lung cancer, etc. In some embodiments, sex hormone-dependent benign or malignant diseases can be prostate cancer or breast cancer. In some embodiments, sex hormone-dependent benign or malignant conditions are castration-resistant prostate cancer or castration-sensitive prostate cancer. In some embodiments, sex hormone-dependent benign or malignant conditions can be metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer. The syndrome caused by androgen excess and / or the syndrome caused by glucocorticoid excess such as hypercortisolemia that can be treated with the method include any of those described herein. In some embodiments, the methods herein may be methods for treating non-neoplastic syndromes caused by androgen excess in a subject, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classic or nonclassical congenital adrenal hyperplasia), precocious puberty, hirsutism, etc. In some embodiments, the methods herein may be methods for treating non-neoplastic syndromes caused by excess glucocorticoids (e.g., Cortisol), such as Cushing's syndrome or Cushing's disease.

[0216] The method herein can be used together with one or more additional therapies for corresponding diseases or conditions. For example, the method can include administering one or more other drugs or medicaments (for example, lactation described herein, such as another cancer chemotherapy drug, hormone replacement drug or hormone ablation drug) to the subject simultaneously or sequentially by the same route of administration or different routes of administration. In some embodiments, the subject can also be treated with gonadotropin-releasing hormone analogs and / bilateral orchiectomy.

[0217] As discussed herein, abiraterone is a 17α-hydroxylase / C17,20-lyase (CYP17) inhibitor, which can lead to decreased biosynthesis of androgens (such as testosterone), decreased glucocorticoids (such as cortisol), and excess mineralocorticoids (e.g., increased progesterone). Adrenal insufficiency has also been noted with abiraterone therapy, such as It has been demonstrated that intramuscular administration of the pharmaceutical composition comprising abiraterone decanoate herein provides effective plasma levels of abiraterone and inhibits CYP17A1 in vivo for a long time, while progesterone levels are increased and cortisol levels are decreased.

[0218] In some embodiments, the method herein (for example, treating prostate cancer, or treating classic or non-classical congenital adrenal hyperplasia) may include administering a medicament to a subject, which counteracts the reduction of glucocorticoids associated with the administration of abiraterone decanoate as described herein. In some embodiments, the method may include administering to a subject in need an effective treatment of one or more symptoms associated with adrenal insufficiency, such as an agent of acute stress, fatigue, etc. In some specific embodiments, the method may include administering steroids, such as corticosteroids, to the subject. In some embodiments, the method may include administering glucocorticoids to the subject. In some specific embodiments, the method also includes administering prednisone, prednisolone and / or methylprednisolone to the subject. In some embodiments, the method also includes administering to the subject an agent that effectively treats cortisol deficiency, such as hydrocortisone, prednisone, prednisolone, methylprednisolone and / or dexamethasone. In any such embodiment, the agent may be administered to the subject simultaneously or sequentially in any order via the same or different routes of administration.

[0219] In some embodiments, the method herein may be characterized by weekly or even lower frequency of administration. Typically, the scope of administration frequency can be from weekly to once every several months, such as from weekly to once every three months, or from weekly to once every eight weeks, such as once a month. In some embodiments, the method includes applying a pharmaceutical composition (for example, a unit dosage form described herein) comprising decanoic acid abiraterone to a subject once a week, once every two weeks, once every three weeks, once a month, or more than a month. In some embodiments, the method includes applying a pharmaceutical composition (for example, a unit dosage form described herein) comprising decanoic acid abiraterone to a subject once every two weeks, once a month, or more than a month. In some embodiments, the dosage of each dose is about 50mg to about 2000mg (for example, about 100mg, about 350mg, about 500mg, about 1000mg, about 1500mg, or any range between the values) decanoic acid abiraterone. In some embodiments, the dosage of each dose of abiraterone decanoate is 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 between the values) subject body weight. In some embodiments, administration is via intramuscular injection. In some embodiments, the administration provides at least one week, e.g., at least two weeks, such as at least three weeks, at least four weeks, and up to six weeks or eight weeks or longer time periods of therapeutically effective abiraterone plasma concentrations. In some embodiments, the administration provides a plasma concentration of abiraterone above 1.0 ng / ml (e.g., between 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 at least one week, e.g., at least two weeks, such as at least 3 weeks, at least 4 weeks, and up to 6 weeks or 8 weeks or more. In some embodiments, the administration provides a steady-state C of abiraterone above 1.0 ng / ml. min (e.g., between about 1 ng / ml and about 8 ng / ml, about 2 ng / ml or more, about 4 ng / ml or more, about 5 ng / ml or more, or about 8 ng / ml or more.) In some embodiments, the administration provides a single dose or steady-state C of abiraterone. maxBetween about 10ng / ml to about 400ng / ml, such as about 10ng / ml, about 15ng / ml, about 20ng / ml, about 30ng / ml, about 50ng / ml, about 60ng / ml, about 100ng / ml, about 150ng / ml, about 160ng / ml or any range between the values ​​listed, for example, about 10-30ng / ml, about 20-60ng / ml, about 15-160ng / ml or about 50-100ng / ml. In some embodiments, the decanoic acid abiraterone formulation can be applied to a subject in need thereof as the sole source of abiraterone. However, in some embodiments, the decanoic acid abiraterone formulation can also be applied to a subject in need thereof as a supplement to another abiraterone therapy.

[0220] In some specific examples, the present disclosure provides a method for treating prostate cancer, the method comprising administering Abiraterone decanoate to a subject in need thereof once a week, such as once a month or once a month, via intramuscular injection, intradermal injection or subcutaneous injection, each 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 between the values) Abiraterone decanoate. In some embodiments, Abiraterone decanoate is administered via intramuscular injection. In some embodiments, prostate cancer is castration-resistant prostate cancer or castration-sensitive prostate cancer. In some embodiments, prostate cancer is metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer.

[0221] In some specific examples, the present disclosure provides a method for treating prostate cancer, the method comprising administering a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) to a subject in need thereof via intramuscular injection, intradermal injection, or subcutaneous injection, once a week or more than once a week, such as once a month or more than once a month, each 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 between the values) of abiraterone decanoate or each dose of abiraterone decanoate is 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 between the values) of the subject's body weight. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the prostate cancer is castration-resistant prostate cancer or castration-sensitive prostate cancer. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer.

[0222] In some specific examples, the present disclosure provides a method for treating prostate cancer, the method comprising administering the unit dosage form described herein to a subject in need thereof via intramuscular injection, intradermal injection or subcutaneous injection, once a week or more than once a week, such as once a month or more than once a month, each 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 between the values) of abiraterone decanoate or each dose of abiraterone decanoate is 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 between the values) of the subject's body weight. 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.

[0223] In some specific embodiments, the present disclosure also provides a method of delivering abiraterone to a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) via intramuscular injection, intradermal injection, or subcutaneous injection, once a week or more than once a week, such as once a month or more than once a month, each 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 between the values) of abiraterone decanoate or each dose of abiraterone decanoate is 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 between the values) of the subject's body weight. In some embodiments, the pharmaceutical composition is administered via intramuscular injection.In some embodiments, the subject suffers from a hormone-dependent benign or malignant condition, a syndrome caused by androgen excess, and / or a syndrome caused by glucocorticoid excess (such as, for example, hypercortisolemia described herein).

[0224] In some specific embodiments, the present disclosure also provides a method of inhibiting CYP17A1 activity in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) via intramuscular injection, intradermal injection, or subcutaneous injection once a week or more than once a week, such as once a month or more than once a month, each 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 between the values) of abiraterone decanoate or each dose of abiraterone decanoate is 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 between the values) of the subject's body weight. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the subject suffers from a sex hormone-dependent benign or malignant condition, for example, as described herein. In some embodiments, the subject suffers from a syndrome caused by androgen excess and / or a syndrome caused by glucocorticoid excess (such as hypercortisolemia as described herein).

[0225] In some specific embodiments, the present disclosure also provides a method of reducing the level of a glucocorticoid (e.g., Cortisol) in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) via intramuscular injection, intradermal injection, or subcutaneous injection once a week or more than once a week, such as once a month or more than once a month, each 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 between the values) of abiraterone decanoate or each dose of abiraterone decanoate is 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 between the values) of the subject's body weight. In some embodiments, the pharmaceutical composition is administered via intramuscular injection.In some embodiments, the subject has hypercortisolemia as described herein, such as Cushing's syndrome or Cushing's disease.

[0226] In some specific embodiments, the present disclosure also provides a method of reducing the level of androgens (e.g., testosterone and / or dihydrotestosterone) and / or estrogens in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) via intramuscular injection, intradermal injection, or subcutaneous injection, once a week or more than once a week, such as once a month or more than once a month, each dose is about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 100 mg, about 2000 mg, about 2000 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 ...500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 100 mg, about 2000 mg, about 300 mg, about 300 mg, about 400 mg, about 500 mg, about 500 mg, about In some embodiments, the subject is administered with abiraterone decanoate (e.g., about 0.5 mg / kg to about 100 mg / kg, about 100 mg / kg, about 500 mg / kg, about 1000 mg, about 1500 mg, or any range between the values) or each dose of abiraterone decanoate is 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 between the values). In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the subject suffers from a syndrome caused by excessive androgen, such as congenital adrenal hyperplasia (e.g., classic and non-classical congenital adrenal hyperplasia), endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc. In some embodiments, the subject suffers from androgen and / or estrogen related cancers, such as prostate cancer or breast cancer.

[0227] Other abiraterone prodrugs

[0228] Although the present disclosure describes the embodiments about Abiraterone decanoate in more detail, it will be understood by those skilled in the art that similar embodiments are also applicable to other Abiraterone prodrugs of the present disclosure in view of the description herein. For example, as with Abiraterone decanoate, pharmacokinetic studies have shown that intramuscular injection of Abiraterone isocaprylate formulations can also provide a therapeutically effective amount of plasma Abiraterone over a long period of time. Therefore, the embodiments described herein, particularly for Abiraterone decanoate formulations and methods of treatment, can also be similarly applicable to Abiraterone isocaprylate, wherein Abiraterone decanoate is substituted with Abiraterone isocaprylate.

[0229] For example, in some specific embodiments, the disclosure also provides a method for treating a sex hormone-dependent benign or malignant condition, a syndrome caused by excessive androgen, and / or a syndrome caused by excessive glucocorticoids such as hypercortisolemia, the method comprising administering a therapeutically effective amount of a pharmaceutical composition (e.g., a unit dosage form described herein) comprising isoleic acid abiraterone as described herein to a subject in need thereof. In some embodiments, a pharmaceutical composition (e.g., a unit dosage form described herein) comprising isoleic acid abiraterone as described herein may be administered to a subject in need thereof with or without food. Suitable sex hormone-dependent benign or malignant conditions, syndromes caused by excessive androgen, syndromes caused by excessive glucocorticoids (such as hypercortisolemia), dosage regimens, conjoint therapies, etc. include those described herein, such as those related to decanoic acid abiraterone.

[0230] In some specific examples, the present disclosure provides a method for treating prostate cancer, the method comprising administering a pharmaceutical composition comprising abiraterone isocaprylate as described herein to a subject in need thereof via intramuscular injection, intradermal injection or subcutaneous injection, once a week or more than once a week, such as once a month or more than once a month, each dose of abiraterone isocaprylate 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 between the values) or each dose of abiraterone isocaprylate of about 0.5 mg / kg to about 100 mg / kg (e.g., about 0.5 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 50 mg / kg, about 90 mg / kg, about 100 mg / kg or any range between the values) of the subject's body weight. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the prostate cancer is castration-resistant prostate cancer or castration-sensitive prostate cancer. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer.

[0231] In some specific examples, the present disclosure provides a method for treating prostate cancer, the method comprising administering a unit dosage form comprising abiraterone isocroate as described herein to a subject in need thereof via intramuscular injection, intradermal injection or subcutaneous injection, once a week or more than once a week, such as once a month or more than once a month, each 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 between the values) of abiraterone isocroate or each dose of abiraterone isocroate is 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 between the values) of the subject's body weight. 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.

[0232] In some specific embodiments, the present disclosure also provides a method of delivering abiraterone to a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising abiraterone isocaprylate as described herein (e.g., a unit dosage form as described herein) via intramuscular injection, intradermal injection, or subcutaneous injection, once a week or more than once a week, such as once a month or more than once a month, each 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 between the values) of abiraterone isocaprylate or each dose of abiraterone isocaprylate is 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 between the values) of the subject's body weight. In some embodiments, the pharmaceutical composition is administered via intramuscular injection.In some embodiments, the subject suffers from a hormone-dependent benign or malignant condition, a syndrome caused by androgen excess, and / or a syndrome caused by glucocorticoid excess (such as, for example, hypercortisolemia described herein).

[0233] In some specific embodiments, the present disclosure also provides a method of inhibiting CYP17A1 activity in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising abiraterone isocaprylate as described herein (e.g., a unit dosage form as described herein) via intramuscular injection, intradermal injection, or subcutaneous injection, once a week or more than once a week, such as once a month or more than once a month, each 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 between the values) of abiraterone isocaprylate or each dose of abiraterone isocaprylate is 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 between the values) of the subject's body weight. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the subject suffers from a sex hormone-dependent benign or malignant condition, for example, as described herein. In some embodiments, the subject suffers from a syndrome caused by androgen excess and / or a syndrome caused by glucocorticoid excess (such as, for example, hypercortisolemia as described herein).

[0234] In some specific embodiments, the present disclosure also provides a method of reducing the level of a glucocorticoid (e.g., Cortisol) in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising abiraterone isoleate as described herein (e.g., a unit dosage form as described herein) via intramuscular injection, intradermal injection, or subcutaneous injection, once a week or more than once a week, such as once a month or more than once a month, each dose is about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 50 ... In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the subject suffers from hypercortisolemia as described herein, such as Cushing's syndrome or Cushing's disease.

[0235] In some specific embodiments, the present disclosure also provides a method of reducing the level of androgens (e.g., testosterone and / or dihydrotestosterone) and / or estrogens in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising abiraterone isoleate as described herein (e.g., a unit dosage form as described herein) via intramuscular injection, intradermal injection, or subcutaneous injection, once a week or more than once a week, such as once a month or more than once a month, each dose is about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 400 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 100 mg, about 2000 mg, about 300 mg, about 400 mg, about 5 ... In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the subject suffers from syndromes caused by excessive androgen, such as congenital adrenal hyperplasia (e.g., classic and non-classical congenital adrenal hyperplasia), endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc. In some embodiments, the subject suffers from androgen and / or estrogen related cancers, such as prostate cancer or breast cancer.

[0236] Non-limiting exemplary embodiments

[0237] In some embodiments, the present disclosure also provides non-limiting exemplary embodiments 1-66 as shown below:

[0238] Embodiment 1. An abiraterone formulation suitable for parenteral administration to a subject suffering from a hormone-dependent benign or malignant disease, comprising:

[0239] (a) one or more lipophilic esters of abiraterone, and

[0240] (b) one or more pharmaceutically acceptable carriers, diluents or excipients,

[0241] wherein following said administering to said subject, said abiraterone prodrug formulation achieves a therapeutic plasma concentration of abiraterone.

[0242] Embodiment 2. The abiraterone prodrug formulation of embodiment 1, wherein the therapeutic plasma concentration of abiraterone is at least 1.0 ng / ml.

[0243] Embodiment 3. The abiraterone prodrug formulation of embodiment 1, wherein the therapeutic plasma concentration of abiraterone is at least 8 ng / ml.

[0244] Embodiment 4. The abiraterone prodrug formulation of embodiment 1, wherein the therapeutic plasma concentration of abiraterone is sustained for at least two weeks.

[0245] Embodiment 5. The abiraterone prodrug formulation of embodiment 1, wherein the parenteral administration is selected from intramuscular injection, intradermal injection, and subcutaneous injection.

[0246] Embodiment 6. The abiraterone prodrug formulation of embodiment 1, wherein the lipophilic ester form is selected from acetate, propionate, butyrate, valeric acid ester, caprylate, enanthate, cypionate, isocrylate, butyrate, cyclohexanecarboxylate, phenyl propionate, decanoate and undecanoate.

[0247] Embodiment 7. The abiraterone prodrug formulation of embodiment 1, wherein the hormone-dependent benign or malignant disorder is selected from androgen-dependent disorders and estrogen-dependent disorders.

[0248] Embodiment 8. The abiraterone prodrug formulation of embodiment 1, wherein the hormone-dependent benign or malignant condition is selected from prostate cancer and breast cancer.

[0249] Embodiment 9. The abiraterone prodrug formulation of embodiment 8, wherein the prostate cancer is selected from castration-resistant prostate cancer and castration-sensitive prostate cancer.

[0250] Embodiment 10. A method of treating a hormone-dependent benign or malignant condition comprising parenterally administering to a subject in need of such treatment an effective dose of at least one abiraterone prodrug formulation comprising:

[0251] (a) one or more lipophilic esters of abiraterone, and

[0252] (b) one or more pharmaceutically acceptable carriers, diluents or excipients,

[0253] wherein following said administering, said at least one abiraterone prodrug formulation achieves a therapeutic plasma concentration of abiraterone.

[0254] Embodiment 11. The method of embodiment 10, wherein the therapeutic plasma concentration of abiraterone is at least 1.0 ng / ml.

[0255] Embodiment 12. The method of embodiment 10, wherein the therapeutic plasma concentration of abiraterone is at least 8.0 ng / ml.

[0256] Embodiment 13. The method of embodiment 10, wherein the therapeutic plasma concentration of abiraterone is sustained for at least two weeks.

[0257] Embodiment 14. The method of embodiment 10, wherein the parenteral administration is selected from intramuscular injection, intradermal injection, and subcutaneous injection.

[0258] Embodiment 15. A method as described in embodiment 10, wherein the lipophilic ester form is selected from acetate, propionate, butyrate, valeric acid ester, caprylate, enanthate, cyclopentyl propionate, isocrylate, butyrate, cyclohexanecarboxylate, phenyl propionate, decanoate and undecanoate.

[0259] Embodiment 16. The method of embodiment 10, wherein the hormone-dependent benign or malignant condition is selected from the group consisting of androgen-dependent conditions and estrogen-dependent conditions.

[0260] Embodiment 17. The method of embodiment 10, wherein the hormone-dependent benign or malignant condition is selected from prostate cancer and breast cancer.

[0261] Embodiment 18. The method of embodiment 17, wherein the prostate cancer is selected from castration-resistant prostate cancer and castration-sensitive prostate cancer.

[0262] Embodiment 19. The method of embodiment 10, wherein the method further comprises administering the at least one abiraterone prodrug formulation once a month.

[0263] Embodiment 20. The method of embodiment 10, wherein the at least one abiraterone prodrug formulation is administered in divided doses.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] Embodiment 24. A kit for treating a hormone-dependent benign or malignant condition according to embodiment 10, comprising at least one abiraterone prodrug formulation.

[0268] Embodiment 25. A method of preparing abiraterone decanoate formulation suitable for parenteral administration to a subject suffering from a hormone-dependent benign or malignant condition, comprising the steps of:

[0269] (a) preparing and purifying abiraterone decanoate,

[0270] (b) preparing an oil and co-solvent mixture,

[0271] (c) combining the prepared and purified abiraterone decanoate with one of the oil and alcohol mixtures from step (b),

[0272] (d) sterilizing the mixture formed in step (c), and

[0273] (e) optionally combining the sterile mixture of step (d) with one or more pharmaceutically acceptable carriers, diluents or excipients.

[0274] Embodiment 26. The method of embodiment 25, wherein the prepared and purified abiraterone decanoate has the following chemical properties: LCMS m / z 504.4 (M+H); 1H NMR (CDCl3, 200MHz): δH 0.877 (3H, t, J=7Hz), 1.043 (3H, s), 1.082 (3H, s), 1.268 (16H, m), 1.64 3(15H,m), 1.842(3H,m), 2.065(3H,m), 2.290(5H,m), 4.602(1H,m), 5.4 04 (1H, d, J = 5Hz), 5.998 (1H, q, J = 5Hz), 7.215 (1H, ddd, J = 1, 5, 8Hz), 7.643 (1H, dt, J = 2, 8Hz), 8.455 (1H, dd, J = 2, 5Hz), 8.617 (1H, dd, J = 1, 2Hz).

[0275] Embodiment 27. The method of embodiment 25, wherein the oil and co-solvent mixture is selected from 90% castor oil / 10% benzyl alcohol and 90% corn oil / 10% benzyl alcohol.

[0276] Embodiment 28. A compound of formula I or a pharmaceutically acceptable salt thereof,

[0277]

[0278] Where R 1 For R 10 , OR 10 or NHR 10 ,

[0279] Where R 10 Selected from:

[0280] C 7-30 Alkyl; C 7-30 Alkenyl; C 7-30 Alkynyl; alkyl having a total of 5 to 16 carbon atoms substituted by cycloalkyl; alkyl having a total of 7 to 16 carbon atoms substituted by phenyl; cycloalkyl having a total of 5 to 16 carbon atoms optionally substituted by one or more alkyl groups; and

[0281] Embodiment 29. The compound or pharmaceutically acceptable salt thereof as described in Embodiment 28, wherein R 10 It is C 7-16 alkyl.

[0282] Embodiment 30. The compound according to Embodiment 28 or a pharmaceutically acceptable salt thereof, wherein R 10 It is C 3-6 The cycloalkyl-substituted alkyl group has a total carbon number of 6 to 12.

[0283] Embodiment 31. A compound according to Embodiment 28 or a pharmaceutically acceptable salt thereof, wherein R1 It is C 7-16 alkyl.

[0284] Embodiment 32. The compound or pharmaceutically acceptable salt thereof as described in Embodiment 28, wherein R 1 It has the formula -(CH2) n -CH3 alkyl, wherein n is an integer between 6 and 12, such as 6, 7, 8, 9, 10, 11 or 12.

[0285] Embodiment 33. The compound or pharmaceutically acceptable salt thereof as described in Embodiment 28, wherein R 1 From the formula -(CH2) n -Cy represents, wherein n is an integer from 1 to 6, and Cy is C 3-6 Cycloalkyl or phenyl.

[0286] Embodiment 34. The compound of Embodiment 33, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2 and Cy is cyclopentyl, cyclohexyl or phenyl.

[0287] Embodiment 35. The compound or pharmaceutically acceptable salt thereof according to Embodiment 28, wherein R 1 for

[0288] Embodiment 36. The compound or pharmaceutically acceptable salt thereof according to Embodiment 28, wherein R 1 for

[0289] Embodiment 37. A pharmaceutical composition comprising a compound as described in any one of Embodiments 28-36 or a pharmaceutically acceptable salt thereof.

[0290] Embodiment 38. The pharmaceutical composition of embodiment 37, formulated for parenteral administration.

[0291] Embodiment 39. The pharmaceutical composition of embodiment 38, which is formulated for intramuscular injection, intradermal injection or subcutaneous injection.

[0292] Embodiment 40. The pharmaceutical composition of embodiment 37, further comprising a pharmaceutically acceptable carrier.

[0293] Embodiment 41. A pharmaceutical composition as described in Embodiment 40, wherein the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil, for example, an oil suitable for use as a vehicle for injection, such as an oil of plant origin or a synthetic fatty acid mono- or diglyceride, for example, vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil or soybean oil.

[0294] Embodiment 42. The pharmaceutical composition of embodiment 40 or 41, further comprising a pharmaceutically acceptable solvent, such as benzyl alcohol.

[0295] Embodiment 43. The pharmaceutical composition of any one of Embodiments 37-42, which is a non-aqueous solution or suspension.

[0296] Embodiment 44. A pharmaceutical composition comprising a compound of formula II or a pharmaceutically acceptable salt thereof,

[0297]

[0298] Where R 2 YesR 20 , OR 20 or NHR 20 ,

[0299] Where R 20 Selected from:

[0300] C 1-30 Alkyl; C 2-30 Alkenyl; C 2-30 alkynyl; alkyl having a total of 4 to 30 carbon atoms substituted by a cycloalkyl group; alkyl having a total of 7 to 30 carbon atoms substituted by a phenyl group; and cycloalkyl having a total of 3 to 30 carbon atoms optionally substituted by one or more alkyl groups,

[0301] The pharmaceutical composition is formulated for intramuscular injection, intradermal injection or subcutaneous injection, and the compound of formula II or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 25 mg / ml to about 500 mg / ml.

[0302] Embodiment 45. The pharmaceutical composition according to embodiment 44, wherein R in Formula II 2 Selected from C 1-16 alkyl; alkyl having a total of 5 to 16 carbon atoms substituted by cycloalkyl; alkyl having a total of 7 to 16 carbon atoms substituted by phenyl; cycloalkyl having a total of 5 to 16 carbon atoms optionally substituted by one or more alkyl groups.

[0303] Embodiment 46. The pharmaceutical composition according to embodiment 44, wherein R in Formula II 2 It has the formula -(CH2) n -CH3 alkyl, wherein n is an integer between 0 and 12.

[0304] Embodiment 47. The pharmaceutical composition according to embodiment 44, wherein R in Formula II 2 From the formula -(CH2) n -Cy represents, wherein n is an integer from 1 to 6, and Cy is C3-6 Cycloalkyl or phenyl.

[0305] Embodiment 48. The pharmaceutical composition according to embodiment 44, wherein R in Formula II 2 for

[0306] Embodiment 49. The pharmaceutical composition of any one of Embodiments 44-48, which is a non-aqueous solution or suspension.

[0307] Embodiment 50. A pharmaceutical composition as described in any of Embodiments 44-49, wherein the compound of Formula II or a pharmaceutically acceptable salt thereof is dissolved or suspended in a pharmaceutically acceptable oil, for example, an oil suitable for use as a vehicle for injection, such as an oil of plant origin or a synthetic fatty acid monoglyceride or diglyceride, for example, vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil or soybean oil.

[0308] Embodiment 51. A pharmaceutical composition as described in any one of Embodiments 44-50, further comprising a pharmaceutically acceptable solvent, such as benzyl alcohol.

[0309] Embodiment 52. A pharmaceutical composition as described in any of Embodiments 44-51, comprising an amount of a compound of Formula II or a pharmaceutically acceptable salt thereof sufficient to provide a therapeutically effective plasma concentration of abiraterone for at least two weeks after a single administration to a subject with a hormone-dependent benign or malignant condition (e.g., metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer).

[0310] Embodiment 53. The pharmaceutical composition of embodiment 52, wherein the therapeutically effective plasma concentration of abiraterone is about 1 ng / ml or higher.

[0311] Embodiment 54. The pharmaceutical composition of embodiment 53, wherein the therapeutically effective plasma concentration of abiraterone is about 8 ng / ml or higher.

[0312] Embodiment 55. A method for treating a hormone-dependent benign or malignant condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 28-36, or a pharmaceutical composition as described in any one of Embodiments 37-54.

[0313] Embodiment 56. The method of embodiment 55, wherein the administration is intramuscular injection, intradermal injection or subcutaneous injection.

[0314] Embodiment 57. The method of embodiment 55 or 56, wherein administration is performed regardless of whether the subject has eaten, i.e., the compound or pharmaceutical composition is administered with or without food.

[0315] Embodiment 58. The method of any one of Embodiments 55-57, wherein the hormone-dependent benign or malignant condition is prostate cancer or breast cancer.

[0316] Embodiment 59. The method of any one of embodiments 55-57, wherein the hormone-dependent benign or malignant condition is castration-resistant prostate cancer or castration-sensitive prostate cancer.

[0317] Embodiment 60. The method of any one of embodiments 55-57, wherein the hormone-dependent benign or malignant condition is metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer.

[0318] Embodiment 61. The method of any one of Embodiments 55-60, wherein the subject is treated with a gonadotropin-releasing hormone analog and / or bilateral orchiectomy.

[0319] Embodiment 62. The method of any one of Embodiments 55-61, further comprising administering to the subject an effective amount of prednisone or prednisolone.

[0320] Embodiment 63. A method as described in any of embodiments 55-62, wherein the pharmaceutical composition is administered to the subject once a week or more than once a week, for example, the dosing frequency ranges from once a week to once every few months, such as once a week to once every eight weeks, or once a week to once every three months.

[0321] Embodiment 64. The method of any one of Embodiments 55-63, wherein the administration provides a plasma concentration of abiraterone above 1.0 ng / ml for at least two weeks.

[0322] Embodiment 65. The method of any one of Embodiments 55-63, wherein the administration provides a plasma concentration of abiraterone above 8.4 ng / ml for at least two weeks.

[0323] Embodiment 66. The method of any one of Embodiments 55-65, wherein the administration provides a single dose or steady-state C of abiraterone between about 10 ng / ml and about 400 ng / ml. max (e.g., about 50 ng / ml to about 100 ng / ml, or about 15 ng / ml to about 160 ng / ml).

[0324] Provided herein are preparations, methods and kits for treating a subject suffering from sex hormone-dependent benign or malignant conditions such as prostate cancer. Also provided are preparations that can be used for treating a subject suffering from sex hormone-dependent benign or malignant conditions (such as prostate cancer), syndromes caused by androgen excess and / or syndromes caused by glucocorticoid excess such as hypercortisolemia.Representative embodiments will now be described in detail, examples of which are shown in the accompanying drawings.

[0325] As used herein, the term "subject" means, but is not limited to, animals or humans who need or can receive chemotherapy for sex hormone-dependent benign or malignant conditions such as androgen-dependent conditions or estrogen-dependent conditions (including prostate cancer and breast cancer), animals or humans who need or can receive treatment for non-tumor syndromes caused by androgen excess, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classic or non-classical congenital adrenal hyperplasia), precocious puberty, hirsutism, etc., and / or non-tumor syndromes caused by glucocorticoid excess such as hypercortisolemia, such as Cushing's syndrome or Cushing's disease. In a preferred embodiment, the subject is a human subject.

[0326] As used herein, the term "other drug or agent" (e.g., when referring to at least one other drug or agent being administered before, simultaneously with, and after at least one abiraterone prodrug formulation) means at least one other compound, formulation, molecule, biologic, etc. that can enhance the efficacy of the formulation, reduce adverse side effects of the formulation, or improve the treatment of a particular condition. Any suitable route of administration of such "other drugs or agents" may be used, such as oral administration, parenteral administration, etc. Those skilled in the art of treating patients with sex hormone-dependent benign or malignant conditions (such as androgen-dependent conditions or estrogen-dependent conditions), syndromes caused by androgen excess syndromes, and / or syndromes caused by glucocorticoid excess (such as hypercortisolemia) will know and understand how to select and use such "other drugs or agents" to achieve the intended purpose.

[0327] The formulation can be optionally administered via a modified release device or method. As used herein, the term "modified release" is understood to include delayed release, long-term or extended release, sustained release or targeted release, etc. For example, in some embodiments, the modified release device or method can further prolong the release of abiraterone of the prodrug and formulation of the present disclosure. In some embodiments, the modified release device or method can also include any device or method (and can include, for example, implants) that can release a medicament or product (e.g., a drug or biologic) for a period of time after its administration rather than immediately. Various modified release devices have been described (Stubbe et al., Pharm. Res. 21: 1732, 2004) and can be applied to representative embodiments. Those skilled in the art can identify and adopt modified release devices and methods without excessive experimentation after considering all criteria and using best judgment on behalf of the subject.

[0328] The preparations and medicaments of the embodiment are used in pharmacologically or physiologically acceptable and effective amounts to reduce or eliminate, for example, the presence of prostate tumor tissue and abnormal or malignant prostate cells in a subject suffering from prostate cancer. Similarly, the preparations and medicaments of the embodiment are used in combination with a preventive or therapeutically effective amount alone or with other therapeutic agents or treatment modalities (e.g., radiotherapy and surgery), and the preventive or therapeutically effective amount is understood to meet the intended preventive or therapeutic purpose, and provides the amount of the benefit obtainable from using such preparations and medicaments.

[0329] As used herein, the terms "effective amount", "effective dose" and "therapeutic plasma concentration" mean but are not limited to the amount, dosage or concentration that can treat, delay, slow down, inhibit or eliminate the onset, presence or progression of a disease, disease or condition. For example, "effective amount", "effective dose" or "therapeutic plasma concentration" can reduce or eliminate the presence of prostate tumor tissue and abnormal or malignant prostate cells in a subject with prostate cancer, which is sufficient to cure (partially or completely) the disease or prevent the onset or further spread of a disease, disease or condition. For example, the effective amount of a formulation refers to the amount that is administered alone or in combination with other therapeutic agents or treatment modalities (e.g., radiotherapy and surgery) to achieve a clinically significant reduction in tumor load. Those skilled in the art will understand that the clinically significant reduction in tumor load (or the improvement of sex hormone-dependent benign or malignant conditions or another condition or syndrome described herein) occurs after the formulation is administered. "Effective amount", "effective dose" or "therapeutic plasma concentration" should be understood as not being seriously harmful to the subject, and in any case, any harmful side effects are exceeded by the amount, dosage or concentration of the benefit. By way of example only, an effective amount or dose of an abiraterone prodrug formulation means an amount capable of achieving an abiraterone 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 in a subject following parenteral administration of the prodrug formulation, and an effective plasma concentration is achieved for at least one week, e.g., at least two weeks (e.g., four, six, eight, or more weeks) after administration.

[0330] In general, the dosage ranges used for applying the formulations according to the present disclosure are those that produce the desired effects. The useful dosage to be applied will vary according to the age, weight and health status of the subject being treated, the mode of administration, approach and plan, the response of the individual subject and the type or staging (or the severity of sex hormone-dependent benign or malignant conditions or another syndrome or condition described herein) of the prostate cancer being sought to be treated with the formulation. The dosage will also vary with the nature or severity of the primary tumor and other potential symptoms, epidemiological conditions, the concomitant use of other active compounds and the route of administration. In addition, the dosage will be determined by the presence of any adverse side effects such as local hypersensitivity, systemic adverse reactions and immune tolerance.

[0331] The effective dosage of the formulation (and other agents) can be determined by one skilled in the art without undue experimentation (e.g., by pharmacokinetic studies) after considering all criteria and using the best judgment on behalf of the patient (and will most often depend on the specific formulation utilized). The dosage to be administered will depend on the specific circumstances, but in any case, the dosage is an amount sufficient to induce a clinical benefit or improvement thereof for sex hormone-dependent benign or malignant conditions (such as prostate cancer), syndromes caused by androgen excess, and / or syndromes caused by glucocorticoid excess (such as hypercortisolemia).

[0332] The formulations and medicaments of the embodiments may optionally be administered in combination with (or may include) one or more pharmaceutically acceptable carriers, diluents or excipients. Formulations, administration techniques, pharmaceutical compositions, methods for preparing pharmaceutical compositions, and pharmaceutically acceptable carriers, diluents and excipients are known in the art and are described, for example, in "Remington: The Science and Practice of Pharmacy" (formerly known as "Remington's Pharmaceutical Sciences," University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia, Pa. (2005)), the disclosure of which is hereby incorporated by reference. Those skilled in the art may use known injectable, physiologically acceptable sterile solutions. In order to prepare ready-to-use solutions 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 may be present as a lyophilisate or a dry preparation, which may be reconstituted with a known injectable solution under sterile conditions directly before use, for example as a kit of parts. In addition, the formulation may include one or more acceptable carriers (which may include, for example, solvents, dispersion media, coatings, adjuvants, stabilizers, diluents, preservatives, antibacterial and antifungal agents, isotonic agents, absorption regulators, etc. "Diluents" may include water, saline, phosphate buffered saline (PBS), glucose, ethanol, glycerol, etc. Isotonic agents may include sodium chloride, glucose, mannitol, sorbitol, and lactose, etc. Stabilizers include albumin and alkali metal salts of ethylenediaminetetraacetic acid, etc.

[0333] Any suitable route of administration can be used to provide an effective amount / dose of the formulations and medicaments according to the representative embodiments to the subject. The technicians in the fields of pharmacology, immunology, medicine, oncology, etc. can easily determine the suitable route of administration without undue experimentation. However, it is expected that the formulation is mainly suitable for parenteral administration, such as via intramuscular injection, intradermal injection or subcutaneous injection.

[0334] Abbreviations used herein have their conventional meanings in the fields of chemistry and biology.

[0335] This is also meant to be understood that a specific embodiment of a variable portion herein may be the same as or different from another specific embodiment having the same identifier.

[0336] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the CAS version of the Periodic Table of the Elements, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described herein. In addition, the general principles of organic chemistry and specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wile V & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way by the exemplary list of substituents described herein.

[0337] As used herein, the term "alkyl" as used independently or as part of another group refers to a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, an alkyl group may include one to thirty carbon atoms (i.e., C 1-30 Alkyl or alternatively represented by C1-C 30 In one embodiment, the alkyl group is a straight chain C 1-16 In another embodiment, the alkyl group is a branched C 3-16 alkyl.

[0338] As used herein, the term "cycloalkyl" as used alone or as part of another group refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having three to twelve carbon atoms (i.e., C 3-12 In one embodiment, the cycloalkyl group has two rings. In one embodiment, the cycloalkyl group has one ring. In another embodiment, the cycloalkyl group is C 3-8 In another embodiment, the cycloalkyl group is C 3-6 Cycloalkyl. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the carbon number continues to specify the number of carbons in the cycloalkyl ring system. Non-limiting exemplary cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalinyl, adamantyl, cyclopentenyl, and cyclohexenyl.

[0339] As used herein, the term "alkenyl" as used independently 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-carbon double bonds. In one embodiment, alkenyl is C 2-16 Alkenyl.

[0340] As used herein, the term "alkynyl" as used alone or as part of another group refers to a straight or branched aliphatic hydrocarbon containing one or more (e.g., 1, 2, or 3) carbon-carbon triple bonds. In one embodiment, the alkynyl group has one carbon-carbon triple bond. In one embodiment, the alkynyl group is C 2-16 Alkynyl.

[0341] As used herein, the term "abiraterone prodrug of the present disclosure" refers to any compound described herein according to Formula I or Formula II, a lipophilic ester of an abiraterone prodrug, or any of Example Nos. 2A-2H, an isotope-labeled compound thereof (e.g., a tritium-enriched compound), its possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures), its tautomers, its conformers, and / or its pharmaceutically acceptable salts (e.g., acid addition salts, such as hydrochlorides). Hydrates and solvates of the prodrugs of the present disclosure are considered to be compositions of the present disclosure, wherein the prodrugs are associated with water or solvents, respectively. Some prodrugs of the present disclosure may also exist in various polymorphic or amorphous forms. The prodrugs described herein include those compounds that are easily subjected to chemical changes under physiological conditions to provide active abiraterone. In addition, the prodrugs may be transformed by chemical or biochemical methods in an ex vivo environment. As used herein, the term "abiraterone prodrug formulation of the present disclosure" refers to any pharmaceutical composition or formulation comprising any one or more abiraterone prodrugs of the present disclosure, for example, any formulation prepared in Examples 3A-3J. In any embodiment described herein, unless directly contradicted by the context, the abiraterone prodrug of the present disclosure may be abiraterone decanoate. In any embodiment described herein, unless directly contradicted by the context, the abiraterone prodrug formulation of the present disclosure may be any pharmaceutical composition comprising abiraterone decanoate as described herein. In any embodiment described herein, unless directly contradicted by the context, the abiraterone prodrug of the present disclosure may also be abiraterone isocanoate. In any embodiment described herein, unless directly contradicted by the context, the abiraterone prodrug formulation of the present disclosure may also be any pharmaceutical composition comprising abiraterone isocanoate as described herein.

[0342] The abiraterone prodrugs disclosed herein may be present in an isotopically labeled or enriched form, containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number found most abundantly in nature. Isotopes may be radioactive isotopes or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, oxygen, and nitrogen include, but are not limited to 2 H. 3 H. 13 C. 14 C. 15 N and 18 O. Compounds containing other isotopes of these and / or other atoms are within the scope of the present disclosure.

[0343] Solid and dashed wedge bond lines represent stereochemistry customary in the art.

[0344] The following examples are provided for illustrative purposes only, and are in no way intended to limit the scope of the claimed subject matter.

[0345] Example 1 Long-acting injectable formulation of abiraterone prodrug

[0346] The formulation includes a long-acting injectable oil-based formulation of a lipophilic abiraterone prodrug, such as (1) 3β-alkanoic acid abiraterone and (2) C-2 to C-16 carbon straight chain, branched, cyclic and aromatic alkanoic acid esters (i.e., aliphatic and aromatic esters consisting of 2 to 16 carbon atoms). Abiraterone esters may include, for example, the following esters: acetate, propionate, butyrate, (valeric acid) valerate, isocrylate, butyrate, cyclohexanecarboxylate, phenylpropionate, caprylate (hexanoate), enanthate (enanthate) (heptanoate), cyclopentylpropionate, octanoate, nonanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate and hexadecanoate. In representative embodiments, the abiraterone ester is abiraterone acetate, abiraterone propionate and abiraterone decanoate.

[0347] Preparation can comprise the solution or suspension of Abiraterone prodrug in pharmaceutically acceptable oil, and the oil such as pharmaceutically acceptable oil for injection includes oil of plant origin or synthetic fatty acid monoglyceride or diglyceride.In some embodiments, pharmaceutically acceptable oil can include the triglyceride composed of fatty acid (polyunsaturated, monounsaturated and saturated) such as following: vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil (arachis oil), poppy seed oil, tea seed oil and soybean oil.Vegetable oil is selected based on the solubility of prodrug in oil.It is determined that acetic acid Abiraterone is most soluble in castor oil, and castor oil includes triglyceride, and wherein fatty acid component is mainly rich in oleic acid (a kind of hydroxylated monounsaturated fatty acid). On the contrary, it is determined that the more lipophilic prodrugs (abiraterone propionate and abiraterone decanoate) are more soluble in corn oil, which includes triglycerides, wherein the fatty acid components are mainly linoleic acid (non-hydroxylated polyunsaturated fatty acids), oleic acid (non-hydroxylated unsaturated fatty acids), palmitic acid (non-hydroxylated saturated fatty acids) and stearic acid (non-hydroxylated saturated fatty acids). Surprisingly, it is determined that the solubility of abiraterone butyrate in both castor oil and corn oil is lower than that of acetate, propionate or decanoate prodrugs. It is also noted that there is a negative correlation between the melting point and solubility of prodrugs in vegetable oils. The melting points of various abiraterone prodrugs are measured by differential scanning calorimetry, as shown in Table 1.

[0348] Table 1: Melting points of abiraterone prodrugs.

[0349] Abiraterone prodrug Melting point Acetate 127-130℃ Propionate 102℃ Butyrate 147℃ Decanoate 38℃

[0350] The formulation may contain pharmaceutically 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 determined that additives / co-solvents benzyl alcohol and benzyl benzoate have the advantage of increasing the solubility of the prodrug and reducing the viscosity and slip of the solution, see e.g. Figures 13A-13E and Tables 2A-2D, which provide a more concentrated solution that is more easily injected through a needle of acceptable gauge for intramuscular injection (e.g., 20-27 gauge such as 22-25 gauge). In practice, the cosolvent is selected based on its ability to reduce the viscosity of the vehicle to allow injection through a suitable injection needle or cannula. Benzyl alcohol as an additive in intramuscular or subcutaneous injection also has the advantage of acting as a local anesthetic at the injection site (Wilson et al., Ann. Emer. Med. 33(5), 495, 1999).

[0351] The solubility of the abiraterone ester can be affected after adding a cosolvent to the vegetable oil vehicle. Thus, in some embodiments, the abiraterone ester is completely dissolved in the composition, while in other embodiments, the abiraterone ester is partially dispersed in the composition. In one embodiment, the abiraterone ester is completely dissolved in the vehicle.

[0352] The formulation may also contain pharmaceutically acceptable preservatives, polymers, antioxidants, antimicrobial agents, chelating agents and other excipients, such as citric acid, glucose, ascorbic acid, benzalkonium chloride, benzoic acid, sodium sulfobutyl ether β-cyclodextrin, calcium chloride, sodium carboxymethylcellulose, chlorobutanol, creatine, cross-linked carboxymethylcellulose, dipotassium hydrogen phosphate, sodium docusate, sodium edetate, glycerin, sodium hyaluronate, hydroxypropyl β-cyclodextrin, lactic acid, lactose, lecithin. lipids, maleic acid, mannitol, meglumine, methylcellulose, methylparaben, microcrystalline cellulose, mepiridium chloride, monothioglycerol, phenol, poloxamer 188, polysaccharide lactic acid, polysorbate 20, polysorbate 40, polysorbate 80, propylparaben, sodium acetate, sodium benzoate, sodium citrate, sorbitan monolaurate, sorbitol, sucrose, tartaric acid, trisodium citrate, tromantanamide, tromethamine, and urea.

[0353] The formulations can be sterilized by methods known to those skilled in the art (eg, gamma irradiation, micron filtration, and autoclaving).

[0354] Abiraterone prodrug formulations can be prepared at various concentrations, including, for example, 25 mg / ml to 500 mg / ml. In representative embodiments, the concentration is 50 mg / ml to 300 mg / ml.

[0355] The formulation releases an effective amount of abiraterone over a period of at least one week and up to two, three, four or more weeks after intramuscular or subcutaneous injection. The abiraterone therapeutic plasma level achieved after administration of the abiraterone prodrug formulation can be, for example, 6-15 ng / ml 14-28 days after parenteral administration. In a representative embodiment, the therapeutic level is 8-12 ng / ml 14-28 days after parenteral administration. It has been shown that abiraterone C min >8.4 ng / ml is associated with a favorable prostate-specific antigen response and may be a key predictor of progression-free survival in patients with castration-resistant prostate cancer (Carton et al., Eur. J. Cancer, 72:54, 2017).

[0356] Example 2. Synthesis of Abiraterone Prodrug

[0357] Abiraterone acetate

[0358] Abiraterone acetate was obtained from Hetero Labs Limited, India.

[0359] Other abiraterone esters are usually prepared by combining abiraterone with R 2 COOH or a suitable activated form thereof such as R 2 COCl reaction to synthesize. The reaction is usually carried out in an aprotic solvent such as CHCl3 with a suitable base such as triethylamine. The examples of the preparation of abiraterone propionate, abiraterone butyrate, abiraterone valerate, abiraterone caproate, abiraterone enanthate, abiraterone isoleate, abiraterone cypionate and abiraterone decanoate are as follows.

[0360]

[0361] Example 2A. Preparation of Abiraterone Propionate

[0362] Abiraterone propionate was prepared as follows:

[0363] 15.0g (42.9mmol) of abiraterone was added to a 500ml round-bottom flask, followed by the addition of 450ml of chloroform and 11.96ml (85.8mmol, 2.0 equivalents) of triethylamine. The flask was purged with nitrogen and the mixture was cooled to 0°C in an ice bath. After stirring the mixture for 15 minutes, 4.12ml (47.2mmol, 1.1 equivalents) of propionyl chloride were added dropwise, followed by the addition of 6.57ml (47.2mmol, 1.1 equivalents) of triethylamine. The ice bath was removed, and the solution was stirred for another 2 hours. The reactant was cooled to 0°C again, and 4.12ml of propionyl chloride and 6.57mL of triethylamine were slowly added again. The ice bath was removed again, and the reactant was stirred for another 16 hours. The solution was then washed twice with 300ml of water and once with 300ml of brine. The organic phase was dried over sodium sulfate, concentrated in vacuo 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 30% ethyl acetate. The pure fractions were combined and concentrated in vacuo to provide 8.2 g of abiraterone propionate as a yellow solid with a purity of 97.8% according to HPLC analysis. Other chemical properties are as follows: LCMS m / z 406.3 (M+H); 1 H NMR (CDCl3, 200MHz): 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 = 5Hz), 5.992 (1H, q, J =5Hz), 7.215 (1H, ddd, J = 1, 5, 8Hz), 7.677 (1H, dt, J = 2, 8Hz), 8.456 (1H, dd, J = 2, 5Hz), 8.619 (1H, dd, J = 1, 2Hz); melting point (DSC) 101°C.

[0364] Example 2B. Preparation of Abiraterone Butyrate

[0365] Abiraterone butyrate was prepared as follows:

[0366] 7.0g (20.0mmol) of abiraterone was added to a 500ml round-bottomed flask, followed by the addition of 210ml of chloroform and 5.58ml (40.0mmol, 2.0 equivalents) of triethylamine. The flask was purged with nitrogen and the mixture was cooled to 0°C in an ice bath. After stirring the mixture for 15 minutes, 2.28ml (22.0mmol, 1.1 equivalents) of propionyl chloride were added dropwise, and then 3.07ml (22.0mmol, 1.1 equivalents) of triethylamine were added. The ice bath was removed, and the solution was stirred for another 2 hours. The reactant was cooled to 0°C again, and 2.28ml of butyryl chloride and 3.07mL of triethylamine were slowly added. The ice bath was removed again, and the reactant was stirred for another 16 hours. During the reaction, the color quickly changed from a white mixture to a yellow solution, and then slowly changed to a red solution. After the reaction was completed by TLC and LCMS confirmation, the solution was then washed twice with 150ml water and once with 150ml brine. The organic phase was dried over sodium sulfate, concentrated in vacuo and loaded onto silica. The crude compound was purified by flash chromatography using ethyl acetate / hexane solvent system. The desired compound was eluted with approximately 25% ethyl acetate. The pure fractions were combined and concentrated in vacuo to provide 5.5 g of abiraterone butyrate as a yellow solid. The chemical properties are as follows: LCMS m / z 420.4 (M+H); 1 H NMR (CDCl3, 200MHz): 8H 0.948 (3H, t, J=7Hz), 1.043 (3H, s), 1.090 (3H, s), 1.633 (15H, m), 1.84 2(3H,m), 2.065(3H,m), 2.297(5H,m), 4.608(1H,m), 5.413(1H,d,J=5Hz ), 5.990 (1H, q, J = 5Hz), 7.215 (1H, ddd, J = 1, 5, 8Hz), 7.643 (1H, dt, J = 2, 8Hz), 8.455 (1H, dd, J = 2, 5Hz), 8.615 (1H, dd, J = 1, 2Hz); melting point (DSC) 147°C.

[0367] Example 2C. Preparation of Abiraterone Decanoate

[0368]

[0369] Abiraterone decanoate was prepared as follows:

[0370] 10.0g (28.6mmol) of abiraterone was added to a 500ml round-bottomed flask, followed by the addition of 300ml of chloroform and 7.97ml (57.2mmol, 2.0 equivalents) of triethylamine. The flask was purged with nitrogen and the mixture was cooled to 0°C in an ice bath. After stirring the mixture for 15 minutes, 6.53ml (31.5mmol, 1.1 equivalents) of caprylic chloride was added dropwise, followed by the addition of 4.39ml (31.5mmol, 1.1 equivalents) of triethylamine. The ice bath was removed, and the solution was stirred for another 2 hours. The reactant was cooled to 0°C again, and 6.53ml of caprylic chloride and 4.39mL of triethylamine were slowly added. The ice bath was removed again, and the reactant was stirred for another 16 hours. During the reaction, the color quickly changed from a white mixture to a yellow solution, and then slowly changed to a red solution. After the reaction was completed by TLC and LCMS, the solution was then washed twice with 200ml water and once with 200ml brine. The organic phase was dried over sodium sulfate, concentrated in vacuo and loaded onto silica. The crude compound was purified by flash chromatography using ethyl acetate / hexane solvent system. The desired compound was eluted with approximately 20% ethyl acetate. The pure fractions were combined and concentrated in vacuo to provide 8.0 g of abiraterone decanoate as a yellow solid. The chemical properties are as follows: LCMS m / z 504.4 (M+H); 1 H NMR (CDCl3, 200 MHz): δH m), 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.

[0371] Example 2D. Preparation of Abiraterone Valerate

[0372]

[0373] Abiraterone valerate was prepared using a procedure similar to that for abiraterone decanoate (Example 2C), except that valeric acid chloride was used instead of decanoyl chloride. LCMS m / z 434.3 (M+H); 1 H NMR (CDCl3, 200 MHz): δ H0.9-2.2 (32H, m), 4.61 (1H, m), 5.41 (1H, d, J = 5Hz), 5.99 (1H, q, J = 5Hz), 7.22 (1H, ddd , J=1, 5, 8Hz), 7.63 (1H, dt, J=2, 8Hz), 8.45 (1H, dd, J=2, 5Hz), 8.62 (1H, dd, J=1, 2Hz).

[0374] Example 2E. Preparation of Abiraterone Hexanoate

[0375]

[0376] Abiraterone hexanoate was prepared using a procedure similar to that for 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, 200 MHz): δ H 0.9-2.2 (34H, m), 4.60 (1H, m), 5.40 (1H, d, J = 5Hz), 5.98 (1H, q, J = 5Hz), 7.21 (1H, ddd , J=1, 5, 8Hz), 7.62 (1H, dt, J=2, 8Hz), 8.43 (1H, dd, J=2, 5Hz), 8.60 (1H, dd, J=1, 2Hz).

[0377] Example 2F. Preparation of Abiraterone Heptanoate

[0378]

[0379] Abiraterone heptanoate was prepared using a procedure similar to that for 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, 200 MHz): δ H 0.9-2.2 (36H, m), 4.61 (1H, m), 5.40 (1H, d, J = 5Hz), 6.00 (1H, q, J = 5Hz), 7.21 (1H, ddd , J=1, 5, 8Hz), 7.64 (1H, dt, J=2, 8Hz), 8.45 (1H, dd, J=2, 5Hz), 8.61 (1H, dd, J=1, 2Hz).

[0380] Example 2G. Preparation of Abiraterone Isocaprylate

[0381]

[0382] Abiraterone isoleate was prepared using a procedure similar to that for 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, 200 MHz): δ H 0.9-2.2 (34H, m), 4.61 (1H, m), 5.40 (1H, d, J = 5Hz), 6.00 (1H, q, J = 5Hz), 7.22 (1H, ddd , J=1, 5, 8Hz), 7.64 (1H, dt, J=2, 8Hz), 8.45 (1H, dd, J=2, 5Hz), 8.62 (1H, dd, J=1, 2Hz).

[0383] Example 2H. Preparation of Abiraterone Cypionate

[0384]

[0385] Abiraterone cypionate was prepared using a procedure similar to that for abiraterone decanoate (Example 2C), except that 3-cyclopentylpropionyl chloride was used instead of decanoyl chloride. LCMS m / z 474.4 (M+H); 1 H NMR (CDCl3, 200 MHz): δ H 1 H NMR (CDCl3, 200 MHz): δ H 0.9-2.3 (36H, m), 4.62 (1H, m), 5.41 (1H, d, J = 5Hz), 6.00 (1H, q, J = 5Hz), 7.22 (1H, ddd , J=1, 5, 8Hz), 7.63 (1H, dt, J=2, 8Hz), 8.45 (1H, dd, J=2, 5Hz), 8.62 (1H, dd, J=1, 2Hz).

[0386] Example 3. Preparation of Abiraterone Prodrug Formulation

[0387] Example 3A. Preparation of Abiraterone Acetate Castor Oil Solution

[0388] Prepare abiraterone acetate injectable (intramuscular depot) castor oil solution as follows:

[0389] Weigh 490mg of Abiraterone acetate and place it in a 10mL serum vial with a crimped stopper. Place 8mL of castor oil in a separate 10mL serum vial with a crimped stopper. Then wrap the two vials in aluminum foil and sterilize using a 30-minute liquid cycle in an autoclave. After sterilization, move the vial to a laminar flow hood. Then, take out 7mL of sterile castor oil and add to sterile Abiraterone acetate, and re-stopper the vial and crimp it closed. Then dissolve Abiraterone acetate by ultrasonic treatment, vortexing and placing the vial on a rotator. The final concentration of the Abiraterone acetate sterile solution is 70mg / ml.

[0390] Example 3B. Preparation of Abiraterone Acetate 90% Castor Oil, 10% Benzyl Alcohol Solution

[0391] Prepare Abiraterone acetate injectable (intramuscular depot) 90% castor oil, 10% benzyl alcohol solution as follows:

[0392] 700 mg of Abiraterone acetate was weighed and placed in a 10 mL serum vial with a crimped stopper. 8 mL of a 90% castor oil / 10% benzyl alcohol mixture was placed in a separate 10 mL serum vial with a crimped stopper. Both vials were then wrapped in aluminum foil and sterilized using a 30-minute liquid cycle in an autoclave. After sterilization, the vials were moved to a laminar flow hood. Then, 7 mL of a sterile 90% castor oil / 10% benzyl alcohol solution was taken out and added to the sterile Abiraterone acetate, and the vial was re-stopped and crimped closed. The Abiraterone acetate was then dissolved by sonication, vortexing, and placing the vial on a rotator. The final concentration of the Abiraterone acetate sterile solution was 91 mg / ml.

[0393] Example 3C. Preparation of Abiraterone Acetate 50% Castor Oil, 50% Benzyl Benzoate Solution

[0394] Prepare Abiraterone acetate injectable (intramuscular depot) 50% castor oil, 50% benzyl benzoate solution as follows:

[0395] Weigh 980mg of Abiraterone acetate and place it in a 10mL serum vial with a crimped stopper. Place 8mL of a 50% castor oil / 50% benzyl benzoate mixture in a separate 10mL serum vial with a crimped stopper. Then wrap both vials in aluminum foil and sterilize using a 30-minute liquid cycle in an autoclave. After sterilization, move the vials to a laminar flow hood. Then, take out 7mL of a sterile 50% castor oil / 50% benzyl benzoate mixture solution and add it to the sterile Abiraterone acetate, and re-stopper the vial and crimp it closed. Then dissolve the Abiraterone acetate by ultrasonic treatment, vortexing, and placing the vial on a rotator. The final concentration of the Abiraterone acetate sterile solution is 124mg / ml.

[0396] Example 3D. Preparation of Abiraterone Propionate 90% Castor Oil, 10% Benzyl Alcohol Solution

[0397] Prepare Abiraterone Propionate Injectable (Intramuscular Depot) 90% Castor Oil, 10% Benzyl Alcohol Solution as follows:

[0398] 1,050 mg of Abiraterone Propionate was weighed and placed in a 10 mL serum vial with a crimped stopper. 8 mL of the 90% castor oil / 10% benzyl alcohol mixture was placed in a separate 10 mL serum vial with a crimped stopper. The vehicle vial was then wrapped in aluminum foil and sterilized using a 30-minute liquid cycle in an autoclave. After sterilization, the vial was moved to a laminar flow hood. Then, 8 mL of the sterile 90% castor oil / 10% benzyl alcohol solution was taken out and added to the Abiraterone Propionate, and the vial was re-stopped and crimped closed. The Abiraterone Propionate was then dissolved by sonication, vortexing, and placing the vial on a rotator. The final concentration of the Abiraterone Propionate sterile solution was 197 mg / ml.

[0399] Example 3E. Preparation of Abiraterone Propionate 90% Corn Oil, 10% Benzyl Alcohol Solution

[0400] Prepare Abiraterone Propionate Injectable (Intramuscular Depot) 90% corn oil, 10% benzyl alcohol solution as follows:

[0401] 1,050 mg of abiraterone propionate was weighed and placed in a 10 mL serum vial with a crimped stopper. 8 mL of the 90% corn oil / 10% benzyl alcohol mixture was placed in a separate 10-mL serum vial with a crimped stopper. The vehicle vial was then wrapped in aluminum foil and sterilized using a 30-minute liquid cycle in an autoclave. After sterilization, the vial was moved to a laminar flow hood. Then, 8 mL of the sterile 90% corn oil / 10% benzyl alcohol solution was taken out and added to the abiraterone propionate, and the vial was re-stopped and crimped closed. The abiraterone propionate was then dissolved by sonication, vortexing, and placing the vial on a rotator. The final concentration of the sterile abiraterone propionate solution was 168 mg / ml.

[0402] Example 3F. Preparation of Abiraterone Decanoate 90% Castor Oil, 10% Benzyl Alcohol Solution

[0403] Prepare Abiraterone decanoate injectable (intramuscular depot) 90% castor oil, 10% benzyl alcohol solution as follows:

[0404] Weigh 1,260mg Abiraterone Decanoate and place it in a 10mL serum vial with a crimped stopper. 8mL of 90% castor oil / 10% benzyl alcohol mixture is placed in a separate 10mL serum vial with a crimped stopper. Then wrap the vehicle vial in aluminum foil and sterilize using a 30-minute liquid cycle in an autoclave. After sterilization, move the vial to a laminar flow hood. Then, take out 8mL of sterile 90% castor oil / 10% benzyl alcohol solution and add to Abiraterone Decanoate, and re-stopper the vial and crimp it closed. Then dissolve Abiraterone Decanoate by ultrasonic treatment, vortexing and placing the vial on a rotator. The final concentration of the Abiraterone Decanoate sterile solution is 160mg / ml.

[0405] Example 3G. Preparation of Abiraterone Decanoate 90% Corn Oil, 10% Benzyl Alcohol Solution

[0406] Prepare Abiraterone decanoate injectable (intramuscular depot) 90% corn oil, 10% benzyl alcohol solution as follows:

[0407] 1,260 mg of Abiraterone Decanoate was weighed and placed in a 10 mL serum vial with a crimped stopper. 8 mL of a 90% corn oil / 10% benzyl alcohol mixture was placed in a separate 10 mL serum vial with a crimped stopper. The vehicle vial was then wrapped in aluminum foil and sterilized using a 30-minute liquid cycle in an autoclave. After sterilization, the vial was moved to a laminar flow hood. Then, 8 mL of a sterile 90% corn oil / 10% benzyl alcohol solution was taken out and added to the Abiraterone Decanoate, and the vial was re-stopped and crimped closed. The Abiraterone Decanoate was then dissolved by sonication, vortexing, and placing the vial on a rotator. The final concentration of the Abiraterone Decanoate sterile solution was 170 mg / ml.

[0408] Example 3H. Abiraterone Decanoate (~200 MG / ML) 70% corn oil, 10% benzyl alcohol, 20% benzyl benzoate Solution preparation

[0409] Abiraterone decanoate injectable (intramuscular depot -200 mg / ml) 70% corn oil, 10% benzyl alcohol, 20% benzyl benzoate solution was prepared as follows:

[0410] 2,500 mg of Abiraterone Decanoate was weighed and placed in a 20 mL serum vial with a crimped stopper. 60 mL of a 70% corn oil / 10% benzyl alcohol / 20% benzyl benzoate mixture was placed in a separate 100 mL serum vial with a crimped stopper. The vehicle vial was then wrapped in aluminum foil and sterilized using a 30-minute liquid cycle in an autoclave. After sterilization, the vial was moved to a laminar flow hood. Then, 10 mL of a sterile 70% corn oil / 10% benzyl alcohol / 20% benzyl benzoate solution was taken out and added to the Abiraterone Decanoate, and the vial was re-stopped and crimped closed. The Abiraterone Decanoate was then dissolved by sonication, vortexing, and placing the vial on a rotator. The final concentration of the Abiraterone Decanoate sterile solution was 209 mg / ml.

[0411] Example 3I. Abiraterone Decanoate (~240 MG / ML) 70% corn oil, 10% benzyl alcohol, 20% benzyl benzoate Solution preparation

[0412] Prepare Abiraterone decanoate injectable (intramuscular depot -240 mg / ml) 70% corn oil, 10% benzyl alcohol, 20% benzyl benzoate solution as follows:

[0413] Weigh 3,125mg Abiraterone Decanoate and place it in a 20mL serum vial with a crimped stopper. 60mL of 70% corn oil / 10% benzyl alcohol / 20% benzyl benzoate mixture is placed in a separate 100mL serum vial with a crimped stopper. Then wrap the vehicle vial in aluminum foil and sterilize using a 30-minute liquid cycle in an autoclave. After sterilization, move the vial to a laminar flow hood. Then, take out 10mL of sterile 70% corn oil / 10% benzyl alcohol / 20% benzyl benzoate solution and add to Abiraterone Decanoate, and re-stopper the vial and crimp it closed. Then dissolve Abiraterone Decanoate by ultrasonic treatment, vortexing and placing the vial on a rotator. The final concentration of the Abiraterone Decanoate sterile solution is 242mg / ml.

[0414] Example 3J. Preparation of Abiraterone Isocaprylate 90% Corn Oil, 10% Benzyl Alcohol Solution

[0415] Prepare Abiraterone Isocaprylate Injectable (Intramuscular Depot) 90% corn oil, 10% benzyl alcohol solution as follows:

[0416] Weigh 1190mg of abiraterone isocaprylate and place it in a 10mL serum vial with a crimped stopper. 8mL of a 90% corn oil / 10% benzyl alcohol mixture is placed in a separate 10mL serum vial with a crimped stopper. Then wrap the vehicle vial in aluminum foil and sterilize using a 30-minute liquid cycle in an autoclave. After sterilization, move the vial to a laminar flow hood. Then, take out 6.4mL of sterile 90% corn oil / 10% benzyl alcohol solution and add to abiraterone isocaprylate, and re-stopper the vial and crimp it closed. Then dissolve abiraterone isocaprylate by ultrasonic treatment, vortexing and placing the vial on a rotator. The final concentration of the sterile solution of abiraterone isocaprylate is 158mg / ml.

[0417] Example 4A. Solubility test of abiraterone prodrug

[0418] The solubility of various abiraterone prodrugs was tested as follows. The results are shown in Table 2.

[0419] For each solvent studied, a sufficient amount of prodrug is weighed into a separate glass vial and 1-2 ml of solvent is added. The resulting suspension is subjected to ultrasonic treatment and vortexing. If the prodrug is completely dissolved, more prodrug is added until excess material is observed. If there is a large amount of excess undissolved prodrug, diluent can be added again. Record the total mass and volume used. Each vial is tightly capped and wrapped with foil to protect from light when necessary. The vial is placed on a laboratory rotator in a 25°C incubator (or any other desired temperature). Before assessing solubility, the sample is balanced for at least 1 day. A second time point later is also taken, usually at about 1 week, to confirm the solubility of each prodrug.

[0420] At the appropriate time point, the vial is removed from the incubator. A small amount of supernatant from each vial is transferred to a microcentrifuge tube containing a 0.22 or 0.45um filter. The tube is centrifuged at 10,000rpm until all the liquid passes through the filter to the bottom of the tube. Alternatively, the sample is filtered using a 0.22 or 0.45μm syringe filter. The filtered liquid is measured using HPLC. Dilute the sample if necessary so that the sample concentration is within the standard range.

[0421] Table 2: Solubility of abiraterone prodrugs.

[0422]

[0423]

[0424] Table 2: Solubility of abiraterone prodrugs (continued).

[0425]

[0426] Parenteral formulations must be sterilized prior to administration. This can be achieved by a variety of techniques, including heat sterilization (e.g., dry or moist heat), radiation sterilization (e.g., gamma ray sterilization), filtration sterilization (e.g., 0.22 micron membrane filter), or gas sterilization (e.g., formaldehyde or ethylene oxide gas).

[0427] Example 4B. Solubility, viscosity and slip test of abiraterone decanoate formulation or oil vehicle

[0428] This example tests the properties of various abiraterone decanoate formulations and oil vehicles.

[0429] First, further solubility studies showed 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 for the studies in Table 2A was obtained from Example 6A.

[0430] Table 2A. Solubility study of abiraterone decanoate in different vehicles

[0431]

[0432]

[0433] As can be seen from this study, the combination of benzyl alcohol and benzyl benzoate can significantly enhance the solubility of abiraterone decanoate in corn oil. Fig.13A and Fig. 13B .

[0434] Additional experiments also showed that the inclusion of benzyl benzoate reduced the viscosity and glide of the oil vehicle. It is expected that such oil vehicles can be advantageously used to formulate the abiraterone prodrugs herein to provide abiraterone prodrug formulations with lower viscosity and lower glide when desired.

[0435] The sliding force test is performed with a tension and compression tester (e.g., Lloyd press or equivalent), NEXYGEN Plus material testing software, or an equivalent Load cell 250 N. 5-mL Luer-Lok syringe (e.g., Becton, Dickinson and Company / BD, P / N 309646), or an equivalent 23-gauge, 1.5-inch long, thin-wall, precision sliding needle (e.g., Becton, Dickinson and Company / BD, P / N 305194), or an equivalent 27-gauge, 1.5-inch long, regular-wall, precision sliding needle (e.g., Becton, Dickinson and Company / BD, P / N 301629), or an equivalent.

[0436] Table 2B shows the viscosity of various oil vehicles without additives or with 10% benzyl alcohol, 20% benzyl benzoate, or a combination of 10% benzyl alcohol and 20% benzyl benzoate. Fig. 13C .

[0437] Table 2B. Viscosity of various oils containing additives (Pa*s)

[0438]

[0439]

[0440] Tables 2C and 2D show the glide forces (N) for various oil vehicles using a 23 gauge needle or a 27 gauge needle, respectively, without additives or with 10% benzyl alcohol, 20% benzyl benzoate, or a combination of 10% benzyl alcohol and 20% benzyl benzoate. Fig.13D and Fig.13E .

[0441] Table 2C. Sliding force (N) of various oils with additives, 23 gauge needle

[0442]

[0443] Table 2D. Sliding force (N) of various oils with additives, 27 gauge needle

[0444]

[0445] Example 5

[0446] Plasma pharmacokinetics of abiraterone in rats and dogs after administration of abiraterone prodrug formulations

[0447] Example 5A. PK Study of Abiraterone and Abiraterone Acetate in Rats and Dogs

[0448] Several formulations were considered in the initial rat study. 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 intramuscular formulations follows the general process of placing the drug in a vial and the solubilizing solution in a second vial and sterilizing each vial. Once the components are sterilized, they are mixed together under aseptic conditions to produce the final product. Sterilization is performed separately because the drug may degrade during the sterilization process when it is in solution. In addition, due to the viscosity of the oil or the suspension properties of the two formulations, this sterilization process was selected instead of filtration sterilization.

[0449] Another study was conducted using dogs as an animal model instead of rats. Four formulations were used in this study and they included abiraterone acetate solution in an aqueous system (administered intravenously) and abiraterone acetate solution in castor, 90% castor oil and 10% benzyl alcohol, or abiraterone acetate solution in 50% castor oil and 50% benzyl benzoate.

[0450] The above formulations were administered as intravenous injections or as intramuscular injections into the hind leg of each animal in rats or dogs. Plasma samples were drawn throughout the study and analyzed for prodrug and abiraterone. The results of the rat study are presented in Tables 3 and Figure 1 Available in.

[0451] Table 3: Group mean plasma pharmacokinetic parameters of abiraterone following intramuscular injection of various abiraterone or abiraterone acetate formulations in rats.

[0452]

[0453]

[0454] Group 1: Abiraterone acetate solution in castor oil (70 mg / ml); Group 2: Abiraterone acetate suspension in sodium phosphate buffer, 0.1% Tween (70 mg / ml); Group 3: Abiraterone suspension in castor oil (62.5 mg / ml); Group 4: Abiraterone suspension in sodium phosphate buffer, 0.1% Tween (62.5 mg / ml)

[0455] Data from the rat study showed that the formulations containing abiraterone acetate performed significantly better than the formulations containing abiraterone. In addition, Group 1 formulations containing abiraterone acetate in solution performed better than Group 2 formulations containing abiraterone acetate in a suspension control solution.

[0456] Figure 1 Depicted is a curve of mean plasma concentration of abiraterone in rats versus time after intramuscular injection of abiraterone acetate formulations into the thigh muscle of five male rats at a dose of 35 mg / kg. Blood samples for evaluation of systemic exposure after intramuscular depot administration of abiraterone acetate were collected at 1, 2, 4, 8, 24, 48, 72 and 168 hours after administration and analyzed for abiraterone and abiraterone acetate. In this study, abiraterone acetate castor oil solution formulation was compared to an abiraterone acetate aqueous suspension formulation as well as an abiraterone aqueous suspension and an abiraterone castor oil suspension.

[0457] Initially, we attempted to administer abiraterone intramuscularly to rats as a suspension consisting of vegetable oil and water. Surprisingly, very low plasma levels were achieved with abiraterone alone (see Figure 1 ). Also, surprisingly, the use of abiraterone acetate in an aqueous suspension produced low plasma levels (see Figure 1 In contrast, abiraterone acetate in a vegetable oil solution produced not only the highest plasma levels in rats when injected intramuscularly, but also the longest prolonged abiraterone plasma concentrations (see Figure 1 ).

[0458] The abiraterone acetate castor oil intramuscular depot solution formulation showed higher abiraterone plasma concentrations over a 168-hour period compared to abiraterone and abiraterone acetate aqueous suspension and castor oil suspension.

[0459] The results of the canine studies are presented in Tables 4 and Figure 2 Available in.

[0460]

[0461]

[0462] Data from canine studies indicate that abiraterone acetate administered as a solution in castor oil (with or without benzyl alcohol) produced measurable blood levels up to 504 hours. Additionally, while formulations containing benzyl benzoate produced measurable levels of abiraterone acetate, the formulation was found to be irritating to the dogs at the injection site; one or two dogs licked the injection site and developed open wounds. This resulted in a significant reduction in the fraction of prodrug absorbed from these animals and a significant reduction in the mean fraction absorbed in this dose group (61.7%). The absolute bioavailability of these formulations was found to range from 61.7% to 86.2%.

[0463] Figure 2 Depicted are the mean plasma concentrations of abiraterone in dogs versus time following intramuscular injection of various abiraterone acetate formulations at doses of 19, 27, and 38 mg / kg into the thigh muscle of male dogs (three dogs per formulation). Blood samples for evaluation of systemic exposure following intramuscular depot administration of abiraterone acetate were collected at 0.5, 1, 2, 3, 4, 5, 8, 24, 48, 60, 120, 168, 336, and 504 hours after administration and analyzed for abiraterone and abiraterone acetate.

[0464] Intramuscular depot solution formulations of abiraterone acetate in castor oil, castor oil / benzyl alcohol, and castor oil / benzyl benzoate showed prolonged abiraterone plasma concentrations over a period of 504 hours.

[0465] Intravenous administration of abiraterone acetate (at a dose of 10 mg / kg) was included in this study to measure the bioavailability of the intramuscular depot formulation. The bioavailability was determined to be 86.2%; 85.7% and 61.7%.

[0466] Computer modeling was used to predict the human pharmacokinetic profile of abiraterone prodrug administered intramuscularly to humans based on data obtained from intramuscular rat and canine studies. The modeling predicted that administration of 600 mg to 2,000 mg intramuscular doses of abiraterone acetate to human subjects every 2 to 4 weeks would produce the desired plasma pharmacokinetic profile in human subjects (i.e., bioavailability greater than 80%, C of abiraterone greater than 100%). min The value is higher than 1.0 ng / ml to 8.4 ng / ml, such as higher than 1 ng / ml, higher than 2 ng / ml, higher than 4 ng / ml or higher than 8.4 ng / ml, and the C max The predicted 600 mg abiraterone acetate intramuscular dose administered every two weeks should be compared with the current 1,000 mg / day The higher bioavailability of intramuscular delivery together with the elimination of the food effect will result in lower patient variability, which together with higher and less frequent plasma trough levels should result in better efficacy (Ref. C min >8.4 ng / ml is associated with improved prostate-specific antigen response and improved progression-free survival in patients with castration-resistant prostate cancer) (Carton et al., Eur. J. Can. 72:54, 2017).

[0467] Example 5B. PK Study of Abiraterone Propionate and Abiraterone Decanoate in Dogs

[0468] This was a single-dose bioavailability study of several abiraterone prodrugs (propionate and decanoate) given as intramuscular (IM) and intravenous injections to beagle dogs.

[0469] The formulations and doses used in this study are as follows:

[0470] 1) Intramuscular (IM); Abiraterone propionate 197 mg / mL solution in 10% benzyl alcohol / 90% castor oil; administered at 41 mg / kg;

[0471] 2) Intramuscular (IM); abiraterone propionate 168 mg / mL solution in 10% benzyl alcohol / 90% corn oil; administered at 41 mg / kg;

[0472] 3) Intramuscular (IM); Abiraterone decanoate 160 mg / mL solution in 10% benzyl alcohol / 90% castor oil; administered at 50 mg / kg:

[0473] 4) Intramuscular (IM); Abiraterone decanoate 170 mg / mL solution in 10% benzyl alcohol / 90% corn oil; administered at 50 mg / kg;

[0474] 5) Intravenous (IV); 0.57 mg / mL solution of abiraterone propionate in 40% HP-b-CD / 25 mM sodium phosphate (pH 7.4); administered at 1 mg / kg; and

[0475] 6) Intravenous (IV); 0.37 mg / mL solution of abiraterone decanoate in 40% HP-b-CD / 25 mM sodium phosphate (pH 7.4); dosed at 1.2 mg / kg.

[0476] Table 5 below summarizes the study design:

[0477] Table 5. Experimental study design

[0478]

[0479] *Dosage is prodrug concentration.

[0480] The equivalent abiraterone active dose is 0.82 mg / kg for intravenous administration and 35 mg / kg for intramuscular administration

[0481] All animals were administered via intravenous administration. After the 72-hour clearance period, all canines were administered via intramuscular route. Dosage was based on an assumed 10 kg body weight. After intravenous administration, blood was collected at 0.083, 0.1667, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 24 hours after the dose was administered. After intramuscular administration, blood was collected at 0.5, 1, 2, 3, 4, 5, 8 and 12 hours and 1, 2, 3, 5, 7, 14, 21, 28, 35, 42, 49, 56 days (only decanoate) and 63 days (only decanoate) after the dose was administered (collection time was similar to the dose administration time). Blood was processed into plasma and the prodrug and abiraterone of the obtained plasma samples were analyzed.

[0482] Following intravenous administration of abiraterone propionate, animals had only 1 or 2 quantifiable plasma concentrations, thus making it impossible to assess reliable pharmacokinetic parameters.

[0483] Pharmacokinetic analysis of plasma concentration versus time data was performed using Phoenix WinNonlin (v 8.1) non-compartmental analysis functions (linear trapezoidal rule for AUC calculations). Calculations were performed using nominal dose values ​​and sampling times. For the purposes of PK calculations, any concentration reported as "BLQ" was set equal to zero.

[0484] Determination of C by direct evaluation of concentration versus time data max and the corresponding T max All AUC calculations were performed using the linear trapezoidal rule.

[0485] The terminal elimination rate constant (lambda z, λz) was calculated when the data allowed. The value of λz was determined from the slope of the regression line of the natural log-transformed concentration versus time with the following constraints:

[0486] Data points should be randomly distributed around a straight line;

[0487] C should be used in regression max At least three data points after

[0488] Regression correlation coefficient (R 2 ) should be greater than 0.80;

[0489] To optimize the reliability of the identified terminal phase (λz), data points used to define λz were manually selected where possible. λz curves that did not meet the above criteria were excluded from the AUC for that animal curve with an asterisk.INF ,t 1 / 2 , CL / F, and Vz / F parameters and excluded the results from the summary descriptive statistics.

[0490] AUC INF The value is calculated as follows: AUC 最后 +(C 最后 / λz). CL / F is calculated as follows: Dose per dosing interval / (AUC INF ) and Vz / F was calculated as follows: Dose per dosing interval / (AUC INF *λz). Terminal t 1 / 2 It was calculated as follows: ln(2) / λz. If the λz interval was not at least 2 times the calculated half-life, the half-life value was marked as unreliable with an asterisk and excluded from the descriptive statistics.

[0491] Mean plasma concentration vs. time data are presented as standard deviation (SD) and coefficient of variation percentage (CV%) and reported to three significant figures. PK parameter values ​​are presented as mean, SD, and CV%. max are reported to two significant figures, while all other values ​​and descriptive statistics are reported to three significant figures.

[0492] The individual animal and group average PK parameters for the prodrug and abiraterone after intravenous administration are presented in Tables 6 and 7. The individual animal and group average PK parameters for the prodrug and abiraterone after intramuscular administration are presented in Tables 8 and 9. The group average plasma concentrations versus time after administration to dogs are plotted in Figures 5 to 10 middle.

[0493] Intravenous administration results: After intravenous administration of abiraterone decanoate (prodrug), the average CL value of the prodrug was calculated to be 8.88 mL / min / kg, which is considered to be a low clearance rate. Using a dose value of 0.84 mg / kg (assuming 100% conversion of the prodrug to abiraterone), the average CL / F value of abiraterone was 97.8 mL / min / kg. The average Vz value of the prodrug was 0.659 L / kg and the average Vz / F value of abiraterone was 13.0 L / kg. The average t 1 / 2 The values ​​are 0.86 hours and 1.5 hours respectively.

[0494] Abiraterone propionate exposure was observed only at the first 2 time points after dosing, so reliable PK parameters could not be calculated. After intravenous 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 is 2.1 hours.

[0495] Although abiraterone Cmax values ​​were almost 4-fold higher following intravenous administration of abiraterone propionate, AUC values ​​were comparable (within 2-fold), suggesting marginal differences between the prodrugs.

[0496] Results for intramuscular administration: Mean abiraterone T for either decanoate formulation after intramuscular administration of the two decanoate formulations. max The value was 5.0 days, and the average decanoate T between formulations was max The values ​​ranged from 0.11 to 0.26 days. The mean exposure of the prodrug and abiraterone (measured by C max and AUC values) were within 2-fold. Beyond the 7-day time point, the terminal elimination phase of the prodrug did not reach a stable negative slope, so additional disposition parameters could not be assessed. For abiraterone, the mean t 1 / 2 Value (final t 1 / 2 ) are 23 and 24 days after administration in both vehicles. The mean AUC after intravenous administration (145 h*ng / mL) and intramuscular administration (corrected values ​​for dose and time units = 104 h*ng / mL (for Group 5) and 134 h*ng / mL (for Group 6)) was used INF The absolute bioavailability of abiraterone was estimated using the values ​​of 72% and 92% in Group 5 and Group 6, respectively.

[0497] After intramuscular administration of the two propionate formulations, the mean abiraterone T max The values ​​ranged from 0.56 to 0.61 days and the average T max The values ​​ranged from 0.11 to 0.26 days (2.3 and 6.2 hours). The mean exposure of the prodrug and abiraterone (measured by C max Excluding the 7-day time point (no values ​​after 7 days), the mean t1 / 2 values ​​of the prodrugs ranged from 0.98 to 1.7 days after administration of the 2 different vehicles. For abiraterone, the mean t 1 / 2 Values ​​are 1.8 days and 4.5 days after administration in the 2 vehicles. The mean AUC after intravenous administration (127 h*ng / mL) and intramuscular administration (corrected values ​​for dose and time units = 105 h*ng / mL (for Group 3) and 94.1 h*ng / mL (for Group 4)) was used. INF The absolute bioavailability of abiraterone was calculated using the values ​​of 83% and 74% in Group 3 and Group 4, respectively.

[0498] Table 6-9 and Figure 5-10 A summary of the PK studies for this example is provided.

[0499] Based on the data obtained from rat and canine studies, computer modeling is used to predict the human pharmacokinetic curve of abiraterone decanoate administered intramuscularly to humans. Pharmacokinetic (PK) modeling and simulation are performed using WinNonlin Phoenix version (8.1) that has been fully verified. The linear PK (exponential) model is fitted to the plasma concentration-time curve of abiraterone after intravenous administration of abiraterone (acetic acid ester or decanoate formulation) to rats and dogs. The derived PK parameters of clearance (CL) and volume of distribution (Vss) are predicted in humans by allometric scaling. The bioavailability (K01) and extent (F) of abiraterone after intramuscular administration to dogs are estimated by deconvolution; it is assumed that the values ​​of K01 and F are equal in humans. The plasma concentration-time curve (assuming the linear kinetics of abiraterone) after intramuscular administration with various prescribed dosage regimens in humans is simulated using the predicted PK parameters (CL, Vss, K01 and F). Modeling predicted that intramuscular doses as low as 120 mg abiraterone decanoate every two weeks would achieve therapeutically effective abiraterone plasma concentrations in humans, with a C of abiraterone at steady state. min The value is greater than about 8 ng / ml, and the C of abiraterone at steady state max The modeling also predicts that the intramuscular dose of abiraterone decanoate is suitable for a once-a-month or more dosing regimen in humans, which can provide therapeutically effective abiraterone plasma concentrations. For example, an intramuscular dose of about 350 mg of abiraterone decanoate once every 4 weeks is sufficient to provide an abiraterone C of greater than about 8 ng / ml at steady state. min The C of abiraterone at steady state max Values ​​are generally proportional to dose. See also Fig.11A , Fig. 11B , Fig. 11C and Fig.11D . According to the present disclosure, in some cases, the dosing regimen may also include an initial dosing period with a higher dosing frequency or with a different abiraterone drug to achieve a certain exposure of abiraterone in the treated subject, and then the initial dosing period is followed by a dosing regimen as described herein once a month (or more than once a month). For example, in some cases, the dosing regimen may include an initial intramuscular dose of abiraterone decanoate once every two weeks, such as about 2-3 doses, and then the initial intramuscular dose is followed by abiraterone decanoate administered once a month. Computer modeling predicts that such a dosing regimen can achieve a C of abiraterone at steady state during treatment. min Values ​​were greater than about 8 ng / ml.

[0500]

[0501]

[0502]

[0503]

[0504] Example 6A. Large-Scale Preparation of Abiraterone Decanoate from Decanoic Acid

[0505]

[0506] To a suspension of abiraterone (381.9 g, 1.09 mol) in dichloromethane (3500 mL) was added triethylamine (165 g, 1.64 mol) and a catalytic amount of DMAP (13.35 g, 0.109 mol). Decanoic acid (225 g, 1.31 mol) as a solution in dichloromethane (500 mL) was added to the suspension followed by EDCI (293 g, 1.53 mol) and the reaction was then stirred at 20-25 °C for 19 hours.

[0507] Then add 10 wt% NaH2PO4 aqueous solution (4000mL) and stir the reactant for 20 minutes. Separate the organic layer and extract with 10 wt% NaH2PO4 aqueous solution (2000mL) and brine (2000mL). The organic layer is solvent exchanged and concentrated to 3100g with acetonitrile (4750mL), keeping the bath temperature <40°C. Dilute the suspension with acetonitrile (900g). Obtain 510g of crude decanoic acid abiraterone by filtering and separating the solid.

[0508] 510g crude abiraterone decanoate was dissolved in acetone (4000mL) at 40°C. The solution was filtered through filter paper. The filtrate was transferred to a 12L 3-necked flask, diluted to 5100g 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 (1020mL) and stirred overnight at room temperature. The solid was filtered and the flask was rinsed with the filtrate and transferred to a filter funnel. The wet cake was transferred to a drying pan and dried overnight in a vacuum oven at 40-45°C to obtain 457.1g (90% yield) of a white solid. 1 H NMR (CDCl3, 400MHz): d H8.62 (d, 1H, J = 1.9Hz), 8.31 (dd, 1H, J = 4.9, 1.6Hz), 7.64 (dt, 1H, J = 7.9, 1.9Hz), 7.21 (ddd, 1 H, J=8.0, 4.9, 0.8Hz), 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 value (corrected for 0.055% water content): C, 81.0%, H, 9.8%, N, 2.8%; measured value: C, 81.1%, H, 10.2%, N, 2.8%.

[0509] The decanoic acid abiraterone obtained in this embodiment was determined to have a purity of 99.7% by weight using the HPLC method. For HPLC analysis, a decanoic acid abiraterone sample with a concentration of 0.05 mg / mL (for assay analysis) or 5 mg / mL (for impurity analysis) was prepared in methanol. HPLC conditions are 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 from 65 / 35 MPA / MPB, within 35 minutes, reaching 100% MPB, maintaining at 100% MPB to 40 minutes, at 40.10 minutes, returning to 65 / 35 MPA / MPB, and maintaining at 65 / 35 MPA / MPB until the end of 45 minutes.

[0510] The white solid obtained in this example was also characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). XRPD was performed using a Bruker D8 Discover X-rat diffractometer with a Theta\theta vertical goniometer and a Vantec-500 as a detector. Standard conditions: voltage 40 kV, current 40 mA, radiation, Cu, temperature, ambient, X-ray source exit slit size, 0.5 mm pinhole, nose collimator, 0.5 mm, sample holder, ground quartz plate. Working conditions: detector distance, 30 cm, Chi integration range, 4-40 degrees 2θ, counting time, 120 seconds / frame, number of frames: 3, θ1 position, 4 degrees, θ2 position, 4 degrees, frame width, 12, scanning axis, coupled. The software used included GADD software, General Area Detector Diffraction System, version 4.1.50; and DIFFRAC.EVA, version 4.0. DSC was performed using a TA Instruments Q2000 (Thermal Advantage V 5.0.0 – qualified) with a sample size of 2-10 mg, a heating range of 25°C to 250°C, and a heating rate of 10°C / min. Representative XRPD and DSC spectra are shown in Figures 12A-12B Thermogravimetric analysis (TGA) was also performed on the 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 to 150°C, and a heating rate of 10°C / min. A representative TGA trace is shown in Fig. 12C middle.

[0511] Example 6B. Preparation of Abiraterone Decanoate Salt

[0512] Preparation of Abiraterone Decanoate Oxalate

[0513] Make a solution of Abiraterone decanoate (374g, 744 mmol) dissolved in isopropyl acetate to 5200g and put it into a 12L reactor. Load oxalic acid (18.0g) and stir for 2 hours. The suspension is warmed to 72°C and stirred for 2 hours. After cooling to 60°C, load oxalic acid (20g) and isopropyl acetate (1000g). Continue heating at 60°C for 30 minutes. Load more oxalic acid (20g) and isopropyl acetate (600g) and continue heating at 60°C. After 30 minutes, load more oxalic acid (15.7g) and isopropyl acetate (600g). Raise the reaction temperature to 72°C and keep heating for 18 hours.

[0514] The reactant was then cooled to room temperature and further cooled to 5-10°C, and the slurry was stirred at the same temperature for 2 hours. The solid was filtered and rinsed with cold isopropyl acetate (520mL). The wet cake was transferred to a drying tray and dried in a vacuum oven at 45-50°C until a constant weight of 410g (92.8% yield). The HPLC display purity of decanoic acid abiraterone oxalate was 99.62A%. 1 H NMR (CDCl3, 400MHz): d H 12.62 (brs, 2H), 8.84 (d, 1H, J=1.8Hz), 8.69 (d, 1H, J=5.5, 1.1Hz), 8.24 (dt, 1H , J=8.3, 1.7Hz), 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=7.5Hz), 2.20-2.00(m, 3 H), 1.93-1.47 (m, 11H), 1.38-1.11 (m, 14H), 1.10 (s, 6H), 0.88 (t, 3H, J=6.9Hz).

[0515] Preparation of Abiraterone Decanoate HCl Salt

[0516] A solution of abiraterone decanoate (20 mmol) in EtOAc (140 mL) was treated with 2M HCl / ether (12 mL; 24 mmol; 1.2 eq.). The suspension was heated at 50°C overnight; then cooled to 0-5°C for 2 hours. The solid was filtered fairly quickly and rinsed with EtOAc to obtain 7.97 g (14.76 mmol; 74% yield) of abiraterone decanoate HCl salt as a white solid. 1 H NMR (CDCl3, 400MHz): d H 8.70 (d, 1H, J = 1.6Hz), 8.58 (dd, 1H, J = 1.6, 5.6Hz), 8.34 (dt, 1H, J = 8.3, 1.6Hz), 7.8 4(dd, 1H, J=8.3, 5.6Hz), 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=7.5Hz), 2.20-2.00(m, 3H), 1.92-1.45(m, 13H), 1.3 6-1.23 (m, 13H), 1.21-1.10 (m, 2H), 1.09 (s, 3H), 1.08 (s, 3H), 0.88 (t, 3H, J=6.9Hz).

[0517] Preparation of Abiraterone Decanoate Besylate

[0518] 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, 400MHz): d H 8.87 (d, 1H, J = 1.7Hz), 8.81 (brd, 1H, J = 5.6Hz), 8.32 (dt, 1H, J = 8.1, 1.4Hz), 7.97-7.92 (m, 2H), 7.8 6(dd, 1H, J=8.1, 5.6Hz), 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=7.5Hz), 2.17-2.00 (m, 4H), 1.91-1.54 (m, 10H), 1.47 (dt, 1H, J=12 .1, 4.7Hz), 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=7.2Hz).

[0519] Preparation of Abiraterone Decanoate p-Toluenesulfonate

[0520] 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 salt was isolated by filtration (64% yield). 1 H NMR (CDCl3, 400MHz): d H8.85 (d, 1H, J = 1.7Hz), 8.81 (brd, 1H, J = 5.6Hz), 8.31 (dt, 1H, J = 8.4, 1.6Hz), 7.85 (dd, 1H, J = 8.3, 5 .8Hz), 7.82 (dt, 1H, J=8.3, 1.6Hz), 7.18 (d, 2H, J=8.0Hz), 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=7.5Hz), 2.19-2.00(m, 4H), 1.93-1.54(m, 10H), 1.46 (dt, 1H, J=4.8, 1.20Hz), 1.36-1.10 (m, 16H), 1.08 (s, 3H), 1.06 (s, 3H), 0.88 (t, 3H, J=6.9Hz).

[0521] Preparation of Abiraterone Decanoate Phosphate

[0522] 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 (0.39 g, 65% yield) was isolated by filtration. 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=6.9Hz).

[0523] Example 7. Studies of Abiraterone Decanoate in Rats and Monkeys and Allometric Analysis of Plasma Distribution in Humans Release and prediction

[0524] Example 7A. Abiraterone Decanoate Study in Monkeys

[0525] In the monkey PK study, the abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 192 mg / ml abiraterone decanoate) was administered intramuscularly at 90 mg / kg in male cynomolgus monkeys (n=3).

[0526] An intravenous dose of abiraterone decanoate (0.4 mg / ml in 40% HP-β-cyclodextrin 25 mM sodium phosphate buffer (pH 7.4) was used as a comparison (average n=3) at 1.2 mg / kg. For the intravenous dose, blood samples were collected at 0 hours, 0.083 hours, 0.17 hours, 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours. The results are shown in Tables 10A and Fig.14A middle.

[0527] Table 10A. Monkey intravenous PK parameters (arithmetic means)

[0528]

[0529] A single dose PK study was conducted by intramuscular injection of abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 192 mg / ml abiraterone decanoate) at 90 mg / kg in male cynomolgus monkeys (n=3). The abiraterone decanoate formulation was injected intramuscularly using a 27 gauge needle, with 2 injections into the thigh of each hind leg. Blood samples were collected at 0 hours, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 120 hours, 168 hours, 336 hours, 504 hours, 672 hours, 840 hours, 1008 hours, 1176 hours, and 1344 hours. The plasma concentrations of abiraterone decanoate and abiraterone were determined. The results are shown in Tables 10B and 10B. Fig. 14B middle.

[0530] Table 10B. Monkey Single Dose PK Parameters (Geometric Means; Tmax is the median)

[0531]

[0532] Progesterone, cortisol, and testosterone levels were also analyzed in this single-dose PK study. Fig. 14C As shown, after a single intramuscular dose, long-lasting CYP17A1 inhibition was achieved, as evidenced by a sustained increase in progesterone levels and a decrease in cortisol and testosterone levels. Since the monkeys in this study were not castrated, the decrease in testosterone levels was modest.

[0533] A multiple dose PK study was also conducted. In this study, multiple doses (90 mg / kg per dose) of abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 192 mg / ml abiraterone decanoate) were injected intramuscularly on days 0, 7, and 35 in male cynomolgus monkeys (n=3). Each dose of abiraterone decanoate formulation was injected intramuscularly using a 27-gauge needle, divided into 2 injections into the thigh of each hind leg. Blood samples were collected at 0 hours, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 120 hours, 168 hours, 192 hours, 216 hours, 240 hours, 288 hours, 336 hours, 504 hours, 672 hours, 840 hours, 864 hours, 888 hours, 912 hours, 960 hours, 1008 hours, 1176 hours, 1344 hours, 1512 hours, and 1680 hours. The plasma concentrations of abiraterone decanoate and abiraterone were measured. The results are shown in Fig.14E middle.

[0534] Example 7B. Study of the Effect of Benzyl Benzoate on Abiraterone Exposure in Monkeys

[0535] This example compares the pharmacokinetic behavior of two different abiraterone decanoate formulations following intramuscular injection:

[0536] Formulation 1, abiraterone decanoate in 90% corn oil, 10% benzyl alcohol, abiraterone decanoate concentration of 207 mg / ml

[0537] • Formulation 2 - Abiraterone decanoate in 70% corn oil, 10% benzyl alcohol, 20% benzyl benzoate, the concentration of abiraterone decanoate was 209 mg / ml.

[0538] Formulations 1 and 2 were administered intramuscularly to male cynomolgus monkeys (n=1) at 100 mg / kg. 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 Fig.14F middle.

[0539] like Fig.14F As shown, the intramuscular injection of Formulation 2 unexpectedly provided significantly higher abiraterone plasma concentrations in monkeys compared to the same dose of intramuscular injection of Formulation 1. This trend was also confirmed by parallel studies at different dose levels.

[0540] Example 7C. Study of Abiraterone Decanoate in Rats

[0541] In a rat PK study, the abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 172 mg / ml abiraterone decanoate) was administered intramuscularly at 90 mg / kg in male rats (n=5).

[0542] An intravenous dose of abiraterone decanoate (0.4 mg / ml in 40% HP-β-cyclodextrin 25 mM sodium phosphate buffer (pH 7.4) was used as a comparison at 1.2 mg / kg (average n=5). For the intravenous dose, blood samples were collected at 0 hours, 0.083 hours, 0.17 hours, 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours. The results are shown in Tables 11A and Fig.15A middle.

[0543] Table 11A. Rat intravenous PK parameters

[0544]

[0545] A single dose PK study was conducted by intramuscular injection of abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 172 mg / ml abiraterone decanoate) at 90 mg / kg in male rats (n=5). The abiraterone decanoate formulation was injected intramuscularly into the thigh muscle of the hind leg using a 27 gauge needle. Blood samples were collected at 0 hours, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 120 hours, 168 hours, 336 hours, 504 hours, 672 hours, 840 hours, 1008 hours, 1176 hours, 1344 hours. The plasma concentrations of abiraterone decanoate and abiraterone were determined. The results are shown in Tables 11B and 11B. Fig. 15B middle.

[0546] Table 11B. PK parameters of a single intramuscular dose in rats

[0547]

[0548] A multiple dose PK study was also performed. In this study, multiple doses (each dose was 90 mg / kg) of abiraterone decanoate formulation (90% corn oil, 10% benzyl alcohol, 172 mg / ml abiraterone decanoate) were injected intramuscularly on days 0, 7, and 35 in male rats (n=5). Each dose of abiraterone decanoate formulation was injected intramuscularly into the thigh of the hind leg using a 27-gauge needle. Blood samples were collected at 0 hours, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 120 hours, 168 hours, 192 hours, 216 hours, 240 hours, 288 hours, 336 hours, 504 hours, 672 hours, 840 hours, 864 hours, 888 hours, 912 hours, 960 hours, 1008 hours, 1176 hours, 1344 hours, 1512 hours, and 1680 hours. The plasma concentrations of abiraterone decanoate and abiraterone were measured. The results are shown in Fig. 15C middle.

[0549] Example 7D. Allometric Scaling and Prediction of Abiraterone Plasma Distribution in Humans

[0550] This pharmacokinetic (PK) analysis involves modeling of abiraterone plasma concentrations following single intravenous (IV) and intramuscular (IM) administration of abiraterone in rats, dogs, and monkeys. PK parameters were derived from the PK models following IV and IM administration in rats, dogs, and monkeys to predict the plasma profile of abiraterone in humans following intramuscular administration of abiraterone decanoate by deconvolution and allometric scaling.

[0551] Abiraterone decanoate was administered intravenously (1.2 mg / kg) and intramuscularly (90 mg / kg) to rats and monkeys; each animal received both intravenous and intramuscular doses. Abiraterone decanoate was administered intravenously (1.2 mg / kg) and intramuscularly (50 mg / kg) to dogs, and Abiraterone decanoate was administered intramuscularly (87 mg / kg) to dogs. After a single intravenous administration in rats, dogs, and monkeys and a single intramuscular administration in dogs, plasma samples were collected until 24 hours. After a single intramuscular administration in rats, dogs, and monkeys, plasma samples were collected until 1344 hours. PK results are reported herein.

[0552] Pharmacokinetic Modeling: Pharmacokinetic models (one- and two-compartment with zero-order input) were fitted (with or without weighting by 1 / C predicted values) to the abiraterone plasma concentration profiles in each animal following a single intravenous administration of abiraterone to rats, dogs, and monkeys using WinNonlin Phoenix version 8.2. The modeling was based on the assumptions of linear (proportional to dose) and time-invariant kinetics and complete conversion of the abiraterone decanoate prodrug to abiraterone. The function (representing a one-compartment arrangement with zero-order absorption) was WinNonlin Model 2 and the function (representing a two-compartment arrangement with zero-order absorption) was WinNonlinModel 10. Weighting was included, depending on the residual pattern (residual Y versus predicted concentration or time) and the precision of the estimated parameters. The appropriate model was selected based on: (i) visual inspection of the model fit to the data, (ii) minimization of the Akaike Information Criterion (AIC), and (iii) precision of the estimated parameters (CV). Systemic clearance (CL) and apparent volume of distribution (V ss ) is derived from the exponential function.

[0553] Deconvolution: The input rate and extent from intramuscular administration were simulated by deconvolution using WinNonlin Phoenix version 8.2. Deconvolution is based on linear system analysis and is defined by the convolution integral: G(t) = R(t) * H(t). G(t) is the plasma concentration curve measured after intramuscular administration, H(t) is represented by the exponential function described in Section 3.2, and R(t), the input rate of the intramuscular reservoir over time, is obtained by deconvolution of the above expression. The slope of the input rate versus time generates the input rate constant (K 01 ). The integration of input rate versus time generates a cumulative input function and an estimate of absolute bioavailability.

[0554] Allometric scaling to humans: Plasma concentration profiles in humans following intramuscular administration were simulated based on predictions of CL and Vss (describing the disposition of abiraterone) and the rate and extent of input (absorption) into the systemic circulation (bioavailability). The PK parameters (CL and Vss) derived from the exponential model were ss ) to characterize the disposition of abiraterone in animals. CL and V in humans ss It is composed of CL and V in animals ss Predicted by allometric method. V ss =aW x , where a is the intercept, W is body weight, and x is the allometric exponent; then, log V ss = x·log W + log a (by comparing the body weight of the three species with V ss CL in humans was derived by Tang’s data-driven approach. [5]; That is, CL human / kg = 0.407·CL monkey / kg. The rate and extent of input are obtained by deconvolution.

[0555] Results: A biexponential function was considered to best represent the plasma concentration-time curve of abiraterone after a single intravenous administration to rats, dogs, and monkeys, respectively. The plasma clearance (CL) of abiraterone was 11414, 6469, and 2578 mL / h / kg in rats, dogs, and monkeys, respectively. The apparent volume of distribution (V) of abiraterone at steady state was ss ) in rats, dogs and monkeys were 22313, 14205 and 5732 mL / kg, respectively. See Table 12A below.

[0556] Table 12A Summary of PK parameters of abiraterone following intravenous and intramuscular administration of abiraterone decanoate in rats, dogs and monkeys

[0557]

[0558] Allometric scaling predicts CL in humans (predicted from monkeys, considering only very high CL values ​​in rats and dogs) and V ss (predicted from rats, dogs and monkeys) are 73 L / h and 437 L, respectively. Predicted V in humans ss This is significantly greater than the total water volume of the human body (42 L), indicating a wide distribution in tissues. The predicted CL in humans is not significantly different from liver blood flow (80 L / h).

[0559] Deconvolution of the intramuscular curve with the intravenous curve provides an estimate of the rate and extent of abiraterone bioavailability. The intramuscular bioavailability in rats, dogs, and monkeys was 19%, 56%, and 14%, respectively. The infusion (release from the intramuscular depot) half-life after intramuscular administration was 325, 319, and 325 hours in rats, dogs, and monkeys, respectively.

[0560] Therefore, using CL (73L / h), V ss (437L), K01(0.00213h -1 ) and F (56%) parameters simulate the plasma distribution in humans. See Table 12B, Fig.16A and Fig. 16B .

[0561] Table 12B. Predictive parameters for abiraterone following intramuscular administration of abiraterone decanoate in humans*

[0562]

[0563] *Predictions assume a one-compartment arrangement with a first-order absorption model and linear kinetics in humans.

[0564] After monthly (i.e., every 4 weeks) administration of 1000 mg intramuscular doses of abiraterone to humans, the predicted C min The value is 5 ng / mL at steady state. Fig. 16C The inventors believe that the human bioavailability of once-monthly intramuscular administration at this dosing level may be higher than Fig. 16C The predicted bioavailability is 56% and close to complete. Assuming complete bioavailability, the inventors believe that after monthly administration of a 1000 mg intramuscular dose of abiraterone to humans, the predicted C min The value is 9.3 ng / mL at steady state. Fig.16D .

[0565] Conclusion: The volume of distribution in humans (V ss )(437L) was predicted by allometric methods with adequate correlation between rat, dog, and monkey. ss =Indicates extensive tissue distribution in humans. Systemic clearance (CL) in humans (73 L / h) was predicted allometrically in monkeys. CL in humans does not differ significantly from hepatic blood flow. Absorption rate (absorption half-life of 325 hours) and bioavailability (F of 56%) were predicted based on deconvolution of intramuscular and intravenous data. Following administration of a 1000 mg intramuscular dose of abiraterone decanoate to humans every four weeks, the predicted C min At steady state it is 5ng / mL.

[0566] Example 8. Study of Abiraterone Isocaprylate and Abiraterone Decanoate in Dogs

[0567] The aim of this study was to compare the pharmacokinetics (PK) of two different abiraterone esters (isocaprylate and decanoate) from intramuscular (IM) formulations after a single administration to beagle dogs relative to a single intravenous (IV) formulation of abiraterone isocaprylate to enable calculation of the absolute bioavailability of isocaprylate.

[0568] Naive male beagle dogs were obtained from Marshall Bioresources, North Rose, NY for use in this study. Animals were 6-7 months of age and weighed 7.0-7.9 kg at the time of first dose administration.

[0569] Two groups of three male dogs / groups were evaluated for PK standards, such as body weight, clinical observation and blood sampling. One group of three dogs was administered intravenously with isocaprylic acid abiraterone (test article #1, isocaprylic acid abiraterone in 40% HP-β-cyclodextrin) on the 1st day. After the minimum 72-hour clearance period, all six dogs were administered intramuscularly. The three dogs receiving the isocaprylic acid abiraterone of intravenous dose were given isocaprylic acid abiraterone intramuscular formulation (test article #2, isocaprylic acid abiraterone in 90% corn oil / 10% benzyl alcohol) and the remaining three dogs were administered with decanoic acid abiraterone intramuscular formulation (test article #3, decanoic acid abiraterone in 90% corn oil / 10% benzyl alcohol). Dosage is based on the assumed body weight of 10 kg, which may affect the calculated CL (or CL / F), Vz (or Vz / F) value and bioavailability assessment. The research design is summarized in the following table:

[0570]

[0571] *Concentration of prodrug.

[0572] Blood was collected before dosing and after intravenous administration at 0.083, 0.1667, 0.25, 0.5, 0.75, 1, 2, 4 and 24 hours after dosing. Blood was collected just before dosing and after intramuscular injection at 0.5, 1, 2, 3, 4, 5, 8 and 24 hours after dosing and 2, 3, 5, 7, 14, 21, 28, 35 and 49 days (collection time is close to the time of dosing). Blood was processed into plasma and the resulting plasma samples were analyzed for prodrug and abiraterone.

[0573] Pharmacokinetic analysis of plasma concentration versus time data was performed using Phoenix WinNonlin (v 8.1) non-compartmental analysis functions (linear trapezoidal rule for AUC calculations). See, e.g., Example 5B.

[0574] Results: Single-dose pharmacokinetics of abiraterone and abiraterone following intravenous administration of 1 mg / kg abiraterone: Evidence of systemic exposure to abiraterone and abiraterone was observed in all treated dogs following intravenous administration (Tables 13A and Fig.17A ). After intravenous administration of abiraterone isoleate (prodrug), the average CL value of the prodrug was calculated to be 62.8 mL / min / kg, which is considered to be a high clearance rate. Using a dose value of 0.78 mg / kg (assuming 100% conversion of the prodrug to abiraterone), the average CL / F value of abiraterone was 63.3 mL / min / kg. The average Vz value of the prodrug was 1.91 L / kg and the average Vz / F value of abiraterone was 4.22 L / kg. The average t 1 / 2The values ​​are 0.350 hours and 0.773 hours respectively.

[0575] Single-dose pharmacokinetics of abiraterone and abiraterone isocaprylate following intramuscular administration: Evidence of systemic exposure to abiraterone and abiraterone isocaprylate was observed in all treated dogs following intramuscular administration (Tables 13B and Fig. 17B ), but attention should be paid to the exposure parameter (C max The mean T values ​​of abiraterone and isocorticoid prodrug after intramuscular administration were high in variability (P < 0.05). max The values ​​were 1.7 days and 0.19 days, respectively. The average C max The values ​​were 20.2 and 106 ng / mL, respectively. The average AUC of abiraterone and isocorticoid prodrug 最后 The values ​​were 266 and 281 days*ng / mL, respectively. The average t 1 / 2 The values ​​are 9.3 days and 7.4 days respectively.

[0576] The mean AUC after intravenous administration of 0.78 mg / kg abiraterone isocaprylate (206 h*ng / mL, or 131 h*ng / mL corrected for dose) and intramuscular administration of 60 mg / kg abiraterone isocaprylate (corrected value for dose and time units = 114 h*ng / mL) was used. INF The estimated abiraterone bioavailability from isocaprylate was calculated to be 87%, however these data should be interpreted with caution as the doses were based on an assumed body weight of 10 kg.

[0577] Single-Dose Pharmacokinetics of Abiraterone and Abiraterone Decanoate Following Intramuscular Administration of Abiraterone Decanoate: Evidence of systemic exposure to abiraterone and abiraterone decanoate was observed in all treated dogs following intramuscular administration (Tables 13B and Fig. 17C Abiraterone exposure parameters (C max The variability of exposure parameters for abiraterone and the decanoate prodrug (CV and AUC values) ranged from 60% to 70%, while the variability of exposure parameters for the decanoate ester was lower, with CV% values ​​<27%. max The average C values ​​of abiraterone and decanoate prodrug were 5.7 days and 0.71 days, respectively. max The values ​​were 7.82 and 45.0 ng / mL, respectively. The average AUC final values ​​of abiraterone and decanoate prodrug were 176 and 298 days*ng / mL, respectively. The average t 1 / 2The mean AUC after intravenous administration of 0.86 mg / kg abiraterone decanoate (145 h*ng / mL, or 169 h*ng / mL when corrected for dose) and intramuscular administration of 60 mg / kg (corrected value for dose and time units = 70.4 h*ng / mL) was used. INF The estimated bioavailability of abiraterone was calculated to be 42%, however these data should be interpreted with caution as the doses were based on an assumed body weight of 10 kg. Fig.17D Comparison of mean abiraterone plasma concentration profiles following intramuscular administration of abiraterone isoleate or abiraterone decanoate is shown in FIG.

[0578]

[0579]

[0580] Conclusions of Example 8: Evidence of systemic exposure to abiraterone was observed in all treated dogs following dosing. max and C max The comparison of the values ​​showed that the isocaprylate prodrug was absorbed faster than the decanoate prodrug, with a T max The value is shorter and C max The values ​​are higher. When compared with the decanoate prodrug, the average abiraterone AUC values ​​after intramuscular administration of the isocrolate prodrug appear to be less than 2 times higher. The long half-life values ​​observed after intramuscular administration relative to those observed after intravenous administration indicate that the prodrug has a slow release / absorption profile when administered via the intramuscular route. There is some evidence that the half-life of abiraterone appears to be longer after decanoate administration, which may be due to the slower absorption of the decanoate prodrug.

[0581] Each reference mentioned in this disclosure is hereby incorporated by reference in its entirety.

[0582] As used herein, the term "about" to modify quantities related to the present disclosure refers to variations in numerical quantities that may occur, for example, by routine testing and processing; by inadvertent errors in such testing and processing; by differences in the purity of the components / materials employed in the present disclosure, etc. As used herein, "about" a particular value also includes a particular value, for example, about 10% includes 10%. Whether or not modified by the term "about", the claims include equivalent values ​​of the recited quantities. In one embodiment, the term "about" means within 20% of the reported value.

[0583] With respect to aspects of the disclosure described as a genus, all individual species are considered separately as independent aspects of the disclosure. If an aspect of the disclosure is described as "comprising" a feature, embodiments are also contemplated as "consisting of" or "consisting essentially of" that feature.

[0584] All of the various aspects, embodiments and options described herein may be combined in any and all variations.

[0585] Having now described several embodiments of the present invention, it will be apparent to those skilled in the art that the foregoing is illustrative and non-restrictive and is presented by way of example only. Many modifications and other embodiments are within the scope of those of ordinary skill in the art and are contemplated to fall within the scope of the present invention and any equivalents thereof. It will be appreciated that variations of the present invention will be apparent to those skilled in the art, and the present invention is intended to include those alternatives. In addition, since many modifications are readily conceivable to those skilled in the art, it is not desirable to limit the present invention to the exact configuration and operation illustrated and described, and therefore, all suitable modifications and equivalents may be employed to fall within the scope of the present invention.

Claims

1. Abiraterone decanoate having the following structure, or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising abiraterone decanoate or a pharmaceutically acceptable salt thereof as claimed in claim 1, and a pharmaceutically acceptable carrier.

3. A pharmaceutical composition comprising the abiraterone decanoate as claimed in claim 1, and a pharmaceutically acceptable carrier.

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

5. The pharmaceutical composition of claim 2 or 3, wherein the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil and optionally another pharmaceutically acceptable solvent.

6. The pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable oil comprises a triglyceride and the another pharmaceutically acceptable solvent, if present, comprises an alcohol, ester and / or acid solvent.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable oil is selected from castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil and soybean oil, and the another pharmaceutically acceptable solvent, if present, comprises benzyl alcohol, benzyl benzoate or a combination thereof.

8. The pharmaceutical composition of claim 2 or 3, comprising abiraterone decanoate or a pharmaceutically acceptable salt thereof in an amount sufficient to provide a therapeutically effective abiraterone plasma concentration, or an abiraterone plasma concentration of 1 ng / ml or more, for a period of at least two weeks after a single administration to a subject suffering from one or more conditions selected from sex hormone-dependent benign or malignant conditions, syndromes caused by excess androgens, and syndromes caused by excess glucocorticoids.

9. The use of any one of the pharmaceutical compositions of claims 2-8 in the preparation of a medicament for treating one or more conditions of a subject, wherein the one or more conditions are selected from sex hormone-dependent benign or malignant conditions, syndromes due to androgen excess, and syndromes due to glucocorticoid excess.

10. The use according to claim 9, wherein the drug is a drug administered via intramuscular injection, intradermal injection or subcutaneous injection.

11. The use according to claim 9, wherein the pharmaceutical composition is administered to the subject with or without food.

12. The method of claim 9, wherein the one or more conditions are selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, lung cancer, endometriosis, polycystic ovary syndrome, Cushing's syndrome, Cushing's disease, classic or nonclassical congenital adrenal hyperplasia, precocious puberty, hirsutism, and combinations thereof.

13. The use according to claim 9, wherein the one or more disorders are sex hormone-dependent benign or malignant disorders selected from castration-resistant prostate cancer and castration-sensitive prostate cancer.

14. The use according to claim 9, wherein the one or more disorders are sex hormone-dependent benign or malignant disorders selected from metastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer.

15. The use of claim 9, wherein the subject is treated with gonadotropin-releasing hormone analogs and / or bilateral orchiectomy.

16. The use as claimed in claim 9, wherein the medicament is combined with a corticosteroid.

17. The use according to claim 9, wherein the medicament is combined with hydrocortisone, prednisone, prednisolone and / or dexamethasone.

18. The use of claim 9, wherein the pharmaceutical composition is administered to the subject once a week or more than once a week.

19. The use of any one of claims 10, 11 and 18, wherein the administration provides (a) an abiraterone plasma concentration greater than 1.0 ng / ml for a period of at least two weeks; or (b) a single dose or steady-state C of abiraterone between 10 ng / ml and 400 ng / ml. max ; or (c) both (a) and (b).

20. A pharmaceutical composition comprising abiraterone decanoate as claimed in claim 1, a pharmaceutically acceptable oil and a pharmaceutically acceptable solvent, wherein the abiraterone decanoate is in its basic form and is present at a concentration of 25 mg / ml to 500 mg / ml, wherein the pharmaceutical composition is formulated for intramuscular injection, intradermal injection or subcutaneous injection, wherein the pharmaceutical composition comprises abiraterone decanoate in an amount of 50 mg to 2,000 mg.

21. The pharmaceutical composition of claim 20, wherein the pharmaceutically acceptable oil comprises a triglyceride and the another pharmaceutically acceptable solvent comprises an alcohol, an ester and / or an acid solvent.

22. The pharmaceutical composition of claim 21, wherein the pharmaceutically acceptable oil comprises castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil or soybean oil, the pharmaceutically acceptable solvent comprises benzyl alcohol and / or benzyl benzoate, and wherein the abiraterone decanoate is present at a concentration of 50 mg / mL to 300 mg / mL.

23. Use of the pharmaceutical composition according to any one of claims 20 to 22 in the preparation of a medicament for treating prostate cancer, wherein the medicament is administered via intramuscular injection, intradermal injection or subcutaneous injection once a month or more than once a month.

24. The use according to claim 23, wherein the drug is a drug for intramuscular injection.

25. A method for preparing abiraterone decanoate formulation suitable for parenteral administration to a subject suffering from sex hormone-dependent benign or malignant conditions, syndromes caused by androgen excess, and syndromes caused by glucocorticoid excess, comprising: a) abiraterone decanoate having the following formula: mixed in a pharmaceutically acceptable carrier to form a mixture; and optionally b) sterilizing the mixture formed in a).

26. The method of claim 25, wherein the mixing comprises mixing a crystalline form of abiraterone decanoate in the pharmaceutically acceptable carrier, wherein the crystalline form is characterized by (a) an X-ray powder diffraction (XRPD) pattern having one or more of the following peaks: 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6 and 20.8, degrees 2θ, ±0.2°; or (b) a differential scanning calorimetry (DSC) pattern having an endothermic peak with an onset temperature of about 69.0°C; or (c) a combination of (a) and (b).

27. The method of claim 25 or 26, wherein the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil and a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable oil comprises castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil or soybean oil, the pharmaceutically acceptable solvent comprises benzyl alcohol or benzyl benzoate, and wherein the abiraterone decanoate is present at a concentration of 50 mg / mL to 300 mg / mL.

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