Oral abiraterone formulations

Abstract

Provided herein are oral abiraterone prodrug formulations, related methods and kits, for oral administration to subjects having, e.g., sex hormone dependent benign or malignant disorders, e.g., prostate cancer, androgen receptor-driven cancers, syndromes due to androgen excess, and / or syndromes due to glucocorticoid excess, e.g., hypercortisolism.

Description

[Technical field]

[0001]

[0001] The present disclosure relates generally to novel oral formulations of abiraterone prodrugs. The disclosure is directed to a wide range of applications, such as for administration to patients suffering from androgen or estrogen hormone-dependent benign or malignant disorders, or androgen receptor-driven cancers, including various cancers (e.g., prostate cancer, bladder cancer, hepatocellular carcinoma, lung cancer, breast cancer, endometrial cancer, and ovarian cancer, etc.), as well as for the treatment of non-neoplastic syndromes resulting from overproduction of androgens (including both classical and non-classical congenital adrenal hyperplasia, endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc.), or from overproduction of glucocorticoids, typically cortisol, in conditions such as Cushing's syndrome or Cushing's disease. Background

[0002]

[0002] Abiraterone ((3β)-17-(pyridin-3-yl)androsta-5,16-dien-3-ol; CAS number: 154229-19-3; formula: C 24 H 31NO; molecular weight: 349.5 g / mol) is an inhibitor of CYP17A1, a member of the cytochrome P450 superfamily of enzymes that catalyze the synthesis of cholesterol, steroids, and other lipids and are involved in drug metabolism. CYP17A1 has both 17α-hydroxylase and 17,20-lyase activities. Abiraterone potently and selectively inhibits both the 17α-hydroxylase and 17,20-lyase enzyme activities of CYP17A1. The 17α-hydroxylase activity of CYP17A1 is required for the production of glucocorticoids such as cortisol. However, both the hydroxylase and 17,20-lyase activities of CYP17A1 are required for the production of androgenic (e.g., androstenedione, testosterone, and dihydrotestosterone) and estrogenic (estrone, estradiol, estratriol) steroids through the conversion of 17α-hydroxypregnenolone to the sex steroid precursor, dehydroepiandrosterone, see Figure 1. Thus, abiraterone interferes with the synthesis of androgens and estrogens in the gonads (mainly the testes and ovaries) as well as outside the gonads (e.g., the adrenal glands and the tumor itself).

[0003]

[0003] Abiraterone itself is poorly absorbed, but can be administered orally as an abiraterone acetate prodrug. Abiraterone acetate is also poorly absorbed, but can be converted in the gastrointestinal tract to abiraterone, which is poorly absorbed into the bloodstream following cleavage of the acetate ester prodrug. Abiraterone acetate ((3β)-17-(3-pyridyl)androsta-5, acetate ester; CAS number 154229-18-2) is approved in the United States for the treatment of castration-resistant or castration-sensitive prostate cancer under the trade name Zytiga®. Abiraterone acetate is also now available worldwide.

[0004]

[0004] It is known that orally administered abiraterone acetate prodrugs are not significantly absorbed in the gastrointestinal tract (and small prodrugs can be detected in plasma). Instead, abiraterone acetate is hydrolyzed to abiraterone in the vaginal environment leading to the generation of abiraterone supersaturation, which has been shown to be involved in creating a strong driving force for abiraterone absorption (Stappaerts et al., Eur. J. Pharmaceutics Biopharmaceutics 90:1, 2015).

[0005]

[0005] Because abiraterone blocks the normal physiological production of steroids by the adrenal glands, prodrug formulations of abiraterone are usually prescribed along with low-dose steroids to prevent adrenal insufficiency. In fact, Zytiga® (250 mg tablets) is approved in the United States only in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) and patients with metastatic castration-sensitive prostate cancer (CSPC). The prescribing information provided with Zytiga® encourages oral administration of 1,000 mg (4 x 250 mg tablets) once daily in combination with prednisone (5 mg) orally administered twice daily for CRPC patients or once daily for CSPC patients. In Europe, the use of Zytiga® is approved only in combination with either prednisone or prednisolone.

[0006]

[0006] Because administration of abiraterone acetate with food increases the absorption of abiraterone acetate (and thus the increased variability may result in higher exposure, potentially causing various side effects including cardiovascular side effects and / or hepatotoxicity), the prodrug must be consumed on an empty stomach at least 1 hour before or 2 hours after a meal. In fact, the prescribing information for Zytiga® states that it must be taken on an empty stomach, with a meal at least 2 hours before and at least 1 hour after oral dosing.

[0007]

[0007] The prescribing information indicates that the steady-state C max The C value was 226 ± 178 ng / mL (mean ± SD) and the area under the curve (AUC) value was 1173 ± 690 ng.hr / mL (mean ± SD). In a single dose (1,000 mg) crossover study of Zytiga® in healthy subjects, it was found that systemic exposure of abiraterone was increased when Zytiga® was administered with food. In particular, the C value of abiraterone max and AUC values ​​were approximately 7-fold and 5-fold higher, respectively, when Zytiga® was administered with a low-fat meal (7% fat, 300 calories), and approximately 17-fold and 10-fold higher, respectively, when Zytiga® was administered with a high-fat meal (57% fat, 825 calories).

[0008]

[0008] The currently approved solid oral dosage forms of the prodrug abiraterone acetate have several shortcomings. For example, it has a very low bioavailability that requires a large daily pill loading dose for patients (4 x 250 mg tablets taken once daily). In addition, the combination of low bioavailability and a large food effect causes highly variable blood levels in patients. Furthermore, because abiraterone is rapidly eliminated, this approved dosing regimen requires a high daily C of abiraterone. min This is thought to result in reduced efficacy of treatment in patients with metastatic CRPC.

[0009] [overview]

[0009] The present disclosure relates generally to novel oral abiraterone prodrug formulations and methods of using the oral abiraterone prodrug formulations in the treatment of subjects having, for example, sex hormone-dependent benign or malignant disorders, androgen receptor-induced cancers, and / or syndromes resulting from androgen and / or glucocorticoid excess.

[0010]

[0010] U.S. Patent No. 10,792,292 B2, issued on October 6, 2020 to Propella Therapeutics, Inc., and U.S. Provisional Patent Application Nos. 63 / 073,502, filed on September 2, 2020, and 63 / 149,550, filed on February 15, 2021, disclose, for example, the daily C α observed with oral administration of abiraterone acetate. min We describe useful abiraterone prodrugs, particularly abiraterone decanoate, as a breakthrough over the currently marketed Zytiga® tablets, which provide increased bioavailability, elimination of food effect, reduced pill burden, reduced dosing frequency, and sustained effective plasma levels of abiraterone at higher than normal plasma levels, e.g., for at least one week, typically at least two weeks, and up to 10 weeks or more following administration of the abiraterone prodrug formulation. It has been demonstrated that the novel abiraterone prodrugs and formulations thereof are suitable for weekly, monthly, bimonthly, trimonthly, or less frequent dosing for treating subjects with sex hormone-dependent benign or malignant disorders, androgen receptor-induced cancers, syndromes due to androgen excess, and / or syndromes due to glucocorticoid excess.

[0011]

[0011] The present disclosure is based in part on the fact that with a suitable lipid-based drug delivery system, abiraterone decanoate can be orally bioavailable with good to excellent oral bioavailability based on plasma abiraterone concentrations, and can achieve effective plasma concentrations of abiraterone for regulating serum steroid levels, such as lowering serum androgen levels. With improved bioavailability, the oral abiraterone decanoate formulations herein are suitable for dosing frequencies ranging from once daily to once weekly, for example, once daily or once every two or three days. As shown herein, a single oral administration of the pharmaceutical composition herein can achieve sustained inhibition of CYP17A1 for a period of 24 hours or more. Thus, the present disclosure provides an alternative method for administering an abiraterone prodrug, such as an abiraterone lipophilic ester, particularly abiraterone decanoate, to treat various diseases or disorders as described herein, such as prostate cancer as described herein, which may also be advantageous compared to the currently marketed Zytiga® tablets.

[0012]

[0012] In some embodiments, the present disclosure provides the following exemplary embodiments.

[0013] [1] A pharmaceutical composition comprising: (a) abiraterone decanoate; and (b) a lipid-based drug delivery system, wherein the abiraterone decanoate has the following structure: [ka] wherein the pharmaceutical composition is formulated for oral delivery of abiraterone decanoate.

[0014] [2] The pharmaceutical composition of [1], wherein the lipid-based drug delivery system comprises: (1) a triglyceride, a monoglyceride, a diglyceride, and / or a propylene glycol ester; and (2) a surfactant including a polyglyceryl ester and / or a polyoxyglyceride.

[0015] [3] The pharmaceutical composition described in [1] or [2], wherein the lipid-based drug delivery system includes a triglyceride.

[0016] [4] The pharmaceutical composition of [1] or [2], wherein the lipid-based drug delivery system comprises a medium-chain triglyceride (e.g., Labrafac® Lipofile WL1349, or a medium-chain triglyceride of caprylic acid (C8) and capric acid (C10)).

[0017] [5] The pharmaceutical composition according to any one of the embodiments [1] to [4], wherein the lipid-based drug delivery system comprises a monoglyceride and / or a diglyceride.

[0018] [6] Lipid-based drug delivery systems include glycerol / glyceryl linoleate (e.g., Maisine® CC, primarily linoleic acid (C 18:2 ) and oleic acid (C 18:1 The pharmaceutical composition according to any one of the embodiments [1] to [4], comprising a mono-, di-, and triglyceride, diester fraction of glycerol, glycerol, and / or glycerol.

[0019] [7] The pharmaceutical composition according to any one of the embodiments [1] to [6], wherein the lipid-based drug delivery system comprises a propylene glycol ester.

[0020] [8] The pharmaceutical composition according to any one of the embodiments of [1] to [6], wherein the lipid-based drug delivery system comprises propylene glycol monocaprylate (e.g., Capmul PG-8) and / or propylene glycol monolaurate (e.g., Capmul PG-12 or Lauroglycol (trademark) 90).

[0021] [9] The pharmaceutical composition according to any one of the embodiments of [1] to [8], wherein the lipid-based drug delivery system comprises a surfactant comprising a polyglycerol ester.

[0022]

[10] The pharmaceutical composition according to any one of the embodiments of [1] to [8], wherein the lipid-based drug delivery system comprises a surfactant including polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)).

[0023]

[11] The pharmaceutical composition according to any one of the embodiments [1] to

[10] , wherein the lipid-based drug delivery system comprises a surfactant comprising a polyoxyglyceride.

[0024]

[12] The pharmaceutical composition according to any one of the embodiments of [1] to

[10] , wherein the lipid-based drug delivery system comprises a surfactant including macrogolglycerol hydroxystearate (e.g., Corifol RH40), oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) or lauroyl polyoxyl-6 glyceride (e.g., Labrafil 2130).

[0025]

[13] The pharmaceutical composition according to any one of the embodiments of [1] to

[12] , wherein abiraterone decanoate is dispersed, e.g., uniformly dispersed or dissolved, in a lipid-based drug delivery system at a concentration in the range of about 1 mg / g to about 250 mg / g, e.g., about 20 mg / g to about 150 mg / g.

[0026]

[14] The pharmaceutical composition according to any one of the embodiments [1] to

[13] , which is formulated in the form of an oral dosage form such as a capsule (e.g., a soft gel capsule).

[0027]

[15] The pharmaceutical composition according to any one of the embodiments of [1] to

[14] , characterized by one or more of the following: (1) the pharmaceutical composition is stable for storage at room temperature; (2) the recovery of abiraterone decanoate is greater than 50% when the pharmaceutical composition is assessed using an in vitro dispersion test; and (3) when orally administered to a mammal, the pharmaceutical composition is capable of delivering a sufficient amount of abiraterone decanoate to the mammal to achieve a therapeutically effective plasma concentration of abiraterone to treat a disease or disorder described herein, such as prostate cancer described herein.

[0028]

[16] The pharmaceutical composition according to any one of [1] to

[14] , having an oral bioavailability of greater than 30% based on the abiraterone plasma concentration profile when tested in rats.

[0029]

[17] A pharmaceutical composition comprising abiraterone decanoate dissolved in a lipid-based drug delivery system at a concentration ranging from about 10 mg / g to about 150 mg / g, the lipid-based drug delivery system comprising: (a) lipid in an amount of about 10-80% by weight of the lipid-based drug delivery system; and (b) one or more non-ionic surfactants in an amount of about 20-90% by weight of the lipid-based drug delivery system, wherein the abiraterone decanoate has the following structure: [ka] 1. A pharmaceutical composition comprising:

[0030]

[18] The pharmaceutical composition of

[17] , wherein the lipid comprises, for example, a medium chain triglyceride of caprylic acid (C8) and capric acid (C10) (e.g., Labrafac™ Lipofile WL1349) in an amount of about 10% to about 50% by weight, for example about 20 to 40% by weight, of the lipid-based drug delivery system.

[0031]

[19] The pharmaceutical composition of

[17] or

[18] , wherein the lipid comprises, for example, glycerol / glyceryl linoleate (e.g., Mycin® CC) in an amount of about 10% to about 50% by weight, for example about 20 to 40% by weight, of the lipid-based drug delivery system.

[0032]

[20] The pharmaceutical composition according to any one of the embodiments of

[17] to

[19] , wherein the lipid further comprises propylene glycol monocaprylate (e.g., Capmul PG-8) or propylene glycol monolaurate (e.g., Capmul PG-12, or Lauroglycol (trademark) 90) in an amount of about 10% to about 50% by weight, for example about 20 to 40% by weight, of the lipid-based drug delivery system.

[0033]

[21] The pharmaceutical composition according to any one of the embodiments

[17] to

[20] , wherein the lipid-based drug delivery system comprises two or more, for example two or three, nonionic surfactants.

[0034]

[22] The pharmaceutical composition according to any one of the embodiments of

[17] to

[21] , wherein the one or more nonionic surfactants include macrogolglycerol hydroxystearate (e.g., Corifol RH40) and / or polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)).

[0035]

[23] The pharmaceutical composition according to any one of the embodiments

[17] to

[22] , wherein the one or more nonionic surfactants further comprise oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) and / or lauroyl polyoxyl-6 glyceride (e.g., Labrafil 2130).

[0036]

[24] The pharmaceutical composition according to any one of the embodiments of

[17] to

[23] , comprising abiraterone decanoate dissolved in a lipid-based drug delivery system at a concentration ranging from about 20 mg / g to about 120 mg / g, wherein the lipid-based drug delivery system comprises: (a) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) in an amount of about 20 to 40% by weight of the lipid-based drug delivery system; (b) macrogolglycerol hydroxystearate (e.g., Corifol RH40) in an amount of about 10 to 30% by weight of the lipid-based drug delivery system; (c) polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)) in an amount of about 10 to 30% by weight of the lipid-based drug delivery system; and (d) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) in an amount of about 20 to 40% by weight of the lipid-based drug delivery system.

[0037]

[25] Abiraterone decanoate dissolved in a lipid-based drug delivery system at a concentration ranging from about 20 mg / g to about 120 mg / g, the lipid-based drug delivery system comprising: (a) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 10-40% by weight of the lipid-based drug delivery system; (b) macrogolglycerol hydroxystearate (e.g., Corifol RH40) in an amount of about 10-30% by weight of the lipid-based drug delivery system; (c) polyglyceryl oleate (e.g., protease inhibitor) in an amount of about 10-30% by weight of the lipid-based drug delivery system; (d) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) in an amount of about 10-40% by weight of the lipid-based drug delivery system; and (e) propylene glycol monocaprylate (e.g., Capmul PG-8) and / or propylene glycol monolaurate (e.g., Capmul PG-12, or Lauroglycol™ 90) in an amount of about 10-40% by weight of the lipid-based drug delivery system.

[0038]

[26] Abiraterone decanoate dissolved in a lipid-based drug delivery system at a concentration ranging from about 20 mg / g to about 120 mg / g, the lipid-based drug delivery system comprising: (a) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 10-40% by weight of the lipid-based drug delivery system; (b) macrogolglycerol hydroxystearate (e.g., Corifol RH40) in an amount of about 10-30% by weight of the lipid-based drug delivery system; (c) a lipid-based drug delivery system comprising: (d) oleoyl polyoxyl-6 glyceride (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)) in an amount of about 10-30% by weight of the delivery system; (e) glycerol / glyceryl linoleate (e.g., Mycin® CC, mainly linoleic acid (C)) in an amount of about 0-40% by weight of the lipid-based drug delivery system; and (f) glycerol / glyceryl linoleate (e.g., Mycin® CC, mainly linoleic acid (C)) in an amount of about 10%-40% by weight of the lipid-based drug delivery system. 18:2 ) and oleic acid (C 18:1 The pharmaceutical composition according to any one of the embodiments

[17] to

[23] , comprising mono-, di-, and triglyceride, and diester fractions of glycerol, glycerol, and / or glycerol.

[0039]

[27] The pharmaceutical composition described in

[17] , comprising a vehicle as described in any of the examples herein.

[0040]

[28] The pharmaceutical composition according to any one of the embodiments

[17] to

[27] , which is formulated for oral administration, such as in the form of a capsule (e.g., a softgel capsule).

[0041]

[29] The pharmaceutical composition described in any one of

[17] to

[28] , characterized by one or more of the following: (1) the pharmaceutical composition is stable for storage at room temperature; (2) the recovery of abiraterone decanoate is greater than 50% when the pharmaceutical composition is assessed using an in vitro dispersion test; and (3) when orally administered to a mammal, the pharmaceutical composition is capable of delivering a sufficient amount of abiraterone decanoate to the mammal to achieve a therapeutically effective plasma concentration of abiraterone to treat a disease or disorder described herein, such as prostate cancer described herein.

[0042]

[30] The pharmaceutical composition described in any one of

[17] to

[29] , having an oral bioavailability of greater than 30% based on the abiraterone plasma concentration profile when tested in rats.

[0043]

[31] The pharmaceutical composition according to any one of the embodiments of [1] to

[30] , wherein the lipid-based drug delivery system is a self-dispersing drug delivery system, for example a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system.

[0044]

[32] The pharmaceutical composition according to any one of the embodiments of [1] to

[31] , wherein, when orally administered to a mammal, at least a portion of abiraterone decanoate is absorbed through the lymphatic system.

[0045]

[33] The pharmaceutical composition according to any one of [1] to

[32] , wherein the abiraterone decanoate is substantially pure and characterized as having a purity of at least 95% by weight, preferably at least 98%, e.g., about 98.5%, about 99%, about 99.5% or more.

[0046]

[34] Abiraterone decanoate is less than 1% by weight (e.g., less than 0.5% by weight, e.g., less than 0.3% by weight, less than 0.2% by weight, or less than 0.1% by weight) of the formula: [ka] The pharmaceutical composition according to

[33] , characterized as having ethyl prasterone decanoate having the formula:

[0047]

[35] The pharmaceutical composition of

[33] , wherein the abiraterone decanoate is characterized as having no detectable amount of ethyl prasterone decanoate.

[0048]

[36] The pharmaceutical composition according to any one of

[33] to

[35] , wherein the abiraterone decanoate is characterized as having a palladium content of less than 50 ppm.

[0049]

[37] The pharmaceutical composition according to any one of

[33] to

[35] , wherein the abiraterone decanoate is characterized as having a palladium content of less than 10 ppm.

[0050]

[38] A method for treating or preventing a disease or disorder in a subject in need thereof, comprising the step of administering to the subject an effective amount of the pharmaceutical composition described in any one of the embodiments [1] to

[37] , wherein the disease or disorder is selected from sex hormone-dependent benign or malignant disorders, androgen receptor-induced cancer, syndromes caused by androgen excess, and syndromes caused by glucocorticoid excess.

[0051]

[39] The method according to

[38] , wherein the disease or disorder is selected from prostate cancer, breast cancer, endometrial cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, lung cancer, endometriosis, polycystic ovary syndrome, Cushing's syndrome, Cushing's disease, classic or non-classic congenital adrenal hyperplasia, precocious puberty, hirsutism, and combinations thereof.

[0052]

[40] The method according to

[38] , wherein the disease or disorder is sex hormone-dependent or androgen receptor-induced cancer.

[0053]

[41] The method according to

[40] , wherein the sex hormone-dependent or androgen receptor-induced cancer is androgen receptor-positive salivary duct carcinoma or androgen receptor-positive glioblastoma multiforme.

[0054]

[42] The method according to

[38] , wherein the disease or disorder is prostate cancer.

[0055]

[43] The method of

[42] , wherein the subject having prostate cancer is characterized as having an elevated amount of prostate specific antigen, for example following radical prostatectomy.

[0056]

[44] The method according to

[42] , wherein the prostate cancer is localized prostate cancer, e.g., high-risk localized prostate cancer.

[0057]

[45] The method according to

[42] , wherein the prostate cancer is metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer, non-metastatic castration-resistant prostate cancer, or metastatic castration-resistant prostate cancer.

[0058]

[46] The method according to

[42] , wherein the prostate cancer is newly diagnosed high-risk metastatic hormone-sensitive prostate cancer.

[0059]

[47] The method of

[42] , wherein the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC), the subject is asymptomatic or mildly symptomatic after failure of androgen deprivation therapy, and chemotherapy is not yet clinically indicated in the subject.

[0060]

[48] ​​The method of

[42] , wherein the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC) and the subject's disease has progressed on or after a taxane-based, e.g., docetaxel-based, chemotherapy regimen.

[0061]

[49] The method according to

[42] , wherein the prostate cancer is refractory prostate cancer.

[0062]

[50] The method according to any one of the embodiments

[38] to

[49] , further comprising a step of treating the subject with radiation therapy or surgery.

[0063]

[51] The method according to any one of the embodiments of

[38] to

[50] , further comprising the step of administering to the subject one or more other agents selected from anti-cancer agents, hormone ablation agents, anti-androgen agents, differentiation agents, anti-neoplastic agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotics, immune agents, interferon-type agents, intercalating agents, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloproteinase inhibitors, genetic therapeutic agents, or combinations thereof.

[0064]

[52] The method according to any one of the embodiments

[38] to

[51] , further comprising a step of administering to the subject one or more agents selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone.

[0065]

[53] The method according to any one of the embodiments

[38] to

[52] , further comprising the step of administering to the subject one or more other agents selected from chemotherapy agents, hormone replacement agents, or hormone ablation agents.

[0066]

[54] The method according to any one of the embodiments

[38] to

[53] , further comprising a step of treating the subject with androgen deprivation therapy.

[0067]

[55] The method according to any one of the embodiments

[38] to

[53] , wherein the subject is a non-castrated subject.

[0068]

[56] The method according to any one of the embodiments of

[38] to

[53] , wherein the subject is not treated with a gonadotropin releasing hormone agonist and / or antagonist in an amount effective to lower serum testosterone levels in the subject.

[0069]

[57] The method of

[56] , wherein the subject is not treated with a drug selected from buserelin, leuprolide, deslorelin, fertirelin, histrelin, gonadorelin, resilin, goserelin, nafarelin, perforelin and triptorelin.

[0070]

[58] The method of

[56] , wherein the subject is not treated with a drug selected from abarelix, cetrorelix, degarelix, ganirelix, elagolix, linzagolix, and relugolix.

[0071]

[59] The method according to any one of the embodiments

[55] to

[58] , wherein the subject is sensitive to or otherwise intolerant to gonadotropin releasing hormone antagonists and / or agonists.

[0072]

[60] The method according to any one of the embodiments

[55] to

[59] , wherein the subject is not treated with glucocorticoid replacement therapy.

[0073]

[61] The method according to any one of the embodiments of

[38] to

[60] , further comprising the step of administering to the subject a poly ADP ribose polymerase (PARP) inhibitor, such as niraparib, rucaparib, olaparib, talazoparib, veliparib, and fluzoparib.

[0074]

[62] The method according to any one of

[38] to

[61] , further comprising the step of administering to the subject a first generation androgen receptor antagonist, for example, proxartamide, bicalutamide, flutamide, nilutamide, or topirutamide.

[0075]

[63] The method according to any one of the embodiments

[38] to

[62] , further comprising a step of administering a second-generation androgen receptor antagonist (e.g., apalutamide, darolutamide or enzalutamide) to the subject.

[0076]

[64] The method of any one of

[38] to

[63] , further comprising administering to the subject a third generation androgen receptor antagonist (e.g., an N-terminal domain inhibitor) or an androgen receptor degrader molecule, alone or in combination with one or more first generation or second generation androgen receptor antagonists.

[0077]

[65] The method according to any one of the embodiments of

[38] to

[64] , further comprising the step of administering to the subject a chemotherapeutic agent, such as a taxane-based chemotherapeutic agent (e.g., docetaxel, cabazitaxel, paclitaxel, etc.) or a platinum-based chemotherapeutic agent (e.g., cisplatin, carboplatin, oxaliplatin, etc.).

[0078]

[66] The method according to any one of the embodiments of

[38] to

[65] , further comprising the step of administering an immunotherapy to the subject, such as sipuleucel-T, an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody, e.g., pembrolizumab or nivolumab, or an anti-PD-L1 antibody, e.g., avelumab or atezolizumab), or an anti-CTLA-4 antibody (e.g., ipilimumab).

[0079]

[67] The method according to any one of the embodiments of

[38] to

[66] , further comprising a step of administering a bispecific T cell engager (BiTE) therapy, such as blinatumomab or solitomab, to the subject.

[0080]

[68] The method according to any one of the embodiments of

[38] to

[67] , further comprising a step of administering to the subject a kinase inhibitor, such as sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivasertib, onvansertib, ipatasertib, afuresertib, alisertib, apitolisib, or opaganib.

[0081]

[69] The method of any one of

[38] to

[68] , further comprising administering to the subject a bone protective agent (e.g., denosumab, zoledronic acid), wherein the subject is characterized as having prostate cancer with bone metastasis (e.g., CRPC).

[0082]

[70] 1) anti-IL23 targeted monoclonal antibodies, e.g., tildrakizumab; 2) selenium, e.g., sodium selenite; 3) EZH2 inhibitors, e.g., CPI-1205, GSK2816126, or tazemetostat; 4) CDK4 / 6 inhibitors, e.g., palbociclib, ribociclib, abemaciclib; 6) bromodomain and extra-terminal domain (BET) inhibitors, e.g., CCS1477, INCB057643, allobresib, ZEN-3694, or molibresib (GSK525762); 7) anti-CD105 antibodies, e.g., TRC105 or carotuximab; 8) niclosamide; 9) A2A receptor antagonists, e.g., AZD4635; 10) PI3K inhibitors, e.g. The method of any one of

[38] to

[69] , further comprising a step of administering to the subject a therapeutic agent selected from the group consisting of: 1) an additional non-steroidal CYP17A1 inhibitor, such as AZD-8186, buparlisib, or dactolisib; 2) an additional non-steroidal CYP17A1 inhibitor, such as seviteronel; 3) an antiprogestogen, such as onapristone; 4) navitoclax; 5) an HSP90 inhibitor, such as onarespib (AT13387); 6) an HSP27 inhibitor, such as OGX-427; 7) an HSP27 inhibitor, such as OGX-427; 8) an HSP90 inhibitor, such as onarespib (AT13387); 9) an HSP27 inhibitor, such as OGX-427; 10) an HSP90 inhibitor, such as onarespib (AT13387); 11) an HSP27 inhibitor, such as OGX-427; 12) an HSP90 inhibitor, such as onarespib (AT13387); 13) an HSP27 inhibitor, such as OGX-427; 14) an HSP90 inhibitor, such as onarespib (AT13387); 15) an HSP27 inhibitor, such as OGX-427; 16) an HSP27 inhibitor, such as OGX-427; 17) metformin; 18) AMG-386; 19) dextromethorphan; 20) theophylline; 21) hydroxychloroquine; and 22) lenalidomide.

[0083]

[71] The method according to any one of the embodiments of

[38] to

[70] , further comprising administering to the subject one or more kinase regulators selected from an FLT-3 (FMS-like tyrosine kinase) inhibitor, an AXL (anexelekto) inhibitor (e.g., gilteritinib), a CDK (cyclin-dependent kinase) inhibitor, such as a CDK1, 2, 4, 5, 6, 7, or 9 inhibitor, a retinoblastoma (Rb) inhibitor, a protein kinase B (AKT) inhibitor, an SRC inhibitor, an I kappa B kinase 1 (IKK1) inhibitor, a PIM-1 regulator, a lemur tyrosine kinase 2 (LMTK2) regulator, a Lyn inhibitor, an Aurora A inhibitor, an ANPK (nuclear protein kinase) inhibitor, an extracellular signal-regulated kinase (ERK) regulator, a c-jun N-terminal kinase (JNK) regulator, a big MAP kinase (BMK) regulator, a p38 mitogen-activated protein kinase (MAPK) regulator, and combinations thereof.

[0084]

[72] The method according to any one of the embodiments

[38] to

[71] , wherein the subject has not undergone chemotherapy or has not undergone hormone therapy prior to administration of the pharmaceutical composition.

[0085]

[73] The method according to any one of the embodiments

[38] to

[72] , wherein the subject has not undergone prostatectomy.

[0086]

[74] The method according to any one of the embodiments of

[38] to

[73] , wherein the subject is treated with radiation therapy, e.g., stereotactic body radiation therapy, neutron radiation.

[0087]

[75] The method according to any one of the embodiments

[38] to

[74] , wherein the subject is administered radium-223.

[0088]

[76] The method of

[38] , wherein the disease or disorder is breast cancer, e.g., molecular apocrine HER2-negative breast cancer, metastatic breast cancer, e.g., ER+ metastatic breast cancer, ER+ and HER2-negative breast cancer, AR+ triple-negative breast cancer, etc.

[0089]

[77] The method of

[76] , further comprising the step of administering an aromatase inhibitor, e.g., exemestane, to the subject.

[0090]

[78] The method according to

[38] , wherein the disease or disorder is associated with 21-hydroxylase deficiency.

[0091]

[79] The method according to any one of the embodiments

[38] to

[78] , wherein the pharmaceutical composition is administered orally.

[0092]

[80] The method according to any one of the embodiments,

[38] to

[79] , wherein the pharmaceutical composition is administered to the subject in the range of once a day to once a week, for example once a day or once every two or three days.

[0093]

[81] The method according to any one of the embodiments

[38] to

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

[0094]

[82] An emulsion comprising: (a) abiraterone decanoate; (b) a lipid; and (c) a non-ionic surfactant, wherein the lipid phase of the emulsion comprises abiraterone decanoate dispersed in a lipid, the abiraterone decanoate having the following structure: [ka] An emulsion having

[0095]

[83] The emulsion of

[82] , wherein the lipid comprises a medium chain triglyceride of caprylic acid (C8) and capric acid (C10) (e.g., Labrafac™ Lipofile WL1349).

[0096]

[84] The emulsion of

[82] or

[83] , wherein the lipid comprises glycerol / glyceryl linoleate (e.g., Mycin® CC).

[0097]

[85] The emulsion according to any one of the embodiments of

[82] to

[84] , wherein the lipid further comprises propylene glycol monocaprylate (e.g., Capmul PG-8) or propylene glycol monolaurate (e.g., Capmul PG-12 or Lauroglycol (trademark) 90).

[0098]

[86] The emulsion according to any one of the embodiments

[82] to

[85] , comprising two or more, for example two or three, nonionic surfactants.

[0099]

[87] The emulsion according to any one of the embodiments of

[82] to

[86] , wherein the nonionic surfactant comprises macrogolglycerol hydroxystearate (e.g., Corifol RH40) and / or polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)).

[0100]

[88] The emulsion of

[87] , wherein the surfactant further comprises oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) and / or lauroyl polyoxyl-6 glyceride (e.g., Labrafil 2130).

[0101]

[89] An emulsion produced by mixing the pharmaceutical composition described in any one of the embodiments of [1] to

[37] with water.

[0102]

[90] An emulsion produced by administering the pharmaceutical composition described in any one of the embodiments of [1] to

[37] to a mammal.

[0103]

[91] A method for treating or preventing a disease or disorder in a subject in need thereof, comprising the step of administering to the subject an effective amount of the emulsion described in any one of the embodiments

[82] to

[90] , wherein the disease or disorder is selected from the group consisting of sex hormone-dependent benign or malignant disorders, androgen receptor-induced cancers, syndromes caused by androgen excess, and syndromes caused by glucocorticoid excess.

[0104]

[0013] Embodiments of the present disclosure may fulfill a long felt need in the field of sex hormone dependent disorders and oncology, including the treatment of sex hormone dependent or androgen receptor induced cancers such as prostate cancer. Embodiments of the present disclosure may also fulfill a long felt need in the field of treatment of syndromes resulting from androgen excess and / or syndromes resulting from glucocorticoid excess, such as hypercortisolism. Embodiments of the present disclosure may overcome major shortcomings and drawbacks of prior art formulations of abiraterone acetate (including commercially available oral dosage forms) by providing novel oral abiraterone prodrug formulations, methods of making oral abiraterone prodrug formulations, methods of treatment using oral abiraterone prodrug formulations, and kits for convenient administration of the formulations to subjects in need of therapy for various disorders, including prostate cancer.

[0105]

[0014] Thus, features have been outlined rather broadly in order that the detailed description of the invention that follows may be better understood, and in order that the present contribution to the art may be better appreciated. Of course, there are additional features that are further described below. Indeed, it should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the present disclosure.

[0106]

[0015] In this aspect, before describing at least one embodiment in detail, it is to be understood that the invention is not limited to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

[0107]

[0016] Thus, those skilled in the art will appreciate that the concepts on which this disclosure is based may be readily utilized as a basis for the design of other formulations, methods, systems, kits, and compositions for carrying out some of the purposes of this disclosure. It is therefore important that equivalent structures are included in this disclosure without departing from the spirit and scope of the disclosure.

[0108]

[0017] The accompanying drawings are included to provide a further understanding, and are incorporated in and constitute a part of this specification, illustrating several embodiments and, together with the description, explaining the principles. [Brief description of the drawings]

[0109] [Figure 1] Biochemical pathways showing the effect of CYP17A1 inhibition on the synthesis of androgens, estrogens, glucocorticoids, progesterone, and mineralocorticoids are presented. [Figure 2A] 1 provides a representative X-ray powder diffraction (XRPD) spectrum of the solid form of abiraterone decanoate (alternatively abbreviated herein as "AbiDec," "ADEC," or "AbDec") prepared in Example 1A, designated Form A. [Figure 2B] 1 shows a representative differential scanning calorimetry (DSC) spectrum of the solid form of abiraterone decanoate prepared in Example 1A, designated Form A. [Figure 2C] 1 shows a representative thermogravimetric analysis (TGA) of the solid form of abiraterone decanoate prepared in Example 1A, designated Form A. [Figure 2D-1] A representative XRPD spectrum of abiraterone decanoate in form B is presented. [Figure 2D-2] A representative XRPD spectrum of abiraterone decanoate in form B is presented. [Figure 2E] 1 shows a representative DSC spectrum of abiraterone decanoate in form B. [Figure 2F] 1 shows a representative TGA of abiraterone decanoate in Form B. [Figure 2G-1]A representative XRPD spectrum of abiraterone decanoate in Form C is presented. [Figure 2G-2] A representative XRPD spectrum of abiraterone decanoate in Form C is presented. [Figure 2H] 1 shows a representative DSC spectrum of abiraterone decanoate in form C. [Figure 2I] 1 shows a representative TGA of abiraterone decanoate in Form C. [Diagram 3] Graphs are presented showing the mean plasma concentrations of abiraterone and abiraterone decanoate in plasma following oral administration of abiraterone decanoate in two different formulations. Ranked from maximum Cmax to minimum Cmax in absolute values, the following are true: abiraterone from treatment group 2, abiraterone from treatment group 3, abiraterone decanoate from treatment group 2, and abiraterone decanoate from treatment group 3. [Figure 4A] Graphs are presented showing the mean plasma concentrations of progesterone ("Prog") following oral administration of vehicle (Group 1 or Grp1), Formulation 1 (Group 2 or Grp2), and Formulation 2 (Group 3 or Grp3). [Figure 4B] A graph is presented showing the mean plasma concentrations of progesterone ("Prog") following oral administration of Formulation 1 (Group 2 or Grp2) and Formulation 2 (Group 3 or Grp3) compared to the mean plasma concentrations from oral administration of vehicle (Group 1 or Grp1). [Figure 5A] Graphs are presented showing mean plasma concentrations of corticosterone ("Cortico") following oral administration of vehicle (Group 1 or Grp1), Formulation 1 (Group 2 or Grp2), and Formulation 2 (Group 3 or Grp3). [Figure 5B] A graph is presented showing the mean plasma concentrations of corticosterone ("Cortico") following oral administration of Formulation 1 (Group 2 or Grp2) and Formulation 2 (Group 3 or Grp3) compared to the mean plasma concentrations from oral administration of vehicle (Group 1 or Grp1). [Figure 6A]Graphs are presented showing the mean plasma concentrations of androstenedione ("Andro") following oral administration of vehicle (Group 1 or Grp1), formulation 1 (Group 2 or Grp2), and formulation 2 (Group 3 or Grp3). [Figure 6B] A graph is presented showing the mean plasma concentrations of androstenedione ("Andro") following oral administration of Formulation 1 (Group 2 or Grp2) and Formulation 2 (Group 3 or Grp3) compared to the mean plasma concentrations from oral administration of vehicle (Group 1 or Grp1). [Figure 7A] Graphs are presented showing the mean plasma concentrations of testosterone ("T") following oral administration of vehicle (Group 1 or Grp1), Formulation 1 (Group 2 or Grp2), and Formulation 2 (Group 3 or Grp3). [Figure 7B] A graph is presented showing the mean plasma concentrations of testosterone ("T") following oral administration of Formulation 1 (Group 2 or Grp2) and Formulation 2 (Group 3 or Grp3) compared to the mean plasma concentrations from oral administration of vehicle (Group 1 or Grp1). [Figure 8] Graphs are presented showing the mean plasma concentrations of luteinizing hormone following oral administration of vehicle (Group 1 or Grp1), formulation 1 (Group 2 or Grp2) and formulation 2 (Group 3 or Grp3). The ranking based on last observed concentration (72 hours) is as follows: Group 2>Group 3>Group 1. [Figure 9] 1 presents a bar graph showing the mean tissue concentrations of abiraterone in tissues following oral administration of Formulation 1 (Group 2 or Grp2) and Formulation 2 (Group 3 or Grp3). Detailed Description

[0110]

[0039] In a broad aspect, the present disclosure relates to novel oral abiraterone prodrug formulations, methods for regulating serum steroid hormone levels in a subject in need thereof, and methods for treating or preventing diseases or disorders associated with such steroid hormones. Embodiments of the present disclosure are based in part on the fact that abiraterone prodrugs, particularly abiraterone decanoate, can be orally administered to a subject to achieve sustained inhibition of CYP17A1 activity and reduced serum androgen levels.

[0111] As detailed in U.S. Patent No. 10,792,292 B2, and U.S. Provisional Patent Applications Nos. 63 / 073,502 and 63 / 149,550, the contents of each of which are incorporated herein by reference in their entirety, parenteral administration of abiraterone prodrugs, such as abiraterone decanoate, may be advantageous over existing methods in many aspects, including rapid and sustained reduction in serum testosterone, no need for castration, low or no liver toxicity compared to methods using oral abiraterone acetate formulations, improved bioavailability, elimination of the food effect associated with oral abiraterone acetate formulations, reduced pill burden, better patient compliance, less frequent dosing, sustained and stable blood levels of active drug, reduced C-terminal agonist activity, and reduced C-terminal agonist activity, which may be associated with side effects. max These include, but are not limited to, a decrease in

[0112]

[0041] As discussed herein, it has been found that with an appropriate lipid-based drug delivery system, abiraterone decanoate can be orally bioavailable with good to excellent bioavailability to achieve effective plasma concentrations of abiraterone for regulating serum steroid levels, such as lowering serum androgen levels. This provides an alternative method for administering abiraterone prodrugs, such as abiraterone lipophilic esters, particularly abiraterone decanoate, to treat various diseases or disorders described herein, such as prostate cancer, as described herein.

[0113]

[0042] Thus, in various embodiments, the present disclosure provides novel oral abiraterone prodrug formulations, methods for regulating serum steroid hormone levels, such as lowering testosterone levels, and / or novel methods for treating or preventing diseases or disorders mediated by or associated with such steroids, such as sex hormone dependent or androgen receptor-induced cancers.

[0114] Abiraterone decanoate formulations In some embodiments, the present disclosure provides abiraterone prodrugs, such as abiraterone lipophilic esters, particularly those having the following structure: [ka] The present invention provides various formulations comprising abiraterone decanoate having the formula:

[0115]

[0044] Typically, the pharmaceutical composition herein comprises (a) abiraterone decanoate; and (b) a lipid-based drug delivery system, and is formulated for oral delivery of abiraterone decanoate.

[0116]

[0045] The lipid-based drug delivery system herein broadly refers to any lipid-based vehicle, which, when formulated with abiraterone decanoate, is suitable for oral administration to deliver a sufficient amount of abiraterone decanoate to achieve an effective plasma concentration of abiraterone for inhibiting CYP17A1, regulating various steroid hormone levels, such as androgens, estrogens, glucocorticoids, progesterone and mineralocorticoids, and / or treating diseases or disorders described herein, such as prostate cancer, as described herein. The lipid-based drug delivery system herein can typically be characterized as a self-dispersing drug delivery system, such as a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. Typically, abiraterone decanoate is homogeneously dispersed or dissolved in the lipid-based drug delivery system.

[0117]

[0046] In some embodiments, the pharmaceutical compositions herein are characterized as being capable of delivering at least a portion of abiraterone decanoate through a lymphatic delivery system when orally administered to a mammal. Lymphatic delivery of lipid-based drug delivery systems can result in a better overall pharmacokinetic profile since it can bypass first-pass metabolism. See the general discussion of lymphatic delivery in Punjabi et al., Current Pharmaceutical Design, 27:1992-1998 (2021); Bora et al., Indian Drugs 54(08):5-22 (2017); Pouton et al., Advanced Drug Delivery Reviews 60:625-637 (2008); and Cote et al., Advanced Drug Delivery Reviews 144:16-34 (2019). As shown in the Examples section, a single dose of an exemplary oral formulation herein achieved excellent oral bioavailability in a rat pharmacokinetic study, but also potently reduced circulating androgen levels (androstenedione and testosterone) and increased progesterone levels. Without wishing to be bound by theory, it is believed that upon oral administration to a mammal of a pharmaceutical composition comprising abiraterone decanoate herein (e.g., any of those described herein, e.g., [1]-

[37] in the Summary section of the present specification), at least a portion of abiraterone decanoate is absorbed through the lymphatic system. Lymphatic delivery is also supported by histological studies herein showing that abiraterone was detected in tissues 72 hours after dosing in the mandibular and mesenteric lymph nodes.

[0118]

[0047] The pharmaceutical compositions herein are typically formulated in the form of an oral dosage form, such as a capsule (eg, a softgel capsule).

[0119]

[0048] The pharmaceutical compositions of the present specification (e.g., any of those described herein, e.g., [1]-

[37] in the Summary section of the present specification) are also typically characterized by one or more of the following: (1) the pharmaceutical composition is stable for storage at room temperature; (2) the recovery of abiraterone decanoate is greater than 50% when the pharmaceutical composition is evaluated using an in vitro dispersion test; and (3) when orally administered to a mammal, the pharmaceutical composition is capable of delivering abiraterone decanoate to the mammal in an amount sufficient to achieve a therapeutically effective plasma concentration of abiraterone to treat a disease or disorder described herein, such as, for example, prostate cancer, as described herein. As used herein, "in vitro dispersion test" should be understood to use a procedure according to the procedure described in Example 4 of the present application. By "storage stable" it is meant that upon storage at storage conditions and for a storage period, e.g., at room temperature for one month or more (e.g., about one month, about three months, about six months, or longer), the pharmaceutical composition (1) has substantially the same amount of abiraterone decanoate, e.g., within 80-125% of the amount at the beginning of storage; (2) has substantially the same amount of impurities (total impurities and / or individual impurities), e.g., within 80-125% of the amount at the beginning of storage; and / or (3) does not undergo substantial change in physical properties, e.g., the appearance and dispersibility of an aqueous solution remain substantially the same as at the beginning of storage.

[0120] In a preferred embodiment, the pharmaceutical compositions herein (e.g., any of those described herein, e.g., [1]-

[37] in the Summary section of the present specification) may have an oral bioavailability of greater than 30% based on the abiraterone plasma concentration profile when tested in rats. Oral bioavailability can be readily determined by one of skill in the art. An exemplary method for determining oral bioavailability in rats is provided in the Examples section of the present specification.

[0121] Lipid-Based Drug Delivery Systems

[0050] The lipid-based drug delivery system herein typically includes one or more lipids and one or more surfactants. Suitable lipids and surfactants and amounts thereof include those generally accepted for pharmaceutical use, such as those listed in the Inactive Ingredients Database from the U.S. Food and Drug Administration. The particular lipids and surfactants for the pharmaceutical compositions herein can typically be selected based on the solubility of abiraterone decanoate, the stability of the pharmaceutical composition, the compatibility of excipients, and the dispersibility of the pharmaceutical composition in aqueous solution, etc. For example, in some embodiments, the lipids and surfactants are selected such that the pharmaceutical composition can have abiraterone decanoate dissolved or suspended in the lipid-based drug delivery system at a concentration of about 1 mg / g to about 250 mg / g. Obviously, a concentration of 250 mg / g means that for every gram of mixture of abiraterone decanoate in the lipid-based drug delivery system, there is 250 mg of abiraterone decanoate. The concentrations of abiraterone decanoate in the lipid-based drug delivery system described elsewhere in this disclosure should be understood to be similar. Preferably, the lipids and surfactants are selected such that the pharmaceutical composition can have abiraterone decanoate dissolved in the lipid-based drug delivery system at a concentration of about 20 mg / g to about 150 mg / g. In some embodiments, the lipids and surfactants are selected such that the pharmaceutical composition can be stably stored at room temperature, for example, for one month, three months, six months, or longer. In some embodiments, the lipids and surfactants are selected such that the pharmaceutical composition can include a solution (or homogenous mixture) of abiraterone decanoate in the lipid-based drug delivery system at room temperature, and the solution (or homogenous mixture) can remain in solution (or homogenous), i.e., does not form visible crystals / precipitation of drug and / or excipients, after storage at room temperature for one month, three months, six months, or longer. In some embodiments, the lipids and surfactants are selected such that the recovery of abiraterone decanoate is greater than 50% (e.g., 55%, 60%, 70%, 80%, 90%, or up to 100%, or any range between the recited values) when the pharmaceutical composition is evaluated using an in vitro dispersion test.In some embodiments, the lipids and surfactants are selected such that, upon oral administration to a mammal, the pharmaceutical composition is capable of delivering a sufficient amount of abiraterone decanoate to the mammal to achieve a therapeutically effective plasma concentration of abiraterone, for example, to treat a disease or disorder described herein, such as prostate cancer, as described herein. In some embodiments, the lipids and surfactants are selected such that, upon oral administration to a mammal, the pharmaceutical composition is capable of delivering a sufficient amount of abiraterone decanoate to the mammal to achieve an effective plasma concentration of abiraterone, for example, to inhibit CYP17A1. In some embodiments, the lipids and surfactants are selected such that the pharmaceutical compositions herein may have an oral bioavailability of greater than 30%, for example, up to 60%, 70% or more, based on the abiraterone plasma concentration profile when tested in rats.

[0122]

[0051] Typically, lipids for lipid-based drug delivery systems include triglycerides, monoglycerides, diglycerides, and / or propylene glycol esters. Surfactants for lipid-based drug delivery systems typically include one or more non-ionic surfactants.

[0123]

[0052] In some embodiments, the lipid-based drug delivery system herein includes (1) a lipid, including triglycerides, monoglycerides, diglycerides, and / or propylene glycol esters; and (2) a surfactant, such as a non-ionic surfactant. The surfactant may be any of those described herein, for example, the surfactant may include polyglyceryl esters and / or polyoxyglycerides. Triglycerides, monoglycerides, and diglycerides, as used herein, should be understood as mono-, di-, or triesters of glycerol with fatty acids, and propylene glycol esters, as used herein, should be understood as mono- or diesters of propylene glycol with fatty acids, and the fatty acids may typically be, for example, but are not limited to, medium or long chain fatty acids, which may be saturated or unsaturated. One of ordinary skill in the art will appreciate that medium chain fatty acids include aliphatic tails of 6-12 carbons, and long chain fatty acids include aliphatic tails of 13-21 carbons. Some triglycerides, monoglycerides, diglycerides or propylene glycol esters may also be considered as surfactants.However, as used herein, it should be clearly understood that surfactants for the lipid-based drug delivery system herein require one or more surfactants that are not triglycerides, monoglycerides, diglycerides or propylene glycol esters as defined herein.When calculating the weight percentage of surfactants in lipid-based drug delivery system or pharmaceutical composition herein, only those surfactants that are not triglycerides, monoglycerides, diglycerides or propylene glycol esters should be considered, unless otherwise specified or the content indicates otherwise.

[0124]

[0053] In some embodiments, the lipid-based drug delivery system herein comprises (1) a triglyceride, a monoglyceride, a diglyceride, and / or a propylene glycol ester; and (2) a surfactant including a polyglyceryl ester and / or a polyoxyglyceride. In some embodiments, the lipid-based drug delivery system herein comprises a triglyceride and a surfactant. In some embodiments, the lipid-based drug delivery system herein comprises a diglyceride and a surfactant. In some embodiments, the lipid-based drug delivery system herein comprises a monoglyceride and a surfactant. In some embodiments, the lipid-based drug delivery system herein comprises a propylene glycol ester and a surfactant. In some embodiments, the lipid-based drug delivery system herein comprises (1) a triglyceride and one or more selected from a monoglyceride, a diglyceride, and a propylene glycol ester, and (2) a surfactant. In some embodiments, the lipid-based drug delivery system herein comprises (1) a triglyceride and a propylene glycol ester, and (2) a surfactant. In some embodiments, the lipid-based drug delivery system herein comprises (1) triglycerides, monoglycerides, and diglycerides; and (2) surfactants. In some embodiments, the lipid-based drug delivery system herein comprises (1) triglycerides, monoglycerides, diglycerides, and propylene glycol esters; and (2) surfactants. Suitable triglycerides, monoglycerides, diglycerides, propylene glycol esters, and surfactants include any of those described herein in any combination.

[0125]

[0054] In some embodiments, the lipid-based drug delivery system herein comprises: (1) a medium chain triglyceride; and (2) a surfactant, such as a non-ionic surfactant. The medium chain triglyceride is not particularly limited. For example, in some embodiments, the medium chain triglyceride may be a medium chain triglyceride of caprylic acid (C8) and capric acid (C10), such as that commercially available under the trade name: Labrafac™ Lipofile WL1349. In some embodiments, the surfactant comprises a polyglyceryl ester and / or a polyoxyglyceride.

[0126] In some embodiments, the lipid-based drug delivery system herein comprises monoglycerides and / or diglycerides. For example, in some embodiments, the lipid-based drug delivery system comprises glycerol / glyceryl linoleate, such as that from the product commercially available under the trade name Mycin® CC, which is composed primarily of linoleic acid (C ), with a predominance of the diester fraction. 18:2 ) and oleic acid (C 18:1 ) mono-, di-, and triglycerides.

[0127]

[0056] In some embodiments, the lipid-based drug delivery system herein comprises a propylene glycol ester. Suitable propylene glycol esters include, for example, propylene glycol monocaprylate (e.g., sold under the trade name Capmul PG-8) and / or propylene glycol monolaurate (e.g., sold under the trade name Capmul PG-12, or Lauroglycol™ 90).

[0128]

[0057] In some embodiments, the lipid-based drug delivery system of the present specification comprises a medium chain triglyceride of caprylic acid (C8) and capric acid (C10) (e.g., Labrafac (trademark) Lipofile WL1349) and a surfactant described herein.

[0129] In some embodiments, the lipid-based drug delivery system herein comprises: (1) medium chain triglycerides of caprylic (C8) and capric (C10) acids (e.g., Labrafac™ Lipofile WL1349); (2) glycerol / glyceryl linoleate (e.g., Mycin® CC, mainly linoleic acid (C 18:2 ) and oleic acid (C 18:1 ), in which the mono-, di-, and triglyceride, diester fractions predominate; and surfactants as described herein. In such embodiments (e.g., any of the applicable embodiments described herein, e.g., [6]-

[16] and

[19] -

[37] in the Summary section herein), the weight ratio of medium chain triglyceride to glycerol / glyceryl linoleate is typically in the range of about 5:1 to 1:5, more typically in the range of about 2:1 to about 1:2, e.g., about 1.5:1, about 1:1, about 1:1.5, or about 1:2, or any range between the recited values.

[0130]

[0059] In some embodiments, the lipid-based drug delivery system herein comprises: (1) medium chain triglycerides of caprylic acid (C8) and capric acid (C10) (e.g., Labrafac™ Lipofile WL1349); (2) propylene glycol monocaprylate (e.g., Capmul PG-8); and a surfactant as described herein. In such embodiments (e.g., any of the applicable embodiments described herein, e.g., [8]-

[16] and

[20] -

[37] in the Summary section of the present specification), the weight ratio of medium chain triglycerides to propylene glycol monocaprylate is typically in the range of about 5:1 to 1:5, more typically in the range of about 2:1 to about 1:2, e.g., about 1.5:1, about 1:1, about 1:1.5, or about 1:2, or any range between the values ​​recited.

[0131]

[0060] In some embodiments, the surfactant in the lipid-based drug delivery system may include a polyglycerol ester. Useful polyglycerol esters include, but are not limited to, esters formed from homopolymers of fatty acids and glycerol, such as trimers, tetramers, and the like. For example, in some embodiments, the surfactant in the lipid-based drug delivery system may include a polyglyceryl oleate, such as polyglyceryl-3 dioleate, commercially available under the trade name Pullulol Oleic CC497. Polyglyceryl-3 dioleate has the molecular formula: C 45 H 84 O9 or RO-(CH2-CH(OR)-CH2-O)3-R (wherein R=H), or CO-C 17 H 33 , refers to the dioleate of the homotrimer of glycerin, the major component of which has the CAS number: 9007-48-1.

[0132]

[0061] In some embodiments, the surfactant in the lipid-based drug delivery system may include a polyoxyglyceride. Useful polyoxyglycerides include, but are not limited to, esters formed from fatty acids and ethoxylated glycerol. For example, in some embodiments, the surfactant in the lipid-based drug delivery system may include macrogol glycerol hydroxystearate, such as that available under the trade name Corifol RH40. In some embodiments, the surfactant in the lipid-based drug delivery system may include oleoyl polyoxyl-6 glyceride, such as that available under the trade name Labrafil® M1944CS. Chemically, Labrafil® M1944CS is a polyoxyethylene glycol mono-, di- and triglyceride, as well as oleic acid (C 18:1 In some embodiments, the surfactant in the lipid-based drug delivery system may comprise PEG-6 (MW300) mono- and di-esters of lauroyl polyoxyl-6 glyceride, such as that available under the trade name Labrafil® 2130CS. Chemically, Labrafil® 2130CS is a mixture of mono-, di-, and triglycerides, and lauric acid (C 12) and stearic acid (C 18 ) PEG-6 (MW300) mono and diesters.

[0133]

[0062] In some embodiments, the surfactant for the lipid-based drug delivery system may include (1) macrogolglycerol hydroxystearate (e.g., Corifol RH40); and (2) polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)). When the surfactant for the lipid-based drug delivery system herein includes macrogolglycerol hydroxystearate and polyglyceryl oleate (e.g., any of the applicable embodiments described herein, such as

[12] -

[16] and

[22] -

[37] in the Summary section of this specification), the weight ratio of macrogolglycerol hydroxystearate to polyglyceryl oleate is in the range of about 5:1 to 1:5, more typically in the range of about 2:1 to about 1:2, such as about 1.5:1, about 1:1, or about 1:1.5, or any range between the values ​​described.

[0134]

[0063] In some embodiments, surfactants for lipid-based drug delivery systems may include (1) macrogolglycerol hydroxystearate (e.g., Corifol RH40); (2) polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)); and (3) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS). In such embodiments (e.g., any of the applicable embodiments described herein, e.g., paragraphs

[12] -

[16] and

[23] -

[37] in the Summary section herein), the weight ratio of macrogolglycerol hydroxystearate to polyglyceryl oleate can be in the range of about 5:1 to 1:5, more typically in the range of about 2:1 to about 1:2, such as about 1.5:1, about 1:1, or about 1:1.5, or any range between the recited values; the weight ratio of macrogolglycerol hydroxystearate to oleoyl polyoxyl-6 glyceride can also be in the range of about 5:1 to 1:5, more typically in the range of about 2:1 to about 1:2, such as about 1.5:1, about 1:1, or about 1:1.5, or any range between the recited values.

[0135]

[0064] The combination of lipid and surfactant herein is not particularly limited. For example, in some preferred embodiments, the lipid-based drug delivery system includes (a) medium chain triglycerides of caprylic acid (C8) and capric acid (C10); and (b) macrogol glycerol hydroxystearate (e.g., Corifol RH40). In some embodiments, the lipid-based drug delivery system further includes one or more lipids selected from triglycerides, monoglycerides, diglycerides, and / or propylene glycol esters. For example, in some embodiments, the lipid-based drug delivery system further includes a propylene glycol ester, such as propylene glycol monocaprylate (e.g., Capmul PG-8). In some embodiments, the lipid-based drug delivery system includes mono-, di-, and / or triglycerides, such as glycerol / glyceryl linoleate (e.g., Mycin® CC, mainly linoleic acid (C18:2 ) and oleic acid (C 18:1 ), in which the mono-, di-, and triglyceride, diester fractions of glyceryl ester (predominantly ...

[0136]

[0065] In some preferred embodiments, the lipid-based drug delivery system comprises: (a) medium chain triglycerides of caprylic acid (C8) and capric acid (C10); (b) macrogolglycerol hydroxystearate (e.g., Corifol RH40); and (c) polyglyceryl oleate (e.g., Pullulol Oleic CC497 (Polyglyceryl-3 Dioleate)). In some embodiments, the lipid-based drug delivery system further comprises one or more lipids selected from triglycerides, monoglycerides, diglycerides, and / or propylene glycol esters. For example, in some embodiments, the lipid-based drug delivery system further comprises a propylene glycol ester, such as propylene glycol monocaprylate (e.g., Capmul PG-8). In some embodiments, the lipid-based drug delivery system further comprises a mono-, di-, and / or triglyceride, such as glycerol / glyceryl linoleate (e.g., Mycin® CC, mainly linoleic acid (C 18:2 ) and oleic acid (C 18:1), in which the mono-, di-, and triglyceride, diester fractions of glycerol are predominant. In some embodiments, the lipid-based drug delivery system further comprises one or more surfactants as described herein. For example, in some embodiments, the lipid-based drug delivery system further comprises a polyoxyglyceride, such as oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS).

[0137]

[0066] In some preferred embodiments, the lipid-based drug delivery system includes (a) a medium-chain triglyceride of caprylic acid (C8) and capric acid (C10); (b) macrogolglycerol hydroxystearate (e.g., Corifol RH40); and (c) propylene glycol monocaprylate (e.g., Capmul PG-8). In some embodiments, the lipid-based drug delivery system further includes one or more surfactants as described herein. For example, in some embodiments, the lipid-based drug delivery system further includes a second polyglyceryl ester, such as polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)). In some embodiments, the lipid-based drug delivery system further includes a polyoxyglyceride, such as oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS).

[0138] In some preferred embodiments, the lipid-based drug delivery system comprises: (a) medium chain triglycerides of caprylic (C8) and capric (C10) acids; (b) macrogolglycerol hydroxystearate (e.g., Corifol RH40); and (c) glycerol / glyceryl linoleate (e.g., Mycin® CC, mainly linoleic acid (C 18:2 ) and oleic acid (C 18:1), with the mono-, di-, and triglyceride, diester fractions of glyceryl ester predominating. In some embodiments, the lipid-based drug delivery system further comprises one or more surfactants as described herein. For example, in some embodiments, the lipid-based drug delivery system further comprises a second polyglyceryl ester, such as polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)). In some embodiments, the lipid-based drug delivery system further comprises a polyoxyglyceride, such as oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS).

[0139]

[0068] In some preferred embodiments, the lipid-based drug delivery system may include (a) medium chain triglycerides of caprylic acid (C8) and capric acid (C10); (b) macrogolglycerol hydroxystearate (e.g., Corifol RH40); (c) polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)); and (d) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS).

[0140]

[0069] In some preferred embodiments, the lipid-based drug delivery system may include (a) medium chain triglycerides of caprylic acid (C8) and capric acid (C10); (b) macrogolglycerol hydroxystearate (e.g., Corifol RH40); (c) polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)); (d) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS); and (e) propylene glycol monocaprylate (e.g., Capmul PG-8). In some embodiments, the lipid-based drug delivery system may include (a) medium chain triglycerides of caprylic (C8) and capric (C10); (b) macrogolglycerol hydroxystearate (e.g., Corifol RH40); (c) polyglyceryl oleate (e.g., Pullulol Oleic CC497 (Polyglyceryl-3 Dioleate)); (d) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS); and (e) propylene glycol monolaurate (e.g., Capmul PG-12, or Lauroglycol™ 90).

[0141] In some specific embodiments, the lipid-based drug delivery system comprises: (a) medium chain triglycerides of caprylic (C8) and capric (C10) acids; (b) macrogolglycerol hydroxystearate (e.g., Corifol RH40); (c) polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)); (d) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS); and (e) glycerol / glyceryl linoleate (e.g., Mycin® CC, mainly linoleic (C 18:2 ) and oleic acid (C 18:1 ) in which the mono-, di- and triglyceride, diester fractions predominate.

[0142]

[0071] The weight percentage of the components of the lipid-based drug delivery system is not particularly limited. For example, in some embodiments, the triglyceride, monoglyceride, diglyceride, and / or propylene glycol ester may be about 10-80% by weight (e.g., about 10% by weight, 20% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70% by weight, or 80% by weight, or any range between the values ​​described), and the surfactant is about 20-90% by weight (e.g., about 20% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70% by weight, 80% by weight, or 90% by weight, or any range between the values ​​described, e.g., about 50-80% by weight or about 40-60% by weight) of the lipid-based drug delivery system.

[0143]

[0072] In some preferred embodiments, the lipid-based drug delivery system comprises: (a) medium chain triglycerides of caprylic acid (C8) and capric acid (C10) in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values, such as about 20-40% by weight or 10-30% by weight) of the lipid-based drug delivery system; and (b) macrogolglycerol hydroxystearate (e.g., Corifol RH40) in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the recited values) of the lipid-based drug delivery system. In some embodiments, the lipid-based drug delivery system further comprises one or more lipids selected from triglycerides, monoglycerides, diglycerides, and / or propylene glycol esters. For example, in some embodiments, the lipid-based drug delivery system further comprises a propylene glycol ester, such as propylene glycol monocaprylate (e.g., Capmul PG-8), in an amount of about 10-40% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system. In some embodiments, the lipid-based drug delivery system comprises mono-, di-, and / or triglycerides, such as glycerol / glyceryl linoleate (e.g., Mycin® CC, primarily linoleic acid (C ), in an amount of about 10-40% (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system. 18:2 ) and oleic acid (C 18:1), where the mono-, di-, and triglyceride, diester fractions predominate. In some embodiments, the lipid-based drug delivery system further comprises one or more surfactants as described herein. For example, in some embodiments, the lipid-based drug delivery system further comprises a second polyglyceryl ester, such as polyglyceryl oleate (e.g., pullulol oleic CC497 (polyglyceryl-3 dioleate)), in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the values ​​recited) of the lipid-based drug delivery system. In some embodiments, the lipid-based drug delivery system further comprises a polyoxyglyceride, such as oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS), in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values, such as about 20-40% by weight or 10-30% by weight) of the lipid-based drug delivery system.

[0144] In some preferred embodiments, the lipid-based drug delivery system comprises: (a) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values, such as about 20-40% by weight or 10-30% by weight) of the lipid-based drug delivery system; (b) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values, such as about 20-40% by weight or 10-30% by weight) of the lipid-based drug delivery system; , about 15%, about 20%, about 25%, about 30%, or any range between the values ​​recited); and (c) a polyglyceryl oleate (e.g., pullulol oleic CC497 (polyglyceryl-3 dioleate)) in an amount of about 10-30% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the values ​​recited) of the lipid-based drug delivery system. In some embodiments, the lipid-based drug delivery system further comprises one or more lipids selected from triglycerides, monoglycerides, diglycerides, and / or propylene glycol esters. For example, in some embodiments, the lipid-based drug delivery system further comprises a propylene glycol ester, such as propylene glycol monocaprylate (e.g., Capmul PG-8), in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system. In some embodiments, the lipid-based drug delivery system further comprises a mono-, di-, and / or triglyceride, such as glycerol / glyceryl linoleate (e.g., Mycin® CC, mainly linoleic acid (C 18:2 ) and oleic acid (C 18:1), with the mono-, di-, and triglyceride, diester fractions predominating. In some embodiments, the lipid-based drug delivery system further comprises one or more surfactants as described herein. For example, in some embodiments, the lipid-based drug delivery system further comprises a polyoxyglyceride, such as oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS), in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the values ​​recited, such as about 20-40% by weight or 10-30% by weight, etc.) of the lipid-based drug delivery system.

[0145] In some preferred embodiments, the lipid-based drug delivery system comprises: (a) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system; (b) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 35% by weight, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system; 0%, about 25%, about 30%, or any range between the values ​​recited); and (c) propylene glycol monocaprylate (e.g., Capmul PG-8) in an amount of about 10-40% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40% by weight, or any range between the values ​​recited) of the lipid-based drug delivery system. In some embodiments, the lipid-based drug delivery system further comprises one or more surfactants described herein. For example, in some embodiments, the lipid-based drug delivery system further comprises a second polyglyceryl ester, such as polyglyceryl oleate (e.g., pullulol oleic CC497 (polyglyceryl-3 dioleate)), in an amount of about 10-30% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the values ​​recited) of the lipid-based drug delivery system. In some embodiments, the lipid-based drug delivery system further comprises a polyoxyglyceride, such as oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS), in an amount of about 10-40% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the values ​​recited, such as about 20-40% or 10-30% by weight).

[0146] In some preferred embodiments, the lipid-based drug delivery system comprises: (a) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system; (b) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 35% by weight, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system; (c) macrogol glycerol hydroxystearate (e.g., Corifol RH40) in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values); and (d) glycerol / glyceryl linoleate (e.g., Mycin® CC, mainly linoleic acid (C 18:2 ) and oleic acid (C 18:1 ), with the mono-, di-, and triglyceride, diester fractions predominating. In some embodiments, the lipid-based drug delivery system further comprises one or more surfactants as described herein. For example, in some embodiments, the lipid-based drug delivery system further comprises a second polyglyceryl ester, such as polyglyceryl oleate (e.g., pullulol oleic CC497 (polyglyceryl-3 dioleate)), in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the values ​​recited) of the lipid-based drug delivery system. In some embodiments, the lipid-based drug delivery system further comprises a polyoxyglyceride, such as oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS), in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values, such as about 20-40% by weight or 10-30% by weight) of the lipid-based drug delivery system.

[0147] In some preferred embodiments, the lipid-based drug delivery system comprises: (a) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 20-40% by weight (e.g., about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system; (b) macrogol hydroxystearate glycerol (e.g., Corifol RH4) in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the recited values) of the lipid-based drug delivery system; 0); (c) polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)) in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the recited values) of the lipid-based drug delivery system; and (d) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) in an amount of about 20-40% by weight (e.g., about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system.

[0148] In some preferred embodiments, the lipid-based drug delivery system comprises: (a) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system; % by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the values ​​recited); (c) olein in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the values ​​recited); (d) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) in an amount of about 10 to 40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system; and and (e) propylene glycol monocaprylate (e.g., Capmul PG-8) and / or propylene glycol monolaurate (e.g., Capmul PG-12, or Lauroglycol™ 90) in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system.

[0149] In some preferred embodiments, the lipid-based drug delivery system comprises: (a) medium chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system; (b) macrogol glycerol hydroxystearate (e.g., Corifol RH40) in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the recited values) of the lipid-based drug delivery system; (c) macrogol glycerol hydroxystearate (e.g., Corifol RH40) in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the recited values) of the lipid-based drug delivery system; (d) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) in an amount of about 10-40% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system; and (e) propylene glycol monocaprylate (e.g., Capmul PG-8) in an amount of about 10-40% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system.

[0150] In some specific embodiments, the lipid-based drug delivery system comprises: (a) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system; (b) macrogol glycerol hydroxystearate (e.g., corifol RH40) in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the recited values) of the lipid-based drug delivery system; (c) macrogol glycerol hydroxystearate (e.g., corifol RH40) in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the recited values) of the lipid-based drug delivery system; (d) oleoyl polyoxyl 2 glyceride (e.g., Labrafil® M1944CS) in an amount of about 0-40% by weight (e.g., about 0% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the values ​​recited) of the lipid-based drug delivery system; and (e) glycerol / glyceryl linoleate (e.g., Mycin® CC, mainly linoleic acid (C 18:2 ) and oleic acid (C 18:1 ) in which the mono-, di- and triglyceride, diester fractions predominate.

[0151]

[0080] In some specific embodiments, the lipid-based drug delivery system may include any of the vehicles described in the Examples section.

[0152] In some embodiments, the lipid-based drug delivery system may have about 20% Corifol RH40, about 14% Pullol Oleic CC497, about 33% Labrafil 1944CS, and about 33% Labrafil Lipofile WL1349 by weight of the lipid-based drug delivery system, with "about" referring to within 25% of the stated value. For example, about 20% in such embodiments means 15% to 25%.

[0153]

[0082] In some embodiments, the lipid-based drug delivery system can have about 20% Corifol RH40, about 14% Pullulan Oleic CC497, and about 66% Lauroglycol 90 by weight of the lipid-based drug delivery system, where "about" refers to within 25% of the stated values.

[0154]

[0083] In some embodiments, the lipid-based drug delivery system can have about 20% by weight of Corifol RH40, about 14% by weight of Pullulol Oleic CC497, about 16% by weight of Labrafil 1944CS, about 30% by weight of Mycin CC, and about 20% by weight of Labrafil Lipofile WL1349, with "about" referring to within 25% of the stated value.

[0155]

[0084] In some embodiments, the lipid-based drug delivery system can have about 20% Corifol RH40, about 14% Pullulol Oleic CC497, about 16% Labrafil 1944CS, about 30% Capmul PG-8, and about 20% Labrafac Lipofile WL1349 by weight of the lipid-based drug delivery system, where "about" refers to within 25% of the stated value.

[0156]

[0085] When trade names are used herein, such as those specified in the various pharmacopoeias, including the USP (United States Pharmacopoeia), the European Pharmacopoeia (PhEur), the Japanese Pharmacopoeia, and the Chinese Pharmacopoeia, it should be understood to be meant to include any composition that falls within the specifications of the product associated with the trade name as of the filing date of this application, or, if a generic name for such product is available, within the specifications of such generic product as of the filing date of this application.

[0157] Abiraterone Decanoate The pharmaceutical compositions herein typically include abiraterone decanoate dispersed, e.g., homogeneously dispersed or dissolved, in a lipid-based drug delivery system herein at a concentration ranging from about 1 mg / g to about 250 mg / g, about 10 mg / g, about 20 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g, about 60 mg / g, about 70 mg / g, about 80 mg / g, about 90 mg / g, about 100 mg / g, about 120 mg / g, about 150 mg / g, about 200 mg / g, about 250 mg / g, or any range between the values ​​recited, e.g., about 10 mg / g to about 150 mg / g, about 20-150 mg / g, about 30-80 mg / g, etc. In some embodiments, abiraterone decanoate is dissolved in a lipid-based drug delivery system herein.

[0158] Abiraterone decanoate is typically present in the pharmaceutical compositions herein in its base form and should be understood as such unless otherwise clearly stated to the contrary. However, in some embodiments, the pharmaceutical compositions herein may include abiraterone decanoate in its base form, and / or a pharma- ceutically acceptable salt thereof.

[0159]

[0088] The abiraterone decanoate for the pharmaceutical compositions herein is typically in a substantially pure form as described herein. For example, the pharmaceutical compositions herein can typically be prepared by mixing substantially pure abiraterone decanoate with a lipid-based drug delivery system and optional other ingredients. In some specific embodiments, the substantially pure abiraterone decanoate is a crystalline form as described herein, preferably crystalline form A, and the pharmaceutical compositions can be prepared by mixing (e.g., dissolving, suspending, or otherwise forming a mixture) the crystalline form (e.g., form A) with a lipid-based drug delivery system and optional other ingredients.

[0160]

[0089] In some embodiments, the abiraterone decanoate for the pharmaceutical compositions herein is in a substantially pure form, e.g., having a purity of greater than 80%, preferably greater than 90% (e.g., greater than 95%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%) by weight, HPLC area, or both. In some embodiments, the abiraterone decanoate for the pharmaceutical compositions herein can be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9% by weight and / or HPLC area, or any range between the values. For example, in some embodiments, the abiraterone decanoate for the pharmaceutical compositions herein can be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9% by weight, or any range between the values. In some embodiments, the abiraterone decanoate for the pharmaceutical compositions herein can also be characterized as having a low content of palladium, for example, less than 150 ppm, less than 100 ppm, less than 50 ppm, or less than 10 ppm. In some embodiments, the abiraterone decanoate for the pharmaceutical compositions herein conforms to the specifications set forth in Table 1 herein (see Example 1B). An exemplary procedure for preparing substantially pure abiraterone decanoate is set forth in the Examples section. A suitable HPLC method for measuring the purity of abiraterone decanoate is also described in the Examples section. The substantially pure abiraterone decanoate can be in a solid form (e.g., a crystalline form described herein, preferably Form A, an amorphous form, or a combination thereof), or in a solution, suspension, or another form. For the avoidance of doubt, a pharmaceutical composition herein comprising substantially pure abiraterone decanoate and one or more other ingredients (e.g., a pharmaceutical composition according to

[33] -

[37] in the Summary section of the present specification) should be understood as a mixture of substantially pure abiraterone decanoate as described herein with one or more other ingredients; for example, such a formulation may be obtained directly or indirectly from mixing (e.g., dissolving, suspending, or otherwise forming a mixture) substantially pure abiraterone decanoate with one or more other ingredients, such as a lipid-based drug delivery system as described herein.

[0161] Substantially Pure Abiraterone Decanoate In some specific embodiments, the pharmaceutical compositions herein comprise substantially pure abiraterone decanoate, having the following formula: [ka] or a pharma- ceutically acceptable salt thereof, dispersed or dissolved in the lipid-based drug delivery system herein. In some embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate in its base form, dispersed or dissolved in the lipid-based drug delivery system. In some embodiments, the substantially pure abiraterone decanoate has a purity of at least 95%, preferably at least 98%, for example, about 98.5%, about 99%, about 99.5%, or more by weight. In some embodiments, the substantially pure abiraterone decanoate can be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any range between the values ​​given. In some embodiments, the substantially pure abiraterone decanoate can be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any range between the values ​​given. In some embodiments, the substantially pure abiraterone decanoate can also be characterized as having a low content of palladium, for example, less than 150 ppm, less than 100 ppm, less than 50 ppm, or less than 10 ppm. Abiraterone is typically synthesized in a palladium-catalyzed cross-coupling reaction step. Thus, available abiraterone generally has undesirable levels of palladium residues that may be carried over into the crude abiraterone decanoate product. As described herein, the present disclosure shows that the palladium content of abiraterone decanoate may be reduced to less than 5 ppm, particularly 3.7 ppm in Example 1B, by using a process of recrystallization with acetone and water as solvents and activated carbon. In some embodiments, the substantially pure abiraterone decanoate conforms to the specifications shown in Table 1 herein (see Example 1B). In some embodiments, the substantially pure abiraterone decanoate contains impurities derived from ethyl prasterone. For example, in some embodiments, the substantially pure abiraterone decanoate has the formula: [ka] Typically, if present, substantially pure abiraterone decanoate contains less than 2% by weight, e.g., less than 1% by weight, less than 0.5% by weight, e.g., less than 0.3% by weight, less than 0.2% by weight, or less than 0.1% by weight. The amount of ethyl prasterone decanoate can be readily determined by HPLC methods such as those described herein. In some embodiments, substantially pure abiraterone decanoate also does not contain detectable amounts of ethyl prasterone decanoate. Abiraterone starting material is readily available from commercial sources in high purity. In the cross-coupling reaction [ka] The abiraterone starting material obtained from the process of introducing a 3-pyridyl group into abiraterone using may contain small amounts of impurities that may ultimately be converted to ethyl prasterone. In some embodiments, substantially pure abiraterone decanoate is an abiraterone starting material that does not contain detectable amounts of ethyl prasterone, e.g. [ka] The substantially pure abiraterone decanoate can be prepared from a solid form, such as a crystalline form as described herein. For example, in some embodiments, the substantially pure abiraterone decanoate can be crystalline form A, characterized by an X-ray powder diffraction (XRPD) spectrum with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) of the following peaks: 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6, and 20.8, degrees 2 theta, ±0.2°; a differential scanning calorimetry (DSC) pattern with an endothermic peak with an onset temperature at about 69.0° C.; or a combination thereof. In some embodiments, crystalline form A can be characterized by an XRPD spectrum substantially the same as that shown in Figure 2A, e.g., an XRPD spectrum showing peaks at each diffraction angle (degrees 2 theta, ±0.2°) corresponding to the peaks shown in Figure 2A, regardless of their relative intensities. In some embodiments, crystalline form A can be characterized by a DSC spectrum substantially the same as that shown in Figure 2B.

[0162]

[0091] The pharmaceutical compositions herein comprising abiraterone decanoate are typically solutions or suspensions of abiraterone decanoate in a suitable vehicle as described herein. Typically, the solutions can be prepared by dissolving or suspending one or more of the solid forms of abiraterone decanoate, such as crystalline forms A, B, and / or C, in a suitable vehicle. However, in some embodiments, the pharmaceutical compositions also comprise one or more solid forms of abiraterone decanoate. For example, in some embodiments, the pharmaceutical compositions can comprise crystalline form A as described herein. In some embodiments, the pharmaceutical compositions can comprise crystalline form B as described herein. In some embodiments, the pharmaceutical compositions can comprise crystalline form C as described herein.

[0163]

[0092] In some embodiments, the pharmaceutical compositions herein can also be prepared from abiraterone decanoate comprising crystalline form A. In some embodiments, the pharmaceutical compositions herein can be prepared from crystalline form A of abiraterone decanoate, which is substantially free of abiraterone decanoate forms B and C, e.g., free of detectable amounts of forms B and C, by XRPD. In some embodiments, the pharmaceutical compositions herein can be prepared from crystalline form A of abiraterone decanoate, which is characterized as substantially pure, e.g., crystalline form A has: (1) a palladium content of less than 50 ppm, e.g., less than 10 ppm; (2) a purity of at least 95%, preferably at least 98%, e.g., about 98.5%, about 99%, about 99.5%, or more, by weight; and (3) a palladium content of at least 95% by weight, preferably at least 98%, e.g., about 98.5%, about 99%, about 99.5%, or more, by weight, of the formula: [ka] (4) having less than 1 wt. % (e.g., less than 0.5 wt. %, e.g., less than 0.3 wt. %, less than 0.2 wt. %, or less than 0.1 wt. %) ethyl prasterone decanoate; (5) conforming to the specifications set forth in Table 1, or any combination thereof.

[0164]

[0093] In some embodiments, the pharmaceutical compositions herein can also be prepared from abiraterone decanoate comprising crystalline form B. In some embodiments, crystalline form B can be crystalline form A and can be characterized by an X-ray powder diffraction (XRPD) spectrum having one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) of the following peaks: 4.4, 6.6, 14.8, 16.4, 18.1, 21.6, and 22.2, degrees 2 theta, ±0.2°; a differential scanning calorimetry (DSC) pattern having two endothermic peaks with onset temperatures at about 60.6° C. and about 64.9° C., respectively; or a combination thereof. In some embodiments, crystalline form B can be characterized by an XRPD spectrum that is substantially the same as that shown in FIG. 2D, e.g., the XRPD spectrum shows peaks at each diffraction angle (degrees 2 theta, ±0.2°) corresponding to the peaks shown in FIG. 2D, regardless of their relative intensities. In some embodiments, crystalline form B can be characterized by a DSC spectrum substantially similar to that shown in Figure 2E. Crystalline form B can typically be prepared by dissolving abiraterone decanoate in a suitable solvent, such as methanol, ethanol, ethyl acetate, dimethylacetamide (DMA), methyl tert-butyl ether, 2-propanol, or heptane, to form a solution, and cooling the solution, for example, to about -10°C to about -20°C, to form the crystalline form. An exemplary procedure is provided in Example 1C herein.

[0165]

[0094] In some embodiments, the pharmaceutical compositions herein can also be prepared from abiraterone decanoate comprising crystalline form C. In some embodiments, crystalline form C can be crystalline form A and can be characterized by an X-ray powder diffraction (XRPD) spectrum having one or more of the following peaks: 4.9, 6.3, 14.5, and 15.3, degrees 2 theta, ±0.2°; a differential scanning calorimetry (DSC) pattern having two endothermic peaks with onset temperatures at about 58.7°C and about 66.6°C, respectively; or a combination thereof. In some embodiments, crystalline form C can be characterized by an XRPD spectrum substantially the same as that shown in FIG. 2G, e.g., the XRPD spectrum exhibits peaks at each diffraction angle (degrees 2 theta, ±0.2°) corresponding to the peaks shown in FIG. 2G, regardless of their relative intensities. In some embodiments, crystalline form C can be characterized by a DSC spectrum substantially the same as that shown in FIG. 2H. Crystalline Form C can typically be prepared by dissolving abiraterone decanoate in a suitable solvent, such as a 1:1 mixture of ethanol and 2-butanone, and reducing the amount of solvent, such as by evaporation, to form the crystalline form. An exemplary procedure is provided in Example 1C herein.

[0166] Pharmaceutical Compositions Comprising Nonionic Surfactants

[0095] The pharmaceutical compositions herein typically comprise abiraterone decanoate dissolved in any of the lipid-based drug delivery systems described herein.

[0167] In some embodiments, the present disclosure also provides pharmaceutical compositions comprising abiraterone decanoate dissolved in a lipid-based drug delivery system at a concentration ranging from about 10 mg / g to about 150 mg / g (e.g., about 10 mg / g, 20 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g, about 60 mg / g, about 70 mg / g, about 80 mg / g, about 90 mg / g, about 100 mg / g, about 120 mg / g, about 150 mg / g, or any range between the recited values, e.g., about 30-80 mg / g or about 30-100 mg / g), the lipid-based drug delivery system comprising: (a) a lipid in an amount of about 10-80% by weight of the lipid-based drug delivery system; and (b) one or more non-ionic surfactants in an amount of about 20-90% by weight of the lipid-based drug delivery system, wherein the abiraterone decanoate has the following structure: [ka] has.

[0168] Typically, the weight ratio of lipid to one or more nonionic surfactants ranges from about 5:1 to 1:5, more typically from about 2:1 to about 1:2, such as about 2:1, about 1.5:1, about 1:1, about 1:1.5, about 1:2, or any range between the recited values.

[0169]

[0098] Suitable lipids are not limited to, and may include any of the triglycerides, monoglycerides, diglycerides, and / or propylene glycol esters described herein.

[0170]

[0099] Suitable nonionic surfactants are also not limited to, and can include any of those described herein.

[0171] For example, in some embodiments, the lipid may include medium chain triglycerides of caprylic acid (C8) and capric acid (C10) (e.g., Labrafac™ Lipofile WL1349). In some embodiments, the lipid may include glycerol / glyceryl linoleate (e.g., Mycin™ CC). In some embodiments, the lipid may include propylene glycol monocaprylate (e.g., Capmul PG-8). In some embodiments, the lipid may include propylene glycol monolaurate (e.g., Capmul PG-12, or Lauroglycol™ 90). In some embodiments, the lipid may include medium chain triglycerides of caprylic acid (C8) and capric acid (C10) (e.g., Labrafac™ Lipofile WL1349) and glycerol / glyceryl linoleate (e.g., Mycin™ CC). In some embodiments, the lipids may include medium chain triglycerides of caprylic acid (C8) and capric acid (C10) (e.g., Labrafac™ Lipofile WL1349) and propylene glycol monocaprylate (e.g., Capmul PG-8). Suitable amounts, ratios, or weight percentages of medium chain triglycerides of caprylic acid (C8) and capric acid (C10), glycerol / glyceryl linoleate, propylene glycol monocaprylate, and propylene glycol monolaurate include any of those described herein in any combination.

[0172] Typically, the lipid-based drug delivery system comprises two or more, for example, two or three, nonionic surfactants. For example, in some embodiments, the one or more nonionic surfactants comprise macrogolglycerol hydroxystearate (e.g., Corifol RH40) and / or polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)). In some embodiments, the one or more nonionic surfactants comprise (1) macrogolglycerol hydroxystearate (e.g., Corifol RH40); and (2) polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)). In some embodiments, the one or more nonionic surfactants include (1) macrogolglycerol hydroxystearate (e.g., Corifol RH40); (2) polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)); and (3) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS). In some embodiments, the one or more nonionic surfactants include (1) macrogolglycerol hydroxystearate (e.g., Corifol RH40); (2) polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)); and (3) lauroyl polyoxyl-6 glyceride (e.g., Labrafil 2130). Suitable amounts, ratios, or weight percentages of macrogolglycerol hydroxystearate, polyglyceryl oleate, oleoyl polyoxyl-6 glyceride, and lauroyl polyoxyl-6 glyceride include any of those described herein in any combination.

[0173] In some specific embodiments, the pharmaceutical composition comprises a lipid-based glycerol at a concentration in the range of about 20 mg / g to about 120 mg / g (e.g., about 20 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g, about 60 mg / g, about 70 mg / g, about 80 mg / g, about 90 mg / g, about 100 mg / g, about 120 mg / g, or any range between the recited values, e.g., about 30-80 mg / g or about 30-100 mg / g, etc.). The lipid-based drug delivery system may comprise: (a) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 20-40% by weight (e.g., about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system; (b) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 10-30% by weight (e.g., about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values) of the lipid-based drug delivery system; 0% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited values); (c) a polyglyceryl oleate (e.g., Pullulol Oleic CC497 (Polyglyceryl-3 Dioleate)) in an amount of about 10-30% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited values) of the lipid-based drug delivery system; and (d) an oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) in an amount of about 20-40% by weight (e.g., about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited values) of the lipid-based drug delivery system.

[0174]

[0103] In some specific embodiments, the pharmaceutical composition may comprise abiraterone decanoate dissolved in a lipid-based drug delivery system at a concentration in the range of about 20 mg / g to about 120 mg / g (e.g., about 20 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g, about 60 mg / g, about 70 mg / g, about 80 mg / g, about 90 mg / g, about 100 mg / g, about 120 mg / g, or any range between the recited values, e.g., about 30-80 mg / g or about 30-100 mg / g), wherein the lipid-based drug delivery system is (a) a lipid-based drug delivery system; (b) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values, such as about 20-40% by weight or 10-30% by weight) of the lipid-based drug delivery system; (c) polyglyceryl oleate (e.g., pullulol oleate CC497 (polyglyceryl-3 dioleate)) in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the values ​​recited) of the lipid-based drug delivery system; (d) polyglyceryl oleate (e.g., pullulol oleate CC497 (polyglyceryl-3 dioleate)) in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the values ​​recited) of the lipid-based drug delivery system. and (e) propylene glycol monocaprylate (e.g., Capmul PG-8) in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the values ​​recited, such as about 20-40% by weight or 10-30% by weight) of the lipid-based drug delivery system.

[0175] In some specific embodiments, the pharmaceutical composition comprises decaacetate dissolved in a lipid-based drug delivery system at a concentration in the range of about 20 mg / g to about 120 mg / g (e.g., about 20 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g, about 60 mg / g, about 70 mg / g, about 80 mg / g, about 90 mg / g, about 100 mg / g, about 120 mg / g, or any range between the recited values, e.g., about 30-80 mg / g or about 30-100 mg / g, etc.). The lipid-based drug delivery system may comprise: (a) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values, such as about 20-40% by weight or 10-30% by weight) of the lipid-based drug delivery system; (c) macrogolglycerol hydroxystearate (e.g., Corifol RH40) in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the values ​​recited); (d) polyglyceryl oleate (e.g., Corifol RH40) in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the values ​​recited); For example, Pullulol Oleic CC497 (polyglyceryl-3 dioleate); (d) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values, such as about 20-40% by weight or 10-30% by weight) of the lipid-based drug delivery system;and (e) propylene glycol monolaurate (e.g., Capmul PG-12, or Lauroglycol™ 90) in an amount of about 10-40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited values, such as about 20-40% or 10-30% by weight) of the lipid-based drug delivery system;

[0176] In some specific embodiments, the pharmaceutical composition comprises decanediol dissolved in a lipid-based drug delivery system at a concentration in the range of about 20 mg / g to about 120 mg / g (e.g., about 20 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g, about 60 mg / g, about 70 mg / g, about 80 mg / g, about 90 mg / g, about 100 mg / g, about 120 mg / g, or any range between the recited values, e.g., about 30-80 mg / g or about 30-100 mg / g). The lipid-based drug delivery system may comprise: (a) medium chain triglycerides of caprylic (C8) and capric (C10) in an amount of about 10-40% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values, such as about 20-40% by weight or 10-30% by weight) of the lipid-based drug delivery system; (c) a macrogolglycerol hydroxystearate (e.g., Corifol RH40) in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the values ​​recited); (d) a polyglyceryl oleate (e.g., Corifol RH40) in an amount of about 10-30% by weight (e.g., about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, or any range between the values ​​recited); , Pullulol Oleic CC497 (Polyglyceryl-3 Dioleate); (d) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) in an amount of about 0-40% by weight (e.g., 0% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or any range between the recited values, such as about 20-40% by weight or 10-30% by weight) of the lipid-based drug delivery system;and (e) glycerol / glyceryl linoleate (e.g., Mycin® CC, primarily linoleic acid (C; 18:2 ) and oleic acid (C 18:1 ) containing predominantly mono-, di- and triglyceride and diester fractions.

[0177]

[0106] In some specific embodiments, the pharmaceutical composition may include abiraterone decanoate dissolved in a vehicle described in any of the Examples herein, see, e.g., Examples 2 and 3.

[0178]

[0107] In some embodiments, the pharmaceutical composition can include abiraterone decanoate dissolved in a lipid-based drug delivery system having about 20% by weight of Corifol RH40, about 14% by weight of Pullol Oleic CC497, about 33% by weight of Labrafil 1944CS, and about 33% by weight of Labrafac Lipofile WL1349, where "about" refers to within 25% of the stated value. Abiraterone decanoate is typically dissolved at a concentration ranging from about 20 mg / g to about 120 mg / g (e.g., about 20 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g, about 60 mg / g, about 70 mg / g, about 80 mg / g, about 90 mg / g, about 100 mg / g, about 120 mg / g, or any range between the recited values, e.g., about 30-80 mg / g or about 30-100 mg / g, etc.) of abiraterone decanoate in the lipid-based drug delivery system, up to maximum solubility.

[0179]

[0108] In some embodiments, the pharmaceutical composition can include abiraterone decanoate dissolved in a lipid-based drug delivery system having about 20% by weight of Corifol RH40, about 14% by weight of Pullulol Oleic CC497, and about 66% by weight of Lauroglycol 90, where "about" refers to within 25% of the stated value. Abiraterone decanoate is typically dissolved at a concentration ranging from about 20 mg / g to about 120 mg / g (e.g., about 20 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g, about 60 mg / g, about 70 mg / g, about 80 mg / g, about 90 mg / g, about 100 mg / g, about 120 mg / g, or any range between the recited values, e.g., about 30-80 mg / g or about 30-100 mg / g, etc.) of abiraterone decanoate in the lipid-based drug delivery system, up to maximum solubility.

[0180]

[0109] In some embodiments, the pharmaceutical composition can include abiraterone decanoate dissolved in a lipid-based drug delivery system having about 20% by weight of Corifol RH40, about 14% by weight of Pullol Oleic CC497, about 16% by weight of Labrafil 1944CS, about 30% by weight of Mycin CC, and about 20% by weight of Labrafil Lipofile WL1349, where "about" refers to within 25% of the stated value. Abiraterone decanoate is typically dissolved at a concentration ranging from about 20 mg / g to about 120 mg / g (e.g., about 20 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g, about 60 mg / g, about 70 mg / g, about 80 mg / g, about 90 mg / g, about 100 mg / g, about 120 mg / g, or any range between the recited values, e.g., about 30-80 mg / g or about 30-100 mg / g, etc.) of abiraterone decanoate in the lipid-based drug delivery system, up to maximum solubility.

[0181]

[0110] In some embodiments, the pharmaceutical composition can include abiraterone decanoate dissolved in a lipid-based drug delivery system having about 20% by weight of Corifol RH40, about 14% by weight of Pullulol Oleic CC497, about 16% by weight of Labrafil 1944CS, about 30% by weight of Capmul PG-8, and about 20% by weight of Labrafac Lipofile WL1349, where "about" refers to within 25% of the stated value. Abiraterone decanoate is typically dissolved at a concentration ranging from about 20 mg / g to about 120 mg / g (e.g., about 20 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g, about 60 mg / g, about 70 mg / g, about 80 mg / g, about 90 mg / g, about 100 mg / g, about 120 mg / g, or any range between the recited values, e.g., about 30-80 mg / g or about 30-100 mg / g, etc.) of abiraterone decanoate in the lipid-based drug delivery system, up to maximum solubility.

[0182]

[0111] The pharmaceutical compositions may be typically formulated for oral administration, such as in the form of a capsule (eg, a softgel capsule).

[0183]

[0112] In any of the embodiments described herein, unless otherwise specified or otherwise stated to the contrary, the pharmaceutical compositions herein are also characterized by one or more of the following: (1) the pharmaceutical composition is stable for storage at room temperature; (2) the recovery of abiraterone decanoate is greater than 50% when the pharmaceutical composition is assessed using an in vitro dispersion test (e.g., 55%, 60%, 70%, 80%, 90%, or up to 100%, or any range between the recited values); and (3) when orally administered to a mammal, the pharmaceutical composition is capable of delivering a sufficient amount of abiraterone decanoate to the mammal to achieve a therapeutically effective plasma concentration of abiraterone to treat a disease or disorder described herein, such as prostate cancer, as described herein. For example, in some embodiments, the pharmaceutical composition is stable for storage at room temperature for, for example, one month, three months, six months, or longer. In some embodiments, the pharmaceutical composition comprises a solution at room temperature, and the solution may remain a solution, i.e., does not form visible drug and / or excipient crystals / precipitation, after storage at room temperature for 1 month, 3 months, 6 months, or longer. In some embodiments, the pharmaceutical composition is characterized by a recovery of abiraterone decanoate of greater than 50% (e.g., 55%, 60%, 70%, 80%, 90%, or up to 100%, or any range between the recited values) when the pharmaceutical composition is assessed using an in vitro dispersion test. In some embodiments, the pharmaceutical composition is characterized by, when orally administered to a mammal, the pharmaceutical composition is capable of delivering abiraterone decanoate to the mammal in an amount sufficient to achieve a therapeutically effective plasma concentration of abiraterone, e.g., for treating a disease or disorder described herein, such as prostate cancer, as described herein. In some embodiments, the pharmaceutical composition is characterized by, when orally administered to a mammal, the pharmaceutical composition is capable of delivering abiraterone decanoate to the mammal in an amount sufficient to achieve an effective plasma concentration of abiraterone, e.g., for inhibiting CYP17A1.

[0184]

[0113] In any of the embodiments described herein, unless specified or otherwise to the contrary, the pharmaceutical composition may also be characterized by an oral bioavailability of greater than 30%, e.g., up to 60%, 70% or more, based on the abiraterone plasma concentration profile when tested in rats.

[0185]

[0114] In any of the embodiments described herein, unless specified or otherwise to the contrary, the pharmaceutical composition may be a self-dispersing drug delivery system, such as a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system.

[0186]

[0115] In any of the embodiments described herein, unless specified or otherwise to the contrary, the pharmaceutical composition may be characterized in that, upon oral administration to a mammal, at least a portion of the abiraterone decanoate is absorbed through the lymphatic system.

[0187] Methods for preparing pharmaceutical compositions

[0116] In some embodiments, the present disclosure also provides a method of preparing a pharmaceutical composition comprising abiraterone decanoate and a lipid-based drug delivery system described herein (e.g., any of the applicable embodiments described herein, e.g., [1]-

[37] in the Summary section of the present specification). The method typically includes a step of mixing, e.g., dissolving, abiraterone decanoate (e.g., any of the substantially pure abiraterone decanoate described herein, a crystalline form of abiraterone decanoate, e.g., Form A, B, or C) with a lipid-based drug delivery system (e.g., any of those described herein). The particular sequence of mixing is typically not critical. For example, although not prohibited, it is not necessary to first prepare the lipid-based drug delivery system prior to mixing with abiraterone decanoate. In some embodiments, abiraterone decanoate can be mixed, e.g., dissolved, with one or more components of the lipid-based drug delivery system prior to mixing with other components of the lipid-based drug delivery system. The amounts of abiraterone decanoate and lipid-based drug delivery system include any of those described herein.

[0188] Emulsions

[0117] In some embodiments, the present disclosure also provides an emulsion comprising abiraterone decanoate. In some embodiments, the emulsion may also be considered a pharmaceutical composition as described herein and may be orally administered to a subject in need thereof.

[0189] In some embodiments, the emulsion may comprise: (a) abiraterone decanoate; (b) a lipid; and (c) a non-ionic surfactant, wherein the lipid phase of the emulsion comprises abiraterone decanoate dispersed in a lipid, the abiraterone decanoate having the following structure: [ka] has.

[0190] Typically, the weight ratio of lipid to nonionic surfactant ranges from about 5:1 to 1:5, more typically from about 2:1 to about 1:2, such as about 2:1, about 1.5:1, about 1:1, about 1:1.5, about 1:2, or any range between the recited values.

[0191]

[0120] Suitable lipids are not limited to, and may include any of the triglycerides, monoglycerides, diglycerides, and / or propylene glycol esters described herein.

[0192]

[0121] Suitable nonionic surfactants are also not particularly limited and can include any of those described herein.

[0193] For example, in some embodiments, the lipid may include medium chain triglycerides of caprylic acid (C8) and capric acid (C10) (e.g., Labrafac™ Lipofile WL1349). In some embodiments, the lipid may include glycerol / glyceryl linoleate (e.g., Mycin™ CC). In some embodiments, the lipid may include propylene glycol monocaprylate (e.g., Capmul PG-8). In some embodiments, the lipid may include propylene glycol monolaurate (e.g., Capmul PG-12, or Lauroglycol™ 90). In some embodiments, the lipid may include medium chain triglycerides of caprylic acid (C8) and capric acid (C10) (e.g., Labrafac™ Lipofile WL1349) and glycerol / glyceryl linoleate (e.g., Mycin™ CC). In some embodiments, the lipids may include medium chain triglycerides of caprylic acid (C8) and capric acid (C10) (e.g., Labrafac™ Lipofile WL1349) and propylene glycol monocaprylate (e.g., Capmul PG-8). Suitable amounts, ratios, or weight percentages of medium chain triglycerides of caprylic acid (C8) and capric acid (C10), glycerol / glyceryl linoleate, propylene glycol monocaprylate, and propylene glycol monolaurate include any of those described herein in any combination.

[0194] Typically, the emulsion comprises two or more, for example, two or three, nonionic surfactants. For example, in some embodiments, the nonionic surfactant comprises macrogolglycerol hydroxystearate (e.g., Corifol RH40) and / or polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)). In some embodiments, the nonionic surfactant comprises (1) macrogolglycerol hydroxystearate (e.g., Corifol RH40); and (2) polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)). In some embodiments, the nonionic surfactant includes (1) macrogolglycerol hydroxystearate (e.g., Corifol RH40); (2) polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)); and (3) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS). In some embodiments, the nonionic surfactant includes (1) macrogolglycerol hydroxystearate (e.g., Corifol RH40); (2) polyglyceryl oleate (e.g., Pullulol Oleic CC497 (polyglyceryl-3 dioleate)); and (3) lauroyl polyoxyl-6 glyceride (e.g., Labrafil 2130). Suitable amounts, ratios, or weight percentages of macrogolglycerol hydroxystearate, polyglyceryl oleate, oleoyl polyoxyl-6 glyceride, and lauroyl polyoxyl-6 glyceride include any of those described herein in any combination.

[0195]

[0124] In some embodiments, the present disclosure also provides an emulsion produced by mixing a pharmaceutical composition comprising abiraterone decanoate and a lipid-based drug delivery system herein (e.g., any of those described herein, e.g., [1]-

[37] in the Summary section of the present specification) with water.

[0196]

[0125] In some embodiments, the present disclosure also provides an emulsion produced by administering to a mammal a pharmaceutical composition comprising abiraterone decanoate and a lipid-based drug delivery system herein (e.g., any of those described herein, e.g., [1]-

[37] in the Summary section of the present specification).

[0197] Pharmaceutical Compositions Comprising Abiraterone Prodrugs

[0126] While many of the embodiments herein are directed specifically to abiraterone decanoate, the present disclosure also contemplates oral formulations of abiraterone prodrugs (including abiraterone decanoate) in the lipid-based drug delivery systems herein. For example, in some embodiments, the oral abiraterone prodrug formulation may include an abiraterone lipophilic ester, such as an acetate, propionate, butanoate, (valerate)pentanoate, isocaproate, buciclate, cyclohexanecarboxylate, phenyl propionate, caproate (hexanoate), enanthate (heptanoate), cypionate, octanoate, nonanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tridecanoate, pentadecanoate, or hexadecanoate ester of abiraterone in the lipid-based drug delivery systems herein.

[0198]

[0127] Other suitable abiraterone prodrugs include any of those described in U.S. Patent No. 10,792,292 B2 and U.S. Provisional Patent Applications Nos. 63 / 073,502 and 63 / 149,550, the contents of each of which are incorporated herein by reference in their entirety.

[0199] For example, in some embodiments, the pharmaceutical composition comprises an abiraterone prodrug of formula I: [ka] (In the formula, R1 is R 10 , OR 10 , or NHR 10 and R 10 is C 7~30 Alkyl;C 7~30 Alkenyl; C 7~30 Alkynyl; alkyl substituted with cycloalkyl, typically having a total number of carbons from 5 to 16; alkyl substituted with phenyl, typically having a total number of carbons from 7 to 16; cycloalkyl optionally substituted with one or more alkyl, typically having a total number of carbons from 5 to 16; and [ka] (selected from branched C5 or C6 alkyl such as or a pharma- ceutically acceptable salt thereof.

[0200] In some embodiments, R 10 is C 7~30 As used herein, alkyl is to be understood as unsubstituted unless expressly stated as substituted. However, alkyl can be either straight or branched chain. In some embodiments, R 10 is a linear C 7~30 In some embodiments, R 10 is a branched chain C 7~30 In some embodiments, R 10 is a linear C 7~16 alkyl, e.g., R 10 is the formula -(CH2) n In some embodiments, R 10 is a branched chain C 7~16 It may be alkyl.

[0201] In some embodiments, R 10 can also be an alkyl substituted with a cycloalkyl. Typically in such embodiments, R10 has a total number of carbons from 5 to 16, i.e., the total number of carbons from the alkyl and cycloalkyl portions is 5 to 16. Cycloalkyls are typically unsubstituted. However, in some embodiments, cycloalkyls are optionally substituted with, for example, one or two lower alkyls (e.g., C 1~4 In some embodiments, R 10 is C 3~6 It may be an alkyl substituted with a cycloalkyl, typically having a total number of carbons from 6 to 12. In some embodiments, R 10 is C 3~6 It may be a linear alkyl substituted with a cycloalkyl, for example, R 10 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is C 3~6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, R 10 is the formula -(CH2) n -Cy, n is 1 or 2, and Cy is cyclopentyl or cyclohexyl. 10 Also, C 3~6 Cycloalkyl-substituted branched alkyl (e.g., branched C 2~6 As used herein, a branched C2 alkyl group is to be understood as a 1,1-disubstituted ethyl group, for example, -CH(CH3)-Cy.

[0202] In some embodiments, R 10 can also be an alkyl substituted with a phenyl. Typically, in such embodiments, R 10 has a total number of carbons from 7 to 16, i.e., the total number of carbons from the alkyl and phenyl portions is 5 to 16. 10 can be a linear alkyl substituted with phenyl, e.g., R 10 is the formula -(CH2) n-Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is phenyl. 10 is the formula -(CH2) n -Cy, n is 1 or 2, and Cy is phenyl. 10 Also includes branched alkyl substituted with phenyl (e.g., branched C 2~6 ). Phenyl is typically unsubstituted. However, in some embodiments, phenyl can be substituted with, for example, one or two lower alkyl (e.g., C 1~4 It may be optionally substituted with alkyl.

[0203] In some embodiments, R 10 can be cycloalkyl optionally substituted with one or more alkyl. In such embodiments, R 10 Typically has a total number of carbons from 5 to 16, i.e., the total number of carbons in the cycloalkyl and its optional substituents is 5 to 16. In some embodiments, R 10 is unsubstituted or C 1~4 C either substituted with alkyl 3~6 In some specific embodiments, R 10 teeth, [ka] It could be.

[0204] In some embodiments, R 10 may be a branched C5 or C6 alkyl. In some embodiments, R 10 teeth, [ka] Other branched chain C5 or C6 alkyls are also suitable.

[0205] In some embodiments, R 10 is C 7~30Alkenyl or C 7~30 It may be an unsaturated aliphatic group such as alkynyl.

[0206] In some embodiments, the compound of formula I is an ester of abiraterone, e.g., R 1 is R 10 and R 10 is defined herein. In some embodiments, R of formula I 1 is C 7~16 Alkyl, e.g., -(CH2) n In some embodiments, R of formula I may be an alkyl having a formula of —CH3, where n is an integer from 6 to 12 (e.g., 6, 7, 8, 9, 10, 11, or 12). 1 is the formula -(CH2) n -Cy, n is an integer from 1 to 6, and Cy is C 3~6 For example, in more specific embodiments, n can be 1 or 2 and Cy is cyclopentyl, cyclohexyl, or phenyl. 1 teeth, [ka] In some specific embodiments, R of formula I can be 1 teeth, [ka] It can be. R 1 Other suitable groups for R are as defined herein. 10 Includes any of the following.

[0207] In some embodiments, R of formula I 1 Also, OR 10 or NHR 10 R 10 is defined herein.

[0208]

[0137] In some embodiments, a pharmaceutical composition can include a compound of formula II, or a pharma- ceutically acceptable salt thereof. [ka] (In the formula, R 2 is defined herein)

[0209] In some embodiments, R 2 can be selected such that the compound of formula II is an ester, a carbamate, or a carbamate of abiraterone. 2 is R 20 , OR 20 , or NHR 20 and R 20 is C 1~30 Alkyl;C 2~30 Alkenyl; C 2~30 Selected from alkynyl; alkyl substituted with cycloalkyl, typically having a total number of 4 to 30 carbons; alkyl substituted with phenyl, typically having a total number of 7 to 30 carbons; and cycloalkyl optionally substituted with one or more alkyl, typically having a total number of 3 to 30 carbons.

[0210] In some embodiments, R 20 is C 1~16 In some embodiments, R 20 is a linear C 1~16 In some embodiments, R 20 is a branched chain C 3~16 In some embodiments, R 20 may be a branched C5 or C6 alkyl. In some embodiments, R 20 teeth, [ka] In some embodiments, R 20 is the formula -(CH2) n -CH3, where n is an integer from 0 to 12 (e.g., 6 to 12, such as 6, 7, 8, 9, 10, 11, or 12).

[0211] In some embodiments, R 20 can also be an alkyl substituted with a cycloalkyl. Typically in such embodiments, R 20 has a total number of carbons from 4 to 30, e.g., 5 to 16 (i.e., the total number of carbons from the alkyl and cycloalkyl portions is 5 to 16). Cycloalkyls are typically unsubstituted. However, in some embodiments, cycloalkyls can have, for example, one or two lower alkyls (e.g., C 1~4 In some embodiments, R 20 is C 3~6 It may be an alkyl substituted with a cycloalkyl, typically having a total number of carbons from 6 to 12. In some embodiments, R 20 is C 3~6 It may be a linear alkyl substituted with a cycloalkyl, for example, R 20 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is C 3~6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, R 20 is the formula -(CH2) n -Cy, n is 1 or 2, and Cy is cyclopentyl or cyclohexyl. 20 Also, C 3~6 Cycloalkyl-substituted branched alkyl (e.g., branched C 2~6 ).

[0212] In some embodiments, R 20 can also be an alkyl substituted with a phenyl. Typically, in such embodiments, R 20 has a total number of carbons from 7 to 30, for example 7 to 16 (i.e., the total number of carbons from the alkyl and phenyl portions is 7 to 16). 20 can be a linear alkyl substituted with phenyl, e.g., R 20 is the formula -(CH2) n-Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is phenyl. 20 is the formula -(CH2) n -Cy, n is 1 or 2, and Cy is phenyl. 20 Also includes branched alkyl substituted with phenyl (e.g., branched C 2~6 ). Phenyl is typically unsubstituted. However, in some embodiments, phenyl can be substituted with, for example, one or two lower alkyl (e.g., C 1~4 It may be optionally substituted with alkyl.

[0213] In some embodiments, R 20 can be cycloalkyl optionally substituted with one or more alkyl. In such embodiments, R 20 Typically has a total number of carbons from 3 to 30, e.g., from 5 to 16 (i.e., the total number of carbons in the cycloalkyl and its optional substituents is 5 to 16). 20 is unsubstituted or C 1~4 C either substituted with alkyl 3~6 In some specific embodiments, R 20 teeth, [ka] It could be.

[0214] In some embodiments, R 20 is C 2~30 Alkenyl or C 2~30 It may be an unsaturated aliphatic group such as alkynyl.

[0215] In some preferred embodiments, the compound of formula II is an abiraterone ester, e.g., R 2 is R 20 and R 20 is defined herein. In some embodiments, R of formula II 2 is C1~16 Alkyl, e.g., -(CH2) n In some embodiments, R of Formula II can be an alkyl having a formula of —CH3, where n is an integer from 0 to 12. 2 is the formula -(CH2) n -Cy, n is an integer from 1 to 6, and Cy is C 3~6 For example, in more specific embodiments, n can be 1 or 2 and Cy is cyclopentyl, cyclohexyl, or phenyl. In some specific embodiments, R of formula II is 2 teeth, [ka] It can be. R 2 Other suitable groups for R are as defined herein. 20 In some embodiments, the abiraterone ester can be the acetate, propionate, butanoate, (valerate)pentanoate, isocaproate, bucyclate, cyclohexanecarboxylate, phenyl propionate, caproate (hexanoate), enanthate (heptanoate), cypionate, octanoate, nonanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tridecanoate, pentadecanoate, or hexadecanoate ester of abiraterone. In some embodiments, the abiraterone ester can be abiraterone acetate, abiraterone propionate, and abiraterone decanoate. In some specific embodiments, the abiraterone ester can be abiraterone pentanoate, abiraterone hexanoate, abiraterone heptanoate, abiraterone decanoate, abiraterone isocaproate, or abiraterone cypionate.

[0216] In some embodiments, R of formula II 2 Also, OR 20 or NHR 20 R 20 is defined herein.

[0217] Typically, the compound of formula I or II may be present in the formulation in base form. However, in some embodiments, pharma- ceutically acceptable salts of the compound of formula I or II are also useful. Unless specifically stated as a salt form or otherwise stated to the contrary, the compound of formula I or II may be in its base form in the pharmaceutical compositions described herein. In some embodiments, the compound of formula I or II may be in substantially pure form.

[0218] Treatment Method

[0147] In some embodiments, the present disclosure provides a method of treating a disease or disorder described herein in a subject in need thereof. The method typically comprises orally administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein (e.g., any of those described herein, e.g., [1]-

[37] in the Summary section herein) or an emulsion described herein (e.g., any of those described herein, e.g.,

[82] -

[90] in the Summary section herein). Typically, the oral administration delivers to the subject an amount of abiraterone decanoate sufficient to achieve effective inhibition of CYP17A1 and / or modulation of various steroid hormone levels in the subject, such as androgens, estrogens, glucocorticoids, progesterone, and mineralocorticoids.

[0219]

[0148] U.S. Patent No. 10,792,292 B2 and U.S. Provisional Patent Applications Nos. 63 / 073,502 and 63 / 149,550 demonstrate various advantages of parenteral administration of abiraterone prodrugs, such as abiraterone decanoate, including sustained inhibition of CYP17A1, sustained PD effects, such as elevated progesterone levels, and reduced cortisol, dihydrotestosterone and testosterone levels for up to 70 days or longer, reduced testosterone within a few days following the first administration of another drug, a prodrug that does not require castration or is effective in reducing testosterone levels and is generally well tolerated, e.g., without the liver toxicity observed from intramuscular administration of abiraterone decanoate at the doses tested. As detailed in the applicant's prior applications, without wishing to be bound by theory, the sustained PD effects observed may be due in part to loose and tight binding of CYP17A1 by abiraterone, effectively achieving irreversible inhibition of CYP17A1, see, e.g., Cheong EJY et al., J. Pharmacol. Exp. Ther. 374: 438-451 (2020). Also, without wishing to be bound by theory, it was believed that intramuscular administration of abiraterone prodrugs results in both sustained and effective plasma levels of abiraterone as well as favorable tissue distribution of abiraterone and abiraterone prodrugs, for example to the testes, which may contribute to the observed effects on serum steroids not achieved by oral abiraterone acetate formulations (e.g., Zytiga®).

[0220] As shown in the Examples section herein, oral administration of an exemplary lipid-based formulation of abiraterone decanoate similarly achieved inhibition of CYP17A1 as evidenced by increased progesterone levels and decreased testosterone levels for at least 24 hours or longer. It is believed that oral administration, even as a different dosing regimen, may achieve similar pharmacodynamic effects as observed with the prior intramuscular administration of the present application. It is also believed that since the methods herein do not rely on castration to achieve desired testosterone levels, they may be advantageously used to at least treat subjects who do not wish to be castrated and / or who are sensitive to or otherwise intolerant to drugs that suppress gonadal testosterone. It is further believed that oral administration of abiraterone decanoate is generally well tolerated and may be used to treat subjects suffering from hepatic impairment, such as moderate to severe hepatic impairment (Child-Pugh class B or C), prior to administration of an abiraterone prodrug.

[0221]

[0150] Thus, in some embodiments, the oral formulations herein can be advantageously used to inhibit CYP17A1 activity, to reduce glucocorticoid levels, e.g., cortisol levels, to reduce sex hormone levels, e.g., androgen and / or estrogen levels, and / or to treat disorders associated with high glucocorticoid levels, e.g., cortisol levels, and / or to treat disorders resulting from high sex hormone levels, e.g., androgen and / or estrogen levels.

[0222]

[0151] Thus, in some embodiments, the disclosure provides a method of treating a disease or disorder described herein in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition described herein (e.g., any of those described herein, e.g., [1]-

[37] in the Summary section). In some embodiments, the disclosure provides a method of treating a disease or disorder described herein in a subject in need thereof, comprising administering to the subject an effective amount of an emulsion described herein (e.g., any of those described herein, e.g.,

[82] -

[90] in the Summary section).

[0223]

[0152] Various diseases or disorders are suitable for treatment by the methods herein. For example, in some embodiments, the disease or disorder may be selected from sex hormone-dependent benign or malignant disorders, androgen receptor-induced cancers, syndromes caused by androgen excess, and syndromes caused by glucocorticoid excess, such as prostate cancer, breast cancer, endometrial cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, lung cancer, endometriosis, polycystic ovary syndrome, Cushing's syndrome, Cushing's disease, classical or non-classical congenital adrenal hyperplasia, precocious puberty, hirsutism, and combinations thereof.

[0224]

[0153] In some embodiments, the hormone-dependent benign or malignant disorder may be an androgen-dependent disorder and / or an estrogen-dependent disorder, such as an androgen- or estrogen-dependent cancer. In some embodiments, the sex hormone-dependent benign or malignant disorder may be prostate cancer or breast cancer. In some embodiments, the sex hormone-dependent benign or malignant disorder is CRPC or CSPC. In some embodiments, the sex hormone-dependent benign or malignant disorder may be metastatic CRPC or metastatic CSPC. In some embodiments, the sex hormone-dependent benign or malignant disorder may also be endometrial cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, or lung cancer.

[0225]

[0154] Various non-neoplastic syndromes resulting from androgen excess and / or glucocorticoid excess, e.g., hypercortisolism, e.g., syndromes resulting from androgen excess, e.g., endometriosis, polycystic ovary syndrome, classical or nonclassical congenital adrenal hyperplasia, precocious puberty, hirsutism, etc., and / or syndromes resulting from cortisol excess, e.g., Cushing's syndrome, Cushing's disease, etc., can also be treated by the methods herein.

[0226]

[0155] In some specific embodiments, the methods herein are for treating sex hormone dependent or androgen receptor driven cancers.

[0227]

[0156] In some embodiments, the sex hormone dependent or androgen receptor driven cancer may be androgen receptor positive salivary duct carcinoma or androgen receptor positive glioblastoma multiforme.

[0228] In some embodiments, the sex hormone-dependent or androgen receptor-induced cancer is prostate cancer (e.g., any of those described herein). Prostate cancers suitable for treatment with the methods herein are not particularly limited, and include, but are not limited to, any of the prostate cancers for which abiraterone or a derivative thereof (particularly abiraterone acetate) has been approved for commercial sale (e.g., in the United States or Europe) or for which abiraterone or a derivative thereof (e.g., abiraterone acetate) is in or has been in a clinical trial, e.g., a trial registered on the website clinicaltrials.gov, as of the filing date of this application. For example, in some embodiments, the prostate cancer may be primary / localized prostate cancer (newly diagnosed or early stage), advanced prostate cancer (e.g., after castration for recurrent prostate cancer, locally advanced prostate cancer, etc.), recurrent prostate cancer (e.g., prostate cancer that has not responded to primary therapy), non-metastatic castration-resistant prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer (CRPC), or hormone-sensitive prostate cancer. In some embodiments, the prostate cancer is localized prostate cancer, e.g., high-risk localized prostate cancer. In some embodiments, the subject with prostate cancer is characterized as having an elevated amount of prostate-specific antigen, e.g., following radical prostatectomy. In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer, non-metastatic castration-resistant prostate cancer, or metastatic castration-resistant prostate cancer. In some embodiments, the prostate cancer is newly diagnosed high-risk metastatic hormone-sensitive prostate cancer. In some embodiments, the prostate cancer is metastatic CRPC (mCRPC), the subject is asymptomatic or mildly symptomatic after failure of androgen deprivation therapy, and chemotherapy is not yet clinically indicated in the subject. In some embodiments, the prostate cancer is metastatic CRPC (mCRPC), and the subject's disease is progressing in or after a taxane-based chemotherapy regimen, e.g., a docetaxel-based or cabazitaxel-based chemotherapy regimen. In some embodiments, the prostate cancer is refractory prostate cancer.As used herein, unless otherwise specified, the phrase "refractory prostate cancer" refers to prostate cancer that has not responded to anti-cancer treatment or that has not responded adequately to anti-cancer treatment. Refractory prostate cancer also includes recurrent or relapsing prostate cancer. As used herein, unless otherwise specified, the phrase "relapsing prostate cancer" refers to prostate cancer that once responded to anti-cancer treatment but no longer responds to such treatment or no longer responds adequately to such treatment. As used herein, unless otherwise specified, the phrase "recurrent (or recurrent) prostate cancer" refers to prostate cancer that has recurred after a patient was diagnosed with prostate cancer early and treated, or was previously diagnosed as cancer-free.

[0229]

[0158] In some embodiments, the methods herein can also be used to treat breast cancer. Suitable breast cancers to be treated by the methods herein are not particularly limited. For example, in some embodiments, breast cancer can be molecular apocrine HER2-negative breast cancer, metastatic breast cancer, such as ER+ metastatic breast cancer, ER+ and HER2-negative breast cancer, AR+ triple-negative breast cancer, etc.

[0230]

[0159] In some embodiments, the disease or disorder is associated with 21-hydroxylase deficiency and can also be treated by the methods herein.

[0231]

[0160] In some embodiments, the methods herein can be used to treat a subject having cancer, such as prostate cancer, breast cancer, adrenal cancer, leukemia, lymphoma, myeloma, Waldenstrom's macroglobulinemia, monoclonal gammopathy, benign monoclonal gammopathy, heavy chain disease, bone and connective tissue sarcoma, brain tumor, thyroid cancer, pancreatic cancer, pituitary cancer, eye cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, bile duct cancer, lung cancer, testicular cancer, penile cancer, oral cancer, skin cancer, kidney cancer, Wilms' tumor, and bladder cancer.

[0232]

[0161] In some embodiments, the methods herein may include treating the subject with one or more additional therapies. For example, in some embodiments, the subject is further treated with radiation therapy. In some embodiments, the methods are for treating prostate cancer and include combination therapy, which further includes administering to the subject one or more additional therapies, for example, as described herein below in the section entitled Combination Treatments for Prostate Cancer. Non-limiting examples of useful additional therapies also include any of those described in the Summary section of this specification at

[50] -

[54] and

[61] -

[71] ,

[73] -

[75] , and

[77] .

[0233]

[0162] Subjects suitable for treatment with the methods herein are not particularly limited and include subjects at various stages and other characteristics of disease or treatment. For example, in some embodiments, the subject may be a non-castrated subject. In some embodiments, the subject may be a castrated subject. In some embodiments, the methods herein also allow for administering a pharmaceutical composition herein (e.g., any of [1]-

[37] in the Summary section of the present specification) to a subject, regardless of whether the subject is castrated or not. In some embodiments, the subject has not undergone a prostatectomy. In some embodiments, the subject may be characterized as suffering from liver dysfunction, e.g., moderate to severe liver dysfunction (Child-Pugh class B or C), prior to administration of the abiraterone prodrug. In some embodiments, the subject may be characterized as sensitive to gonadotropin-releasing hormone antagonists and / or agonists or otherwise intolerant to antagonists and / or agonists. In some embodiments, the subject can be characterized as being chemotherapy-naive or hormone therapy-naive before administering the pharmaceutical composition herein.However, in some embodiments, the subject can also be treated with chemotherapy or hormone therapy before administering the pharmaceutical composition herein.For example, in some embodiments, the subject can have a disease or disorder (e.g., prostate cancer) that is progressing in or after chemotherapy and / or hormone therapy, such as a taxane-based chemotherapy regimen, such as docetaxel-based or cabazitaxel-based chemotherapy.In any of the embodiments described herein, the subject can be a human subject, unless directly opposite.

[0234] Suitable pharmaceutical compositions for the methods herein include, but are not limited to, any of those described herein, such as any of the abiraterone decanoate formulations described herein, such as any of those described in the Overview section. Typically, the pharmaceutical composition can be formulated to deliver therapeutically effective plasma levels of abiraterone to a subject over an extended period of time (e.g., at least 1 day, at least 2 days, at least 3 days, etc.) following a single oral administration. In some embodiments, the therapeutically effective plasma concentration of abiraterone can be at a concentration of at least 1 ng / ml, e.g., at least 2 ng / ml, at least 4 ng / ml, at least 8 ng / ml. In some embodiments, the therapeutically effective plasma concentration of abiraterone can also be about 0.5 ng / ml or greater. In some embodiments, the therapeutically effective plasma concentration of abiraterone can also be about 0.1 ng / ml or greater. The pharmaceutical composition can be administered to a subject with or without food.

[0235]

[0164] The dosage amount and frequency for the methods herein are also not particularly limited and include any of those described herein. Generally, the pharmaceutical composition is administered to the subject in the range of once a day to once a week, for example, once a day or once every two or three days. The dosage of abiraterone decanoate for each administration can vary, typically ranging from 0.5 mg / kg to 200 mg / kg, for example about 0.5 mg / kg to about 200 mg / kg of the subject's body weight.

[0236] How to Lower Steroid Hormone Levels

[0165] Some embodiments of the present disclosure are directed to a method of lowering serum steroid hormone levels in a subject in need thereof.

[0237]

[0166] In some particular embodiments, the present disclosure provides a method of reducing serum testosterone levels in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition described herein (e.g., any of those described herein, e.g., [1]-

[37] in the Summary section of the present specification) or an emulsion described herein (e.g., any of those described herein, e.g.,

[82] -

[90] in the Summary section of the present specification).

[0238]

[0167] Subjects suitable for treatment with the methods herein for reducing serum testosterone levels are not particularly limited. For example, in some embodiments, the subject may be a non-castrated subject. In some embodiments, the subject may be a castrated subject. In some embodiments, the methods herein may also be used with the pharmaceutical compositions herein (e.g., any of those described herein, [1]-

[37] in the Summary section of the present specification) administered to a subject, regardless of whether the subject is castrated or not. In some embodiments, another drug that is effective in reducing serum and / or gonadal testosterone levels is not administered to the subject simultaneously with administration of an abiraterone prodrug, during treatment with an abiraterone prodrug, or interfering with treatment with an abiraterone prodrug. For example, in some embodiments, the subject is not treated with a drug that suppresses gonadal testosterone, other than an abiraterone prodrug administered in an amount effective to reduce serum testosterone levels in the subject. In some embodiments, the subject is not treated with a gonadotropin releasing hormone antagonist and / or agonist in an amount effective to reduce serum testosterone levels in the subject. In some embodiments, the subject is not treated with any drug that suppresses gonadal testosterone other than the administered abiraterone prodrug. In some embodiments, the subject is not treated with any gonadotropin releasing hormone antagonist and / or agonist. In some embodiments, the subject is not treated with a drug selected from buserelin, leuprolide, deslorelin, fertirelin, histrelin, gonadorelin, resilelin, goserelin, nafarelin, peforelin, and triptorelin. In some embodiments, the subject is not treated with a drug selected from abarelix, cetrorelix, degarelix, ganirelix, elagolix, linzagolix, and relugolix. In some embodiments, the subject may be sensitive to or otherwise intolerant to gonadotropin releasing hormone antagonists and / or agonists, hi some embodiments, the subject may also be treated with a gonadotropin releasing hormone antagonist and / or agonist, e.g., as described herein.

[0168] A subject in need of testosterone reduction typically suffers from one or more diseases or disorders mediated or associated with androgens. For example, in some embodiments, the subject is characterized as having a sex hormone-dependent cancer or an androgen receptor-induced cancer, such as any of those described herein. In some embodiments, the subject is characterized as having an androgen receptor-positive salivary duct carcinoma or an androgen receptor-positive glioblastoma multiforme. In some embodiments, the subject is characterized as having prostate cancer (e.g., any of those described herein). For example, in some embodiments, the prostate cancer is localized prostate cancer, such as high-risk localized prostate cancer. In some embodiments, the subject has not undergone a prostatectomy. In some embodiments, the subject is further treated with radiation therapy.

[0239]

[0169] In some embodiments, the present disclosure also provides a method of inhibiting CYP17A1 activity, e.g., inhibiting 17α-hydroxylase activity and 17,20-lyase activity, comprising administering to a subject in need thereof any of the pharmaceutical compositions described herein (e.g., any of [1]-

[37] in the Summary section herein). In some embodiments, the present disclosure also provides a method of inhibiting CYP17A1 activity, e.g., inhibiting 17α-hydroxylase activity and 17,20-lyase activity, comprising administering to a subject in need thereof any of the emulsions described herein (e.g., any of those described herein, e.g.,

[82] -

[90] in the Summary section herein). In some embodiments, the subject suffers from a sex hormone-dependent benign or malignant disorder, e.g., as described herein. In some embodiments, the subject suffers from a syndrome resulting from androgen excess and / or a syndrome resulting from glucocorticoid excess, e.g., hypercortisolism, e.g., as described herein. In some embodiments, the subject is afflicted with a sex hormone dependent cancer or an androgen receptor driven cancer as described herein. Pharmaceutical compositions, subjects, dosing regimens, and routes of administration suitable for the methods include any of those described herein in any combination, such as any of those described in connection with the methods set forth in the Summary section herein.

[0240]

[0170] Thus, in some embodiments, the present disclosure provides a method of reducing glucocorticoid (e.g., cortisol) levels in a subject in need thereof, comprising administering to the subject any of the pharmaceutical compositions herein (e.g., any of [1]-

[37] in the Summary section herein). In some embodiments, the present disclosure provides a method of reducing glucocorticoid (e.g., cortisol) levels in a subject in need thereof, comprising administering to the subject any of the emulsions described herein (e.g., any of those described herein, e.g., any of those shown in the Summary section herein, e.g.,

[82] -

[90] ). In some embodiments, the subject suffers from a syndrome resulting from glucocorticoid excess, e.g., hypercortisolism as described herein, e.g., Cushing's syndrome or Cushing's disease. Pharmaceutical compositions, subjects, dosing regimens, and routes of administration suitable for the method include any of those described herein in any combination, e.g., any of those described in connection with the methods shown in the Summary section herein.

[0241]

[0171] In some embodiments, the present disclosure provides a method of reducing androgen (e.g., testosterone) and / or estrogen levels in a subject in need thereof, comprising administering to the subject any of the pharmaceutical compositions herein (e.g., any of [1]-

[37] in the Summary section of the present specification). In some embodiments, the present disclosure provides a method of reducing androgen (e.g., testosterone) and / or estrogen levels in a subject in need thereof, comprising administering to the subject any of the emulsions described herein (e.g., any of those described herein, e.g., any of

[82] -

[90] in the Summary section of the present specification). In some embodiments, the subject suffers from an androgen receptor-induced cancer. In some embodiments, the subject suffers from a syndrome resulting from androgen excess, such as congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc. In some embodiments, the subject suffers from androgen and / or estrogen associated cancer, such as prostate or breast cancer. In some embodiments, the subject suffers from a sex hormone dependent cancer as described herein. Suitable pharmaceutical compositions, subjects, dosing regimens, and routes of administration for the methods include any of those described herein in any combination, such as any of those described in connection with the methods set forth in the Summary section of this specification.

[0242]

[0172] The abiraterone decanoate in the pharmaceutical composition or emulsion is typically included in a therapeutically effective amount for treating a disease or disorder described herein, such as prostate cancer. In some embodiments, the abiraterone decanoate may be present in the pharmaceutical composition or emulsion in an amount suitable for a dosing frequency ranging from once a day to once a week, for example once a day or once every two or three days, for oral administration to subjects with sex hormone-dependent benign or malignant disorders, androgen receptor-induced cancers, syndromes due to androgen excess, and / or syndromes due to glucocorticoid excess, such as hypercortisolism.

[0243] Combination treatment In some embodiments, the methods herein may include administering to the subject one or more other drugs or agents (e.g., another cancer chemotherapy drug, a hormone replacement drug, or a hormone ablation drug) either simultaneously or sequentially, through the same or a different route of administration. In some embodiments, the other drug or agent may be a steroid, such as prednisone, prednisolone, and / or methylprednisolone. In some embodiments, the other drug or agent may be a chemotherapy drug, such as paclitaxel, mitoxantrone, and / or docetaxel. In some embodiments of the methods herein, the other drug or agent may be a GnRH agonist, such as leuprolide, deslorelin, goserelin, or triptorelin, such as leuprolide acetate (e.g., a long-acting IM injectable formulation). In some embodiments, the other agent or drug may be a glucocorticoid, including, but not limited to, seocalcitol, bicalutamide, flutamide, hydrocortisone, prednisone, prednisolone, or dexamethasone. The amount of the other drug or drug administered may vary, and typically may be an amount that is effective to treat the respective disease or disorder (e.g., prostate cancer), either alone or in combination with a pharmaceutical composition herein (e.g., any of [1]-

[37] in the Summary section of this specification).

[0244]

[0174] Additional suitable other drugs or agents include those described herein. For example, useful other drugs or agents include, but are not limited to, anti-cancer agents, hormone ablation agents, anti-androgens, differentiation agents, antineoplastic agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotics, immunological agents, interferon-type agents, intercalating agents, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloproteinase inhibitors, genetic therapeutic agents, and antiandrogens.

[0245]

[0175] For example, suitable anticancer drugs include acemannan, aclacinone, aldesleukin, alemtuzumab, 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, formestane, fotemustine, gallium nitrate, gemcitabine, heptaplatin, ibandronate, imiquimod, iobenguane, irinotecan, irsogladine, lanreotide, leflunomide, lenograstim, lentinan sulfate, letrozole, liarozole, robap latin, lonidamine, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, millimostim, mitoguazone, mitolactol, molgramostim, nafarelin, nartograstim, nedaplatin, nilutamide, noscapine, oprelvekin, osaterone, oxaliplatin, pamidronate, pegaspargase, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, porfimer sodium, raloxifene, raltitrexed, rasbuvir Suitable antiandrogens include, but are not limited to, ricase, rituximab, romurtide, sargramostim, sizofiran, sobuzoxane, sonermin, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alpha, topotecan, toremifene, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, ubenimex, valrubicin, verteporfin, and vinorelbine. Suitable antiandrogens include, but are not limited to, bicalutamide, flutamide, and nilutamide. Suitable differentiation agents include polyamine inhibitors; vitamin D and its analogs, such as calcitriol,doxercalciferol and seocalcitol; metabolites of vitamin A such as ATRA, retinoic acid, retinoids; short chain fatty acids; phenylbutyrates; and anti-neoplastic agents including, but not limited to, nonsteroidal anti-inflammatory agents, tubulin interacting agents, topoisomerase inhibitors and agents, acitretin, alstonine, amonafide, amfetinil, amsacrine, anquinomycin, antineoplastic agents, aphidicolin glycinate, asparaginase, baccharin, batracycline, benflurone, benzotrypto, bromofosfamide, caracemide, carmethizole hydrochloride, chlorsulfaquinoxalone, clanfenur, claviridenone, crisnatol, curaderm, cytarabine, cytocytin, dacarbazine, dateriptinium, dihema Toporphyrin ether, dihydrolenperone, dinaline, distamycin, docetaxel, elipravine, elliptinium acetate, epothilone, ergotamine, etoposide, etretinate, fenretinide, gallium nitrate, genquadaphnine, hexadecylphosphocholine, homoharringtonine, hydroxyurea, irmophosine, isoglutamine, isotretinoin, leukoregulin, lonidamine, merbarone, merocyanine derivatives, me Chiranilinoacridine, minactivin, mitonafide, mitoxantrone, mopidamol, motretinide, N-(retinoyl)amino acids, N-acylated dehydroalanine, nafazatrom, nocodazole derivatives, octreotide, oxanocin, paclitaxel, pancratistatin, pazeriptin, piroxantrone, polyhematoporphyrin, polypreic acid acid), probimane, procarbazine, proglumide, razoxane, leterliptin, spatol, spirocyclopropane derivatives, spirogermanium, stripoldinone, superoxide dismutase, teniposide, thaliblastine, tocotrienol, topotecan, ukrain, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, and withanolides,Kinase inhibitors, including p38 inhibitors and CDK inhibitors, TNF inhibitors, metallomatrix protease inhibitors (MMPs), COX-2 inhibitors, including celecoxib, rofecoxib, parecoxib, valdecoxib and etoricoxib, SOD mimetics or alpha, vSuitable antimetabolites may be selected from, but are not limited to, 5-FU-fibrinogen, acantifolic acid, aminothiadiazole, brequinar sodium, carmofur, cyclopentylcytosine, cytarabine stearate phosphate, cytarabine conjugates, desaguanine, dideoxycytidine, dideoxyguanosine, didox, doxifluridine, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2'-furanidyl)-5-fluorouracil, isopropylpyrrolidine, methobenzaprim, methotrexate, norspermidine, pentostatin, piritrexim, plicamycin, thioguanine, tiazofurin, trimetrexate, tyrosine kinase inhibitors, and uricytin. Suitable alkylating agents may be selected from, but are not limited to, aldophosphamide analogs, altretamine, anaxylon, bestrabucil, budotitane, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cyplatate, diphenylspiromustine, diplatinum cytostatic, ermustine, estramustine sodium phosphate, fotemustine, hepsulfame, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, oxaliplatin, prednimustine, ranimustine, semustine, spiromustine, tauromustine, temozolomide, teroxylon, tetraplatin, and trimelamol.Suitable antibiotics include akrasinone, actinomycin D, actinoplanon, adriamycin, aeroprisinin derivatives, amrubicin, anthracyclines, azinomycin A, viscaverin, bleomycin sulfate, bryostatin 1, calicheamicin, chromoximycin, dactinomycin, daunorubicin, ditrysarubicin B, dexamethasone, doxorubicin, doxorubicin-fibrinogen, elsamycin A, epirubicin, arbustatin, esorubicin, esperamicin A1, esperamicin A1b, fostriecin, glidobactin, gregatin A, glicamycin, haemolytic angiogenesis inhibitors, and the like. The steroids may be selected from, but are not limited to, hydrocortisone, idarubicin, iludin, kazusamycin, kesarilodin, menogaril, mitomycin, neoenactin, oxalicin, oxaunomycin, peplomycin, pyratin, pirarubicin, polothramycin, prednisone, prednisolone, pyrindancin A, rapamycin, rhizoxin, rodorubicin, sivanomycin, siwenmycin, solangicin A, sparsomycin, tallysomycin, terpentesin, thorazine, triclozaline A, and zorubicin. Non-limiting examples of suitable steroids include hydrocortisone, prednisone, prednisolone, or dexamethasone.

[0246] Combination Treatment for Prostate Cancer

[0176] Prostate cancer treatment often involves multiple therapies, including, for example, radiation therapy, surgery, androgen deprivation therapy, hormonal therapy, chemotherapy, immunotherapy, and various drug combinations. A search on the website clinicaltrials.gov identified over 250 clinical trials with abiraterone / abiraterone acetate listed as the intervention agent, and many of these trials include combination therapies for treating prostate cancer. The pharmaceutical compositions of the present specification (e.g., any of those described herein, e.g., any of [1]-

[37] in the Summary section of the present specification) can also be advantageously used in various combination therapies that replace or supplement oral administration of abiraterone acetate.

[0247] In embodiments in which the methods treat a non-castrated subject, the methods herein may include a combination treatment in which the subject is not treated with drugs that suppress gonadal testosterone other than an abiraterone prodrug administered in an amount effective to reduce serum testosterone levels in the subject. For example, in some embodiments, the methods herein may include a combination treatment in which the subject is not treated with any GnRH agonists and antagonists.

[0248]

[0178] In some embodiments, the present disclosure provides a method of treating prostate cancer (e.g., any of those described herein) with a combination therapy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition herein (e.g., any of those described herein, e.g., any of [1]-

[37] in the Summary section of the present specification) and one or more additional therapies. The one or more additional therapies can be administered to the subject simultaneously with the pharmaceutical composition herein or sequentially in any order with the pharmaceutical composition, and can be via the same route of administration or different routes of administration. In some embodiments, the method of the present invention comprises treating the subject with radiation therapy or surgery. In some embodiments, the method includes administering to the subject one or more other agents selected from anti-cancer agents, hormone ablating agents, anti-androgen agents, differentiation agents, anti-neoplastic agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotics, immune agents, interferon-type agents, intercalating agents, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloprotease inhibitors, genetic therapeutic agents, or combinations thereof. In some embodiments, the method includes administering to the subject one or more other agents selected from chemotherapeutic agents, hormone replacement agents, or hormone ablating agents. In some embodiments, the method includes treating the subject with androgen deprivation therapy. Although many of the combination therapies below are described in connection with various treatments for prostate cancer, the disclosure is not so limited. In some embodiments, the combination therapies described below can also be used to treat other diseases or disorders described herein, such as other cancers described herein.

[0249] In more detailed embodiments, the combination therapy typically includes administering a glucocorticoid to the subject. For example, in some embodiments, the method includes administering to the subject one or more agents selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone. However, in some embodiments, glucocorticoid replacement therapy (e.g., administering a glucocorticoid, such as hydrocortisone, prednisone, prednisolone, methylprednisolone, or dexamethasone) is undesirable. For example, glucocorticoids may be contraindicated in subjects who may have an underlying condition, such as diabetes. In some embodiments, the method may also be characterized in that the subject is not treated with glucocorticoid replacement therapy. In some embodiments, the subject is not treated with an agent selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone. In some embodiments, the method may include administering to the subject a mineralocorticoid receptor antagonist, such as eplerenone. For example, in any of the embodiments herein, if glucocorticoid replacement therapy is not desired and / or is not administered, the method may include administering to the subject a mineralocorticoid receptor antagonist, such as eplerenone.

[0250]

[0180] The combination therapy for the methods herein may also include androgen deprivation therapy, such as through administration of a gonadotropin releasing hormone (GnRH) analog to the subject. If included, suitable GnRH analogs for combination therapy include, but are not limited to, both GnRH agonists and GnRH antagonists. For example, in some embodiments, the method may include administering to the subject a gonadotropin releasing hormone (GnRH) agonist, such as buserelin, leuprolide, deslorelin, fertirelin, histrelin, gonadorelin, resilelin, goserelin, nafarelin, peforelin, or triptorelin, and / or a GnRH antagonist, such as abarelix, cetrorelix, degarelix, ganirelix, elagolix, linzagolix, or relugolix. In some embodiments, the subject is not administered any of the GnRH agonists and GnRH antagonists described herein.

[0251] Inhibition of androgen receptor activity

[0181] In some embodiments, the combination therapy includes treating a subject to reduce androgen receptor (AR) activity, for example with an AR antagonist or agent, or to downregulate or inhibit AR activity.

[0252]

[0182] In some embodiments, the method may include administering to the subject an androgen receptor (AR) antagonist. Various AR antagonists are known in the art, including but not limited to first and second generation AR antagonists (see, e.g., Rice, MA, et al., Front Oncol. 9:801 (2019)), as well as third generation AR antagonists, such as N-terminal domain inhibitors. In some embodiments, the method includes administering to the subject a first generation androgen receptor antagonist, including but not limited to proxaltamide, bicalutamide, flutamide, nilutamide, topirutamide, and the like. In some embodiments, the method includes administering to the subject a second generation androgen receptor antagonist, including but not limited to apalutamide, darolutamide, or enzalutamide. In some embodiments, the method includes administering to the subject apalutamide. In some embodiments, the method includes administering to the subject enzalutamide. In some embodiments, the method includes administering to the subject a third generation androgen receptor antagonist, such as an N-terminal domain inhibitor. N-terminal domain inhibitors are known in the art. Useful non-limiting examples include any of those described in U.S. Application Publication No. 2020 / 0123117, the contents of which are incorporated herein by reference. It should be noted that in embodiments in which an AR antagonist is administered, one or more such antagonists can be administered and can be selected from a first, second, or third AR antagonist, either alone or in any combination.

[0253] In addition to agents that directly target the androgen receptor, other methods and / or agents that modulate androgen receptor activity, including, for example, modulating upstream kinase activity and / or androgen receptor transcriptional activity, can also be used in the combination therapy herein. For example, in some embodiments, the combination therapy can include administering to the subject one or more upstream kinase regulators, the activation or inhibition of which can reduce AR activity. Such upstream kinases are described, for example, in Shah, K. and Bradbury, NA, Cancer cell microenviron. 2(4):doi:10.14800 / ccm.1023 (2015), and Koul HK et al., Genes & Cancer 4(9-10):342-359 (2013), and are known in the art. In some embodiments, the method includes the use of an FLT-3 (FMS-like tyrosine kinase) inhibitor, an AXL (anexelect) inhibitor (e.g., gilteritinib), a CDK (cyclin-dependent kinase) inhibitor, such as a CDK1, 2, 4, 5, 6, 7, or 9 inhibitor, a retinoblastoma (Rb) inhibitor, a protein kinase B (AKT) inhibitor, an SRC inhibitor, an I kappa B kinase 1 (IKK1) inhibitor, a PIM-1 regulator, a Lemur tyrosine kinase 2 (LMTK2) regulator, a Lyn inhibitor, an Aurora A inhibitor, an ANPK (nuclear protein kinase) inhibitor, an extracellular signal-regulated kinase (ERK) regulator, a c-jun inhibitor, a cytotoxic T cell receptor antagonist ... The method includes administering to the subject one or more kinase modulators selected from N-terminal kinase (JNK) modulators, big MAP kinase (BMK) modulators, p38 mitogen-activated protein kinase (MAPK) modulators, and combinations thereof. Suitable kinase modulators / inhibitors include, but are not limited to, any of those known in the art, such as small molecule drugs, polypeptides including antibodies, such as monoclonal antibodies or antigen-binding fragments thereof, RNA or DNA based drugs.

[0254] In some embodiments, the combination therapy may include administering to the subject an agent that downregulates AR or otherwise inhibits AR activity. Without wishing to be bound by theory, AR activity may affect the genome and / or transcription level of AR itself, or the genome and / or transcription level of the upstream target of AR and the downstream target regulated by AR that play a role in regulating AR activity, using various molecules that interfere with transcription and / or translation (e.g., RNA silencing agents (e.g., antisense, siRNA, shRNA, microRNA), ribozyme and DNAzyme), or the protein level, using, for example, antagonists, enzymes that cleave polypeptides, small molecules that interfere with the activity of proteins (e.g., competitive ligands), etc.

[0255] In some embodiments, downregulation of AR or inhibition of AR activity can be achieved through RNA silencing of target genes (such as AR or suitable up- and down-targets of AR as described herein). As used herein, the phrase "RNA silencing" refers to a group of regulatory mechanisms mediated by RNA molecules that result in the inhibition or "silencing" of the expression of corresponding protein-coding genes (e.g., RNA interference (RNAi), transcriptional gene silencing (TGS), post-transcriptional gene silencing (PTGS), quelling, co-suppression, and translational repression). RNA silencing has been observed in many types of organisms, including plants, animals, and fungi.

[0256]

[0186] As used herein, the term "RNA silencing agent" refers to an RNA that is capable of specifically inhibiting or "silencing" the expression of a target gene. In some embodiments, the RNA silencing agent is capable of preventing complete processing (e.g., full translation and / or expression) of an mRNA molecule through a post-transcriptional silencing mechanism. RNA silencing agents include non-coding RNA molecules, such as RNA duplexes that include paired helical structures, as well as precursor RNAs that can produce such small non-coding RNAs. Exemplary RNA silencing agents include double-stranded RNAs (dsRNAs), such as short interfering RNAs (siRNAs), miRNAs, and shRNAs. In one embodiment, the RNA silencing agent is capable of inducing RNA interference. In another embodiment, the RNA silencing agent is capable of mediating translational suppression. The helical structures of double-stranded interfering RNAs (e.g., siRNAs) combine to form hairpin or stem-loop structures (e.g., shRNAs or sh-RNAs). Thus, as noted, the RNA silencing agents of some embodiments of the present disclosure can also be short hairpin RNA (shRNA).

[0257]

[0187] It is understood that the RNA silencing agents of some embodiments of the present disclosure need not be limited to those molecules containing only RNA, but further include chemically modified nucleotides and non-nucleotides.

[0258] In some embodiments, the RNA silencing agents provided herein may be functionally associated with a cell-penetrating peptide. As used herein, a "cell-penetrating peptide" is a peptide that includes a short (about 12-30 residues) amino acid sequence or functional motif that confers energy-independent (i.e., non-endocytic) translocation properties associated with transport of a membrane-permeable complex through the plasma and / or nuclear membrane of a cell.

[0259] According to another embodiment, the RNA silencing agent can be a miRNA or a mimic thereof. The terms "microRNA", "miRNA" and "miR" are synonymous and refer to a collection of non-coding single-stranded RNA molecules of about 19-28 nucleotides in length that regulate gene expression. miRNAs are found in a wide range of organisms and have been shown to play a role in development, homeostasis, and pathogenesis of disease. The term "microRNA mimic" refers to synthetic non-coding RNAs that are capable of entering the RNAi pathway and regulating gene expression. miRNA mimics mimic the function of endogenous microRNAs (miRNAs) and can be designed as mature double-stranded molecules or mimic precursors (e.g., or pre-miRNAs).

[0260]

[0190] Downregulation of AR or inhibition of AR activity can also be achieved by gene editing of target genes (such as AR or suitable up- and down-targets of AR as described herein). Gene editing can be performed, for example, with the clustered regularly interspaced short palindromic repeats CRISPR-CAS9 system. The CRISPR-CAS9 system has been described in the literature and can include, for example, CAS9 and guide RNA. Other gene editing techniques have also been described in the literature and can also be used.

[0261] Another agent capable of downregulating a target (such as AR or suitable up- and down-targets of AR described herein) is a DNAzyme molecule capable of specifically cleaving a target's mRNA transcript or DNA sequence. DNAzymes are single-stranded polynucleotides capable of cleaving both single- and double-stranded target sequences (Breaker et al., Chemistry and Biology 1995;2:655; Santoro et al., Proc. Natl. Acad. Sci. USA 1997;943:4262). A general model for DNAzymes (the "10-23" model) has been proposed. The "10-23" DNAzyme has a catalytic domain of 15 deoxyribonucleotides flanked by two substrate recognition domains of 7-9 deoxyribonucleotides each. This type of DNAzyme can efficiently cleave its substrate RNA at purine:pyrimidine junctions (Santoro et al., Khachigian, Curr. Opin. Mol. Ther. 2002;4:119-121).

[0262]

[0192] Downregulation of a target (e.g., AR or suitable up- and down-targets of AR described herein) can also be affected by using antisense polynucleotides capable of specifically hybridizing with the mRNA transcript encoding the target.

[0263] Another agent capable of downregulating a target (such as AR or the preferred up- and down-targets of AR described herein) is a ribozyme molecule capable of specifically cleaving the mRNA transcript encoding the target. Ribozymes are increasingly being used for sequence-specific inhibition of gene expression by cleaving the mRNA encoding the protein of interest (Welch et al., Curr. Opin. Biotechnol. 1998;9:486-96).

[0264] Another agent capable of downregulating a target (such as AR or suitable up- and down-targets of AR as described herein) is any molecule that binds to and / or cleaves the target. Such a molecule may be an antagonist of the target or an inhibitory peptide of the target.

[0265]

[0195] Another agent that can be used with some embodiments of the present disclosure that downregulate a target (e.g., AR or suitable up- and down-targets of AR described herein) is a molecule that prevents activation of the target and / or binding of a substrate.

[0266] Another agent that can be used with some embodiments of the present disclosure to downregulate AR or inhibit AR activity is an androgen receptor degrader, such as one based on proteolysis-inducing chimeric molecule (PROTAC) technology. See, e.g., Kregel, S. et al., Neoplasia 22(2):111-119 (2020).

[0267] Another agent that can be used with some embodiments of the present disclosure that downregulate a target (such as AR or suitable up- and down-targets of AR described herein) is one that suppresses or downregulates the transcriptional activity of the target, more specifically, the activation of the transcriptional activity of AR. For example, such agents can interfere with the nuclear translocation of AR, downregulate the protein level of AR, reduce hormone binding to AR, interfere with the recruitment of transcriptional cofactors (e.g., steroid receptor coactivator 1 (SRC1) and transcriptional intermediary factor 2 (TIF2)), interfere with AR-DNA binding, such as binding to specific DNA response elements (ARE or androgen response elements), inhibit AR recruitment to AR target gene enhancers, and / or inhibit AR chromatin binding, or otherwise inhibit DNA-binding-dependent or non-DNA-binding-dependent AR signaling pathways. Suitable agents that can inhibit or interfere with AR transcriptional activity include any of those known in the art and any of those agents exemplified herein that are capable of inhibiting or interfering with such activity. For example, certain AR antagonists, such as first generation AR antagonists (e.g., bicalutamide), are known to inhibit AR transcription activity by inhibiting AR nuclear translocation.Other drugs, such as arsenic compounds (e.g., arsenic trioxide), are also known to inhibit AR transcription activity.See, for example, Rosenblatt AE et al., Mol.Endocrinol.23(3):412-421 (2009).

[0268] In some embodiments, the combination therapy may include administering one or more chemotherapeutic agents to the subject. Suitable chemotherapeutic agents include any known in the art. In some embodiments, the method includes administering to the subject a taxane-based chemotherapeutic agent (e.g., docetaxel, cabazitaxel, paclitaxel, etc.) and / or a platinum-based chemotherapeutic agent (e.g., cisplatin, carboplatin, oxaliplatin, etc.).

[0269] In some embodiments, the combination therapy may include treating the subject with radiation therapy. Suitable radiation therapies include any known in the art. In some embodiments, the method includes treating the subject with stereotactic body radiation therapy or neutron radiation.

[0270]

[0200] In some embodiments, the combination therapy may include treating the subject with an injection of radium-223, for example, Xofigo (radium-223 dichloride).

[0271] In some embodiments, the combination therapy may include administering one or more immunotherapies to the subject. Suitable immunotherapies include any known in the art. In some embodiments, the method includes administering sipuleucel-T to the subject. In some embodiments, the method includes administering an immune checkpoint inhibitor to the subject. For example, in some embodiments, the method includes administering an anti-PD-1 antibody, such as pembrolizumab or nivolumab, and / or an anti-PD-L1 antibody, such as avelumab or atezolizumab, to the subject. In some embodiments, the method includes administering an anti-CTLA-4 antibody, such as ipilimumab, to the subject.

[0272]

[0202] In some embodiments, the combination therapy may include administering a bispecific T cell engager (BiTE) therapy, such as blinatumomab or solitomab, to the subject.

[0273] In some embodiments, the combination therapy may include administering to the subject one or more poly ADP ribose polymerase (PARP) inhibitors. In some embodiments, the subject with prostate cancer also has a DNA repair deficiency. In some embodiments, the subject with prostate cancer does not have a DNA repair deficiency. Suitable PARP inhibitors include any of those known in the art. For example, in some embodiments, the method includes administering to the subject a PARP inhibitor selected from niraparib, rucaparib, olaparib, talazoparib, veliparib, and fluzoparib.

[0274] In some embodiments, the combination therapy may include administering one or more kinase inhibitors to the subject. In some embodiments, the subject is characterized as having an abnormal level of each kinase. In some embodiments, the kinase inhibitor may reduce the activity of the androgen receptor or may otherwise be beneficial to cancer treatment. Suitable kinase inhibitors include any known in the art. For example, in some embodiments, the method includes administering to the subject a kinase inhibitor selected from sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivasertib, onvansertib, ipatasertib, afuresertib, alisertib, apitolisib, and opaganib.

[0275]

[0205] In some embodiments, the combination therapy may include administering one or more bone protective agents to the subject. In such embodiments, typically, the subject is characterized as having prostate cancer with bone metastasis (e.g., CRPC). Suitable bone protective agents include any known in the art. For example, in some embodiments, the method includes administering to the subject a bone protective agent selected from denosumab and zoledronic acid.

[0276]

[0206] In some embodiments, the combination therapy may include administering to the subject one or more additional agents useful for treating prostate cancer, either alone or in combination with an abiraterone drug, such as an abiraterone prodrug herein. Such additional agents are not limited. For example, in some embodiments, the method includes the use of: 1) an anti-IL23 targeted monoclonal antibody, e.g., tildrakizumab; 2) selenium, e.g., sodium selenite; 3) an EZH2 inhibitor, e.g., CPI-1205, GSK2816126, or tazemetostat; 4) a CDK4 / 6 inhibitor, e.g., palbociclib, ribociclib, abemaciclib; 6) a bromodomain and extra-terminal domain (BET) inhibitor, e.g., CCS1477, INCB057643, allobresib, ZEN-3694, or molibresib (GSK525762); 7) an anti-CD105 antibody, e.g., TRC105 or carotuximab; 8) niclosamide; 9) an A2A receptor antagonist, e.g., AZD463. 5; 10) a phosphoinositide 3-kinase (PI3K) inhibitor, e.g., AZD-8186, buparlisib, or dactolisib; 11) an additional non-steroidal CYP17A1 inhibitor, e.g., ceviteronel; 12) an antiprogestogen, e.g., onapristone; 13) navitoclax; 14) an HSP90 inhibitor, e.g., onarespib (AT13387); 15) an HSP27 inhibitor, e.g., OGX-427; 16) a 5-alpha-reductase inhibitor, e.g., dutasteride; 17) metformin; 18) AMG-386; 19) dextromethorphan; 20) theophylline; 21) hydroxychloroquine; and 22) lenalidomide.In some embodiments, the combination therapy may include administering to the subject one or more kinase modulators selected from FLT-3 (FMS-like tyrosine kinase) inhibitors, AXL (anexelect) inhibitors (e.g., gilteritinib), CDK (cyclin-dependent kinase) inhibitors, such as CDK1, 2, 4, 5, 6, 7, or 9 inhibitors, retinoblastoma (Rb) inhibitors, protein kinase B (AKT) inhibitors, SRC inhibitors, I kappa B kinase 1 (IKK1) inhibitors, PIM-1 modulators, lemur tyrosine kinase 2 (LMTK2) modulators, Lyn inhibitors, Aurora A inhibitors, ANPK (nuclear protein kinase) inhibitors, extracellular signal-regulated kinase (ERK) modulators, c-jun N-terminal kinase (JNK) modulators, big MAP kinase (BMK) modulators, p38 mitogen-activated protein kinase (MAPK) modulators, and combinations thereof. In some embodiments, cell therapy, such as T cell-mediated cell therapy including central memory T cells, may also be part of the combination therapy.

[0277]

[0207] In some embodiments, the combination therapy includes: 1) a poly(ADP-ribose) polymerase (PARP) inhibitor, including but not limited to olaparib, niraparib, rucaparib, talazoparib; 2) an androgen receptor ligand binding domain inhibitor, including but not limited to enzalutamide, apalutamide, darolutamide, bicalutamide, nilutamide, flutamide, ODM-204, TAS3681; 3) an additional inhibitor of CYP17, including but not limited to galeterone, abiraterone, abiraterone acetate; 4) docetaxel, 4) Microtubule inhibitors, including but not limited to paclitaxel, cabazitaxel (XRP-6258); 5) PD-1 or PD-L1 modulators, including but not limited to pembrolizumab, durvalumab, nivolumab, atezolizumab; 6) Gonadotropin-releasing hormone agonists, including but not limited to cyproterone acetate, leuprolide; 7) 5-alpha reductase inhibitors, including but not limited to finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE28260, SKF105,111. 8) Vascular endothelial growth factor inhibitors, including but not limited to bevacizumab (Avastin); 9) Histone deacetylase inhibitors, including but not limited to OSU-HDAC42; 10) Integrin alpha-v-beta-3 inhibitors, including but not limited to VITAXIN; 11) Receptor tyrosine kinase inhibitors, including but not limited to sunitinib; 12) Phosphoinositide 3-kinase inhibitors, including but not limited to alpelisib, buparlisib, idelalisib; 13) Crizotinib, Alectinib 14) endothelin receptor A antagonists, including but not limited to ZD-4054; 15) anti-CTLA4 inhibitors, including but not limited to MDX-010 (ipilimumab); 16) heat shock protein 27 (HSP27) inhibitors, including but not limited to OGX427; 17) androgen receptor degraders, including but not limited to ARV-330, ARV-110; 18) androgen receptor DNA binding domain inhibitors, including but not limited to VPC-14449;19) Bromodomain and extraterminal motif (BET) inhibitors, including but not limited to BI-894999, GSK525762, GS-5829; 20) Androgen receptor N-terminal domain inhibitors, including but not limited to synthokamide; 21) Alpha particle emitting radiotherapeutic agents, including but not limited to radium 233 or a salt thereof; 22) Niclosamide; or related compounds thereof; 23) Tamoxifen, Raloxifene, Toremifene, 23) Selective estrogen receptor modulators (SERMs), including but not limited to arzoxifene, bazedoxifene, pipindoxifene, lasofoxifene, enclomiphene; 24) Selective estrogen receptor degraders (SERDs), including but not limited to fulvestrant, ZB716, OP-1074, elaquestrant, AZD9496, GDC0810, GDC0927, GW5638, GW7604; 25) anastrozole, 26) Aromatase inhibitors, including but not limited to exemestane, letrozole; 26) Selective progesterone receptor modulators (SPRMs), including but not limited to mifepristone, lonaprison, onapristone, asoprisnil, lonaprisnil, ulipristal, telapristone; 27) Mifepristone, COR108297, COR125281, ORIC-101, PT 150, 28) CDK4 / 6 inhibitors, including but not limited to palbociclib, abemaciclib, ribociclib; 29) HER2 receptor antagonists, including but not limited to trastuzumab, neratinib; and 30) mammalian target of rapamycin (mTOR) inhibitors, including but not limited to everolimus, temsirolimus.

[0278]

[0208] The combination therapy of the present invention is not particularly limited to any particular number of additional therapies. For example, in addition to administering the pharmaceutical composition of the present invention and optional glucocorticoids, such as hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone, the combination therapy can typically include an additional 1, 2, 3, 4, 5, 6, or more therapies described herein. For example, in some embodiments, the combination therapy can include one additional therapy, such as any one of those described herein, such as a GnRH agonist, a GnRH antagonist, an androgen receptor antagonist, chemotherapy, a PARP inhibitor, a kinase inhibitor, immunotherapy, radiation therapy, surgery, androgen deprivation therapy, etc. In some embodiments, the combination therapy can include two or more additional therapies described herein. For example, in some specific embodiments, the combination therapy can include administering to the subject a PARP inhibitor and androgen deprivation therapy. In some embodiments, the combination therapy may include administering a GnRH agonist and radiation therapy to the subject. In some embodiments, the combination therapy may include administering a GnRH agonist, a chemotherapeutic agent, and radiation therapy to the subject. In some embodiments, the combination therapy may include administering an androgen receptor antagonist (e.g., a first, second, and / or third generation AR antagonist), a GnRH agonist, and optionally radiation therapy, a chemotherapeutic agent, indomethacin, or a 5-alpha reductase inhibitor to the subject. In some embodiments, the combination therapy may include administering an androgen receptor antagonist (e.g., a first, second, and / or third generation AR antagonist) and radiation therapy to the subject. In some embodiments, the combination therapy may include administering an androgen receptor antagonist (e.g., a first, second, and / or third generation AR antagonist) and a chemotherapeutic agent to the subject. In some embodiments, the combination therapy can include administering to a subject an androgen receptor antagonist (eg, a first, second, and / or third generation AR antagonist) and an anti-CTLA4 antibody.It should be understood that these combinations discussed are examples of useful combinations and are not limiting, and other combinations of additional therapies described herein are also possible.

[0279] It should be noted that in some embodiments, the methods of treating prostate cancer herein (e.g., any of those described herein) are not combined with a combination therapy. For example, the method includes administering to a subject a therapeutically effective amount of a pharmaceutical composition herein without one or more additional therapies described herein.

[0280]

[0210] The pharmaceutical compositions 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 oral administration of abiraterone acetate, such as the Zytiga® formulation, either simultaneously or sequentially in any order. In some embodiments, a subject can use the pharmaceutical compositions herein as a supplement to existing abiraterone therapy.

[0281]

[0211] Provided herein are formulations, methods, and kits for treating a subject with a sex hormone dependent benign or malignant disorder, e.g., prostate cancer. Also provided are methods for preparing formulations useful for treating a subject with, e.g., a sex hormone dependent benign or malignant disorder (e.g., prostate cancer), androgen receptor-induced cancer, syndromes due to androgen excess, and / or syndromes due to glucocorticoid excess, e.g., hypercortisolism. Representative embodiments will now be described in detail, examples of which are illustrated in the accompanying drawings.

[0282]

[0212] The term "subject" as used herein means, but is not limited to, an animal or human who needs or can undergo chemotherapy for a sex hormone-dependent benign or malignant disorder, such as androgen-dependent or estrogen-dependent disorders (including prostate and breast cancer), androgen receptor-induced cancer, a non-neoplastic syndrome resulting from androgen excess, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), precocious puberty, hirsutism, etc., and / or a syndrome resulting from glucocorticoid excess, such as hypercortisolism, e.g., Cushing's syndrome or Cushing's disease. In a preferred embodiment, the subject is a human subject.

[0283]

[0213] The term "other drug or agent" as used herein (e.g., when referring to administration before, simultaneously with, and after administration of at least one other drug or agent, including at least one abiraterone prodrug formulation) means at least one other compound, formulation, molecule, biological agent, etc., that can improve the efficacy of the formulation(s), reduce the undesirable side effect(s) of the formulation(s), or improve the treatment of a particular disorder. Any suitable route of administration of such "other drug or agent" can be used, e.g., oral administration, parenteral administration, etc. A person skilled in the art of treating a subject having a sex hormone-dependent benign or malignant disorder (e.g., androgen-dependent disorder or estrogen-dependent disorder), androgen receptor-induced cancer, syndrome resulting from androgen excess syndrome, and / or syndrome resulting from glucocorticoid excess, e.g., hypercortisolism, knows and understands how to select and use such "other drug or agent" for the intended purpose(s).

[0284] The formulation can be optionally administered via a modified release device or method. The term "modified release" as used herein should be understood to include delayed release, extended or prolonged release, sustained release, or targeted release, and the like. For example, in some embodiments, a modified release device or method can further prolong the release of the abiraterone of the prodrugs and formulations of the present disclosure. In some embodiments, a modified release device or method can also include any device or method capable of releasing a drug or product (e.g., a drug or biological agent) at a time point later than immediately after administration (e.g., can include an implant). Various modified release devices have been described (Stubbe et al., Pharm. Res. 21:1732, 2004) and may be applicable to the representative embodiments. A modified release device or method can be identified and utilized without undue experimentation by one of ordinary skill in the art after considering all criteria and uses of best judgment for the benefit of the subject.

[0285]

[0215] The formulations and medicaments of the embodiments are administered in an amount that is pharmacologically or physiologically acceptable and effective, for example, to reduce or eliminate the presence of prostate tumor tissue and abnormal or malignant prostate cells, in a subject with prostate cancer. Similarly, the formulations and medicaments of the embodiments are administered in a prophylactically or therapeutically effective amount, alone or in combination with other therapeutic agents or treatment modalities (e.g., radiation therapy and surgery), where a prophylactically or therapeutically effective amount should be understood as an amount that meets the intended prophylactic or therapeutic purpose and provides the benefits available from the administration of such formulations and medicaments.

[0286]

[0216] The terms "effective amount", "effective dose" and "therapeutic plasma concentration" as used herein refer to, but are not limited to, an amount, dose, or concentration capable of treating, delaying, slowing, inhibiting, or eliminating the onset, presence, or progression of a disorder, disease, or condition. For example, an "effective amount", "effective dose" or "therapeutic plasma concentration" is capable of reducing or eliminating the presence of prostate tumor tissue and abnormal or malignant prostate cells in a subject with prostate cancer, and is sufficient to cure (partially or completely) the disease, or prevent the onset or further spread of a disorder, disease, or condition. Further, for example, an effective amount of a formulation refers to an amount administered alone or in combination with other therapeutic agents or treatment modalities (e.g., radiation therapy and surgery) to achieve a clinically significant reduction in tumor burden. One of skill in the art will understand when a clinically significant reduction in tumor burden (or improvement in a sex hormone-dependent benign or malignant disorder or another disorder or syndrome described herein) has occurred following administration of the formulation. An "effective amount," "effective dose," or "therapeutic plasma concentration" is understood to be an amount, dosage, or concentration that is not clinically harmful to a subject, and in any case, the benefits outweigh any adverse side effects. By way of example only, an effective amount or dose of an abiraterone decanoate formulation means an amount that is capable of achieving a plasma concentration of at least 1 ng / ml of abiraterone in a subject following oral administration of a pharmaceutical composition herein, e.g., at least 1 ng / ml, at least 2 ng / ml, at least 4 ng / ml, or at least 8 ng / ml, wherein the effective plasma concentration is achieved 12 hours or more, preferably 24 hours or more, following administration.

[0287]

[0217] In general, the dosage range of administration of the formulations according to the present disclosure is one that produces the desired effect(s). The useful dosage administered will vary depending on the age, weight and health of the subject to be treated, the mode, route and schedule of administration, the response of the individual subject, and the type or stage of prostate cancer (or the severity of sex hormone-dependent benign or malignant disorders or other syndromes or disorders described herein) for which treatment with the formulation is sought. The dosage will also vary depending on the nature or severity of the primary tumor and other underlying conditions, epidemiological conditions, the concurrent 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 effects, and immune tolerance.

[0288]

[0218] The effective dose of the formulation (and other drug(s)) can be determined without undue experimentation (e.g., pharmacokinetic studies) by those skilled in the art after considering all criteria and uses of best judgment to the benefit of the subject (most often dependent on the particular formulation utilized). The dose administered depends on the particular case, not on any event, and is an amount sufficient to induce a clinical benefit or improvement in sex hormone-dependent benign or malignant disorders (e.g., prostate cancer), androgen receptor-induced cancer, syndromes due to androgen excess, and / or syndromes due to glucocorticoid excess, such as hypercortisolism.

[0289]

[0219] The formulations and medicaments of the embodiments may optionally be administered in combination with (or may include) one or more pharma- ceutically acceptable carriers, excipients, or additives. Formulations, administration techniques, pharmaceutical compositions, methods of preparing pharmaceutical compositions, and pharma- ceutically acceptable carriers, excipients, and additives are known in the art and described, for example, in "Remington: The Science and Practice of Pharmacy" (formerly "Remington's Pharmaceutical Sciences", University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia, Pa. (2005)), the disclosures of which are incorporated herein by reference.

[0290]

[0220] The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0291]

[0221] Headings and subheadings are used for convenience and / or formal compliance only, do not limit the subject art, and do not refer to interpretation of the description of the subject art. Features described under one heading or subheading of the subject disclosure may be combined with features described under other headings or subheadings in various embodiments. Moreover, not all features under a single heading or subheading may necessarily be used with an embodiment.

[0292]

[0222] As used herein, the term "about" as a modification of a quantity related to this disclosure refers to variations in the numerical amount that may occur, for example, through routine testing and handling; through errors in such testing and handling; through differences in manufacture, source, or purity of the components / materials utilized in this disclosure; and the like. As used herein, a particular value associated with "about" also includes the particular value, for example, about 10% includes 10%. Whether or not modified by the term "about," the claims include the equivalent of the recited amount. In one embodiment, the term "about" means within 25% of the reported numerical value.

[0293]

[0223] It should also be understood that a specific embodiment of a variable portion herein may be the same as or different from another specific embodiment having a similar identifier.

[0294]

[0224] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry and specific functional moieties and reactivities are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987. This disclosure is not intended to be limited in any way by the exemplary enumeration of substituents described herein.

[0295]

[0225] As used herein, the term "alkyl" when used alone or as part of another group refers to a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, alkyl is an alkyl group having 1 to 30 carbon atoms (i.e., C 1~30 Alkyl or alternatively C1-C 30 alkyl) or a specified number of carbons (i.e., C alkyl, such as methyl, C alkyl, such as ethyl, C alkyl, such as propyl or isopropyl, etc.). In one embodiment, the alkyl group is a straight chain C1~16 In another embodiment, the alkyl group is a branched C 3~16 Obviously, when a range of carbon numbers is recited, it encompasses each individual integer within the range and subranges between such integers as would be understood by one of ordinary skill in the art. For example, the "C 7~16 " is C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 7~16 , C 7~15 , C 7~14 , C 7~13 , C 7~12 , C 7~11 , C 7~10 , C 7~9 , C 7~8 , C 8~16 , C 8~15 , C 8~14 , C 8~13 , C 8~12 , C 8~11 , C 8~10 , C 8~9 , C 9~16 , C 9~15 , C 9~14 , C 9~13 , C 9~12 , C 9~11 , C 9~10 , C 10~16 , C 10~15 , C 10~14 , C 10~13 , C 10~12 , C 10~11 , C 11~16 , C 11~15 , C 11~14 , C 11~13 , C 11~12 , C 12~16 , C 12~15 , C 12~14 , C 12~13 , C 13~16 , C 13~15 , C 13~14 , C 14~16 , C 14~15 , and C 15~16 Other ranges described herein, such as "5 to 16 carbon atoms," should be understood similarly.

[0296] As used herein, the term "cycloalkyl" when used alone or as part of another group means an alkyl group having 3 to 12 carbon atoms (i.e., C 3~12 Cycloalkyl refers to saturated and partially saturated (e.g., containing one or two double bonds) cyclic aliphatic hydrocarbons containing 1 to 3 rings having the specified number of carbons. In one embodiment, a cycloalkyl group has two rings. In one embodiment, a cycloalkyl group has one ring. In another embodiment, a cycloalkyl group has C 3~8 In another embodiment, the cycloalkyl group is 3~6 Cycloalkyl groups. "Cycloalkyl" also includes ring systems in which the cycloalkyl ring as defined above is fused to one or more aryl or heteroaryl groups whose attachment points are on the cycloalkyl ring, in which case the number of carbon atoms remains as specified for the number of carbon atoms in the cycloalkyl ring system. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl.

[0297]

[0227] As used herein, the term "alkenyl" when used alone 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, an alkenyl group is selected from the group consisting of C 2~16 It is an alkenyl group.

[0298] As used herein, the term "alkynyl" when used alone 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 triple bonds. In one embodiment, an alkynyl has one carbon-carbon triple bond. In one embodiment, an alkynyl group is a C 2~16 It is an alkynyl group.

[0299] As used herein, the term "abiraterone prodrug(s)" includes any of the compounds described herein according to Formula I or II, lipophilic esters of abiraterone, its isotopically labeled compound(s) (e.g., deuterium-enriched compounds), its possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures), its tautomers, its conformers, and / or its pharma- ceutically acceptable salts (e.g., acid addition salts such as HCl salts). Hydrates and solvates of the prodrugs are considered compositions of the present disclosure, in which the prodrug(s) are associated with water or solvent, respectively. Some of the prodrugs may also exist in various polymorphic or amorphous forms. The abiraterone prodrugs described herein also include those compounds that readily undergo chemical changes under physiological conditions that result in active abiraterone. In addition, the prodrugs may be converted by chemical or biochemical methods in an ex vivo environment. In any of the embodiments described herein, unless otherwise specified or to the contrary by context, the abiraterone prodrug may be abiraterone decanoate.

[0300]

[0230] The abiraterone prodrugs described herein may exist in 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 most commonly found in nature. The isotopes may be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, oxygen, and nitrogen are 2 H, 3 H, 13 C. 14 C. 15 N, and 18 This includes, but is not limited to, O. Compounds containing these other isotopes and / or other atoms are within the scope of the disclosure.

[0301]

[0231] The solid and dashed wedge bonds indicate stereochemistry as conventional in the art.

[0302]

[0232] The following examples are offered for illustrative purposes only and are not intended to limit the scope of the claimed subject matter.

[0303] Example 1A. Large-Scale Preparation of Abiraterone Decanoate from Decanoic Acid [ka] 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) was added as a solution in dichloromethane (500 mL) to the suspension, followed by EDCI (293 g, 1.53 mol), and the reaction was then stirred at 20-25° C. for 19 hours.

[0304]

[0234] 10 wt% aqueous NaH2PO4 (4000 mL) was then added and the reaction was stirred for 20 minutes. The organic layer was separated and extracted with 10 wt% aqueous NaH2PO4 (2000 mL) and brine (2000 mL). The organic layer was solvent exchanged with acetonitrile (4750 mL) and concentrated to 3100 g, maintaining the bath temperature below 40°C. The suspension was diluted with acetonitrile (900 g). The solid was isolated by filtration to give 510 g of crude abiraterone decanoate.

[0305] 510 g of crude abiraterone decanoate was dissolved in acetone (4000 mL) at 40° C. The solution was filtered through filter paper. The filtrate was transferred to a 12 L three-neck flask, diluted to 5100 g, and reheated to 40° C. to form a solution. The solution was slowly cooled to 20° C. to form a suspension. This was diluted with water (1020 mL) and stirred at room temperature overnight. The solid was filtered, the flask was rinsed with the filtrate, and transferred to a filter funnel. The wet cake was transferred to a drying tray and dried in a vacuum oven overnight at 40-45° C. to obtain 457.1 g (90% yield) as a white solid, the crystalline form of which is designated as Form A. 1H NMR (CDCl3, 400MHz): H 8.62(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,1H,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=7.6Hz),2.12-2.00(m,3H) , 1.91-1.54(m, 10H), 1.49(dt, 1H, J=11.9, 5.1Hz), 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=6.8Hz). Elemental analysis, theoretical (corrected for 0.055% moisture level): C, 81.0%, H, 9.8%, N, 2.8%; found: C, 81.1%, H, 10.2%, N, 2.8%. The differential scanning calorimetry (DSC) pattern of this solid shows an endothermic peak with an onset temperature at about 69.0°C, see Figure 2B.

[0306]

[0236] The abiraterone decanoate obtained in this example was determined to have a purity of 99.7% by weight using HPLC methods. For HPLC analysis, samples of abiraterone decanoate were prepared in methanol at a concentration of 0.05 mg / mL (for assay analysis) or 5 mg / mL (for impurity analysis). 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: start at 65 / 35 MPA / MPB, achieve 100% MPB for 35 minutes, maintain at 100% MPB until 40 minutes, return to 65 / 35 MPA / MPB at 40.10 minutes, maintain at 65 / 35 MPA / MPB until end at 45 minutes.

[0307] The white solid obtained in this example was also characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). XRPD was performed on a Bruker D8 Discover X-ray diffractometer with a theta / theta vertical goniometer using a Vantec-500 as detector. Standard conditions: voltage 40 kV, current 40 mA, radiation, Cu, temperature, ambient, slit size at X-ray source exit, 0.5 mm pinhole, beak collimator, 0.5 mm, sample holder, ground quartz plate. Operating conditions: detector distance, 30 cm, chi integral range, 4-40 degrees 2θ, count time, 120 sec / frame, number of frames: 3, theta 1st, 4 degrees, theta 2nd, 4 degrees, frame width, 12, scan axis, coupling. Software used included GADD software, General Area Detector Diffraction System, version 4.1.50; and DIFFRAC.EVA, version 4.0. DSC was performed on a TA Instruments Q2000 (Thermal Advantage V5.0.0-qualified) with sample sizes of 2-10 mg and heated in the range of 25° C. to 250° C. at a heating rate of 10° C. / min. Representative XRPD and DSC spectra are shown in Figures 2A-2B. Thermogravimetric analysis (TGA) was also performed on this sample. TGA was performed on a TA Instruments TGA Q500 (Thermal Advantage V5.2.5-qualified) with sample sizes of 5-20 mg and heated in the range of 25° C. to 150° C. at a heating rate of 10° C. / min. Representative TGA traces are shown in Figure 2C.

[0308] Example 1B. Preparation of High Purity Abiraterone Decanoate

[0238] This example illustrates a process for purifying abiraterone decanoate to remove residual palladium. The abiraterone decanoate used in this example was prepared using a procedure similar to that shown in Example 1A.

[0309]

[0239] Crude abiraterone decanoate (7.17 kg) was dissolved in acetone (142 kg) at room temperature. Activated carbon (1.43 kg) was added and the resulting slurry was stirred at room temperature for 4 hours. The mixture was filtered to remove the activated carbon and the solid was washed with acetone (142 kg). The combined acetone filtrate was concentrated by vacuum distillation at 40°C. The concentrated filtrate, which contained about 72 L of acetone, was then cooled to 20°C and water (4.3 kg) was slowly added. The mixture was stirred at 20°C for 12 hours and abiraterone decanoate was collected by filtration. The product was washed with 1:1 acetone / water (7.2 kg) and dried under vacuum at 40°C to obtain 5.524 kg of pure abiraterone decanoate (Form A). Analytical data is consistent with that described in Example 1A. A representative specification of the analysis of the obtained abiraterone decanoate is shown in Table 1 below.

[0310] [Table 1]

[0311] Ethyl prasterone decanoate may be an impurity and has the following structure: [ka] It is believed to have the following.

[0312] The purity of the obtained abiraterone decanoate was analyzed using a reversed-phase HPLC method. Separation is performed on an Advanced Materials Technology Halo C8 reversed-phase column using dimensions of 3.0×100 mm and particle size of 2.7 μm. A linear gradient program (20 min) is used with a mobile phase consisting of 25 mM aqueous ammonium acetate buffer and a mixture of methanol and acetonitrile (see gradient profile below in Table 2). Working standard and sample solutions were prepared in methanol diluent. Typical injection volume is 5 μL and detection wavelength is 210 nm.

[0313] [Table 2]

[0314]

[0242] The crude abiraterone decanoate contained 130 ppm Pd. Recrystallization from acetone / water alone reduced the Pd level to 120 ppm. However, by utilizing the process described in this example, the final abiraterone decanoate can be purified to have a Pd content of only 3.7 ppm.

[0315] Example 1C. Polymorph Screening of Abiraterone Decanoate

[0243] Polymorph screening studies were also performed on abiraterone decanoate. In addition to Form A, two other polymorphs of abiraterone decanoate, Form B and Form C, were identified, as shown in Example 1A.

[0316] Crystallization by cooling at -15°C: Approximately 30 mg of abiraterone decanoate was dissolved in a minimum volume of solvent. If not completely dissolved, the sample was heated at 50°C for 1 hour. The sample was placed in a freezer and filtered after 2 days (if a precipitate was visible). Results using this crystallization method are shown in Table E1 below.

[0317] [Table 3]

[0318] Evaporation from a binary 1:1 solvent mixture: Approximately 25 mg of abiraterone decanoate was dissolved in approximately 10 mL total volume of solvent. The sample was evaporated under a 1 psi nitrogen purge. Results using this crystallization method are shown below in Table E2.

[0319] [Table 4]

[0320] Anti-solvent addition: Approximately 25 mg of abiraterone decanoate was dissolved in 1-2 mL of solvent followed by the addition of 2-4 mL of anti-solvent. If a precipitate formed, the sample was filtered. Results using this crystallization method are shown below in Table E3.

[0321] [Table 5]

[0322] Solvent Recrystallization from a Single Solvent: Abiraterone decanoate was recrystallized using a variety of solvents. The scale of the recrystallization experiments ranged from approximately 2 to 10 mL. Saturated solutions were prepared by stirring excess abiraterone decanoate in contact with the various solvent systems at saturation temperature. If the solids did not completely dissolve in the solvent, the mother liquor was separated from the remaining solids by filtration. The mother liquor was then heated above the saturation temperature to dissolve any remaining solids. The temperature of each solution was then adjusted to the growth temperature and a controlled nitrogen shear flow was introduced to initiate solvent evaporation. The recrystallization conditions for the panel based on the solvents used during this study are summarized in Tables E4-E5. XRD analysis was performed.

[0323] [Table 6]

[0324] [Table 7]

[0325] Noncompetitive Slurry Experiments: Noncompetitive slurry experiments were performed by exposing abiraterone decanoate in Form A to a solvent and stirring the resulting suspension at ambient temperature for one week. The solid was filtered and analyzed by XRD to determine the resulting form(s). Solvents used in this study include water, acetonitrile, isopropyl ether / acetonitrile (1:4), 2-butanol / water (1:1), 1-propanol / water (1:1), t-butanol / water (1:1), ethanol / water (1:1), THF / water (1:1), acetone / water (1:1), dioxane / water (1:1), 2-butanone / water (1:1), methanol, DMF / water (1:1), ethyl acetate / water (1:1), and heptane. Based on X-ray scattering behavior, all of the noncompetitive slurry experiments did not result in any change from the starting material.

[0326] A competitive study was also performed. Competitive Slurry: Approximately 20 mg of abiraterone decanoate was suspended in 1-2 mL of solvent. The sample was stirred for 3 days and filtered. The results of the competitive study are shown below in Table E6.

[0327] [Table 8]

[0328] Morphology Characterization: Solids produced from the solvent-based recrystallization panel were analyzed by powder XRD. To mitigate favorable particle effects, a two-dimensional detection system was used to collect all XRD screening data. The two-dimensional detector integrated along concentric Debye cones, which helped to reduce pattern variation. Bright spots appearing in the cone rings indicate strong favorable particle effects that can result in significant variability in the observed diffraction patterns, including changes in peak intensities. Some samples of abiraterone decanoate exhibited favorable particle effects based on the appearance of scattering behavior.

[0329]

[0251] The results of this analysis revealed that the material exists as at least three major polymorphs. The forms observed were designated as Forms A, B, and C.

[0330]

[0252] After sorting the data into the different forms based on their diffraction behavior, each form was examined to determine whether other properties of the forms could be differentiated. Characterization of each form began by comparing the diffraction data representative of each form with data from the other forms. This was typically followed by NMR, DSC, and TGA.

[0331]

[0253] The initial material used in this study was Form A and is consistent with the representative characterization data shown in Experiment 1A, see also summary Table E7 below.

[0332] Form B was obtained in various crystallization experiments, especially those carried out at low temperatures (-10 to -20°C). The characteristic diffraction behavior of Form B is shown in a representative XRPD spectrum, FIG. 2D. 1 The H NMR spectrum shows no organic impurities and is consistent with the expected structure of ADEC. Representative DSC and TGA spectra of Form B are shown in Figures 2E and 2F.

[0333] Form C was obtained by evaporation from a 1:1 mixture of ethanol and 2-butanone. The characteristic diffraction behavior of Form C is shown in a representative XRPD spectrum, FIG. 2G. It should be noted that the diffractogram obtained for one "pure" Form C sample may contain some Form A, since it shows significant overlap with Form A at higher diffraction angles. 1 The H NMR spectrum shows no organic impurities and is consistent with the expected structure of ADEC. Representative DSC and TGA spectra of Form C are shown in Figures 2H and 2I.

[0334]

[0256] Table E7 below summarizes representative analyses of abiraterone decanoate forms A, B, and C.

[0335] [Table 9]

[0336]

[0257] Recrystallization experiments in the polymorph screen produced either Form A, B, C, or a mixture of forms. Form A is expected to be the thermally stable form under ambient conditions based on noncompetitive and competitive slurry experiments.

[0337] Example 2. Solubility of Abiraterone Decanoate in Different Vehicles In this example, the solubility of abiraterone decanoate was tested in four vehicles, each with a unique base: a medium chain triglyceride (MCT) / polyoxyglyceride, a long chain (LC) monodiglyceride, and two propylene glycol (PG) monoesters, caprylic and lauryl.

[0259] Vehicle 1: MCT / Polyoxyglyceride base: 20% Koriphor RH40 / 14% Pullol Oleic CC497 / 33% Labrafil 1944CS / 33% Labrafac Lipofile WL1349 Vehicle 2: PG monoester base: 20% Corifol RH 40 / 14% Pullulol Oleic CC 497 / 66% Lauroglycol 90

[0261] Vehicle 3: PG monoester base: 20% Koriphor RH40 / 14% Pullulol Oleic CC497 / 66% Capmul PG-8 Vehicle 4: LC monodiglyceride base: 20% Corifol RH40 / 14% Pullulol Oleic CC497 / 66% Mycin CC

[0338] The solubility of abiraterone decanoate in different vehicles was tested according to the following procedure: Prepare 5 g of vehicle by weight In a 4 mL vial, weigh out approximately 350 mg of drug and then add 2 mL of vehicle. All samples were sonicated, vortexed, and then placed on a rotator at 25 °C. At the end of the day, check the samples to see if the drug has completely dissolved. If so, use wax paper to transfer additional drug and record the additional amount added. After 2-3 days, remove approximately 0.5 mL from each sample and filter using a microcentrifuge. 0.45 um filter paper can be used. Return the vials to the 25 °C incubator for subsequent time points. The samples were analyzed for solubility using an HPLC method, and results were obtained for samples after 2 and 7 days.

[0339]

[0264] The solubility of abiraterone decanoate in these vehicles is shown below and reflects the average of the 2-day and 7-day results.

[0340] [Table 10]

[0341] Example 3. Solubility of Abiraterone Decanoate in Additional Vehicles

[0265] This example examines the solubility of abiraterone decanoate in additional vehicles.

[0266] The vehicle tested has the following composition: Vehicle 1 (see Example 2): 20% Koriphor RH40 / 14% Pullol Oleic CC497 / 33% Labrafil 1944CS / 33% Labrafac Lipofile WL1349, used as a control.

[0268] Vehicle 5: 20% Corifol RH40 / 14% Pullol Oleic CC497 / 33% Mycin CC / 33% Labrafac Lipofile WL1349 *

[0269] Vehicle 6: 20% Corifol RH40 / 14% Pullol Oleic CC497 / 16% Labrafil 1944CS / 30% Mycin CC / 20% Labrafil Lipofile WL1349

[0270] Vehicle 7: 20% Koriphor RH40 / 14% Pullol Oleic CC497 / 16% Labrafil 1944CS / 30% Capmul PG-8 / 20% Labrafac Lipofile WL1349

[0271] Vehicle 8: 20% Korifor RH40 / 14% Pullol Oleic CC497 / 16% Labrafil 1944CS / 30% Capmul PG-12 / 20% Labrafac Lipofile WL1349

[0272] Vehicle 9: 20% Koriphor RH40 / 14% Pullol Oleic CC497 / 16% Labrafil 1944CS / 30% Labrafil M2130CS / 20% Labrafac Lipofile WL1349

[0342]

[0273] The procedures for preparing the samples and solubility testing were similar to those described in Example 2. The results are shown in the table below.

[0343] [Table 11]

[0344]

[0274] The results of Examples 2 and 3 show that abiraterone decanoate has good solubility in a variety of lipid-based vehicles.

[0345] Example 4. Dispersion of Abiraterone Decanoate Formulations

[0275] This example tests the dispersibility of abiraterone decanoate formulations in different vehicles. Formulations were prepared using Vehicles 1-4 (shown in Example 2) and Vehicle 9 (Capmul PG-8).

[0346] Dispersion testing was performed according to the following general procedure: Each formulation is prepared with an abiraterone decanoate (AbDec) concentration of less than 10% solubility in the respective vehicle; Equilibrate 7.92 mL of 0.1 M HCl in a vial on a rotator at 37 °C; Add 0.08 mL of formulation to 0.1 M HCl medium at 37°C and start the rotator. Draw the dispersion medium up into the pipette and expel it several times to dispense 80 uL; At 60 minutes, filter the entire 8 mL volume through 25 mm 0.45 um PVDF filter paper; Prepare each formulation for the assay by diluting it to a concentration less than that of the standard using IPA (isopropyl alcohol); Perform HPLC assays on formulation and dispersion samples and standards; Also prepare a sample of abiraterone in IPA at a concentration similar to the AbDec top standard. This sample will demonstrate that if the HPLC method is capable of detecting free Ab, it should form during dispersion testing.

[0347]

[0277] The results of this dispersion test are shown in the table below.

[0348] [Table 12]

[0349]

[0278] Based on this example, abiraterone decanoate in vehicles 1 and 2 was found to have excellent recovery or dispersibility in HCl medium.

[0350] Example 5. Dispersion of Additional Abiraterone Decanoate Formulations

[0279] This example tests additional abiraterone decanoate formulations in different vehicles. Formulations were prepared using vehicles 1 (Example 2) and 5-8 (shown in Example 3).

[0351]

[0280] Dispersion testing was performed according to the general procedure set forth in Example 4. The results are shown in the table below.

[0352] [Table 13]

[0353]

[0281] The results show that abiraterone decanoate in vehicles 1, 6, and 7 has excellent recovery or dispersibility in HCl medium.

[0354] Example 6. Efficacy Study of a Single Oral Dose of Abiraterone Decanoate in CD® [Crl:CD® (SD)] Rats

[0282] The objective of this study was to evaluate the relative absorption of two different oral formulations of abiraterone decanoate over a 72-hour period following a single oral gavage dose in male rats.

[0355]

[0283] This example also determines the plasma pharmacokinetics of abiraterone and abiraterone decanoate in rats, serum concentrations of luteinizing hormone, and serum concentrations of the steroids androstenedione, corticosterone, progesterone, and testosterone following a single oral administration of abiraterone decanoate to two groups of CD® [Crl:CD® (SD)] rats (Group 2, Formulation 1 at 100 mg / kg; Group 3, Formulation 2 at 100 mg / kg). An additional group of animals (Group 1) received the vehicle for Formulation 2 and served as a control. In addition, tissues were collected from all animals 72 hours after dosing to determine concentrations of abiraterone and abiraterone decanoate.

[0356]

[0284] The following table shows the experimental design for this example.

[0357] [Table 14]

[0358]

[0285] Details of the test materials are as follows: Abiraterone decanoate Formulation 1: 40 mg abiraterone decanoate / mL in vehicle 1: 20% Corifol RH40 / 14% Pullol Oleic CC497 / 33% Labrafil 1944CS / 33% Labrafac Lipofile WL1349. Abiraterone decanoate formulation 2: 40 mg abiraterone decanoate / mL in vehicle 2: 20% Corifol RH 40 / 14% Pullulol Oleic CC 497 / 66% Lauroglycol 90. The control article is Vehicle 2: 20% Korifor RH 40 / 14% Pullulol Oleic CC497 / 66% Lauroglycol 90.

[0359]

[0286] Male rats (strain CD® [Crl:CD® (SD)]) from Charles River Laboratories, Inc. were used in this study.

[0360]

[0287] Plasma and serum samples were collected at 0 minutes, 1 hour, 2 hours, 4 hours, 24 hours, 48 ​​hours and 72 hours (endpoint) after dosing for pharmacokinetic or steroid analysis.

[0361]

[0288] Plasma abiraterone and abiraterone decanoate concentrations, serum luteinizing hormone concentrations, and serum steroid concentrations are used to determine, if possible, the following parameters: T max , C max , T last , C last , AUC last , AUC inf , AUC inf (estimated %) was determined.

[0362]

[0289] Pharmacokinetic analysis was completed using the software package Phoenix64 (8.3.1.5014) (Certara, Inc.).

[0363]

[0290] Tissues (adrenal, brain, femur, liver, lung, mandibular lymph, mesenteric lymph, prostate, sternum and testis) were harvested 72 hours after dosing and concentrations at that time point are presented.

[0364]

[0291] Result: Pharmacokinetic parameters derived from plasma concentrations of abiraterone and abiraterone decanoate are presented in Tables 3 and 4, with the plasma profiles shown in Figure 3. The effect of oral administration of Formulations 1 and 2 on plasma steroid concentrations is shown graphically in Figures 4A, 4B, 5A, 5B, 6A, 6B, 7A, and 7B. Mean plasma concentrations of luteinizing hormone are shown graphically in Figure 8. Mean and individual tissue concentrations of abiraterone and abiraterone decanoate are presented in Tables 5 and 6, and graphically shown in Figure 9.

[0365] [Table 15]

[0366] [Table 16]

[0367] [Table 17]

[0368] [Table 18]

[0369]

[0293] Plasma concentrations of abiraterone and abiraterone decanoate:

[0294] Following a single oral dose of Formulation 1, max was 404ng / mL, and T max is the 2-hour time point, and AUC last The C for abiraterone following a single oral dose of formulation 2 was 3418 ng.h / mL. max was 128ng / mL, and T max is between 1 and 4 hours, and AUC last The relative exposure of abiraterone from an oral dose of formulation 1 was 1,591 ng.h / mL, and 1,591 ng.h / mL, respectively. max and AUC lastAbiraterone plasma concentration based oral bioavailability for formulations 1 and 2 is approximately 59% and 27% based on the following IV data: IV AbiDec 1.2 mg / kg: Abi AUC=69.8 ng.h / mL (equivalent to 5817 ng.h / ml for the 100 mg / kg dose).

[0370] C for abiraterone decanoate following a single oral dose of Formulation 1 max was 54.4ng / mL, and T max is between 1 and 4 hours, and AUC last The C for abiraterone decanoate following a single oral dose of formulation 2 was 151 ng.h / mL. max was 2.96ng / mL, and T max is between 1 and 4 hours, and AUC last From this, the relative exposure of abiraterone decanoate from an oral dose of formulation 1 was 2.5-3.1 mg / mL, whereas that of formulation 2 was 2.5-3.1 mg / mL. max and AUC last were 18.3 and 5.92 times higher than those of the control.

[0371]

[0296] Tissue concentrations of abiraterone and abiraterone decanoate: At 72 hours following oral administration of Formulation 1, abiraterone was detected in all tissues except femur at levels that tended to be relatively low, with highest concentrations in the liver (63.6 ng / g) and mesenteric lymph node (31.0 ng / g). Following oral administration of Formulation 2, abiraterone concentrations were low or BLQ in all tissues, with highest concentrations in the liver (19.7 ng / g) and mesenteric lymph node (14.2 ng / g), consistent with the results for Formulation 1.

[0372]

[0298] Consideration:

[0299] This study was a comparison of two different formulations of abiraterone decanoate for oral administration. In rats, abiraterone and abiraterone decanoate exposure was higher following oral administration of Formulation 1, which showed better relative absorption compared to Formulation 2.

[0373] Both formulations decreased plasma concentrations of androstenedione, increased concentrations of progesterone, and decreased concentrations of testosterone. There was no effect on corticosterone concentrations. The effects of each formulation appeared to be similar (less than 2-fold difference), but the effect of Formulation 1 tended to be greater than Formulation 2, consistent with the higher exposure of abiraterone.

[0374]

[0301] Consistent with the effects of steroids, exposure to luteinizing hormone was increased in both formulations, although exposure tended to be higher in Formulation 1 than in Formulation 2.

[0375]

[0302] Abiraterone, but not abiraterone decanoate, was detected in tissues 72 hours after dosing, with the highest concentrations in the liver and mesenteric lymph nodes being from Formulation 1, which had higher concentrations from Formulation 2.

[0376]

[0303] Each reference mentioned within this disclosure is incorporated herein in its entirety.

[0377]

[0304] For aspects of the disclosure described as genus, all individual species are considered individually as separate aspects of the disclosure. When aspects of the disclosure are described as "comprising" a feature, it is contemplated that the embodiment also "consists of" or "consists essentially of" the feature.

[0378]

[0305] All of the various aspects, embodiments, and options described in this specification can be combined in any and all variations.

[0379]

[0306] Although several embodiments of the present invention have been described herein, it should be apparent to those skilled in the art that the above are merely illustrative, not limiting, and are presented by way of example only. Numerous modifications and other embodiments are within the scope of one of the knowledge of the art and are contemplated to be included within the scope of the present invention and any equivalents thereof. Modifications of the present invention will be readily apparent to those skilled in the art, and it can be understood that the present invention is intended to include alternatives thereof. Furthermore, since many modifications will be readily apparent to those skilled in the art, it is not desired to limit the present invention to the exact same structure and operation as shown and described, and therefore all suitable modifications and equivalents may be used and are included within the scope of the present invention.

Claims

1. 1. A pharmaceutical composition comprising: (a) abiraterone decanoate and (b) a lipid-based drug delivery system, wherein the abiraterone decanoate has the following structure: 【Chemical 1】 and the lipid-based drug delivery system comprises: (1) a triglyceride, a monoglyceride, a diglyceride, and / or a propylene glycol ester; and (2) a surfactant comprising a polyglyceryl ester and / or a polyoxyglyceride; A pharmaceutical composition, wherein the pharmaceutical composition is formulated for oral delivery of abiraterone decanoate.

2. 10. The pharmaceutical composition of claim 1, wherein the lipid-based drug delivery system comprises a triglyceride, and optionally the lipid-based drug delivery system comprises a medium chain triglyceride, optionally a medium chain triglyceride of caprylic acid (C8) and capric acid (C10).

3. 10. The pharmaceutical composition of claim 1, wherein the lipid-based drug delivery system comprises monoglycerides and / or diglycerides, and optionally the lipid-based drug delivery system comprises glycerol / glyceryl linoleate.

4. 10. The pharmaceutical composition of claim 1, wherein the lipid-based drug delivery system comprises a propylene glycol ester, and optionally the lipid-based drug delivery system comprises propylene glycol monocaprylate and / or propylene glycol monolaurate. (i) the lipid-based drug delivery system comprises a surfactant comprising a polyglycerol ester, optionally the lipid-based drug delivery system comprises a surfactant comprising polyglyceryl oleate, optionally polyglyceryl-3 dioleate; and / or (ii) The pharmaceutical composition of claim 1, wherein the lipid-based drug delivery system comprises a surfactant comprising a polyoxyglyceride, and optionally the lipid-based drug delivery system comprises a surfactant comprising macrogolglycerol hydroxystearate, oleoyl polyoxyl-6 glyceride, or lauroyl polyoxyl-6 glyceride.

6. 2. The pharmaceutical composition of claim 1, wherein the abiraterone decanoate is dispersed, e.g., homogeneously dispersed or dissolved, in the lipid-based drug delivery system at a concentration ranging from about 1 mg / g to about 250 mg / g, optionally from about 20 mg / g to about 150 mg / g.

7. 10. The pharmaceutical composition of claim 1, formulated in the form of a capsule, optionally a softgel capsule.

8. The pharmaceutical composition of claim 1, wherein the abiraterone decanoate is dissolved in the lipid-based drug delivery system at a concentration ranging from about 10 mg / g to about 150 mg / g, and the lipid-based drug delivery system comprises: (a) lipid in an amount of about 10 to 80% by weight of the lipid-based drug delivery system; and (b) one or more non-ionic surfactants in an amount of about 20 to 90% by weight of the lipid-based drug delivery system. (i) the lipid comprises medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 10% to about 50% by weight, e.g., about 20-40% by weight, of the lipid-based drug delivery system; and / or (ii) the lipid comprises glycerol / glyceryl linoleate in an amount of about 10% to about 50% by weight, e.g., about 20-40% by weight, of the lipid-based drug delivery system; and / or (iii) the lipid further comprises propylene glycol monocaprylate or propylene glycol monolaurate in an amount of about 10% to about 50% by weight, e.g., about 20-40% by weight, of the lipid-based drug delivery system; and / or (iv) the lipid-based drug delivery system comprises two or more, e.g., two or three, non-ionic surfactants; and / or (v) the one or more non-ionic surfactants comprise macrogolglycerol hydroxystearate and / or polyglyceryl oleate; and / or (vi) the one or more nonionic surfactants further comprise oleoyl polyoxyl-6 glyceride and / or lauroyl polyoxyl-6 glyceride; and / or (vii) abiraterone decanoate dissolved in the lipid-based drug delivery system at a concentration ranging from about 20 mg / g to about 120 mg / g; and (A) the lipid-based drug delivery system comprises: (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 20-40% by weight of the lipid-based drug delivery system; (b) macrogolglycerol hydroxystearate in an amount of about 10-30% by weight of the lipid-based drug delivery system; (c) polyglyceryl oleate in an amount of about 10-30% by weight of the lipid-based drug delivery system; and (d) oleoyl polyoxyl-6 glyceride in an amount of about 20-40% by weight of the lipid-based drug delivery system; or (B) the lipid-based drug delivery system comprises: (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 10-40% by weight of the lipid-based drug delivery system; (b) macrogolglycerol hydroxystearate in an amount of about 10-30% by weight of the lipid-based drug delivery system; (c) polyglyceryl oleate in an amount of about 10-30% by weight of the lipid-based drug delivery system; (d) oleoyl polyoxyl-6 glyceride in an amount of about 10-40% by weight of the lipid-based drug delivery system; and (e) propylene glycol monocaprylate and / or propylene glycol monolaurate in an amount of about 10-40% by weight of the lipid-based drug delivery system; or (C) the lipid-based drug delivery system comprises: (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 10-40% by weight of the lipid-based drug delivery system; (b) macrogolglycerol hydroxystearate in an amount of about 10-30% by weight of the lipid-based drug delivery system; (c) polyglyceryl oleate in an amount of about 10-30% by weight of the lipid-based drug delivery system; (d) oleoyl polyoxyl-6 glyceride in an amount of about 0-40% by weight of the lipid-based drug delivery system; and (e) glycerol / glyceryl linoleate in an amount of about 10-40% by weight of the lipid-based drug delivery system; and / or (viii) The pharmaceutical composition of claim 8, formulated in the form of a capsule, optionally a softgel capsule. (i) the lipid-based drug delivery system is a self-dispersing drug delivery system, such as a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system; and / or (ii) the abiraterone decanoate is characterized as having a purity of at least 95%, preferably at least 98%, e.g., about 98.5%, about 99%, about 99.5%, or more by weight; and optionally, (A) the abiraterone decanoate has less than 1% by weight, optionally less than 0.5%, less than 0.3%, less than 0.2%, or less than 0.1% by weight of the formula: 【Chemistry 2】 and optionally, the abiraterone decanoate is characterized as having no detectable amount of ethyl prasterone decanoate; and / or (B) The pharmaceutical composition of claim 1, wherein the abiraterone decanoate is characterized as having a palladium content of less than 50 ppm, and optionally the abiraterone decanoate is characterized as having a palladium content of less than 10 ppm.

11. for use in a method of treating or preventing a disease or disorder in a subject in need thereof; 11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the method comprises the step of administering an effective amount of the pharmaceutical composition to the subject, and the disease or disorder is selected from sex hormone-dependent benign or malignant disorders, androgen receptor-induced cancer, syndromes caused by androgen excess, and syndromes caused by glucocorticoid excess.

12. (i) The disease or disorder is selected from prostate cancer, breast cancer, endometrial cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, lung cancer, endometriosis, polycystic ovary syndrome, Cushing's syndrome, Cushing's disease, classic or non-classic congenital adrenal hyperplasia, precocious puberty, hirsutism, and combinations thereof, and optionally, the disease or disorder is: (A) a sex hormone dependent or androgen receptor-induced cancer, optionally wherein the sex hormone dependent or androgen receptor-induced cancer is androgen receptor-positive salivary duct carcinoma or androgen receptor-positive glioblastoma multiforme, or (B) prostate cancer, and optionally: (a) the subject with prostate cancer is characterized as having an elevated amount of prostate specific antigen; or (b) the prostate cancer is localized prostate cancer, or (c) the prostate cancer is metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer, non-metastatic castration-resistant prostate cancer, or metastatic castration-resistant prostate cancer; or (d) the prostate cancer is newly diagnosed high-risk metastatic hormone-sensitive prostate cancer; or (e) the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC), the subject is asymptomatic or mildly symptomatic after failure of androgen deprivation therapy, and chemotherapy is not yet clinically indicated in the subject; or (f) the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC) and the subject's disease has progressed on or after a taxane-based, e.g., docetaxel-based, chemotherapy regimen; or (g) the prostate cancer is refractory prostate cancer, and / or (ii) the method further comprises treating the subject with radiation therapy or surgery; and / or (iii) the method further comprises administering to the subject one or more other agents selected from an anti-cancer agent, a hormone ablation agent, an anti-androgen agent, a differentiation agent, an anti-neoplastic agent, a kinase inhibitor, an antimetabolite, an alkylating agent, an antibiotic agent, an immunological agent, an interferon-type agent, an intercalating agent, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, a mitotic inhibitor, a matrix metalloproteinase inhibitor, a genetic therapy agent, or a combination thereof; and / or (iv) the method further comprises administering to the subject one or more agents selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone; and / or (v) the method further comprises administering to the subject one or more other agents selected from a chemotherapeutic agent, a hormone replacement agent, or a hormone ablation agent; and / or (vi) the method further comprises treating the subject with androgen deprivation therapy; or (vii) the subject is (A) is a non-castrated subject; or (B) the subject is not being treated with a gonadotropin-releasing hormone agonist and / or antagonist in an amount effective to decrease serum testosterone levels in said subject, and optionally (a) said subject is not being treated with a drug selected from buserelin, leuprolide, deslorelin, fertirelin, histrelin, gonadorelin, lecirelin, goserelin, nafarelin, peforelin, and triptorelin, or optionally (b) said subject is not being treated with a drug selected from abarelix, cetrorelix, degarelix, ganirelix, elagolix, linzagolix, and relugolix, and / or (C) sensitive to or otherwise intolerant to gonadotropin-releasing hormone antagonists and / or agonists, and / or (D) not treated with glucocorticoid replacement therapy, and / or (viii) the method further comprises administering to the subject a poly ADP ribose polymerase (PARP) inhibitor, optionally selected from niraparib, rucaparib, olaparib, talazoparib, veliparib, and fluzoparib; and / or (ix) the method further comprises administering to the subject a first generation androgen receptor antagonist, optionally selected from proxalamide, bicalutamide, flutamide, nilutamide, and topirutamide; and / or (x) the method further comprises administering to the subject a second-generation androgen receptor antagonist; and / or (xi) the method further comprises administering to the subject a third-generation androgen receptor antagonist or an androgen receptor degrader molecule, alone or in combination with one or more first- or second-generation androgen receptor antagonists; and / or (xii) the method further comprises administering to the subject a chemotherapeutic agent, such as a taxane-based chemotherapeutic agent or a platinum-based chemotherapeutic agent; and / or (xiii) the method further comprises administering an immunotherapy to the subject, e.g., administering sipuleucel-T, an immune checkpoint inhibitor, or an anti-CTLA-4 antibody; and / or (xiv) the method further comprises administering to the subject a bispecific T-cell engager (BiTE) therapy, such as blinatumomab or solitomab; and / or (xv) the method further comprises administering to the subject a kinase inhibitor, optionally selected from sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivasertib, onvansertib, ipatasertib, afuresertib, alisertib, apitolisib, and opaganib; and / or (xvi) the method further comprises administering to the subject a bone protective agent, optionally selected from denosumab and zoledronic acid, and the subject is characterized as having prostate cancer with bone metastases; and / or (xvii) the method further comprises administering to the subject a therapeutic agent selected from: 1) an anti-IL23-targeting monoclonal antibody; 2) selenium, e.g., sodium selenite; 3) an EZH2 inhibitor; 4) a CDK4 / 6 inhibitor, 5) a bromodomain and extra-terminal domain (BET) inhibitor; 6) an anti-CD105 antibody; 7) niclosamide; 8) an A2A receptor antagonist; 9) a PI3K inhibitor; 10) an additional non-steroidal CYP17A1 inhibitor; 11) an antiprogestogen; 12) navitoclax; 13) an HSP90 inhibitor; 14) an HSP27 inhibitor; 15) a 5-alpha-reductase inhibitor; 16) metformin; 17) AMG-386; 18) dextromethorphan; 19) theophylline; 20) hydroxychloroquine; and 21) lenalidomide; and / or (xviii) the method further comprises administering to the subject one or more kinase modulators selected from a FLT-3 (FMS-like tyrosine kinase) inhibitor, an AXL (anexselect) inhibitor, a CDK (cyclin-dependent kinase) inhibitor, such as a CDK1, 2, 4, 5, 6, 7, or 9 inhibitor, a retinoblastoma (Rb) inhibitor, a protein kinase B (AKT) inhibitor, an SRC inhibitor, an I kappa B kinase 1 (IKK1) inhibitor, a PIM-1 modulator, a Lemur tyrosine kinase 2 (LMTK2) modulator, a Lyn inhibitor, an Aurora A inhibitor, an ANPK (nuclear protein kinase) inhibitor, an extracellular signal-regulated kinase (ERK) modulator, a c-jun N-terminal kinase (JNK) modulator, a big MAP kinase (BMK) modulator, a p38 mitogen-activated protein kinase (MAPK) modulator, and combinations thereof; and / or (xix) the subject is chemotherapy-naive or hormone-therapy-naive prior to administration of the pharmaceutical composition; and / or (xx) the subject has not undergone a prostatectomy, and / or (xxi) the subject has been treated with radiation therapy, and / or (xxii) the subject has been administered radium-223; or (xxiii) the disease or disorder is (A) breast cancer, optionally wherein the breast cancer is molecular apocrine HER2-negative breast cancer, metastatic breast cancer, e.g., ER+ metastatic breast cancer, ER+ and HER2-negative breast cancer, or AR+ triple-negative breast cancer, optionally further comprising administering to the subject an aromatase inhibitor; or (B) associated with 21-hydroxylase deficiency; and / or (xxiv) the pharmaceutical composition is administered orally, and / or (xxv) the pharmaceutical composition is administered to the subject in a range of once daily to once weekly, e.g., once daily or once every two or three days; and / or (xxvi) The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is administered to the subject with or without food.

13. 1. An emulsion comprising: (a) abiraterone decanoate; (b) a lipid; and (c) a non-ionic surfactant, wherein the lipid phase of the emulsion comprises abiraterone decanoate dispersed in the lipid, and wherein the abiraterone decanoate has the following structure: 【Chemistry 3】 and the lipid is selected from a triglyceride, a monoglyceride, a diglyceride, and / or a propylene glycol ester; An emulsion wherein the nonionic surfactant is selected from surfactants including polyglyceryl esters and / or polyoxyglycerides. (i) the lipid comprises a medium-chain triglyceride of caprylic acid (C8) and capric acid (C10); and / or (ii) the lipid comprises glycerol / glyceryl linoleate; and / or (iii) the lipid further comprises propylene glycol monocaprylate or propylene glycol monolaurate; and / or (iv) comprising two or more, e.g., two or three, nonionic surfactants; and / or (v) The emulsion of claim 13, wherein the non-ionic surfactant comprises macrogolglycerol hydroxystearate and / or polyglyceryl oleate, e.g., polyglyceryl-3 dioleate, and optionally the surfactant further comprises oleoyl polyoxyl-6 glyceride and / or lauroyl polyoxyl-6 glyceride.

15. 1. An emulsion for use in a method of treating or preventing a disease or disorder in a subject in need thereof, comprising:

15. The emulsion of claim 13 or 14, wherein the method comprises administering an effective amount of the emulsion to the subject, and the disease or disorder is selected from sex hormone-dependent benign or malignant disorders, androgen receptor-induced cancers, syndromes caused by androgen excess, and syndromes caused by glucocorticoid excess.

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