Oral abiraterone preparations

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] This disclosure relates in general to novel oral formulations of abiraterone prodrugs. This disclosure is intended for administration to patients with androgen or estrogen-dependent benign or malignant disorders, or androgen receptor-induced cancers, including various cancers (e.g., prostate cancer, bladder cancer, hepatocellular carcinoma, lung cancer, breast cancer, endometrial cancer, and ovarian cancer), and for the treatment of glucocorticoids, typically cortisol-induced non-tumor syndromes resulting from androgen overproduction (including both classical and non-classical congenital adrenal hyperplasia, endometriosis, polycystic ovary syndrome, precocious puberty, and male-pattern hirsutism), or conditions such as Cushing's syndrome or Cushing's disease. Background

[0002]

[0002] Abiraterone ((3β)-17-(pyridine-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 a CYP17A1 inhibitor (a member of the cytochrome P450 superfamily of enzymes that catalyze the synthesis of cholesterol, steroids, and other lipids, and is involved in drug metabolism). CYP17A1 possesses both 17α-hydroxylase activity and 17,20-lyase activity. 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 activity of CYP17A1 are necessary for the production of androgenic (e.g., androstenedione, testosterone, and dihydrotestosterone) and estrogenic (estrone, estradiol, and estratriol) steroids through the conversion of 17α-hydroxypregnenolone to the sex steroid precursor, dehydroepiandrosterone (see Figure 1). Therefore, abiraterone interferes with the synthesis of androgens and estrogens in the gonads (mainly the testes and ovaries) and extragonads (e.g., the adrenal glands and tumors themselves).

[0003]

[0003] Although abiraterone itself has poor absorption, it can be administered orally as an abiraterone acetate prodrug. Although abiraterone acetate also has poor absorption, it can be converted in the gastrointestinal tract to abiraterone, which has poor absorption into the bloodstream following cleavage of the acetate prodrug. Abiraterone acetate ((3β)-17-(3-pyridyl)androsta-5, acetate; CAS number 154229-18-2) is approved in the United States under the trade name Zytiga (registered trademark) for the treatment of castration-resistant or castration-sensitive prostate cancer. 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, it has been shown that abiraterone acetate is hydrolyzed to abiraterone in the vaginal environment, leading to the formation of abiraterone supersaturation, and is 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, abiraterone prodrug formulations are usually prescribed 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 metastatic castration-sensitive prostate cancer (CSPC). Prescription information for Zytiga® recommends an oral dose of 1,000 mg (4 x 250 mg tablets) once daily in combination with prednisone (5 mg) administered orally 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] Since administration of abiraterone acetate with food increases the absorption of abiraterone acetate (and therefore the increased variability may result in a higher exposure, potentially causing a variety of side effects, including cardiovascular and / or hepatotoxicity), the prodrug must be consumed on an empty stomach at least one hour or two hours before a meal. In fact, the prescribing information for Zytiga® states that it must be taken on an empty stomach and that a meal must be taken at least two hours before oral administration and at least one hour after oral administration.

[0007]

[0007] In the prescription information, the daily oral dose of 1,000 mg of Zytiga (registered trademark) in patients with metastatic CRPC is compared to the steady-state C dose of abiraterone. max The value was described as 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 to abiraterone increased when Zytiga® was administered with food. In particular, abiraterone C max The AUC values ​​were approximately 7 times and 5 times higher, respectively, when Zytiga® was administered with a low-fat diet (7% fat, 300 calories), and approximately 17 times and 10 times higher, respectively, when Zytiga® was administered with a high-fat diet (57% fat, 825 calories).

[0008]

[0008] The currently approved solid oral dosage form of the prodrug abiraterone acetate has several disadvantages. For example, it has very low bioavailability, requiring a large daily pill load (4 x 250 mg tablets once daily) for the patient. In addition, the combination of low bioavailability and a large food effect causes highly variable blood levels in the patient. Furthermore, this approved dosing regimen is not suitable for abiraterone once daily because abiraterone is rapidly eliminated. min This is thought to be related to the loss of therapeutic effect in patients with metastatic CRPC.

[0009] [overview]

[0009] This disclosure relates in general to novel oral abiraterone prodrug formulations and methods of use of 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 caused by androgen and / or glucocorticoid excess.

[0010]

[0010] U.S. Patent No. 10,792,292B2 issued by Propella Therapeutics, Inc. on October 6, 2020, and U.S. Provisional Patent Application No. 63 / 073,502 filed on September 2, 2020, and U.S. Provisional Patent Application No. 63 / 149,550 filed on February 15, 2021, for example, the daily C1c observed with oral administration of abiraterone acetate. min We describe useful abiraterone prodrugs, particularly abiraterone decanoate, as a breakthrough across currently marketed Zytiga® tablets, resulting in increased bioavailability, elimination of food effects, reduced pill load, decreased dosing frequency, and sustained and effective plasma levels of abiraterone, for at least one week, typically at least two weeks, and up to 10 weeks or more following administration of abiraterone prodrug formulations. Novel abiraterone prodrugs and their formulations have been demonstrated to be suitable for weekly, monthly, bimonthly, trimonthly, or less frequent dosing for the treatment of subjects with sex hormone-dependent benign or malignant disorders, androgen receptor-induced cancers, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess.

[0011]

[0011] This disclosure is based in part on the fact that abiraterone decanoate may be orally bioavailable with good to excellent oral bioavailability based on plasma abiraterone concentration, and that effective plasma concentrations of abiraterone can be achieved to modulate serum steroid levels, such as reducing serum androgen levels, with a suitable lipid-based drug delivery system. 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 dose of the pharmaceutical composition herein can achieve sustained inhibition of CYP17A1 for a period of 24 hours or more. Therefore, this disclosure provides alternative methods 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, 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 abiraterone decanoate has the following structure: [ka] A pharmaceutical composition having a compound, wherein the pharmaceutical composition is formulated for oral delivery of abiraterone decanoate.

[0014] [2] The pharmaceutical composition according to [1], comprising a lipid-based drug delivery system comprising (1) a triglyceride, monoglyceride, diglyceride, and / or propylene glycol ester; and (2) a surfactant comprising a polyglyceryl ester and / or polyoxyglyceride.

[0015] [3] A pharmaceutical composition according to [1] or [2], comprising a lipid-based drug delivery system, wherein the system comprises a triglyceride.

[0016] [4] A pharmaceutical composition according to [1] or [2], comprising a lipid-based drug delivery system containing a medium-chain triglyceride (e.g., Labrafac® Lipofil WL1349, or a medium-chain triglyceride of caprylic acid (C8) and capric acid (C10)).

[0017] [5] A pharmaceutical composition according to any one embodiment of [1] to [4], wherein the lipid-based drug delivery system comprises monoglycerides and / or diglycerides.

[0018] [6] Lipid-based drug delivery systems include glycerol / glyceryl linoleate (e.g., Maisine (registered trademark) CC, mainly linoleate (C)). 18:2 ) and oleic acid (C 18:1 A pharmaceutical composition according to any one embodiment of [1] to [4], comprising (a predominantly mono, di, and triglyceride and diester fractions of )

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

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

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

[0022]

[10] A pharmaceutical composition according to any one embodiment of [1] to [8], comprising a lipid-based drug delivery system and a surfactant comprising polyglyceryl oleate (e.g., plurol oleic CC497 (polyglyceryl-3 dioleate)).

[0023]

[11] A pharmaceutical composition according to any one embodiment of [1] to

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

[0024]

[12] A pharmaceutical composition according to any one embodiment of [1] to

[10] , wherein the lipid-based drug delivery system comprises a surfactant including macrogol glycerol hydroxystearate (e.g., Corifor 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 embodiment of [1] to

[12] , wherein abiraterone decanoate is dispersed, for example, 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, for example, in the range of about 20 mg / g to about 150 mg / g.

[0026]

[14] A pharmaceutical composition according to any one embodiment of [1] to

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

[0027]

[15] The following is a pharmaceutical composition according to any one embodiment of [1] to

[14] , characterized by one or more of the following: (1) the pharmaceutical composition is stable when stored 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 administered orally to a mammal, the pharmaceutical composition is capable of delivering to a mammal an amount sufficient to achieve a therapeutically effective plasma concentration of abiraterone for treating a disease or disorder described herein, such as prostate cancer as described herein.

[0028]

[16] A pharmaceutical composition according to any one embodiment of [1] to

[14] , having an oral bioavailability of more 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 in the range of approximately 10 mg / g to approximately 150 mg / g, wherein the lipid-based drug delivery system comprises (a) lipids in an amount of approximately 10 to 80% by weight of the lipid-based drug delivery system; and (b) one or more nonionic surfactants in an amount of approximately 20 to 90% by weight of the lipid-based drug delivery system, wherein the abiraterone decanoate has the following structure: [ka] A pharmaceutical composition having the following characteristics.

[0030]

[18] The pharmaceutical composition according to

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

[0031]

[19] The pharmaceutical composition according to

[17] or

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

[0032]

[20] The pharmaceutical composition according to any one embodiment of

[17] to

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

[0033]

[21] A pharmaceutical composition according to any one embodiment of

[17] to

[20] , comprising two or more nonionic surfactants, for example, a lipid-based drug delivery system.

[0034]

[22] A pharmaceutical composition according to any one embodiment of

[17] to

[21] , comprising one or more nonionic surfactants macrogol glycerol hydroxystearate (e.g., Corifor RH40) and / or polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)).

[0035]

[23] A pharmaceutical composition according to any one embodiment of

[17] to

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

[0036]

[24] A pharmaceutical composition according to any one embodiment of

[17] to

[23] , comprising abiraterone decanoate dissolved in a lipid-based drug delivery system at a concentration in the range of approximately 20 mg / g to approximately 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 approximately 20 to 40% by weight of the lipid-based drug delivery system; (b) macrogol glycerol hydroxystearate (e.g., Corifor RH40) in an amount of approximately 10 to 30% by weight of the lipid-based drug delivery system; (c) polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)) in an amount of approximately 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 approximately 20 to 40% by weight of the lipid-based drug delivery system.

[0037]

[25] comprising abiraterone decanoate dissolved in a lipid-based drug delivery system at a concentration ranging from approximately 20 mg / g to approximately 120 mg / g, wherein the lipid-based drug delivery system comprises: (a) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) in amounts of approximately 10-40% by weight of the lipid-based drug delivery system; (b) macrogol glycerol hydroxystearate (e.g., Corifor RH40) in amounts of approximately 10-30% by weight of the lipid-based drug delivery system; and (c) polyglyceryl oleate (e.g., porcine rh40) in amounts of approximately 10-30% by weight of the lipid-based drug delivery system. A pharmaceutical composition according to any one embodiment of

[17] to

[23] , comprising: (d) about 10 to 40% by weight of oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) in a lipid-based drug delivery system; and (e) about 10 to 40% by weight of propylene glycol monocaprylate (e.g., Capmul PG-8) and / or propylene glycol monolaurate (e.g., Capmul PG-12, or Lauroglycol® 90) in a 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, 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 10 to 40% by weight of the lipid-based drug delivery system; (b) macrogol glycerol hydroxystearate (e.g., Kolliphor RH40) in an amount of about 10 to 30% by weight of the lipid-based drug delivery system; (c) polyglyceryl oleate (e.g., Plurol Oleique CC497 (polyglyceryl-3 dioleate)) in an amount of about 10 to 30% by weight of the lipid-based drug delivery system; (d) oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M1944CS) in an amount of about 0 to 40% by weight of the lipid-based drug delivery system; and (e) glycerol / glyceryl linoleate (e.g., Maisine® CC, mainly linoleic acid (C 18:2 ) and oleic acid (C 18:1 ) mono-, di- and triglycerides, with the diester fraction being predominant), the pharmaceutical composition according to any one of embodiments

[17] to

[23] .

[0039]

[27] The pharmaceutical composition according to

[17] , comprising a vehicle described in any one of the embodiments herein.

[0040]

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

[17] to

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

[0041]

[29] The following is a pharmaceutical composition according to any one embodiment of

[17] to

[28] , characterized by one or more of the following: (1) the pharmaceutical composition is stable when stored 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 administered orally to a mammal, the pharmaceutical composition is capable of delivering to a mammal an amount sufficient to achieve a therapeutically effective plasma concentration of abiraterone for treating a disease or disorder as described herein, such as prostate cancer as described herein.

[0042]

[30] A pharmaceutical composition according to any one embodiment of

[17] to

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

[0043]

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

[30] , wherein 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.

[0044]

[32] A pharmaceutical composition according to any one embodiment of [1] to

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

[0045]

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

[32] , characterized in that the abiraterone decanoate is substantially pure and has a purity of at least 95% by weight, preferably at least 98%, for example about 98.5%, about 99%, about 99.5%, or higher.

[0046]

[34] Formulas in which abiraterone decanoate is present in 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): [ka] The pharmaceutical composition according to

[33] , characterized by having ethyl plasterone decanoate having .

[0047]

[35] The pharmaceutical composition according to

[33] , characterized in that it does not contain a detectable amount of aviraterone decanoate.

[0048]

[36] The pharmaceutical composition according to any one embodiment of

[33] to

[35] , characterized in that abiraterone decanoate has a palladium content of less than 50 ppm.

[0049]

[37] The pharmaceutical composition according to any one embodiment of

[33] to

[35] , characterized in that abiraterone decanoate has a palladium content of less than 10 ppm.

[0050]

[38] A method for treating or preventing a disease or disorder of a subject requiring the treatment thereof, comprising the step of administering an effective amount of a pharmaceutical composition according to any one embodiment of [1] to

[37] to the subject, wherein the disease or disorder is selected from sex hormone-dependent benign or malignant disorders, androgen receptor-induced cancers, syndromes resulting from androgen excess, and syndromes resulting from 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, classical or non-classical congenital adrenal hyperplasia, precocious puberty, male-pattern 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 sialolar carcinoma or androgen receptor-positive glioblastoma pleomorphon.

[0054]

[42] The method according to

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

[0055]

[43] The method according to

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

[0056]

[44] The method according to

[42] , wherein the prostate cancer is localized prostate cancer, for example, 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 described in

[42] , wherein the prostate cancer is a 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 according to

[42] , wherein the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC) and the disease has progressed in or after a taxane-based chemotherapy regimen, for example, docetaxel-based.

[0061]

[49] The method described in

[42] for prostate cancer being refractory prostate cancer.

[0062]

[50] The method according to any one embodiment of

[38] to

[49] , further comprising the step of treating the subject with radiotherapy or surgery.

[0063]

[51] The method according to any one embodiment of

[38] to

[50] , further comprising the step of administering to one or more other agents selected from anticancer agents, hormone ablation agents, antiandrogens, differentiation agents, antineoplastic agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotics, immunoassay agents, interferon-type agents, inserts, 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 embodiment of

[38] to

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

[0065]

[53] The method of any one embodiment of

[38] to

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

[0066]

[54] The method according to any one embodiment of

[38] to

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

[0067]

[55] The method according to any one embodiment of

[38] to

[53] , wherein the subject is an uncastrated subject.

[0068]

[56] The method according to any one embodiment of

[38] to

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

[0069]

[57] The method according to

[56] , wherein the subject is not treated with a drug selected from buserelin, leuprolide, deslorerin, fertilelin, histrelin, gonadrelin, resirelin, goserelin, nafarelin, peforelin and triptorelin.

[0070]

[58] The method according to

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

[0071]

[59] The method according to any one embodiment of

[55] to

[58] , wherein the subject is sensitive to or otherwise intolerant to a gonadotropin-releasing hormone antagonist and / or agonist.

[0072]

[60] The method according to any one embodiment of

[55] to

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

[0073]

[61] The method according to any one embodiment of

[38] to

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

[0074]

[62] The method according to any one embodiment of

[38] to

[61] , further comprising the step of administering a first-generation androgen receptor antagonist, such as proxaltoamide, bicalutamide, flutamide, nilutamide, or topirutamide.

[0075]

[63] The method according to any one embodiment of

[38] to

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

[0076]

[64] The method according to any one embodiment of

[38] to

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

[0077]

[65] The method of any one embodiment of

[38] to

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

[0078]

[66] The method according to any one embodiment of

[38] to

[65] , further comprising the step of administering an immunotherapy target, for example ciplucel-T, an immune checkpoint inhibitor (for example, an anti-PD-1 antibody, for example pembrolizumab or nivolumab, or an anti-PD-L1 antibody, for example avelumab or atezolizumab), or an anti-CTLA-4 antibody (for example ipilimumab).

[0079]

[67] The method according to any one embodiment of

[38] to

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

[0080]

[68] The method according to any one embodiment of

[38] to

[67] , further comprising the step of administering a kinase inhibitor, such as sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivacertib, onvancertib, ipatasertib, afresertib, alicertib, apitricib, opaganib, etc.

[0081]

[69] The method according to any one embodiment of

[38] to

[68] , further comprising the step of administering a bone protective agent (e.g., denosumab, zoledronic acid) to a subject characterized as having prostate cancer with bone metastases (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, alloblecib, ZEN-3694, or molyblecib (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 according to any one embodiment of

[38] to

[69] , further comprising the step of administering a therapeutic agent selected from, for example, AZD-8186, buparlisib, or dactricib; 11) further nonsteroidal CYP17A1 inhibitors, e.g., ceviteronel; 12) antiprogestogens, e.g., onapristone; 13) navitoclax; 14) HSP90 inhibitors, e.g., onarespib (AT13387); 15) HSP27 inhibitors, e.g., OGX-427; 16) 5-alpha-reductase inhibitors, e.g., dutasteride; 17) metformin; 18) AMG-386; 19) dextromethorphan; 20) theophylline; 21) hydroxychloroquine; and 22) lenalidomide.

[0083]

[71] The method according to any one embodiment of

[38] to

[70] , further comprising the step of administering one or more kinase modulators selected from FLT-3 (FMS-like tyrosine kinase) inhibitors, AXL (anexelekto) inhibitors (e.g., gilteritinib), CDK (cyclin-dependent kinase) inhibitors (e.g., 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 (nucleoprotein 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.

[0084]

[72] The method according to any one embodiment of

[38] to

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

[0085]

[73] The method according to any one embodiment of

[38] to

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

[0086]

[74] The method according to any one embodiment of

[38] to

[73] , wherein the subject is treated with radiotherapy, for example, stereotactic body radiotherapy or neutron irradiation.

[0087]

[75] The method according to any one embodiment of

[38] to

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

[0088]

[76] The method according to

[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 according to

[76] , further comprising the step of administering an aromatase inhibitor, such as exemestane.

[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 embodiment of

[38] to

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

[0092]

[80] The method according to any one embodiment of

[38] to

[79] , wherein the pharmaceutical composition is administered to a subject at a rate ranging from 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 embodiment of

[38] to

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

[0094]

[82] An emulsion comprising (a) abiraterone decanoate; (b) lipids; and (c) a nonionic surfactant, wherein the lipid phase of the emulsion comprises abiraterone decanoate dispersed in lipids, and the abiraterone decanoate has the following structure: [ka] An emulsion containing the following properties.

[0095]

[83] The emulsion according to

[82] , wherein the lipids include medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) (e.g., Labrafac® Lipofil WL1349).

[0096]

[84] The emulsion according to

[82] or

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

[0097]

[85] The emulsion according to any one embodiment of

[82] to

[84] , further comprising propylene glycol monocaprylate (e.g., Capmul PG-8) or propylene glycol monolaurate (e.g., Capmul PG-12 or Lauroglycol® 90).

[0098]

[86] An emulsion according to any one embodiment of

[82] to

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

[0099]

[87] An emulsion according to any one embodiment of

[82] to

[86] , comprising a nonionic surfactant macrogol glycerol hydroxystearate (e.g., Corifor RH40) and / or polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)).

[0100]

[88] The emulsion according to

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

[0101] An emulsion prepared by mixing a pharmaceutical composition described in any one embodiment of

[89] [1] to

[37] with water.

[0102] An emulsion produced by administering a pharmaceutical composition described in any one embodiment of

[90] [1] to

[37] to a mammal.

[0103]

[91] A method for treating or preventing a disease or disorder of a subject requiring the same, comprising the step of administering an effective amount of the emulsion described in any one embodiment of

[82] to

[90] to the subject, wherein the disease or disorder is selected from sex hormone-dependent benign or malignant disorders, androgen receptor-induced cancers, syndromes resulting from androgen excess, and syndromes resulting from glucocorticoid excess.

[0104]

[0013] Embodiments of the present disclosure can satisfy the long-standing urgent 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 can also satisfy the long-standing urgent need in the field of treatment for syndromes resulting from androgen excess and / or glucocorticoid excess, such as hypercortisolemia. Embodiments of the present disclosure can overcome the 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 for administering oral abiraterone prodrug formulations, and kits for convenient administration of formulations to subjects requiring therapy for various disorders, including prostate cancer.

[0105]

[0014] For this reason, the features are outlined rather broadly so that the detailed description of the present invention below may be better understood and the contribution to the art may be better appreciated. Of course, there are additional features which are further described below. In fact, it should be understood that both the general description above and the detailed description below are illustrative and descriptive and intended to provide further explanation of the present disclosure.

[0106]

[0015] Before describing at least one embodiment in detail in this aspect, it should be understood that the present invention is not limited to the structural details and arrangement of components described below or illustrated in the drawings. Other embodiments of the present invention are possible and can be carried out and implemented in various ways. It should also be understood that the language and terminology used herein are for illustrative purposes only and should not be considered limiting.

[0107]

[0016] Thus, those skilled in the art will understand that the concepts on which this disclosure is based can be readily used as a basis for designing other formulations, methods, systems, kits, and compositions to accomplish some of the purposes of this disclosure. It is therefore important that equivalent structures be included in this disclosure without departing from the spirit and scope of this disclosure.

[0108]

[0017] The accompanying drawings are included to provide further understanding, are incorporated herein and constitute part of this specification, illustrate several embodiments and explain the principles together with the descriptions. [Brief explanation of the drawing]

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

[0110]

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

[0111]

[0040] As detailed in U.S. Patent No. 10,792,292B2 and U.S. Provisional Patent Applications No. 63 / 073,502 and No. 63 / 149,550 (the contents of each are incorporated herein by reference in their entirety), parenteral administration of abiraterone prodrugs such as abiraterone decanoate may be advantageous in many respects over existing methods, including a rapid and sustained decrease in serum testosterone, no need for castration, lower or no hepatotoxicity compared to methods using oral abiraterone acetate formulations, improved bioavailability, elimination of the food effect associated with oral abiraterone acetate formulations, reduced pill load, better patient adherence, reduced dosing frequency, sustained and stable blood levels of the active ingredient, and reduced C levels in relation to side effects. max This includes, but is not limited to, a decline in [something].

[0112]

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

[0113]

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

[0114] Abiraterone decanoate preparation

[0043] In some embodiments, the present disclosure relates to abiraterone prodrugs, such as abiraterone lipophilic esters, in particular the following structures: [ka] The present invention provides various formulations containing abiraterone decanoate, which has the following properties:

[0115]

[0044] Typically, the pharmaceutical compositions of this specification comprise (a) abiraterone decanoate; and (b) a lipid-based drug delivery system, which is formulated for oral delivery of abiraterone decanoate.

[0116]

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

[0117]

[0046] In some embodiments, the pharmaceutical compositions herein are characterized in that, when administered orally to mammals, at least a portion of abiraterone decanoate can be delivered via the lymphatic delivery system. Lymphatic delivery of lipid-based drug delivery systems can bypass first-pass metabolism and may result in a better overall pharmacokinetic profile. See 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 the exemplary oral formulations herein achieved excellent oral bioavailability in rat pharmacokinetic studies, but also potently reduced circulating androgen levels (androstenedione and testosterone) and increased progesterone levels. While we do not wish to be bound by theory, it is thought that at least a portion of abiraterone decanoate is absorbed through the lymphatic system upon oral administration to mammals of pharmaceutical compositions containing abiraterone decanoate herein (e.g., any of those described herein, e.g., in the Summary section [1]-

[37] ). Lymphatic delivery is also supported by the histological studies herein showing that abiraterone was detected in tissue 72 hours after administration in the mandibular and mesenteric lymph nodes.

[0118]

[0047] The pharmaceutical compositions described herein are typically formulated in the form of oral dosage forms such as capsules (e.g., softgel capsules).

[0119]

[0048] The pharmaceutical compositions of this specification (for example, any of those described herein, e.g., in Sections [1] to

[37] of the Summary of this Specification) are also typically characterized by one or more of the following: (1) the pharmaceutical composition is stable when stored 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 administered orally to a mammal, the pharmaceutical composition is capable of delivering to the mammal an amount of abiraterone decanoate sufficient to achieve a therapeutically effective plasma concentration of abiraterone for treating a disease or disorder described herein, such as prostate cancer as described herein. Where used herein, “in vitro dispersion test” should be understood to mean using a procedure that follows the procedure described in Example 4 of this application. "Stable storage" means that, under storage conditions and for a storage period, for example at room temperature for one month or longer (e.g., about one month, about three months, about six months, or longer), the pharmaceutical composition (1) contains substantially the same amount, e.g., 80-125% of the amount of abiraterone decanoate at the start of storage; (2) contains substantially the same amount, e.g., 80-125% of the amount of impurities (total impurities and / or individual impurities) at the start of storage; and / or (3) has no substantial change in its physical properties, for example, the appearance and dispersibility of the aqueous solution remain substantially the same as at the start of storage.

[0120]

[0049] In preferred embodiments, the pharmaceutical compositions of this specification (for example, any of those described herein, e.g., in the Summary section [1] to

[37] of this specification) may have an oral bioavailability of more than 30% based on the abiraterone plasma concentration profile when tested in rats. Oral bioavailability can be readily determined by those skilled in the art. An exemplary method for determining the oral bioavailability of rats is shown in the Examples section of this specification.

[0121] Lipid-based drug delivery systems

[0050] The lipid-based drug delivery systems described herein typically comprise one or more lipids and one or more surfactants. Suitable lipids and surfactants, and their amounts, include those generally accepted for pharmaceutically acceptable use, such as those listed in the inactive ingredients database from the U.S. Food and Drug Administration. Specific lipids and surfactants for the pharmaceutical compositions described herein can typically be selected based on the solubility of abiraterone decanoate, the stability of the pharmaceutical composition, the compatibility of the additives, and the dispersibility of the pharmaceutical composition in aqueous solutions. For example, in some embodiments, the lipids and surfactants are selected so that the pharmaceutical composition may have abiraterone decanoate dissolved or suspended in the lipid-based drug delivery system at concentrations ranging from about 1 mg / g to about 250 mg / g. Obviously, a concentration of 250 mg / g means that there are 250 mg of abiraterone decanoate per gram of each gram of the mixture of abiraterone decanoate in the lipid-based drug delivery system. The concentrations of abiraterone decanoate in lipid-based drug delivery systems described elsewhere in this disclosure should be understood similarly. Preferably, the lipids and surfactants are selected so that the pharmaceutical composition may have abiraterone decanoate dissolved in a 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 so that the pharmaceutical composition can be stored stably at room temperature for, for example, one month, three months, six months, or longer. In some embodiments, the lipids and surfactants are selected so that the pharmaceutical composition contains a solution (or homogeneous mixture) of abiraterone decanoate in a lipid-based drug delivery system at room temperature, and the solution (or homogeneous mixture) may remain in solution (or homogeneous) after storage at room temperature for one month, three months, six months, or longer, i.e., without forming visible crystals / precipitation of the drug and / or additives. 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 values ​​described) when the pharmaceutical composition is evaluated using an in vitro dispersion test.In some embodiments, the lipids and surfactants are selected so that, when administered orally to mammals, the pharmaceutical composition can deliver to mammals an amount sufficient to achieve a therapeutically effective plasma concentration of abiraterone to treat, for example, a disease or disorder described herein, such as prostate cancer described herein. In some embodiments, the lipids and surfactants are selected so that, when administered orally to mammals, the pharmaceutical composition can deliver to mammals an amount sufficient to achieve an effective plasma concentration of abiraterone to inhibit, for example, CYP17A1. In some embodiments, the lipids and surfactants are selected so that, when tested in rats, the pharmaceutical composition herein may have an oral bioavailability of more than 30%, for example, up to 60%, 70%, or more, based on the abiraterone plasma concentration profile.

[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 nonionic surfactants.

[0123]

[0052] In some embodiments, the lipid-based drug delivery systems of this specification include (1) lipids comprising triglycerides, monoglycerides, diglycerides, and / or propylene glycol esters; and (2) surfactants such as nonionic surfactants. 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 of fatty acids, and propylene glycol esters as used herein should be understood as mono or diesters of propylene glycol of fatty acids, and fatty acids may typically be, but not limited to, medium-chain or long-chain fatty acids, which may be saturated or unsaturated, for example. Those skilled in the art will understand that medium-chain fatty acids contain an aliphatic tail of 6 to 12 carbon atoms, and long-chain fatty acids contain an aliphatic tail of 13 to 21 carbon atoms. Some triglycerides, monoglycerides, diglycerides, or propylene glycol esters may also be considered surfactants. However, when used herein, it should be understood that the surfactants for lipid-based drug delivery systems 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 systems or pharmaceutical compositions herein, only these surfactants that are not triglycerides, monoglycerides, diglycerides, or propylene glycol esters should be considered, unless otherwise specified or reversed.

[0124]

[0053] In some embodiments, the lipid-based drug delivery system according to this specification comprises (1) triglycerides, monoglycerides, diglycerides, and / or propylene glycol esters; and (2) surfactants comprising polyglyceryl esters and / or polyoxyglycerides. In some embodiments, the lipid-based drug delivery system according to this specification comprises triglycerides and surfactants. In some embodiments, the lipid-based drug delivery system according to this specification comprises diglycerides and surfactants. In some embodiments, the lipid-based drug delivery system according to this specification comprises monoglycerides and surfactants. In some embodiments, the lipid-based drug delivery system according to this specification comprises propylene glycol esters and surfactants. In some embodiments, the lipid-based drug delivery system according to this specification comprises (1) triglycerides and one or more selected from monoglycerides, diglycerides, and propylene glycol esters, and (2) surfactants. In some embodiments, the lipid-based drug delivery system according to this specification comprises (1) triglycerides and propylene glycol esters, and (2) surfactants. In some embodiments, the lipid-based drug delivery systems described herein include (1) triglycerides, monoglycerides, and diglycerides; and (2) surfactants. In some embodiments, the lipid-based drug delivery systems described herein include (1) triglycerides, monoglycerides, diglycerides, and propylene glycol esters; and (2) surfactants. Suitable triglycerides, monoglycerides, diglycerides, propylene glycol esters, and surfactants include any combination of those described herein.

[0125]

[0054] In some embodiments, the lipid-based drug delivery systems of this specification include (1) medium-chain triglycerides; and (2) surfactants, such as nonionic surfactants. The medium-chain triglycerides are not particularly limited. For example, in some embodiments, the medium-chain triglycerides may be medium-chain triglycerides of caprylic acid (C8) and capric acid (C10), such as those commercially available under the trade name: LabraFac® Lipofil WL1349. In some embodiments, the surfactants include polyglyceryl esters and / or polyoxyglycerides.

[0126]

[0055] In some embodiments, the lipid-based drug delivery systems of this specification include monoglycerides and / or diglycerides. For example, in some embodiments, the lipid-based drug delivery system includes glycerol / glyceryl linoleate, for example, derived from a product commercially available under the trademark name: Mycin® CC, which is predominantly a diester fraction, mainly linoleic acid (C 18:2 ) and oleic acid (C 18:1 It is thought to contain mono, di, and triglycerides.

[0127]

[0056] In some embodiments, the lipid-based drug delivery systems of this specification include propylene glycol esters. Preferred propylene glycol esters include, for example, propylene glycol monocaprylate (e.g., marketed under the trade name: Capmul PG-8) and / or propylene glycol monolaurate (e.g., marketed under the trade name: Capmul PG-12, or Lauroglycol® 90).

[0128]

[0057] In some embodiments, the lipid-based drug delivery systems described herein include medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) (e.g., Labrafac® Lipofil WL1349), as well as surfactants described herein.

[0129]

[0058] In some embodiments, the lipid-based drug delivery systems of this specification include (1) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) (e.g., Labrafac® Lipofil WL1349); (2) glycerol / glyceryl linoleate (e.g., Mycin® CC, mainly linoleic acid (C)). 18:2 ) and oleic acid (C 18:1 ) predominantly consisting of mono, di, and triglyceride and diester fractions; and including surfactants as described herein. In such embodiments (for example, any of the applicable embodiments described herein, e.g., sections [6]-

[16] and

[19] -

[37] of the summary section herein), the weight ratio of medium-chain triglycerides 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 values ​​described herein.

[0130]

[0059] In some embodiments, the lipid-based drug delivery systems of this specification include (1) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) (e.g., Labrafac® Lipofil WL1349); (2) propylene glycol monocaprylate (e.g., Capmul PG-8); and surfactants as described herein. In such embodiments (e.g., any of the applicable embodiments described herein, e.g., sections [8]-

[16] and

[20] -

[37] of the summary section herein), the weight ratio of the medium-chain triglyceride 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 ​​described.

[0131]

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

[0132]

[0061] In some embodiments, the surfactant in the lipid-based drug delivery system may include polyoxyglycerides. Useful polyoxyglycerides are not particularly limited and include esters formed from fatty acids and ethoxylated glycerols. For example, in some embodiments, the surfactant in the lipid-based drug delivery system may include macrogol glycerol hydroxystearate, for example, commercially available under the trade name: Corifor RH40. In some embodiments, the surfactant in the lipid-based drug delivery system may include oleoyl polyoxyl-6 glyceride, for example, commercially available under the trade name: Labrafil® M1944CS. Chemically, Labrafil® M1944CS is mono, di, and triglycerides, as well as oleic acid (C 18:1 ) may have PEG-6(MW300) mono and diesters. In some embodiments, the surfactant in the lipid-based drug delivery system may include lauroyl polyoxyl-6 glycerides, for example, those commercially available under the trademark name: Labrafil® 2130CS. Chemically, Labrafil® 2130CS is mono, di and triglycerides, as well as lauric acid (C 12) and stearic acid (C 18 It may contain PEG-6 (MW300) mono and diesters.

[0133]

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

[12] -

[16] and

[22] -

[37] of the summary section herein), the weight ratio of macrogol glycerol 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, e.g., about 1.5:1, about 1:1, or about 1:1.5, or any range between the values ​​described.

[0134]

[0063] In some embodiments, the surfactant for the lipid-based drug delivery system may include (1) macrogol glycerol hydroxystearate (e.g., Corifor RH40); (2) polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)); and (3) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS). In such embodiments (for example, any of the applicable embodiments described herein, e.g., sections

[12] -

[16] and

[23] -

[37] of the summary section herein), the weight ratio of macrogol hydroxystearate to polyglyceryl oleate may be 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, or about 1:1.5, or any range between the values ​​described; the weight ratio of macrogol hydroxystearate to oleoyl polyoxyl-6 glyceride may 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, e.g., about 1.5:1, about 1:1, or about 1:1.5, or any range between the values ​​described.

[0135]

[0064] The combinations of lipids and surfactants described herein are not particularly limited. For example, in some preferred embodiments, the lipid-based drug delivery system comprises (a) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10); and (b) macrogol glycerol hydroxystearate (e.g., Colifor RH40). 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, e.g., propylene glycol monocaprylate (e.g., Capmul PG-8). In some embodiments, the lipid-based drug delivery system comprises mono, di, and / or triglycerides, e.g., glycerol / glyceryl linoleate (e.g., Mycin® CC, mainly linoleic acid (C)).18:2 ) and oleic acid (C 18:1 The lipid-based drug delivery system further comprises mono, di, and triglyceride and diester fractions of the above. 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, e.g., polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)). In some embodiments, the lipid-based drug delivery system further comprises a polyoxyglyceride, e.g., oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS).

[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) macrogol glycerol hydroxystearate (e.g., Colifor RH40); and (c) polyglyceryl oleate (e.g., Plurol 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, e.g., propylene glycol monocaprylate (e.g., Capmul PG-8). In some embodiments, the lipid-based drug delivery system comprises mono, di, and / or triglycerides, e.g., glycerol / glyceryl linoleate (e.g., Mycin® CC, mainly linoleic acid (C)). 18:2 ) and oleic acid (C 18:1The system further comprises mono, di, and triglyceride and diester fractions of the above. 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 polyoxyglyceride, such as oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS).

[0137]

[0066] In some preferred embodiments, the lipid-based drug delivery system comprises (a) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10); (b) macrogol glycerol hydroxystearate (e.g., Colifor RH40); and (c) propylene glycol monocaprylate (e.g., Capmul PG-8). 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, e.g., polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)). In some embodiments, the lipid-based drug delivery system further comprises a polyoxyglyceride, e.g., oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS).

[0138]

[0067] In some preferred embodiments, the lipid-based drug delivery system includes (a) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10); (b) macrogol glycerol hydroxystearate (e.g., Colifor RH40); and (c) glycerol / glyceryl linoleate (e.g., Mycin® CC, mainly linoleic acid (C)). 18:2 ) and oleic acid (C 18:1The system comprises mono, di, and triglyceride and diester fractions of the above. 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, e.g., polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)). In some embodiments, the lipid-based drug delivery system further comprises a polyoxyglyceride, e.g., 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) macrogol glycerol hydroxystearate (e.g., Corifor RH40); (c) polyglyceryl oleate (e.g., Plurol 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) macrogol glycerol hydroxystearate (e.g., Corifor RH40); (c) polyglyceryl oleate (e.g., Plurol 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 acid (C8) and capric acid (C10); (b) macrogol glycerol hydroxystearate (e.g., Corifor RH40); (c) polyglyceryl oleate (e.g., Plurol 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]

[0070] In some specific embodiments, the lipid-based drug delivery system includes (a) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10); (b) macrogol glycerol hydroxystearate (e.g., Corifor RH40); (c) polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)); (d) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS); and (e) glycerol / linoleyl glyceride (e.g., Mycin® CC, mainly linoleic acid (C)). 18:2 ) and oleic acid (C 18:1 It may contain (primarily mono, di, and triglyceride and diester fractions).

[0142]

[0071] The weight percentages of the components of the lipid-based drug delivery system are not particularly limited. For example, in some embodiments, triglycerides, monoglycerides, diglycerides, and / or propylene glycol esters may be in amounts of about 10 to 80% by weight of the lipid-based drug delivery system (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, or any range between the values ​​described), and surfactants may be in amounts of about 20 to 90% by weight of the lipid-based drug delivery system (e.g., about 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or any range between the values ​​described, e.g., about 50 to 80% or about 40 to 60%).

[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 amounts of about 10 to 40% by weight of the lipid-based drug delivery system (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 ​​described, e.g., about 20 to 40% by weight or 10 to 30% by weight); and (b) macrogol glycerol hydroxystearate (e.g., Colifor RH40) in amounts of about 10 to 30% by weight of the lipid-based drug delivery system (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 ​​described). 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 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 values ​​described) of a propylene glycol ester, such as propylene glycol monocaprylate (e.g., Capmul PG-8). In some embodiments, the lipid-based drug delivery system contains about 10–40% by weight of mono, di, and / or triglycerides, such as glycerol / glyceryl linoleate (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the values ​​described), in the lipid-based drug delivery system. 18:2 ) and oleic acid (C 18:1The lipid-based drug delivery system further comprises mono, di, and triglyceride and diester fractions 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 about 10 to 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 ​​described) of a second polyglyceryl ester, such as polyglyceryl oleate (e.g., Plurol Oleic CC497 (Polyglyceryl-3 Dioleate)) of the lipid-based drug delivery system. In some embodiments, the lipid-based drug delivery system further comprises about 10 to 40% by weight of the lipid-based drug delivery system (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 ​​described, e.g., about 20 to 40% by weight or 10 to 30% by weight, etc.) of polyoxyglycerides, such as oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M1944CS).

[0144]

[0073] In some preferred embodiments, the lipid-based drug delivery system includes (a) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) in amounts of about 10 to 40% by weight of the lipid-based drug delivery system (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 ​​described, e.g., about 20 to 40% by weight or 10 to 30% by weight); and (b) about 10 to 30% by weight of the lipid-based drug delivery system (e.g., about 10% by weight (c) a lipid-based drug delivery system comprising (c) macrogol glycerol hydroxystearate (e.g., Colifor RH40) in amounts of approximately 15% by weight, approximately 20% by weight, approximately 25% by weight, approximately 30% by weight, or any range between the values ​​described; and (d) polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)) in amounts of approximately 10–30% by weight (e.g., approximately 10% by weight, approximately 15% by weight, approximately 20% by weight, approximately 25% by weight, approximately 30% by weight, or any range between the values ​​described). 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 about 10 to 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 ​​described) of 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 about 10 to 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 ​​described) of 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 18:1The lipid-based drug delivery system further comprises mono, di, and triglyceride and diester fractions (which are predominant). 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 about 10 to 40% by weight of the lipid-based drug delivery system (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 ​​described, e.g., about 20 to 40% by weight or 10 to 30% by weight, etc.) of polyoxyglycerides, such as oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS).

[0145]

[0074] In some preferred embodiments, the lipid-based drug delivery system includes (a) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) in amounts of about 10 to 40% by weight of the lipid-based drug delivery system (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the values ​​described); and (b) about 10 to 30% by weight of the lipid-based drug delivery system (e.g., about 10%, about 15%, about 2%) (c) a lipid-based drug delivery system comprising (c) an amount of macrogol glycerol hydroxystearate (e.g., Corifor RH40) in an amount of 0% by weight, about 25% by weight, about 30% by weight, or any range between the values ​​described herein; and (c) an amount of propylene glycol monocaprylate (e.g., Capmul PG-8) 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 values ​​described herein). 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 about 10 to 30% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the values ​​described) of a second polyglyceryl ester, such as polyglyceryl oleate (e.g., Plurol Oleic CC497 (Polyglyceryl-3 Dioleate)) of the lipid-based drug delivery system. In some embodiments, the lipid-based drug delivery system further comprises about 10 to 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 ​​described, e.g., about 20 to 40% or 10 to 30%) of a polyoxyglyceride, such as oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) of the lipid-based drug delivery system.

[0146]

[0075] In some preferred embodiments, the lipid-based drug delivery system comprises (a) about 10 to 40% by weight of the lipid-based drug delivery system (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 ​​described) of medium-chain triglycerides of caprylic acid (C8) and capric acid (C10); (b) about 10 to 30% by weight of the lipid-based drug delivery system (e.g., about 10% by weight, about 15% by weight, about 20% by weight, (c) a lipid-based drug delivery system in an amount of macrogol glycerol hydroxystearate (e.g., Colifor RH40) in an amount of approximately 25% by weight, approximately 30% by weight, or any range between the values ​​listed; and (c) a lipid-based drug delivery system in an amount of approximately 10-40% by weight (e.g., approximately 10% by weight, approximately 15% by weight, approximately 20% by weight, approximately 25% by weight, approximately 30% by weight, approximately 35% by weight, approximately 40% by weight, or any range between the values ​​listed); and (c) a lipid-based drug delivery system in an amount of approximately 10-40% by weight (e.g., approximately 10% by weight, approximately 15% by weight, approximately 20% by weight, approximately 25% by weight, approximately 30% by weight, approximately 35% by weight, approximately 40% by weight), mainly linoleic acid (C) 18:2 ) and oleic acid (C 18:1 The system comprises mono, di, and triglyceride and diester fractions of the above. 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 about 10 to 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 ​​described) of a second polyglyceryl ester, such as polyglyceryl oleate (e.g., Plurol Oleic CC497 (Polyglyceryl-3 Dioleate)) of the lipid-based drug delivery system. In some embodiments, the lipid-based drug delivery system further comprises about 10 to 40% by weight of the lipid-based drug delivery system (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 ​​described, e.g., about 20 to 40% by weight or 10 to 30% by weight, etc.) of polyoxyglycerides, such as oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M1944CS).

[0147]

[0076] In some preferred embodiments, the lipid-based drug delivery system comprises: (a) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) in amounts of about 20–40% by weight (e.g., about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the values ​​described) of the lipid-based drug delivery system; and (b) macrogol glycerol hydroxystearate (e.g., Corifor RH4) in amounts of about 10–30% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the values ​​described) of the lipid-based drug delivery system. (0); (c) an amount of polyglyceryl oleate (e.g., Plurol Oleic CC497 (Polyglyceryl-3 Dioleate)) in about 10 to 30% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the values ​​described) of a lipid-based drug delivery system; and (d) an amount of oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) in about 20 to 40% by weight (e.g., about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the values ​​described) of a lipid-based drug delivery system.

[0148]

[0077] In some preferred embodiments, the lipid-based drug delivery system includes (a) about 10 to 40% by weight of the lipid-based drug delivery system (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 ​​described) of medium-chain triglycerides of caprylic acid (C8) and capric acid (C10); and (b) about 10 to 30% by weight of the lipid-based drug delivery system. (c) A quantity of macrogol glycerol hydroxystearate (e.g., Colifor RH40) in weight percent (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 ​​listed); (c) A quantity of olein in weight 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 ​​listed) in a lipid-based drug delivery system. (d) an amount of oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) in a lipid-based drug delivery system in an amount of about 10 to 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 ​​listed); and (e) The lipid-based drug delivery system may contain 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 values ​​described) of propylene glycol monocaprylate (e.g., Capmul PG-8) and / or propylene glycol monolaurate (e.g., Capmul PG-12, or Lauroglycol® 90).

[0149]

[0078] In some preferred embodiments, the lipid-based drug delivery system includes: (a) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) in amounts of about 10 to 40% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%) of the lipid-based drug delivery system; (b) macrogol glycerol hydroxystearate (e.g., Colifor RH40) in amounts of about 10 to 30% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%) of the lipid-based drug delivery system; and (c) about 10 to 30% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%) of the lipid-based drug delivery system. (d) a lipid-based drug delivery system comprising (a) an amount of polyglyceryl oleate (e.g., Plurol Oleic CC497 (Polyglyceryl-3 Dioleate)) in a quantity of % or any range between the stated values; (a) an amount of oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) in a quantity of about 10 to 40% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the stated values); and (e) a lipid-based drug delivery system comprising an amount of propylene glycol monocaprylate (e.g., Capmul PG-8) in a quantity of about 10 to 40% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the stated values).

[0150]

[0079] In some specific embodiments, the lipid-based drug delivery system includes: (a) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) in amounts of about 10 to 40% by weight of the lipid-based drug delivery system (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the values ​​described); (b) macrogol glycerol hydroxystearate (e.g., Colifor RH40) in amounts of about 10 to 30% by weight of the lipid-based drug delivery system (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the values ​​described); (c) about 10 to 30% by weight of the lipid-based drug delivery system (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or (d) an amount of polyglyceryl oleate (e.g., Plurol Oleic CC497 (Polyglyceryl-3 Dioleate)) in any range between the values ​​listed; (d) an amount of oleoyl polyoxyl 2-glyceride (e.g., Labrafil® M1944CS) in any range between 0 and 40 wt of a lipid-based drug delivery system (e.g., 0 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, or any range between the values ​​listed); and (e) an amount of glycerol / linoleyl glyceryl (e.g., Mycin® CC, mainly linoleic acid (C)) in any range between 10 and 40 wt of a lipid-based drug delivery system (e.g., 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, or any range between the values ​​listed). 18:2 ) and oleic acid (C 18:1 It may contain (primarily mono, di, and triglyceride and diester fractions).

[0151]

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

[0152]

[0081] In some embodiments, the lipid-based drug delivery system may contain about 20% by weight of Corifoll RH40, about 14% by weight of Plurol Oleic CC497, about 33% by weight of Labrafil 1944CS, and about 33% by weight of Labrafac Lipofil WL1349. "About" means within 25% of the stated values. For example, about 20% in such embodiments means 15% to 25%.

[0153]

[0082] In some embodiments, the lipid-based drug delivery system may contain about 20% by weight of colifor RH40, about 14% by weight of plurol oleic CC497, and about 66% by weight of lauroglycol 90, where “about” means within 25% of the stated values.

[0154]

[0083] In some embodiments, the lipid-based drug delivery system may contain about 20 wt% Corifoll RH40, about 14 wt% Plurol Oleic CC497, about 16 wt% Labrafil 1944CS, about 30 wt% Mycin CC, and about 20 wt% Labrafac Lipofil WL1349, where “about” means within 25% of the stated values.

[0155]

[0084] In some embodiments, the lipid-based drug delivery system may have about 20% by weight of Corifoll RH40, about 14% by weight of Plurol Oleic CC497, about 16% by weight of Labrafil 1944CS, about 30% by weight of Capmul PG-8, and about 20% by weight of Labrafac Lipofil WL1349, where “about” means within 25% of the stated values.

[0156]

[0085] When a trademark name is used herein, such as those specified in various pharmacopoeias including the USP (United States Pharmacopoeia), the European Pharmacopoeia (PhEur), the Japanese Pharmacopoeia, and the Chinese Pharmacopoeia, it should be understood that this means including any composition that is included in the product specifications related to the trademark name as of the filing date of this application, or, if a common name for such product is available, in the specifications for such general product as of the filing date of this application.

[0157] Abiraterone decanoate

[0086] The pharmaceutical compositions of this specification typically include abiraterone decanoate dispersed in the lipid-based drug delivery system of this specification, for example, uniformly dispersed or dissolved, at concentrations in the range of 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 ​​described, for example, about 10 mg / g to about 150 mg / g, about 20 to 150 mg / g, about 30 to 80 mg / g. In some embodiments, the abiraterone decanoate is dissolved in the lipid-based drug delivery system of this specification.

[0158]

[0087] Abiraterone decanoate is typically present in the pharmaceutical compositions herein in its base form and should be understood as such unless otherwise clearly indicated by the content. However, in some embodiments, the pharmaceutical compositions herein may contain abiraterone decanoate in its base form and / or a pharmaceutically acceptable salt thereof.

[0159]

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

[0160]

[0089] In some embodiments, abiraterone decanoate for the pharmaceutical compositions herein is in a substantially pure form, such as having a purity of more than 80%, preferably more than 90% (e.g., more than 95%, more than 97%, more than 98%, more than 99%, more than 99.5%) by weight and / or HPLC area. In some embodiments, 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%, or any range between predetermined values ​​by weight and / or HPLC area. For example, in some embodiments, 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%, or any range between predetermined values ​​by weight. In some embodiments, abiraterone decanoate for pharmaceutical compositions according to this specification may 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, abiraterone decanoate for pharmaceutical compositions according to this specification conforms to the specifications shown in Table 1 of this specification (see Example 1B). Exemplary procedures for preparing substantially pure abiraterone decanoate are shown in the Examples section. Suitable HPLC methods for determining the purity of abiraterone decanoate are also described in the Examples section. Substantially pure abiraterone decanoate may be in solid form (e.g., crystalline form as described herein, preferably form A, amorphous form, or a combination thereof), or in solution, suspension, or other form. To avoid misunderstanding, a pharmaceutical composition herein comprising substantially pure abiraterone decanoate and one or more other components (e.g., pharmaceutical compositions according to Sections

[33] to

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

[0161] Essentially pure abiraterone decanoate

[0090] In some specific embodiments, the pharmaceutical compositions of this specification comprise substantially pure abiraterone decanoate and have the following formula: [ka] or a pharmaceutically 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, substantially pure abiraterone decanoate has a purity of at least 95% by weight, preferably at least 98%, for example, about 98.5%, about 99%, about 99.5%, or higher. In some embodiments, 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 predetermined values, by weight and / or HPLC area. In some embodiments, 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 predetermined values, by weight. In some embodiments, substantially pure abiraterone decanoate can also be characterized as having a low content of palladium, e.g., 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 residue that can be carried over to the crude abiraterone decanoate product. As described herein, this disclosure shows that by using acetone and water as solvents, and a recrystallization process on activated carbon, the palladium content of abiraterone decanoate can be reduced to less than 5 ppm, particularly 3.7 ppm, in Example 1B. In some embodiments, substantially pure abiraterone decanoate conforms to the specifications shown in Table 1 herein (see Example 1B). In some embodiments, substantially pure abiraterone decanoate contains impurities derived from ethyl plasterone. For example, in some embodiments, substantially pure abiraterone decanoate has the formula: [ka] It contains ethyl plasterone decanoate. 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 of ethyl plasterone decanoate. The amount of ethyl plasterone decanoate can be readily determined by HPLC methods such as those described herein. In some embodiments, substantially pure abiraterone decanoate also does not contain any detectable amount of ethyl plasterone decanoate. The abiraterone starting material is readily available from commercially available sources of high purity. In cross-coupling reactions [ka] Using the process of introducing a 3-pyridyl group to abiraterone, the abiraterone starting material obtained may contain small amounts of impurities that can ultimately be converted to ethyl plasterone. In some embodiments, substantially pure decanoic acid abiraterone is an abiraterone starting material that does not contain any detectable amount of ethyl plasterone, for example, [ka] It can be prepared from a process that does not involve cross-coupling with . Substantially pure aviraterone decanoate may be in solid form, for example, the crystalline form described herein. For example, in some embodiments, substantially pure aviraterone decanoate may be in crystalline form A and can be characterized by an X-ray powder diffraction (XRPD) spectrum having one or more of the following peaks: 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6, and 20.8 degrees 2 theta, ±0.2° (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9); a differential scanning calorimetry (DSC) pattern having an endothermic peak with an onset temperature of about 69.0°C; or a combination thereof. In some embodiments, crystalline morphology A can be characterized by an XRPD spectrum substantially identical to that shown in Figure 2A, for example, the XRPD spectrum showing peaks at each diffraction angle (2 degrees theta, ±0.2°) corresponding to the peaks shown in Figure 2A, regardless of their relative intensities. In some embodiments, crystalline morphology A can be characterized by a DSC spectrum substantially identical to 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 solid forms of abiraterone decanoate, e.g., crystalline forms A, B, and / or C, in a suitable vehicle. However, in some embodiments, the pharmaceutical compositions also include one or more solid forms of abiraterone decanoate. For example, in some embodiments, the pharmaceutical composition may include crystalline form A as described herein. In some embodiments, the pharmaceutical composition may include crystalline form B as described herein. In some embodiments, the pharmaceutical composition may include crystalline form C as described herein.

[0163]

[0092] In some embodiments, the pharmaceutical compositions of this specification may also be prepared from abiraterone decanoate containing crystalline form A. In some embodiments, the pharmaceutical compositions of this specification may be prepared from crystalline form A of abiraterone decanoate and, in XRPD, substantially free of forms B and C of abiraterone decanoate, for example, free of detectable amounts of forms B and C. In some embodiments, the pharmaceutical compositions of this specification may be prepared from crystalline form A of abiraterone decanoate and are characterized as substantially pure, for example, crystalline form A having (1) a palladium content of less than 50 ppm, for example less than 10 ppm; (2) a purity of at least 95% by weight, preferably at least 98%, for example about 98.5%, about 99%, about 99.5%, or higher; (3) formula: [ka] (4) It has 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 ethyl plasterone decanoate; (5) It conforms to the specifications shown in Table 1, or can be characterized as any combination thereof.

[0164]

[0093] In some embodiments, the pharmaceutical compositions of this specification may also be prepared from abiraterone decanoate containing crystalline form B. In some embodiments, crystalline form B may 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 starting temperatures of 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, for example, the XRPD spectrum showing peaks at each diffraction angle (2 theta, ±0.2°) corresponding to the peaks shown in FIG. 2D, regardless of their relative intensity. In some embodiments, crystalline form B can be characterized by a DSC spectrum substantially the same as that shown in Figure 2E. Crystallized 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 then cooling the solution to, for example, about -10°C to about -20°C to form the crystalline form. An exemplary procedure is shown in Example 1C of this specification.

[0165]

[0094] In some embodiments, the pharmaceutical compositions of this specification may also be prepared from abiraterone decanoate containing crystalline form C. In some embodiments, crystalline form C may 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 theta, ±0.2°; a differential scanning calorimetry (DSC) pattern having two endothermic peaks with starting temperatures of 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 that is substantially the same as that shown in FIG. 2G, for example, the XRPD spectrum showing peaks at each diffraction angle (degree theta, ±0.2°) corresponding to the peaks shown in FIG. 2G, regardless of their relative intensity. In some embodiments, crystalline form C can be characterized by a DSC spectrum that is substantially the same as that shown in Figure 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 then reducing the amount of solvent by evaporation or other means to form the crystalline form. An exemplary procedure is shown in Example 1C of this specification.

[0166] Pharmaceutical composition containing a nonionic surfactant

[0095] The pharmaceutical compositions of this specification typically include abiraterone decanoate dissolved in one of the lipid-based drug delivery systems described herein.

[0167]

[0096] In some embodiments, the present disclosure also provides 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 (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, for example, about 30 to 80 mg / g or about 30 to 100 mg / g), wherein the lipid-based drug delivery system comprises: (a) a lipid in an amount of about 10 to 80 weight percent of the lipid-based drug delivery system; and (b) one or more nonionic surfactants in an amount of about 20 to 90 weight percent of the lipid-based drug delivery system, and abiraterone decanoate has the following structure: [Chemical Formula] .

[0168]

[0097] 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, for example 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 particularly limited and may include any of the triglycerides, monoglycerides, diglycerides, and / or propylene glycol esters described herein.

[0170]

[0099] Suitable nonionic surfactants are also not particularly limited and may include any of those described herein.

[0171]

[0100] For example, in some embodiments, the lipid may include medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) (e.g., LabraFac® Lipofil 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® Lipofil WL1349), as well as 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® Lipofil WL1349) and propylene glycol monocaprylate (e.g., Capmul PG-8). Preferred 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 combination described herein.

[0172]

[0101] Typically, a lipid-based drug delivery system comprises two or more nonionic surfactants, for example, two or three nonionic surfactants. For example, in some embodiments, one or more nonionic surfactants include macrogol glycerol hydroxystearate (e.g., Colifor RH40) and / or polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)). In some embodiments, one or more nonionic surfactants include (1) macrogol glycerol hydroxystearate (e.g., Colifor RH40); and (2) polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)). In some embodiments, one or more nonionic surfactants include (1) macrogol glycerol hydroxystearate (e.g., Colifor RH40); (2) polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)); and (3) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS). In some embodiments, one or more nonionic surfactants include (1) macrogol glycerol hydroxystearate (e.g., Colifor RH40); (2) polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)); and (3) lauroyl polyoxyl-6 glyceride (e.g., Labrafil 2130). Preferred amounts, ratios, or weight percentages of macrogol glycerol hydroxystearate, polyglyceryl oleate, oleoyl polyoxyl-6 glyceride, and lauroyl polyoxyl-6 glyceride include any combination of those described herein.

[0173]

[0102] In some specific embodiments, the pharmaceutical composition is lipid-based in a concentration ranging from about 20 mg / g to about 120 mg / g (for example, 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 values ​​described, for example, about 30 to 80 mg / g or about 30 to 100 mg / g). The lipid-based drug delivery system may contain abiraterone decanoate dissolved in it, and the lipid-based drug delivery system may contain (a) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) in amounts of about 20–40% by weight of the lipid-based drug delivery system (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 values ​​described); and (b) about 10–3% by weight of the lipid-based drug delivery system. (c) comprising 0% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the stated values) of macrogol glycerol hydroxystearate (e.g., Corifor RH40); (c) a lipid-based drug delivery system comprising about 10–30% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the stated values) of polyglyceryl oleate (e.g., Plurol Oleic CC497 (Polyglyceryl-3 Dioleate)); and (d) a lipid-based drug delivery system comprising about 20–40% by weight (e.g., about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the stated values) of oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS).

[0174]

[0103] In some specific embodiments, the pharmaceutical composition may contain 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 (for example, 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 values ​​described, for example, about 30 to 80 mg / g or about 30 to 100 mg / g), the lipid-based drug delivery system may (a) lipid-based drug delivery (b) A medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) in amounts of approximately 10–40% by weight of the delivery system (e.g., approximately 10% by weight, approximately 15% by weight, approximately 20% by weight, approximately 25% by weight, approximately 30% by weight, approximately 35% by weight, approximately 40% by weight, or any range between the values ​​listed, e.g., approximately 20–40% by weight or 10–30% by weight, etc.); (b) Macroglycerides of hydroxystearate in amounts of approximately 10–30% by weight of the lipid-based drug delivery system (e.g., approximately 10% by weight, approximately 15% by weight, approximately 20% by weight, approximately 25% by weight, approximately 30% by weight, or any range between the values ​​listed); (c) Polyglyceryl oleate (e.g., Plurol Oleic CC497 (Polyglyceryl-3 Dioleate)) in amounts of about 10 to 30% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%) of a lipid-based drug delivery system; (d) About 10 to 40% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%) of a lipid-based drug delivery system; (e) comprising (e) an amount of oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) in any range between the values ​​described, for example, about 20-40% by weight or 10-30% by weight; and (e) an amount of propylene glycol monocaprylate (e.g., Capmul PG-8) in any range between 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 ​​described, for example, about 20-40% by weight or 10-30% by weight).

[0175]

[0104] In some specific embodiments, the pharmaceutical composition is dissolved in a lipid-based drug delivery system at a concentration in the range of about 20 mg / g to about 120 mg / g (for example, 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 values ​​described, for example, about 30 to 80 mg / g or about 30 to 100 mg / g). The lipid-based drug delivery system may contain abiraterone benzoate, and the lipid-based drug delivery system includes (a) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) in amounts of about 10 to 40% by weight of the lipid-based drug delivery system (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 ​​described, e.g., about 20 to 40% by weight or 10 to 30% by weight, etc.); and (b) about 1 (c) Macrogol glycerol hydroxystearate (e.g., Colifor RH40) in amounts of 0-30% by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%) or any range between the values ​​listed); (c) Polyglyceryl oleate (e.g., about 10%, about 15%, about 20%, about 25%, about 30%) or any range between the values ​​listed) of a lipid-based drug delivery system For example, Plurololeic CC497 (polyglyceryl-3 dioleate); (d) an amount of oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) in a lipid-based drug delivery system 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 values ​​listed, e.g., about 20 to 40% by weight or 10 to 30% by weight, etc.);(e) comprising about 10–40% by weight of a lipid-based drug delivery system (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 ​​described, e.g., about 20–40% by weight or 10–30% by weight, etc.) of propylene glycol monolaurate (e.g., Capmul PG-12, or Lauroglycol® 90);

[0176]

[0105] In some specific embodiments, the pharmaceutical composition is dissolved in a lipid-based drug delivery system at a concentration in the range of about 20 mg / g to about 120 mg / g (for example, 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 values ​​described, for example, about 30 to 80 mg / g or about 30 to 100 mg / g, etc.) The lipid-based drug delivery system may contain (a) medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) in amounts of about 10-40% by weight of the lipid-based drug delivery system (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 ​​described, e.g., about 20-40% by weight or 10-30% by weight, etc.); (b) about 10- (c) (d) an amount of oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS) in a lipid-based drug delivery system of about 0 to 40% by weight (e.g., 0%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the values ​​listed, e.g., about 20-40% or 10-30% by weight, etc.);(e) a lipid-based drug delivery system 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 ​​described, e.g., about 20–40% by weight or 10–30% by weight, etc.) glycerol / glyceryl linoleate (e.g., Mycin® CC, mainly linoleic acid (C); 18:2 ) and oleic acid (C 18:1 It contains (primarily 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 of this specification; see, for example, Examples 2 and 3.

[0178]

[0107] In some embodiments, the pharmaceutical composition may comprise abiraterone decanoate dissolved in a lipid-based drug delivery system having about 20% by weight of Corifor RH40, about 14% by weight of Plurol Oleic CC497, about 33% by weight of Labrafil 1944CS, and about 33% by weight of Labrafac Lipofil WL1349. "About" means within 25% of the stated values. Abiraterone decanoate is typically dissolved in lipid-based drug delivery systems at concentrations ranging from approximately 20 mg / g to approximately 120 mg / g (e.g., approximately 20 mg / g, approximately 30 mg / g, approximately 40 mg / g, approximately 50 mg / g, approximately 60 mg / g, approximately 70 mg / g, approximately 80 mg / g, approximately 90 mg / g, approximately 100 mg / g, approximately 120 mg / g, or any range between the values ​​listed, e.g., approximately 30–80 mg / g or approximately 30–100 mg / g) at maximum solubility.

[0179]

[0108] In some embodiments, the pharmaceutical composition may comprise abiraterone decanoate dissolved in a lipid-based drug delivery system having about 20% by weight of colifor RH40, about 14% by weight of plurol oleic CC497, and about 66% by weight of lauroglycol 90. "About" means within 25% of the stated values. Abiraterone decanoate is typically dissolved in lipid-based drug delivery systems at concentrations ranging from approximately 20 mg / g to approximately 120 mg / g (e.g., approximately 20 mg / g, approximately 30 mg / g, approximately 40 mg / g, approximately 50 mg / g, approximately 60 mg / g, approximately 70 mg / g, approximately 80 mg / g, approximately 90 mg / g, approximately 100 mg / g, approximately 120 mg / g, or any range between the values ​​listed, e.g., approximately 30–80 mg / g or approximately 30–100 mg / g) at maximum solubility.

[0180]

[0109] In some embodiments, the pharmaceutical composition may comprise abiraterone decanoate dissolved in a lipid-based drug delivery system having about 20% by weight of corifor RH40, about 14% by weight of plurol oleic CC497, about 16% by weight of labrafil 1944CS, about 30% by weight of mycin CC, and about 20% by weight of labrafac lipofil WL1349. "About" means within 25% of the stated values. Abiraterone decanoate is typically dissolved in lipid-based drug delivery systems at concentrations ranging from approximately 20 mg / g to approximately 120 mg / g (e.g., approximately 20 mg / g, approximately 30 mg / g, approximately 40 mg / g, approximately 50 mg / g, approximately 60 mg / g, approximately 70 mg / g, approximately 80 mg / g, approximately 90 mg / g, approximately 100 mg / g, approximately 120 mg / g, or any range between the values ​​listed, e.g., approximately 30–80 mg / g or approximately 30–100 mg / g) at maximum solubility.

[0181]

[0110] In some embodiments, the pharmaceutical composition may comprise abiraterone decanoate dissolved in a lipid-based drug delivery system having about 20% by weight of corifor RH40, about 14% by weight of plurol oleic CC497, about 16% by weight of labrafil 1944CS, about 30% by weight of capmul PG-8, and about 20% by weight of labrafac lipofil WL1349. "About" means within 25% of the stated values. Abiraterone decanoate is typically dissolved in lipid-based drug delivery systems at concentrations ranging from approximately 20 mg / g to approximately 120 mg / g (e.g., approximately 20 mg / g, approximately 30 mg / g, approximately 40 mg / g, approximately 50 mg / g, approximately 60 mg / g, approximately 70 mg / g, approximately 80 mg / g, approximately 90 mg / g, approximately 100 mg / g, approximately 120 mg / g, or any range between the values ​​listed, e.g., approximately 30–80 mg / g or approximately 30–100 mg / g) at maximum solubility.

[0182]

[0111] Pharmaceutical compositions can typically be formulated for oral administration, such as in the form of capsules (e.g., softgel capsules).

[0183]

[0112] In any of the embodiments described herein, unless otherwise specified or contrary to the foregoing, the pharmaceutical compositions herein are also characterized by one or more of the following: (1) the pharmaceutical composition is stable 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 (e.g., 55%, 60%, 70%, 80%, 90%, or up to 100%, or any range between the values ​​described herein); and (3) when administered orally to a mammal, the pharmaceutical composition is capable of delivering to the mammal an amount of abiraterone decanoate sufficient to achieve a therapeutically effective plasma concentration of abiraterone for treating a disease or disorder described herein, such as prostate cancer described herein. For example, in some embodiments, the pharmaceutical composition is stable 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 in solution after being stored at room temperature for one month, three months, six months, or longer, i.e., without forming visible crystals / precipitation of the drug and / or additives. In some embodiments, the pharmaceutical composition is characterized by a recovery of abiraterone decanoate of more than 50% (e.g., 55%, 60%, 70%, 80%, 90%, or up to 100%, or any range between the values ​​described) when the pharmaceutical composition is evaluated using an in vitro dispersion test. In some embodiments, the pharmaceutical composition is characterized by the ability to deliver to a mammal a sufficient amount of abiraterone decanoate to achieve a therapeutically effective plasma concentration of abiraterone for treating, for example, a disease or disorder described herein, such as prostate cancer as described herein. In some embodiments, the pharmaceutical composition is characterized by the ability to deliver to a mammal a sufficient amount of abiraterone decanoate to achieve an effective plasma concentration of abiraterone for, for example, inhibiting CYP17A1 when administered to a mammal.

[0184]

[0113] In any of the embodiments described herein, unless otherwise specified or contrary to the foregoing, the pharmaceutical composition may also be characterized by an oral bioavailability of more than 30%, for example, 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 otherwise specified or otherwise described herein, 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 otherwise specified or otherwise described herein, the pharmaceutical composition may be characterized in that, when administered orally to a mammal, at least a portion of abiraterone decanoate is absorbed through the lymphatic system.

[0187] Method for preparing a pharmaceutical composition

[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, for example, [1] to

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

[0188] Emulsion

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

[0189]

[0118] In some embodiments, the emulsion may comprise (a) abiraterone decanoate; (b) a lipid; and (c) a nonionic surfactant, wherein the lipid phase of the emulsion comprises abiraterone decanoate dispersed in the lipid, and abiraterone decanoate has the following structure: [Chemical Formula] .

[0190]

[0119] Typically, the weight ratio of lipids to nonionic surfactants is in the range of about 5:1 to 1:5, more typically about 2:1 to 1:2, for example, about 2:1, about 1.5:1, about 1:1, about 1:1.5, about 1:2, or any range between the values ​​listed.

[0191]

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

[0192]

[0121] Suitable nonionic surfactants may also include, but are not limited to, any of those described herein.

[0193]

[0122] For example, in some embodiments, the lipid may include medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) (e.g., LabraFac® Lipofil 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® Lipofil WL1349), as well as 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® Lipofil WL1349) and propylene glycol monocaprylate (e.g., Capmul PG-8). Preferred 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 combination described herein.

[0194]

[0123] Typically, the emulsion contains two or more nonionic surfactants, for example, two or three nonionic surfactants. For example, in some embodiments, the nonionic surfactants include macrogol glycerol hydroxystearate (e.g., Colifor RH40) and / or polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)). In some embodiments, the nonionic surfactants include (1) macrogol glycerol hydroxystearate (e.g., Colifor RH40); and (2) polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)). In some embodiments, the nonionic surfactant includes (1) macrogol glycerol hydroxystearate (e.g., Colifor RH40); (2) polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)); and (3) oleoyl polyoxyl-6 glyceride (e.g., Labrafil® M1944CS). In some embodiments, the nonionic surfactant includes (1) macrogol glycerol hydroxystearate (e.g., Colifor RH40); (2) polyglyceryl oleate (e.g., Plurol Oleic CC497 (polyglyceryl-3 dioleate)); and (3) lauroyl polyoxyl-6 glyceride (e.g., Labrafil 2130). Preferred amounts, ratios, or weight percentages of macrogol glycerol hydroxystearate, polyglyceryl oleate, oleoyl polyoxyl-6 glyceride, and lauroyl polyoxyl-6 glyceride include any combination of those described herein.

[0195]

[0124] In some embodiments, the Disclosure also provides emulsions produced by mixing a pharmaceutical composition comprising abiraterone decanoate and a lipid-based drug delivery system of this Spec. (e.g., any of those described herein, e.g., as shown in the Summary section of this Spec. [1] to

[37] ) with water.

[0196]

[0125] In some embodiments, the Disclosure also provides emulsions produced by administering a pharmaceutical composition comprising abiraterone decanoate and a lipid-based drug delivery system of the Spec. (e.g., any of those described herein, e.g., as shown in the Summary section of the Spec. [1] to

[37] ) to a mammal.

[0197] Pharmaceutical composition containing abiraterone prodrug

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

[0198]

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

[0199]

[0128] For example, in some embodiments, the pharmaceutical composition is an abiraterone prodrug of formula I: [ka] (In the formula, R1 R 10 , OR 10 , or NHR 10 And R 10 C 7~30 Alkyl; C 7~30 Alkenil; C 7~30 Alkynyl; alkyls substituted with cycloalkyl and typically having a total of 5 to 16 carbon atoms; alkyls substituted with phenyl and typically having a total of 7 to 16 carbon atoms; cycloalkyls optionally substituted with one or more alkyls and typically having a total of 5 to 16 carbon atoms; and [ka] (Selected from branched-chain C5 or C6 alkyl groups) Or it may contain a pharmaceutically acceptable salt thereof.

[0200]

[0129] In some embodiments, R 10 C 7~30 It is alkyl. Where used herein, alkyl should be understood as unsubstituted unless explicitly stated to be substituted. However, alkyl can be either linear or branched. In some embodiments, R 10 is a linear C 7~30 It may be alkyl. In some embodiments, R 10 is branched chain C 7~30 It may be alkyl. In some embodiments, R 10 is a linear C 7~16 It is alkyl, for example, R 10 This is the formula -(CH2) n -CH3 may have -CH3, where n is an integer between 6 and 15 (e.g., 6 to 12, e.g., 6, 7, 8, 9, 10, 11, or 12). In some embodiments, R 10 is branched chain C 7~16 It can be alkyl.

[0201]

[0130] In some embodiments, R 10 It can also be an alkyl substituted with a cycloalkyl. Typically, in such embodiments, R10 It has a total of 5 to 16 carbon atoms, i.e., the total number of carbon atoms from the alkyl and cycloalkyl moieties is 5 to 16. Cycloalkyls are typically unsubstituted. However, in some embodiments, the cycloalkyl is optionally composed of, for example, one or two lower alkyl groups (e.g., C 1~4 It can be substituted with alkyl. In some embodiments, R 10 C 3~6 It can be an alkyl group substituted with a cycloalkyl group, and typically has a total of 6 to 12 carbon atoms. In some embodiments, R 10 C 3~6 It can be a linear alkyl group substituted with a cycloalkyl group, for example, R 10 This is the formula -(CH2) n -Cy may have -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 It is a cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, R 10 This is the formula -(CH2) n -Cy may be present, n is 1 or 2, and Cy is cyclopentyl or cyclohexyl. In some embodiments, R 10 Also, C 3~6 Branched alkyl groups substituted with cycloalkyl groups (e.g., branched C 2~6 ) may be. As used herein, the branched C2 alkyl should be understood as a 1,1-disubstituted ethyl group, for example, -CH(CH3)-Cy.

[0202]

[0131] In some embodiments, R 10 It can also be a phenyl-substituted alkyl. Typically, in such embodiments, R 10 It has a total of 7 to 16 carbon atoms, i.e., the total number of carbon atoms from the alkyl and phenyl parts is 5 to 16. In some embodiments, R 10 R can be a linear alkyl group substituted with phenyl, for example, 10 This is the formula -(CH2) nmay have -Cy, n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is phenyl. In some embodiments, R 10 is of the formula -(CH2) n -Cy, n is 1 or 2, and Cy is phenyl. In some embodiments, R 10 can also be branched alkyl substituted with phenyl (e.g., branched C 2~6 ). Phenyl is typically unsubstituted. However, in some embodiments, phenyl can be optionally substituted with, for example, one or two lower alkyl groups (e.g., C 1~4 alkyl).

[0203]

[0132] In some embodiments, R 10 can be cycloalkyl optionally substituted with one or more alkyl groups. In such embodiments, R 10 typically has a total of 5 to 16 carbons, that is, the total number of carbons of the cycloalkyl and its optional substituents is 5 to 16. In some embodiments, R 10 is either unsubstituted or substituted with C 1~4 alkyl, and can be C 3~6 cycloalkyl. In some specific embodiments, R 10 is

Chemical Formula

[0204]

[0133] In some embodiments, R 10 can be branched C5 or C6 alkyl. In some embodiments, R 10 is

Chemical Formula

[0205]

[0134] In some embodiments, R 10 is C 7~30alkenyl or C 7~30 it may be an unsaturated aliphatic group such as alkynyl.

[0206]

[0135] In some embodiments, the compound of formula I is an ester of abiraterone, for example, R 1 is R 10 and R 10 is as defined herein. In some embodiments, R of formula I 1 is C 7~16 alkyl, for example, it may be alkyl having the formula -(CH2) n -CH3, and n is an integer of 6 to 12 (e.g., 6, 7, 8, 9, 10, 11, or 12). In some embodiments, R of formula I 1 is represented by the formula -(CH2) n -Cy, n is an integer of 1 to 6, and Cy is C 3~6 cycloalkyl or phenyl; for example, in more specific embodiments, n can be 1 or 2, and Cy is cyclopentyl, cyclohexyl, or phenyl. In some embodiments, R of formula I 1 is Chemical Formula and may be as above. In some specific embodiments, R of formula I 1 is Chemical Formula and may be as above. Other suitable groups for R 1 include any of R 10 as defined herein.

[0207]

[0136] In some embodiments, R of formula I 1 can also be O-R 10 or NHR 10 and R 10 is as defined herein.

[0208]

[0137] In some embodiments, the pharmaceutical composition may comprise a compound of formula II, or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R 2 (as defined herein)

[0209]

[0138] In some embodiments, R 2 The compound of formula II can be selected to be an ester, a carbamate, or a carbamate of abiraterone. In some embodiments, R 2 R 20 , OR 20 , or NHR 20 And R 20 C 1~30 Alkyl; C 2~30 Alkenil; C 2~30 The selection includes alkynyl; alkyls substituted with cycloalkyl and typically having a total of 4 to 30 carbon atoms; alkyls substituted with phenyl and typically having a total of 7 to 30 carbon atoms; and cycloalkyls optionally substituted with one or more alkyls and typically having a total of 3 to 30 carbon atoms.

[0210]

[0139] In some embodiments, R 20 C 1~16 It is alkyl. In some embodiments, R 20 is a linear C 1~16 It may be alkyl. In some embodiments, R 20 is branched chain C 3~16 It may be alkyl. In some embodiments, R 20 This can be a branched C5 or C6 alkyl group. In some embodiments, R 20 teeth, [ka] It is possible. In some embodiments, R 20 This is the formula -(CH2) n -CH3 may have a value where n is an integer from 0 to 12 (e.g., 6 to 12, e.g., 6, 7, 8, 9, 10, 11, or 12).

[0211]

[0140] In some embodiments, R 20 It can also be an alkyl substituted with a cycloalkyl. Typically, in such embodiments, R 20 It has a total number of carbon atoms, for example, 4 to 30, or 5 to 16 (i.e., the total number of carbon atoms from the alkyl and cycloalkyl parts is 5 to 16). Cycloalkyls are typically unsubstituted. However, in some embodiments, the cycloalkyl is, for example, one or two lower alkyl groups (e.g., C 1~4 It can be optionally replaced with alkyl. In some embodiments, R 20 C 3~6 It can be an alkyl group substituted with a cycloalkyl group, and typically has a total of 6 to 12 carbon atoms. In some embodiments, R 20 C 3~6 It can be a linear alkyl group substituted with a cycloalkyl group, for example, R 20 This is the formula -(CH2) n -Cy may have -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 It is a cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, R 20 This is the formula -(CH2) n -Cy may be present, n is 1 or 2, and Cy is cyclopentyl or cyclohexyl. In some embodiments, R 20 Also, C 3~6 Branched alkyl groups substituted with cycloalkyl groups (e.g., branched C 2~6 ) is possible.

[0212]

[0141] In some embodiments, R 20 It can also be a phenyl-substituted alkyl. Typically, in such embodiments, R 20 It has a total number of carbon atoms, for example, 7 to 16 (i.e., the total number of carbon atoms from the alkyl and phenyl parts is 7 to 16). In some embodiments, R 20 R can be a linear alkyl group substituted with phenyl, for example, 20 This is the formula -(CH2) n-Cy may be present, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is phenyl. In some embodiments, R 20 This is the formula -(CH2) n -Cy may be present, n is 1 or 2, and Cy is phenyl. In some embodiments, R 20 Also, phenyl-substituted branched alkyl groups (e.g., branched C 2~6 ) may be. Phenyl is typically unsubstituted. However, in some embodiments, phenyl may be, for example, one or two lower alkyl groups (e.g., C 1~4 It can be optionally substituted with an alkyl group.

[0213]

[0142] In some embodiments, R 20 R may be a cycloalkyl group optionally substituted with one or more alkyl groups. In such embodiments, R 20 It typically has a total of 3 to 30 carbon atoms, for example, 5 to 16 (i.e., the total number of carbon atoms in the cycloalkyl and its optional substituents is 5 to 16). In some embodiments, R 20 is either unsubstituted or C 1~4 Either C substituted with alkyl 3~6 It may be a cycloalkyl. In some specific embodiments, R 20 teeth, [ka] It is possible.

[0214]

[0143] In some embodiments, R 20 C 2~30 Alkenyl or C 2~30 It can be an unsaturated aliphatic group such as an alkynyl group.

[0215]

[0144] In some preferred embodiments, the compound of formula II is an abiraterone ester, for example, R 2 is R 20 And R 20 R is defined herein. In some embodiments, R of formula II 2 C1~16 Alkyl, for example, -(CH2) n It can be an alkyl having the formula -CH3, where n is an integer from 0 to 12. In some embodiments, R of formula II 2 This is the formula -(CH2) n It is represented as -Cy, where n is an integer from 1 to 6, and Cy is C 3~6 It is a cycloalkyl or phenyl compound, and in a more specific embodiment, for example, n may be 1 or 2, and Cy may be cyclopentyl, cyclohexyl, or phenyl. In some specific embodiments, R of formula II 2 teeth, [ka] It is possible. 2 Other suitable groups for R are defined herein. 20 It includes any of the following. In some embodiments, the abiraterone ester may be abiraterone 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. In some embodiments, the abiraterone ester may be abiraterone acetate, abiraterone propionate, and abiraterone decanoate. In some specific embodiments, the abiraterone ester may be abiraterone pentanoate, abiraterone hexanoate, abiraterone heptanoate, abiraterone decanoate, abiraterone isocaproate, or abiraterone cypionate.

[0216]

[0145] In some embodiments, R of formula II 2 Also, OR 20 or NHR 20 It could be, R 20 This is defined herein.

[0217]

[0146] Typically, the compound of formula I or II may exist in the formulation in a base form. However, in some embodiments, pharmaceutically acceptable salts of the compound of formula I or II are also useful. Unless otherwise stated, 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 a substantially pure form.

[0218] Treatment method

[0147] In some embodiments, the Disclosure provides a method for treating a disease or disorder described herein in a subject that requires it. The method typically comprises the step of orally administering a therapeutically effective amount of a pharmaceutical composition of the Spec. (e.g., any of those described herein, e.g., as shown in the Summary section of this Spec. [1] to

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

[82] to

[90] ) to a subject. Typically, the oral administration delivers an amount of abiraterone decanoate to the subject 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. 10,792,292B2, and U.S. Provisional Patent Applications No. 63 / 073,502 and 63 / 149,550 describe the various advantages of parenteral administration of abiraterone prodrugs, such as sustained inhibition of CYP17A1, sustained PD effects, such as increased progesterone levels, and reductions in cortisol, dihydrotestosterone, and testosterone levels for up to 70 days or longer, prodrugs that do not require castration and are effective in reducing testosterone levels and are generally well tolerable, for example, the reduction in testosterone within a few days following a first administration of another drug that does not exhibit hepatotoxicity as observed from intramuscular administration of abiraterone decanoate at the tested dose. As detailed in the applicant's prior application, and without wishing to be bound by theory, the observed sustained PD effect may be partly attributable to the loose and firm binding of abiraterone to CYP17A1, achieved through an irreversible inhibitory effect on CYP17A1, see, for example, Cheong EJY et al., J. Pharmacol. Exp. Ther. 374: pp. 438-451 (2020). Also without wishing to be bound by theory, it was considered that intramuscular administration of abiraterone prodrugs may result in both sustained and effective plasma levels of abiraterone and favorable tissue distribution of abiraterone and abiraterone prodrugs, for example, to the testes, and may contribute to the observed effects on serum steroids that are not achieved by oral abiraterone acetate formulations (e.g., Zytiga®).

[0220]

[0149] As shown in the Examples section of this specification, oral administration of exemplary lipid-based formulations of abiraterone decanoate similarly achieved inhibition of CYP17A1, as demonstrated by an increase in progesterone levels and a decrease in testosterone levels for at least 24 hours or longer. It is considered that oral administration, as well as different dosing regimens, may achieve pharmacodynamic effects similar to those observed with intramuscular administration prior to this application. Similarly, it is considered that the methods herein, since they do not rely on castration to achieve the desired testosterone levels, can be advantageously used to 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 considered that oral administration of abiraterone decanoate is generally well tolerable and can be used to treat subjects suffering from hepatic impairment, e.g., moderate to severe hepatic impairment (Childpew class B or C), before administering abiraterone prodrugs.

[0221]

[0150] Therefore, in some embodiments, the oral formulations of this specification can be advantageously used to inhibit CYP17A1 activity, to lower glucocorticoid levels, such as cortisol levels, to lower sex hormone levels, such as androgens and / or estrogens, and / or to treat disorders associated with high glucocorticoid levels, such as cortisol levels, and / or to treat disorders resulting from high sex hormone levels, such as androgens and / or estrogens.

[0222]

[0151] Accordingly, in some embodiments, the Disclosure provides a method for treating a disease or disorder described herein in a subject that requires it, comprising the step of administering an effective amount of the pharmaceutical composition described herein (e.g., any of those described herein, e.g., Sections [1] to

[37] of the Summary section) to the subject. In some embodiments, the Disclosure provides a method for treating a disease or disorder described herein in a subject that requires it, comprising the step of administering an effective amount of the emulsion described herein (e.g., any of those described herein, e.g., Sections

[82] to

[90] of the Summary section) to the subject.

[0223]

[0152] Various diseases or disorders are suitable for treatment by the methods of this specification. 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 resulting from androgen excess, and syndromes resulting from 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, classic or nonclassical congenital adrenal hyperplasia, precocious puberty, male-type 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 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 may be 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-tumor syndromes resulting from excess androgen and / or excess glucocorticoids, such as hypercortisolemia, syndromes resulting from excess androgen, such as endometriosis, polycystic ovary syndrome, classical or non-classical congenital adrenal hyperplasia, precocious puberty, male-pattern hirsutism, etc., and / or syndromes resulting from excess cortisol, such as Cushing's syndrome, Cushing's disease, etc., can also be treated in accordance with the methods described herein.

[0226]

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

[0227]

[0156] In some embodiments, sex hormone-dependent or androgen receptor-induced cancer may be androgen receptor-positive salivary duct cancer or androgen receptor-positive glioblastoma pleomorphoni.

[0228]

[0157] 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 by the methods herein include, but are not limited to, any prostate cancers in which abiraterone or its derivatives (e.g., abiraterone acetate) is approved for commercial sale (e.g., in the United States or Europe), or in which abiraterone or its derivatives (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, prostate cancer may be primary / localized prostate cancer (newly diagnosed or early stage), advanced prostate cancer (e.g., post-castration for recurrent prostate cancer, locally advanced prostate cancer, etc.), recurrent prostate cancer (e.g., prostate cancer that did not respond 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 by having, for example, an elevated level of prostate-specific antigen 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), and 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 disease in the subject has progressed 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" means prostate cancer that has not responded to anticancer treatment, or has not responded adequately to anticancer treatment. Refractory prostate cancer also includes recurrent or relapsed prostate cancer. As used herein, unless otherwise specified, the phrase "relapsed prostate cancer" means prostate cancer that has responded to anticancer treatment but is no longer responding to such treatment, or is no longer responding adequately to such treatment. As used herein, unless otherwise specified, the phrase "recurrent (or recurring) prostate cancer" means prostate cancer that has recurred after the patient has been diagnosed with and treated for prostate cancer at an early stage, or after being previously diagnosed as cancer-free.

[0229]

[0158] In some embodiments, the methods of this specification can also be used to treat breast cancer. The breast cancers that are suitable for treatment by the methods of this specification are not particularly limited. For example, in some embodiments, breast cancers may be 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.

[0230]

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

[0231]

[0160] In some embodiments, the methods of this specification can be used to treat subjects having cancer, such as prostate cancer, breast cancer, adrenal cancer, leukemia, lymphoma, myeloma, Waldenstrom macroglobulinemia, monoclonal immunoglobulinemia, benign monoclonal immunoglobulinemia, 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 of this specification may include a step of treating the subject with one or more additional therapies. For example, in some embodiments, the subject is further treated with radiotherapy. In some embodiments, the methods are for treating prostate cancer and include combination therapy, which further includes a step of administering one or more additional therapies to the subject, as described herein, for example, in the section titled Combination Therapies for Prostate Cancer described herein. Non-limiting examples of useful additional therapies also include any of those described in the summary sections of this specification

[50] -

[54] and

[61] -

[71] ,

[73] -

[75] , and

[77] .

[0233]

[0162] Subjects suitable for treatment by the methods of this specification are not particularly limited and include subjects with diseases or at various stages and other characteristics of treatment. For example, in some embodiments, the subject may be an uncastrated subject. In some embodiments, the subject may be a castrated subject. In some embodiments, the methods of this specification may also administer the pharmaceutical compositions of this specification (e.g., any of the sections [1] to

[37] in the summary section of this specification) to a subject whether or not the subject is castrated. In some embodiments, the subject has not undergone prostatectomy. In some embodiments, the subject may be characterized as having hepatic impairment, for example, moderate to severe hepatic impairment (Childpew class B or C), prior to administration of the abiraterone prodrug. In some embodiments, the subject may be characterized as being sensitive to gonadotropin-releasing hormone antagonists and / or agonists, or otherwise intolerant to antagonists and / or agonists. In some embodiments, subjects may be characterized as having not undergone chemotherapy or hormone therapy prior to administration of the pharmaceutical compositions herein. However, in some embodiments, subjects may also have been treated with chemotherapy or hormone therapy prior to administration of the pharmaceutical compositions herein. For example, in some embodiments, subjects may have a disease or disorder (e.g., prostate cancer) that has progressed in or after chemotherapy and / or hormone therapy, such as a taxane-based chemotherapy regimen, such as chemotherapy based on docetaxel or cabazitaxel. In any of the embodiments described herein, subjects may be human subjects, unless directly or inversely.

[0234]

[0163] Suitable pharmaceutical compositions for the methods of this specification include, but are not particularly limited, any of those described herein, for example, any of the abiraterone decanoate formulations described herein, for example, any of those described in the Summary section. Typically, the pharmaceutical compositions can be formulated to deliver therapeutically effective plasma levels of abiraterone to a subject over a period of time following a single oral administration (e.g., at least one day, at least two days, at least three days, etc.). In some embodiments, the therapeutically effective plasma concentration of abiraterone may be at least 1 ng / ml, for example, at least 2 ng / ml, at least 4 ng / ml, or at least 8 ng / ml. In some embodiments, the therapeutically effective plasma concentration of abiraterone may also be about 0.5 ng / ml or higher. In some embodiments, the therapeutically effective plasma concentration of abiraterone may also be about 0.1 ng / ml or higher. The pharmaceutical compositions can be administered to a subject with or without food.

[0235]

[0164] The amount and frequency of administration for the methods described herein are also not particularly limited and include any of those described herein. Generally, the pharmaceutical composition is administered to the subject at a rate ranging from 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 may vary, typically ranging from 0.5 mg / kg to 200 mg / kg of the subject's body weight, for example, from about 0.5 mg / kg to about 200 mg / kg.

[0236] Methods to lower steroid hormone levels

[0165] Some embodiments of the present disclosure are directed toward a method for reducing serum steroid hormone levels in a subject that requires it.

[0237]

[0166] In some specific embodiments, the Disclosure provides a method for reducing serum testosterone levels in a subject requiring such reduction, comprising the step of orally administering to a subject any of the pharmaceutical compositions of this Spec. (e.g., any of those described herein, e.g., in the Summary section of this Spec. [1] to

[37] ) or any of the emulsions described herein. (e.g., in the Summary section of this Spec.

[82] to

[90] )

[0238]

[0167] The subjects suitable for treatment by the methods herein for lowering serum testosterone levels are not particularly limited. For example, in some embodiments, the subjects may be uncastrated subjects. In some embodiments, the subjects may be castrated subjects. In some embodiments, the methods herein may also administer the pharmaceutical compositions herein (e.g., any of those described herein, in the summary sections [1] to

[37] herein) to the subject, whether or not the subject is castrated. In some embodiments, another drug effective in lowering serum and / or gonadal testosterone levels is not administered to the subject concurrently with the administration of the abiraterone prodrug, during treatment with the abiraterone prodrug, or in interference with treatment with the abiraterone prodrug. For example, in some embodiments, the subject is not treated with any drug other than the administered abiraterone prodrug that suppresses gonadal testosterone in an amount effective in lowering 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 in lowering serum testosterone levels in the subject. In some embodiments, the subject is not treated with any gonadal testosterone-suppressing drug 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, deslorerin, fertilelin, histrelin, gonadrelin, resirelin, goserelin, nafarelin, peforellin, and triptorelin. In some embodiments, the subject is not treated with a drug selected from abarelix, cetrorelin, degarelix, ganirelix, ellagolix, linzagolix, and relgolix. In some embodiments, the subject may be sensitive to or otherwise intolerant to gonadotropin-releasing hormone antagonists and / or agonists. In some embodiments, the subject may also be treated with gonadotropin-releasing hormone antagonists and / or agonists, such as those described herein.

[0168] Subjects requiring testosterone reduction typically suffer from one or more androgen-mediated or androgen-related diseases or disorders. For example, in some embodiments, subjects are characterized as having either sex hormone-dependent cancer or androgen receptor-induced cancer, e.g., those described herein. In some embodiments, subjects are characterized as having androgen receptor-positive sialolar carcinoma or androgen receptor-positive glioblastoma pleomorphoni. In some embodiments, subjects are characterized as having prostate cancer (e.g., any of those described herein). For example, in some embodiments, the prostate cancer is localized prostate cancer, e.g., high-risk localized prostate cancer. In some embodiments, subjects have not undergone prostatectomy. In some embodiments, subjects are further treated with radiotherapy.

[0239]

[0169] In some embodiments, the Disclosure also provides a method for inhibiting CYP17A1 activity, for example, 17α-hydroxylase activity and 17,20-lyase activity, comprising the step of administering one of the pharmaceutical compositions herein (for example, any of [1] to

[37] in the Summary section of this Specification) to a subject requiring such inhibition. In some embodiments, the Disclosure also provides a method for inhibiting CYP17A1 activity, for example, 17α-hydroxylase activity and 17,20-lyase activity, comprising the step of administering one of the emulsions described herein (for example, any of those described herein, for example, as shown in the Summary section of this Specification) to a subject requiring such inhibition. In some embodiments, the subject suffers from a sex hormone-dependent benign or malignant disorder, for example, as described herein. In some embodiments, the subject suffers from a syndrome caused by excess androgen and / or a syndrome caused by excess glucocorticoids, for example, hypercortisolemia, as described herein. In some embodiments, the subjects suffer from sex hormone-dependent cancer or androgen receptor-induced cancer as described herein. Suitable pharmaceutical compositions, subjects, drug regimens, and routes of administration for the method include any combination of those described herein, for example, those described in relation to the methods shown in the Summary section of this specification.

[0240]

[0170] Accordingly, in some embodiments, the Disclosure provides a method for reducing glucocorticoid (e.g., cortisol) levels in a subject requiring it, comprising the step of administering one of the pharmaceutical compositions herein (e.g., any of [1] to

[37] in the Summary section of this Specification) to a subject. In some embodiments, the Disclosure provides a method for reducing glucocorticoid (e.g., cortisol) levels in a subject requiring it, comprising the step of administering one of the emulsions described herein (e.g., any of those described herein, e.g.,

[82] to

[90] shown in the Summary section of this Specification) to a subject. In some embodiments, the subject suffers from a syndrome resulting from glucocorticoid excess, e.g., hypercortisolemia as described herein, e.g., Cushing's syndrome or Cushing's disease. Suitable pharmaceutical compositions, subjects, drug regimens, and routes of administration for the method include any combination of those described herein, e.g., any of those described in relation to the methods shown in the Summary section of this Specification.

[0241]

[0171] In some embodiments, the Disclosure provides a method for reducing androgen (e.g., testosterone) and / or estrogen levels in a subject requiring such reduction, comprising the step of administering one of the pharmaceutical compositions of this Spec. (e.g., any of [1] to

[37] in the Summary section of this Spec.) In some embodiments, the Disclosure provides a method for reducing androgen (e.g., testosterone) and / or estrogen levels in a subject requiring such reduction, comprising the step of administering one of the emulsions described herein. (e.g., any of the emulsions described herein, e.g.,

[82] to

[90] shown in the Summary section of this Spec.) In some embodiments, the subject suffers from androgen receptor-induced cancer. In some embodiments, the subject suffers from syndromes resulting from androgen excess, such as congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), endometriosis, polycystic ovary syndrome, precocious puberty, and male-pattern hirsutism, etc. In some embodiments, the subject suffers from androgens and / or estrogens associated with cancer, such as prostate cancer or breast cancer. In some embodiments, the subject suffers from sex hormone-dependent cancers as described herein. Suitable pharmaceutical compositions, subjects, drug regimens, and routes of administration for the method include any combination of those described herein, for example, those described in relation to the methods shown in the summary section herein.

[0242]

[0172] Aviratheron decanoate in the pharmaceutical composition or emulsion is typically included in a therapeutically effective amount for treating diseases or disorders described herein, such as prostate cancer. In some embodiments, avirateron decanoate may be present in the pharmaceutical composition or emulsion in an amount suitable for oral administration to subjects having sex hormone-dependent benign or malignant disorders, androgen receptor-induced cancers, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia, at a dosage frequency ranging from once daily to once weekly, for example, once daily or once every two or three days.

[0243] Combined treatment

[0173] In some embodiments, the method herein may include the step of administering one or more other drugs or agents (e.g., another cancer chemotherapy agent, hormone replacement agent, or hormone ablation agent) to a subject simultaneously or sequentially, either through the same or different routes of administration. In some embodiments, the other drugs or agents may be steroids such as prednisone, prednisolone, and / or methylprednisolone. In some embodiments, the other drugs or agents may be chemotherapy agents such as paclitaxel, mitoxantrone, and / or docetaxel. In some embodiments of the method herein, the other drugs or agents may be GnRH agonists, such as leuprolide, deslorerin, goserelin, or triptorelin, such as leuprolide acetate (e.g., a long-acting IM injectable formulation). In some embodiments, other agents or drugs may include, but are not limited to, theocalcitol, bicalutamide, flutamide, hydrocortisone, prednisone, prednisolone, or dexamethasone, and may be glucocorticoids. The amount of other agents or drugs administered may vary and may typically be an amount effective in treating the respective disease or disorder (e.g., prostate cancer), either alone or in combination with the pharmaceutical compositions herein (e.g., any of sections [1] to

[37] of the summary section herein).

[0244]

[0174] Additional suitable drugs or agents include those described herein. For example, other useful drugs or agents include, but are not limited to, anticancer agents, hormone ablation agents, antiandrogens, differentiation agents, antineoplastic agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotics, immunotherapies, interferon-type agents, inserts, 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 agents include acemannan, acracinon, aldesleukin, alemtuzumab, alitretinoin, altretamine, amfostine, amsacrin, anagrelide, anastrozole, ancestim, bexarotene, proxuridine, capecitabine, cermoleukin, cetrorelix, cladribine, clotrimazole, daclizumab, dexrazoxane, dilazep, docosanol, doxifluridine, bromocriptine, carmustine, cytarabine, and diclofena. Edelfosine, Edrecolomab, Eflornithine, Emitefur, Exemestane, Exislind, Fadrozol, Filgrastim, Finasteride, Fludarabine Phosphate, Formestan, Fotemustine, Gallium Nitrate, Gemcitabine, Gemcitabine, Heptaplatin, Ibandronate, Imiquimod, Iobenguan, Irinotecan, Ilsogladine, Lanreotide, Leflunomide, Lenograstim, Lentinan Sulfate, Letrozole, Rialozol, Robap Latin, ronidamin, masopropyl, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mitogwazone, mitractol, moglamostim, nafarelin, naltograstim, nedaplatin, nilutamide, noscapine, oprelbequin, osaterone, oxaliplatin, pamidronic acid, pegasparagase, pentosan sodium polysulfate, pentostatin, picibanil, pirarubicin, porfimer sodium, raloxifene, larcitrexed, rasb This includes, but is not limited to, lycase, rituximab, lomultide, salglamostim, schizophyllan, sobuzoxane, sonelmin, suramin, tasonelmin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfacin, thyrotropin alfa, topotecan, toremifene, trastuzumab, treosulfan, tretinoin, trilostane, trimethrexate, ubenimex, barrubicin, verteporfin, and vinorelbine. Suitable antiandrogens include, but are not limited to, bicalutamide, flutamide, and nilutamide. Suitable differentiation agents include, but are not limited to, polyamine inhibitors; vitamin D and its analogues, e.g., calcitriol.Doxelcalciferol and theocalcitol; vitamin A metabolites, e.g., ATRA, retinoic acid, retinoids; short-chain fatty acids; phenyl butyrate; and antineoplastic agents, including but not limited to nonsteroidal anti-inflammatory drugs, tubulin interaction agents, topoisomerase inhibitors and drugs, acitretin, alstonin, amonafide, amfetinil, amsacrin, ankinomycin, antineoplastic drugs, aphydicolin glycinate, asparaginase, baccharin, batracycline, benflurone, benzotrypto, bromophosphamide, calasemide, carmethizol hydrochloride, chlorsulfaquinoxalone, cranfenull, claviridenon, cristatol, curaderm, cytarabine, cytocytin, dacarbazine, dateliptinium, dihema Toporphyrin ether, dihydrolemperone, dinarin, dystamycin, docetaxel, eripravin, eriptinium acetate, epotilon, ergotamine, etoposide, etretinate, fenretinide, gallium nitrate, genquadahunin, hexadecylphosphocholine, homohalingtonin, hydroxyurea, irmofosin, isoglutamine, isotretinoin, leucolegurin, ronidamine, melbaron, merocyanine derivatives, me Chilanilinoacridine, minactibin, mitonafid, mitokidone, mitoxantrone, mopidamol, motoretinide, N-(retinoyl) amino acids, N-acylated dehydroalanine, naphazatrom, nocodazole derivatives, octreotide, oquizanocinc, paclitaxel, pancratistatin, pazeriptin, pyroxantrone, polyhematoporphyrin, polypreic acid acid), Proviman, Procarbazine, Proglumide, Lazoxane, Leterliptin, Spatol, Spirocyclopropane derivatives, Spirogermanium, Stripoldinone, Superoxide Dismutase, Teniposide, Taliblastine, Tocotrienol, Topotecan, Ukrain, Vinblastine Sulfate, Vincristine, Vindesine, Vinestramide, Vinorelbine, Vintriptol, Binzolidine, and Withanolide,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 mimetic or α, vThe list includes, but is not limited to, β3 inhibitors. Suitable antimetabolites may be selected from, but are not limited to, 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brackinal sodium, carmofur, cyclopentylcytosine, cytarabine stearate phosphate, cytarabine conjugate, desaguanine, dideoxycytidine, dideoxyguanosine, didox, doxifluridine, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2'-flanidyl)-5-fluorouracil, isopropylpyrrolidine, metobenzaprim, methotrexate, norspermidine, pentostatin, pyritrexime, plicamycin, thioguanine, thiazophrine, trimethrexate, tyrosine kinase inhibitors, and uricytin. Suitable alkylating agents may be selected from, but are not limited to, aldofsphamide analogs, altoretamine, anaxylone, bestrabucil, budotitan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cyplatate, diphenylspiromustine, diplatinum cytostatic, ermustine, estramustine sodium phosphate, fotemustine, hepsulfame, ifosfamide, iproplatin, lomustine, maphosphamide, mitractol, oxaliplatin, prednimustine, ranimustine, semustine, spiromustine, tauromustine, temozolomide, teroxylone, tetraplatin, and trimeramol.Suitable antibiotics include acracinon, actinomycin D, actinoplanon, adriamycin, aeropricinin derivatives, amrubicin, anthracycline, azinomycin A, viscabelin, bleomycin sulfate, bryostatin 1, calikemycin, chromoximycin, dactinomycin, daunorubicin, ditrisalubicin B, dexamethasone, doxorubicin, doxorubicin-fibrinogen, erosamycin A, epirubicin, arbstatin, esorubicin, esperamicin A1, esperamicin A1b, fostoliesin, glidobactin, glegatin A, glinkamycin, and A selection of corticosteroids may be made from, but are not limited to, -bimycin, corticosteroids such as hydrocortisone, idarubicin, ilidine, kazusamycin, kesarirosin, menogalil, mitomycin, neoenactin, oxalisin, oxaunomycin, peplomycin, pyratin, pirarubicin, polotoramycin, prednisone, prednisolone, pyrindanycin A, rapamycin, rhizoxin, rhodorubicin, sibanomycin, siwenmycin, solandisin A, sparsomycin, tarisomycin, terpentesin, soladine, triclozarin A, and zolubicin. Non-limited examples of preferred steroids include hydrocortisone, prednisone, prednisolone, or dexamethasone.

[0246] Combination therapy for prostate cancer

[0176] Treatment for prostate cancer often involves a number of therapies, including, for example, radiotherapy, surgery, androgen deprivation therapy, hormone therapy, chemotherapy, immunotherapy, and various drug combinations. A search on the website clinicaltrials.gov identified more than 250 clinical trials with abiraterone / abiraterone acetate listed as the interventional agent, many of which involve combination therapies for treating prostate cancer. The pharmaceutical compositions herein (for example, any of those described herein, e.g., any of the sections [1] to

[37] in the summary section herein) may also be advantageously used in various combination therapies to replace or supplement oral administration of abiraterone acetate.

[0247]

[0177] In embodiments in which the method treats an uncastrated subject, the method herein may include a concomitant treatment in which the subject is not treated with a gonadal testosterone-suppressing drug other than the administered abiraterone prodrug in an amount effective in lowering the subject's serum testosterone level. For example, in some embodiments, the method herein may include a concomitant treatment in which the subject is not treated with any GnRH agonist and antagonist.

[0248]

[0178] In some embodiments, the Disclosure provides a method for treating prostate cancer (e.g., any of those described herein) in combination therapy in a subject requiring such treatment, comprising the steps of administering to the subject a therapeutically effective amount of the pharmaceutical composition herein (e.g., any of those described herein, e.g., any of sections [1] to

[37] in the summary section herein) and one or more additional therapies. The one or more additional therapies may be administered to the subject simultaneously with or sequentially with the pharmaceutical composition herein in any order, and may be administered via the same route of administration or different routes of administration. In some embodiments, the method of the Invention includes the step of treating the subject with radiotherapy or surgery. In some embodiments, the method includes the step of administering to a target one or more other agents selected from anticancer agents, hormone ablation agents, antiandrogens, differentiation agents, antineoplastic agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotics, immunotherapies, interferon-type agents, inserts, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloproteinase inhibitors, genetic therapeutic agents, or combinations thereof. In some embodiments, the method includes the step of administering to a target one or more other agents selected from chemotherapeutic agents, hormone replacement agents, or hormone ablation agents. In some embodiments, the method includes the step of treating the target with androgen deprivation therapy. While many of the following combination therapies are described in relation to various treatments for prostate cancer, this disclosure is not limited thereto. 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]

[0179] In more detailed embodiments, combination therapy typically involves administering a glucocorticoid to the subject. For example, in some embodiments, the method includes the step of administering one or more drugs selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone to the subject. However, in some embodiments, glucocorticoid replacement therapy (e.g., administration of glucocorticoids, e.g., hydrocortisone, prednisone, prednisolone, methylprednisolone, or dexamethasone) is undesirable. For example, glucocorticoids may be contraindicated in subjects who may have underlying conditions 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 drugs selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone. In some embodiments, the method may include a step of administering a mineralocorticoid receptor antagonist, such as eplerenone. For example, in any embodiment of this specification, if glucocorticoid replacement therapy is undesirable and / or not administered, the method may include a step of administering a mineralocorticoid receptor antagonist, such as eplerenone.

[0250]

[0180] Combination therapies for the methods of this specification may also include androgen deprivation therapies such as those involving the administration of gonadotropin-releasing hormone (GnRH) analogs to a target. Where included, suitable GnRH analogs for combination therapy include, but are not particularly limited, both GnRH agonists and GnRH antagonists. For example, in some embodiments, the method may include the step of administering a gonadotropin-releasing hormone (GnRH) agonist, such as buserelin, leuprolide, deslorerin, fertilelin, histrelin, gonadrelin, resirelin, goserelin, nafarelin, peforellin, or triptorelin, and / or a GnRH antagonist, such as abarelix, cetrorelinx, degarelix, ganirelix, ellagolix, linzagolix, or relgolix to a target. In some embodiments, the subject is not administered either a GnRH agonist or a GnRH antagonist as described herein.

[0251] Inhibition of androgen receptor activity

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

[0252]

[0182] In some embodiments, the method may include the step of administering an androgen receptor (AR) antagonist to a subject. Various AR antagonists are known in the art and include, but are not limited to, first and second-generation AR antagonists (see, for example, Rice, MA et al., Front Oncol. 9: p. 801 (2019)) and third-generation AR antagonists, such as N-terminal domain inhibitors. In some embodiments, the method includes the step of administering a first-generation androgen receptor antagonist to a subject, including, but not limited to, proxaltoamide, bicalutamide, flutamide, nilutamide, topirutamide, etc. In some embodiments, the method includes the step of administering a second-generation androgen receptor antagonist to a subject, including, but not limited to, apalutamide, darolutamide, or enzalutamide. In some embodiments, the method includes the step of administering apalutamide to a subject. In some embodiments, the method includes the step of administering enzalutamide to a subject. In some embodiments, the method includes the step of administering a third-generation androgen receptor antagonist, such as an N-terminal domain inhibitor, to a subject. N-terminal domain inhibitors are known in the art. Useful non-limiting examples include any of those described in U.S. Patent Application 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 may be administered, and may be selected from first, second, or third AR antagonists, either alone or in any combination.

[0253]

[0183] In addition to agents that directly target androgen receptors, other methods and / or agents that modulate androgen receptor activity, including, for example, the modulation of upstream kinase activity and / or androgen receptor transcriptional activity, can also be used in combination therapies herein. For example, in some embodiments, combination therapy may involve administering one or more upstream kinase modulators, the activation or inhibition of which upstream kinase modulators can reduce AR activity. Such upstream kinases include, for example, Shah, K. and Bradbury, NA, Cancer cell microenviron.2(4):doi:10.14800 / ccm.1023(2015), and Koul HK et al., Genes & Cancer As described in 4(9~10):342~359 (2013), the method is known in the art. In some embodiments, the method involves FLT-3 (FMS-like tyrosine kinase) inhibitors, AXL (Anexselect) inhibitors (e.g., gilteritinib), CDK (cyclin-dependent kinase) inhibitors (e.g., 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 regulators, lemur tyrosine kinase 2 (LMTK2) regulators, Lyn inhibitors, Aurora A inhibitors, ANPK (nucleoprotein kinase) inhibitors, extracellular signal-regulated kinase (ERK) regulators, c-jun The procedure includes administering 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. Preferred kinase modulators / inhibitors are not particularly limited and include any known ones, such as small molecule drugs, polypeptides containing antibodies or antigen-binding fragments thereof, RNA or DNA-based drugs.

[0254]

[0184] In some embodiments, combination therapy may involve administering agents that downregulate AR or otherwise inhibit AR activity. While we do not wish to be bound by theory, AR activity may affect the genomic and / or transcriptional levels of AR itself, using various molecules that interfere with transcription and / or translation (e.g., RNA silencing agents (e.g., antisense, siRNA, shRNA, microRNA), ribozymes, and DNAzymes), or the genomic and / or transcriptional levels of upstream targets of AR and downstream targets prepared by AR that play a role in regulating AR activity, or the protein level using, for example, antagonists, polypeptide-cleaving enzymes, small molecules that interfere with protein activity (e.g., competitive ligands).

[0255]

[0185] In some embodiments, downregulation of AR or inhibition of AR activity can be achieved through RNA silencing of a target gene (e.g., AR or preferred upward and downward 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 inhibition or “silencing” of the expression of a corresponding protein-coding gene (e.g., RNA interference (RNAi), transcriptional gene silencing (TGS), post-transcriptional gene silencing (PTGS), quering, co-repression, 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 RNA capable of specifically inhibiting or “silencing” the expression of a target gene. In some embodiments, RNA silencing agents can prevent the complete processing of mRNA molecules (e.g., complete translation and / or expression) through a post-transcriptional silencing mechanism. RNA silencing agents include non-coding RNA molecules, such as RNA double helices containing paired helical structures, and precursor RNAs capable of producing such small non-coding RNAs. Exemplary RNA silencing agents include double-stranded RNA (dsRNA), such as short interfering RNA (siRNA), miRNA, and shRNA. In one embodiment, RNA silencing agents can induce RNA interference. In another embodiment, RNA silencing agents can mediate translational repression. The helical structures of double-stranded interfering RNA (e.g., siRNA) bind to form hairpin or stem-loop structures (e.g., shRNA or sh-RNA). Therefore, as described above, the RNA silencing agent in some embodiments of this disclosure may also be short hairpin RNA (shRNA).

[0257]

[0187] The RNA silencing agents of some embodiments of the present disclosure are understood to further include chemically modified nucleotides and non-nucleotides, but are not limited to these molecules containing only RNA.

[0258]

[0188] In some embodiments, the RNA silencing agents provided herein may be functionally related to cell-permeable peptides. As used herein, “cell-permeable peptide” is a peptide comprising a short (about 12 to 30 residues) amino acid sequence or functional motif that confers energy-independent (i.e., non-endocytotic) translocation properties related to the transport of membrane-permeable complexes across the plasma and / or nuclear membrane of cells.

[0259]

[0189] According to another embodiment, the RNA silencing agent may be a miRNA or a mimetic thereof. The terms “microRNA,” “miRNA,” and “miR” are synonymous and refer to a collection of non-coding single-stranded RNA molecules approximately 19 to 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 the pathogenesis of disease, homeostasis, and disease. The term “microRNA mimetic” refers to synthetic non-coding RNA that can enter the RNAi pathway and regulate gene expression. miRNA mimes may be designed to mimic the function of endogenous microRNAs (miRNAs) and may be mature double-stranded molecules or mimetic 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 (e.g., AR or preferred upward and downward targets of AR as described herein). Gene editing can be performed, for example, with clustered, regularly spaced, short-palindromic repeat CRISPR-CAS9 systems. CRISPR-CAS9 systems are described in the literature and may include, for example, CAS9 and guide RNA. Other gene editing techniques are also described in the literature and may be used.

[0261]

[0191] Another agent capable of downcontrolling a target (e.g., AR or preferred upper and lower targets of AR as described herein) is a DNAzyme molecule capable of specifically cleaving the mRNA transcript or DNA sequence of the target. A DNAzyme is a single-stranded polynucleotide capable of cleaving both single-stranded 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 ("10-23" model) has been proposed. A "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 effectively cleave its substrate RNA in a purine:pyrimidine junction (Santoro et al., Khachigian, Curr. Opin. Mol. Ther. 2002; 4: pp. 119-121).

[0262]

[0192] Downcontrol of the target (e.g., AR or preferred upper and lower targets of AR as described herein) can also be influenced by using antisense polynucleotides that are particularly capable of hybridizing with mRNA transcripts encoding the target.

[0263]

[0193] Another agent capable of downregulating a target (e.g., AR or preferred upper and lower targets of AR as described herein) is a ribozyme molecule capable of specifically cleaving mRNA transcripts encoding the target. Ribozymes are increasingly used for sequence-specific inhibition of gene expression by cleaving mRNA encoding the protein of interest (Welch et al., Curr. Opin. Biotechnol. 1998; 9: pp. 486-496).

[0264]

[0194] Another agent capable of downcontrolling a target (e.g., AR or preferred upper and lower 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 in conjunction with some embodiments of the present disclosure to downcontrol a target (e.g., AR or preferred upper and lower targets of AR as described herein) is a molecule that prevents activation of the target and / or binding of the substrate.

[0266]

[0196] Another agent that can be used in conjunction with some embodiments of the present disclosure to downregulate AR or inhibit AR activity is an androgen receptor degrader, for example, based on proteolytic chimeric molecule (PROTAC) technology. See, for example, Kregel, S. et al., Neoplasia 22(2):111-119 (2020).

[0267]

[0197] Another agent that can be used in conjunction with some embodiments of the present disclosure that downcontrol a target (e.g., AR or preferred upward and downward targets of AR as described herein) suppresses or downcontrols the activation of the transcriptional activity of the target, more particularly the transcriptional activity of AR. For example, such agents may interfere with the nuclear translocation of AR, downcontrol the protein level of AR, reduce hormone binding to AR, interfere with the recruitment of transcription cofactors (e.g., steroid receptor co-activator 1 (SRC1) and transcriptional intermediate factor 2 (TIF2)), interfere with AR-DNA binding, e.g., binding to specific DNA response elements (ARE or androgen response elements), inhibit the recruitment of AR 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. Preferred agents that can inhibit or interfere with AR transcriptional activity include any of those known in the art and any of these 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 transcriptional activity by inhibiting AR nuclear translocation. Other drugs, such as arsenic compounds (e.g., arsenic trioxide), are also known to inhibit AR transcriptional activity. See, for example, Rosenblatt AE et al., Mol. Endocrinol. 23(3):412-421 (2009).

[0268]

[0198] In some embodiments, combination therapy may involve administering one or more chemotherapeutic agents to a target. Preferred chemotherapeutic agents include any of those known in the art. In some embodiments, the method includes the step of administering a taxane-based chemotherapeutic agent (e.g., docetaxel, cabazitaxel, paclitaxel, etc.) and / or a platinum-based chemotherapeutic agent (e.g., cisplatin, carboplatin, oxaliplatin, etc.) to a target.

[0269]

[0199] In some embodiments, the combination therapy may include treating the subject with radiotherapy. Preferred radiotherapy includes any of those known in the art. In some embodiments, the method includes the step of treating the subject with stereotactic body radiotherapy or neutron irradiation.

[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]

[0201] In some embodiments, the combination therapy may include administering one or more immunotherapies as targets. Preferred immunotherapies include any of those known in the art. In some embodiments, the method includes the step of administering cipleucel-T as the target. In some embodiments, the method includes the step of administering an immune checkpoint inhibitor as the target. For example, in some embodiments, the method includes the step of administering an anti-PD-1 antibody, e.g., pembrolizumab or nivolumab, and / or an anti-PD-L1 antibody, e.g., avelumab or atezolizumab as the target. In some embodiments, the method includes the step of administering an anti-CTLA-4 antibody, e.g., ipilimumab as the target.

[0272]

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

[0273]

[0203] In some embodiments, the combination therapy may involve administering one or more poly-ADP-ribose polymerase (PARP) inhibitors to a target. In some embodiments, the target having prostate cancer also has a DNA repair defect. In some embodiments, the target having prostate cancer does not have a DNA repair defect. Preferred PARP inhibitors include any of those known in the art. For example, in some embodiments, the method includes the step of administering a PARP inhibitor selected from niraparib, rucaparib, olaparib, talazoparib, veliparib, and fluzoparib to a target.

[0274]

[0204] In some embodiments, the combination therapy may involve administering one or more kinase inhibitors to a target. In some embodiments, the target is characterized as having abnormal levels of each kinase. In some embodiments, the kinase inhibitor may reduce androgen receptor activity or may otherwise be beneficial for cancer treatment. Preferred kinase inhibitors include any of those known in the art. For example, in some embodiments, the method includes the step of administering a kinase inhibitor selected from sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivacertib, onvancertib, ipatasertib, afrecertib, alicertib, apitricib, and opaganib to a target.

[0275]

[0205] In some embodiments, the combination therapy may involve administering one or more osteoprotective agents to a patient. In such embodiments, the patient is typically characterized as having prostate cancer with bone metastases (e.g., CRPC). Preferred osteoprotective agents include any of those known in the art. For example, in some embodiments, the method includes the step of administering an osteoprotective agent selected from denosumab and zoledronic acid to a patient.

[0276]

[0206] In some embodiments, combination therapy may involve administering to a subject one or more additional agents useful for treating prostate cancer, either alone or in combination with an abiraterone agent such as the abiraterone prodrugs herein. Such additional agents are not particularly limited. For example, in some embodiments, the method includes: 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, alloblecib, ZEN-3694, or molyblecib (GSK525762); 7) an anti-CD105 antibody, e.g., TRC105 or carotuximab; 8) niclosamide; 9) an A2A receptor antagonist, e.g., AZD463. The procedure includes the step of administering a therapeutic agent selected from 5;10) phosphoinositide 3-kinase (PI3K) inhibitors, e.g., AZD-8186, buparlisib, or dactricib;11) further nonsteroidal CYP17A1 inhibitors, e.g., ceviteronel;12) ​​antiprogestogens, e.g., onapristone;13) navitoclax;14) HSP90 inhibitors, e.g., onarespib (AT13387);15) HSP27 inhibitors, e.g., OGX-427;16) 5-alpha-reductase inhibitors, e.g., dutasteride;17) metformin;18) AMG-386;19) dextromethorphan;20) theophylline;21) hydroxychloroquine; and 22) lenalidomide.In some embodiments, combination therapy may involve targeting one or more kinase modulators selected from FLT-3 (FMS-like tyrosine kinase) inhibitors, AXL (Anexselect) inhibitors (e.g., gilteritinib), CDK (cyclin-dependent kinase) inhibitors (e.g., 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 (nucleoprotein 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, but is not limited to, olaparib, niraparib, lucaparib, and talazoparib, which are poly(ADP-ribose) polymerase (PARP) inhibitors; 2) includes, but is not limited to, enzalutamide, apalutamide, darolutamide, bicalutamide, nilutamide, flutamide, ODM-204, and TAS3681, which are androgen receptor ligand-binding domain inhibitors; 3) includes, but is not limited to, galeterone, abiraterone, and abiraterone acetate, which are additional CYP17 inhibitors; 4) docetaxel, Microtubule inhibitors, including but not limited to paclitaxel and cabazitaxel (XRP-6258); 5) PD-1 or PD-L1 regulators, including but not limited to pembrolizumab, durvalumab, nivolumab, and atezolizumab; 6) Gonadotropin-releasing hormone agonists, including but not limited to cyproterone acetate and leuprolide; 7) 5-alpha reductators, including but not limited to finasteride, dutasteride, tulosteride, bexrosteride, 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, and idelalisib; 13) Crizotinib and alectinib, 14) Undifferentiated lymphoma kinase (ALK) inhibitors; 15) Endothelin receptor A antagonists, including but not limited to ZD-4054; 16) Anti-CTLA4 inhibitors, including but not limited to MDX-010 (ipilimumab); 17) Heat shock protein 27 (HSP27) inhibitors, including but not limited to OGX427; 18) Androgen receptor degraders, including but not limited to ARV-330 and ARV-110; 19) 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, and GS-5829; 20) Androgen receptor N-terminal domain inhibitors, including but not limited to syntocamide; 21) Alpha particle-emitting radiotherapeutic agents, including but not limited to radium-233 or its salts; 22) Niclosamide; or related compounds thereof; 23) Tamoxifen, raloxifen, toremifene, Selective estrogen receptor modulators (SERMs), including but not limited to alzoxifene, bazedoxifene, pipindoxifene, rasofoxifene, and enclomifene;24) Selective estrogen receptor degraders (SERDs), including but not limited to fulvestrant, ZB716, OP-1074, elacestrant, AZD9496, GDC0810, GDC0927, GW5638, and GW7604;25) Anastrozole, Exemestane, letrozole, and other aromatase inhibitors; 26) Mifepristone, lonaprison, onapristone, asoprisnil, lonaprisnil, ulipristal, terapristone, and other selective progesterone receptor modulators (SPRMs); 27) Mifepristone, COR108297, COR125281, ORIC-101, PT This may include administering one or more agents selected from mammalian targets of 150, but not limited to, glucocorticoid receptor inhibitors; 28) CDK4 / 6 inhibitors, including palbociclib, abemaciclib, and ribociclib; 29) HER2 receptor antagonists, including, but not limited to, trastuzumab and neratinib; and 30) rapamycin (mTOR) inhibitors, including, but not limited to, everolimus and temsirolimus.

[0278]

[0208] The combination therapy of the present invention is not particularly limited to any specific number of additional therapies. For example, in addition to administering the pharmaceutical compositions herein and any optional glucocorticoids, such as hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone, the combination therapy may typically include one, two, three, four, five, six, or more additional therapies described herein. For example, in some embodiments, the combination therapy may 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, radiotherapy, surgery, androgen deprivation therapy, etc. In some embodiments, the combination therapy may include two or more additional therapies described herein. For example, in some particular embodiments, the combination therapy may include administering a PARP inhibitor and androgen deprivation therapy. In some embodiments, the combination therapy may include administration of a GnRH agonist and radiotherapy. In some embodiments, the combination therapy may include administration of a GnRH agonist, a chemotherapeutic agent, and radiotherapy. In some embodiments, the combination therapy may include administration of an androgen receptor antagonist (e.g., first, second, and / or third-generation AR antagonist), a GnRH agonist, and optionally radiotherapy, a chemotherapeutic agent, indomethacin, or a 5-alpha reductase inhibitor. In some embodiments, the combination therapy may include administration of an androgen receptor antagonist (e.g., first, second, and / or third-generation AR antagonist) and radiotherapy. In some embodiments, the combination therapy may include administration of an androgen receptor antagonist (e.g., first, second, and / or third-generation AR antagonist) and a chemotherapeutic agent. In some embodiments, combination therapy may involve administering an androgen receptor antagonist (e.g., a first, second, and / or third-generation AR antagonist) and an anti-CTLA4 antibody.These combinations discussed are examples of useful combinations, not limiting ones, and it should be understood that other combinations of additional therapies described herein are also possible.

[0279]

[0209] It should be noted that in some embodiments, the methods for treating prostate cancer as described herein (e.g., any of those described herein) are not combined with combination therapies. For example, a method may include the step of administering a therapeutically effective amount of the pharmaceutical composition described herein to a target without one or more additional therapies described herein.

[0280]

[0210] The pharmaceutical compositions herein can be administered to subjects requiring abiraterone as their sole source. 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 Zytiga® formulations, either simultaneously or sequentially in any order. In some embodiments, subjects can use the pharmaceutical compositions herein as a supplement to existing abiraterone therapy.

[0281]

[0211] Provided herein are formulations, methods, and kits for treating subjects with sex hormone-dependent benign or malignant disorders, such as prostate cancer. Also provided are methods for preparing formulations useful for treating subjects with, for example, sex hormone-dependent benign or malignant disorders (e.g., prostate cancer), androgen receptor-induced cancers, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia. Representative embodiments are described in detail here, examples of which are illustrated in the accompanying drawings.

[0282]

[0212] The term “subject” as used herein means, but is not limited to, animals or humans who require or can receive chemotherapy for sex hormone-dependent benign or malignant disorders, e.g., androgen-dependent or estrogen-dependent disorders (including prostate cancer and breast cancer), androgen receptor-induced cancers, non-tumor syndromes resulting from androgen excess, e.g., endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), precocious puberty, male-pattern hirsutism, and / or syndromes resulting from glucocorticoid excess, e.g., hypercortisolemia, e.g., Cushing’s syndrome or Cushing’s disease. In preferred embodiments, the subject is a human subject.

[0283]

[0213] The term “other drugs or agents” as used herein (for example, when referring to before, concurrently 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., which is capable of improving the efficacy of the formulation(s), mitigating undesirable side effects(s) of the formulation(s), or improving the treatment of a particular disorder. Any preferred route of administration of such “other drugs or agents,” e.g., oral administration, parenteral administration, etc., may be used. A person skilled in the art of treating subjects with sex hormone-dependent benign or malignant disorders (e.g., androgen-dependent or estrogen-dependent disorders), androgen receptor-induced cancers, syndromes resulting from androgen excess syndromes, and / or syndromes resulting from glucocorticoid excess, e.g., hypercortisolemia, knows and understands how to select and use such “other drugs or agents” for the intended purpose(s).

[0284]

[0214] The formulations may be administered via a controlled-release device or method of choice. The term “controlled-release,” as used herein, should be understood to include delayed release, prolonged or prolonged release, sustained release, or targeted release, etc. For example, in some embodiments, a controlled-release device or method may further prolong the release of abiraterone of the prodrugs and formulations of this disclosure. In some embodiments, a controlled-release device or method may also include any device or method that is capable of releasing the drug or product (e.g., a drug or biological product) at a time later than immediately after administration (e.g., implants may be included). Various controlled-release devices are described (Stubbe et al., Pharm. Res. 21: p. 1732, 2004) and may be applicable to representative embodiments. Controlled-release devices or methods may be identified and utilized by persons skilled in the art without excessive experimentation, after considering all criteria of best judgment regarding the benefit to the subject and the use thereof.

[0285]

[0215] The formulations and agents of the embodiments are administered to subjects with prostate cancer in amounts that are pharmacologically or physiologically acceptable and effective in reducing or eliminating, for example, the presence of prostate tumor tissue and abnormal or malignant prostate cells. Similarly, the formulations and agents of the embodiments are administered in prophylactic or therapeutically effective doses, either alone or in combination with other therapeutic agents or modes of treatment (e.g., radiotherapy and surgery), but the prophylactic or therapeutically effective dose should be understood as the amount that satisfies the intended prophylactic or therapeutic objective and provides the benefits available from the administration of such formulations and agents.

[0286]

[0216] The terms “effective dose,” “effective dosage,” and “therapeutic plasma concentration,” as used herein, mean, but are not limited to, the amount, dose, or concentration that can treat, delay, slow, inhibit, or eliminate the onset, presence, or progression of a disorder, disease, or condition. For example, “effective dose,” “effective dosage,” or “therapeutic plasma concentration” in a subject with prostate cancer is sufficient to reduce or eliminate the presence of prostate tumor tissue and abnormal or malignant prostate cells, to cure the disease (partially or completely), or to prevent the onset or further progression of a disorder, disease, or condition. Furthermore, for example, the effective dose of a formulation means the amount administered alone or in combination with other therapeutic agents or modes of treatment (e.g., radiotherapy and surgery) to achieve a clinically significant reduction of the tumor burden. Those skilled in the art will understand when a clinically significant reduction of the tumor burden (or improvement of a sex hormone-dependent benign or malignant disorder or another disorder or syndrome described herein) occurs following administration of the formulation. "Effective dose," "effective dosage," or "therapeutic plasma concentration" is understood to be a quantity, dosage, or concentration that is not clinically harmful to the subject and in any case the benefits outweigh any adverse side effects. For example, an effective dose or dosage of an abiraterone decanoate preparation means an amount that, following oral administration of the pharmaceutical composition herein, enables the subject to achieve a plasma concentration of at least 1 ng / ml of abiraterone, e.g., at least 1 ng / ml, at least 2 ng / ml, at least 4 ng / ml, or at least 8 ng / ml, where the effective plasma concentration is achieved at least 12 hours, preferably at least 24 hours, following administration.

[0287]

[0217] Generally, the dosage range for administering the formulations described herein is that which produces the desired effect(s). The useful dosage administered will vary depending on the age, weight and health of the subject being 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 disorder or other syndrome or disorder described herein) to which treatment with the formulation is required. The dosage will also vary depending on the nature or severity of the primary tumor and other underlying conditions, the epidemiological status, the concomitant use of other effective 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 a formulation (and other drugs(s)) can be determined by a person skilled in the art without excessive experimentation (e.g., pharmacokinetic studies), after considering all criteria and use of the best judgment regarding the benefit to the subject (most often depending on the specific formulation used). The dose administered depends on the specific case, not on any particular event, and is sufficient to induce clinical benefit or improvement for sex hormone-dependent benign or malignant disorders (e.g., prostate cancer), androgen receptor-induced cancers, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia.

[0289]

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

[0290]

[0220] Abbreviations used herein have their conventional meanings within the chemical and biological fields.

[0291]

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

[0292]

[0222] As used herein, the term “about” modifying a quantity relating to the disclosure means a numerical variation that may occur, for example, through routine testing and handling; through errors in such testing and handling; through differences in the manufacture, source, or purity of the components / materials used in the disclosure. As used herein, a specific value accompanied by “about” also includes the specific value, for example, about 10% includes 10%. Whether modified by the term “about” or not, a claim includes an equivalent of the stated quantity. In one embodiment, the term “about” means within 25% of the reported numerical value.

[0293]

[0223] It should also be understood that specific embodiments of the variable portion of this specification may be the same as or different from other specific embodiments having similar identifiers.

[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, CAS edition, Handbook of Chemistry and Physics, 75th edition, inside front cover, and specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry and specific functional group moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John 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 to any particular method by the exemplary enumeration of substituents described herein.

[0295]

[0225] As used herein, the term “alkyl” means a linear or branched saturated aliphatic hydrocarbon, when used alone or as part of another group. In some embodiments, alkyl has 1 to 30 carbon atoms (i.e., C 1~30 Alkyl or, in other terms, C1-C 30 It may contain an alkyl group or a specified number of carbon atoms (i.e., a C1 alkyl group such as methyl, a C2 alkyl group such as ethyl, a C3 alkyl group such as propyl or isopropyl, etc.). In one embodiment, the alkyl group is a linear C1~16 It is an alkyl group. In another embodiment, the alkyl group is a branched chain C 3~16 It is an alkyl group. Clearly, when a range of carbon numbers is enumerated, it includes each individual integer within the range and the subranges between such integers, as will be understood by those skilled in the art. For example, "C" in this specification 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 This includes the ranges described herein, such as "5 to 16 carbon atoms." Other ranges described herein, such as "carbon number range," should be understood similarly.

[0296]

[0226] As used herein, the term “cycloalkyl” means, when used alone or as part of another group, a group of 3 to 12 carbon atoms (i.e., C 3~12 This refers to saturated and partially saturated (e.g., containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having a specified number of carbon atoms (cycloalkyl). In one embodiment, the cycloalkyl group has two rings. In one embodiment, the cycloalkyl group has one ring. In another embodiment, the cycloalkyl group has C 3~8 It is a cycloalkyl group. In another embodiment, the cycloalkyl group is C 3~6 These are cycloalkyl groups. "Cycloalkyl" also includes ring systems in which the cycloalkyl ring, as defined above, is fused with one or more aryl or heteroaryl groups on the cycloalkyl ring, in which case the carbon number remains as specified for the carbon number of 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” means, when used alone or as part of another group, a straight-chain or branched-chain aliphatic hydrocarbon containing one or more (e.g., 1, 2, or 3) carbon-carbon double bonds. In one embodiment, the alkenyl group is C 2~16 It is an alkenyl group.

[0298]

[0228] As used herein, the term “alkynyl” means, when used alone or as part of another group, a linear or branched aliphatic hydrocarbon containing one or more (e.g., 1, 2, or 3) carbon-carbon triple bonds. In one embodiment, the alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is C 2~16 It is an alkynyl group.

[0299]

[0229] As used herein, the term “abiraterone prodrugs” includes any of the compounds described herein by formula I or II, lipophilic esters of abiraterone, isotopically labeled compounds thereof (e.g., deuterium-rich compounds), possible stereoisomers thereof (including diastereomers, enantiomers, and racemic mixtures), tautomers thereof, conformational isomers thereof, and / or pharmaceutically acceptable salts thereof (e.g., acid addition salts such as HCl salts). Hydrates and solvates of prodrugs are considered compositions of the Disclosure, and prodrugs are associated with water or solvents, respectively. Some prodrugs may also exist in various pleomorphic or amorphous forms. The abiraterone prodrugs described herein also include these compounds that readily undergo chemical changes under physiological conditions that result in active abiraterone. In addition, 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 contrary to the content, the abiraterone prodrug may be abiraterone decanoate.

[0300]

[0230] The abiraterone prodrugs described herein may exist in isotopically labeled or enriched forms containing one or more atoms having atomic masses or mass numbers different from those most commonly found in nature. The isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, oxygen, and nitrogen are 2 H, 3 H, 13 C, 14 C, 15 N, and 18 Compounds containing, but not limited to, O, other isotopes and / or other atoms are within the scope of this disclosure.

[0301]

[0231] The solid and dashed wedge bonds represent stereochemistry as is customary in the art.

[0302]

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

[0303] Example 1A. Large-scale preparation of aviraterone decanoate from decanoic acid [ka]

[0233] To a suspension of abiraterone (381.9 g, 1.09 mol) in dichloromethane (3500 mL), triethylamine (165 g, 1.64 mol) and a catalytic amount of DMAP (13.35 g, 0.109 mol) were added. Decanoic acid (225 g, 1.31 mol) was added to the suspension as a solution in dichloromethane (500 mL), followed by the addition of EDCI (293 g, 1.53 mol), and the reaction mixture was then stirred at 20-25°C for 19 hours.

[0304]

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

[0305]

[0235] 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-necked 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 overnight at room temperature. The solid was filtered, the flask was rinsed with the filtrate, and the contents were transferred to a filtration funnel. The wet cake was transferred to a drying tray and dried overnight in a vacuum oven at 40-45°C to obtain 457.1 g (90% yield) as a white solid, and the crystalline form of this solid is designated as form A. 11H NMR (CDCl3, 400MHz):d 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 values ​​(corrected for a moisture level of 0.055%): C, 81.0%, H, 9.8%, N, 2.8%; measured values: 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 of approximately 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. For HPLC analysis, samples of abiraterone decanoate were prepared in methanol at concentrations of 0.05 mg / mL (for assay analysis) or 5 mg / mL (for impurity analysis). The HPLC conditions were as follows: HPLC column: Halo C8 (2.7 μm, 100 × 3.0 mm); injection volume: 5 μL; column temperature: 40°C; sample temperature: ambient; detection: 210 nm; mobile phase: 25 mM ammonium acetate, pH 8.0 (MPA) and 95 / 5 acetonitrile / tetrahydrofuran (MPB); flow rate: 0.6 ml / min; gradient: 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, and maintain at 65 / 35 MPA / MPB until completion at 45 minutes.

[0307]

[0237] The white solid obtained in this embodiment was also characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). XRPD was performed using a Bruker D8 Discover X-ray diffractometer with a theta / theta vertical goniometer, with a Vantec-500 as the detector. Standard conditions: voltage 40kV, current 40mA, radiation, Cu, temperature, ambient temperature, slit size at X-ray source exit, 0.5mm pinhole, beak-shaped collimator, 0.5mm, sample holder, ground quartz plate. Operating conditions: detector distance, 30cm, chi-integration range, 4~40 degrees 2θ, count time, 120 sec / frame, number of frames: 3, theta 1st position, 4 degrees, theta 2nd position, 4 degrees, frame width, 12, scanning axis, coupled. Software used included GADD software, General Area Detector Diffraction System, version 4.1.50; and DIFFRAC.EVA, version 4.0. DSC was performed using a TA instrument Q2000 (Thermal Advantage V5.0.0-compliant) with sample sizes of 2–10 mg, heated at a heating rate of 10 °C / min in the range of 25 °C to 250 °C. Representative XRPD and DSC spectra are shown in Figures 2A–2B. Thermogravimetric analysis (TGA) was also performed on the same samples. TGA was performed using a TA instrument TGA Q500 (Thermal Advantage V5.2.5-compliant) with sample sizes of 5–20 mg, heated at a heating rate of 10 °C / min in the range of 25 °C to 150 °C. A representative TGA trajectory is shown in Figure 2C.

[0308] Example 1B. Preparation of high-purity avirateron 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 then contained approximately 72 L of acetone, which was 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). The analytical data is consistent with that described in Example 1A. Typical specifications for the analysis of the obtained abiraterone decanoate are shown in Table 1 below.

[0310] [Table 1]

[0311]

[0240] Ethyl prosterone decanoate may be an impurity and has the following structure: [ka] It is thought to have this characteristic.

[0312]

[0241] The purity of the obtained abiraterone decanoate was analyzed using reversed-phase HPLC. Separation was performed using an Advanced Materials Technology Halo C8 reversed-phase column with dimensions of 3.0 × 100 mm and a particle size of 2.7 μm. A linear gradient program (20 min) was 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 solutions and sample solutions were prepared with methanol diluent. A typical injection volume was 5 μL, and the detection wavelength was 210 nm.

[0313] [Table 2]

[0314]

[0242] Crude abiraterone decanoate contained 130 ppm of Pd. The Pd level was reduced to 120 ppm by recrystallization using only acetone / water. However, by using the process described in this embodiment, the final abiraterone decanoate can be purified to have a Pd content of only 3.7 ppm.

[0315] Example 1C. Polymorph screening of aviraterone decanoate

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

[0316]

[0244] Crystallization by cooling at -15°C: Approximately 30 mg of abiraterone decanoate was dissolved in the minimum volume of solvent. If not completely dissolved, the sample was heated at 50°C for 1 hour. The sample was placed in a refrigeration device and filtered after 2 days (if precipitate was visible). The results using this crystallization method are shown in Table E1 below.

[0317] [Table 3]

[0318]

[0245] Evaporation from a two-component 1:1 solvent mixture: Approximately 25 mg of abiraterone decanoate was dissolved in approximately 10 mL of solvent. The sample was evaporated under a nitrogen purge of 1 psi. The results using this crystallization method are shown in Table E2 below.

[0319] [Table 4]

[0320]

[0246] Addition of reverse solvent: Approximately 25 mg of abiraterone decanoate was dissolved in 1-2 mL of solvent, followed by the addition of 2-4 mL of reverse solvent. If a precipitate formed, the sample was filtered. The results using this crystallization method are shown in Table E3 below.

[0321] [Table 5]

[0322]

[0247] Solvent recrystallization from a single solvent: Aviraterone decanoate was recrystallized using various solvents. The scale of the recrystallization experiments was approximately 2–10 mL. Saturated solutions were prepared by contacting various solvent systems at saturation temperature and stirring out excess aviraterone decanoate. If the solid did not completely dissolve in the solvent, the mother liquor was separated from the residual solid by filtration. The mother liquor was then heated above saturation temperature to dissolve any remaining solid. The temperature of each solution was then adjusted to the growth temperature, and solvent evaporation was initiated by introducing a controlled nitrogen shear flow. The recrystallization conditions for the panel based on the solvents used during this experiment are summarized in Tables E4–E5. XRD analysis was performed.

[0323] [Table 6]

[0324] [Table 7]

[0325]

[0248] Non-competitive slurry experiment: The non-competitive slurry experiment was 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 test included 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 non-competitive slurry experiments resulted in no change from the starting material.

[0326]

[0249] Competitive testing 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 then filtered. The results of the competitive testing are shown in Table E6 below.

[0327] [Table 8]

[0328]

[0250] Morphological Characterization: Solids produced from solvent-based recrystallization panels were analyzed by powder XRD. To mitigate favorable particle effects, all XRD screening data were collected using a two-dimensional detection system. The two-dimensional detector was integrated along a concentric Debye cone to help reduce pattern variation. When bright spots appear in the conical ring, it indicates a strong and favorable particle effect, which can result in significant variability in the observed diffraction pattern, including variations in peak intensity. Some samples of aviraterone decanoate exhibited a favorable particle effect 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 observed forms were designated as forms A, B, and C.

[0330]

[0252] After classifying the data into different forms based on diffraction behavior, each form was tested to determine if other characteristics of the form could be differentiated. Characterization of each form began by comparing the diffraction data representative of each form with data from other forms. This is generally followed by NMR, DSC, and TGA.

[0331]

[0253] The initial material used in this test is morphology A, which matches the representative characterization data shown in Experiment 1A. See also summary table E7 below.

[0332]

[0254] Morphology B was obtained through various crystallization experiments, particularly those performed at low temperatures (-10 to -20°C). The characteristic diffraction behavior of morphology B is shown in a representative XRPD spectrum, FIG. 2D. 1 The 1H NMR spectrum shows no organic impurities and is consistent with the expected structure of ADEC. Representative DSC and TGA spectra of morphology B are shown in Figures 2E and 2F.

[0333]

[0255] Morphology C was obtained by evaporation from a 1:1 mixture of ethanol and 2-butanone. The characteristic diffraction behavior of morphology C is shown in a representative XRPD spectrum, FIG. 2G. It should be noted that the diffraction pattern obtained for one "pure" morphology C sample shows significant overlap with morphology A at larger diffraction angles, indicating that it may contain some morphology A. 1 The 1H NMR spectrum shows no organic impurities and is consistent with the expected structure of ADEC. Representative DSC and TGA spectra of morphology C are shown in Figures 2H and 2I.

[0334]

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

[0335] [Table 9]

[0336]

[0257] Recrystallization experiments of the polymorph screen produced either morphology A, B, C, or a mixture of morphologies. Morphology A is expected to be a thermodynamically stable morphology under ambient conditions based on non-competitive and competitive slurry experiments.

[0337] Example 2. Solubility of abiraterone decanoate in different vehicles

[0258] In this example, the solubility of aviraterone decanoate was tested in the following four vehicles. Each vehicle has a unique base, namely a medium-chain triglyceride (MCT) / polyoxyglyceride, a long-chain (LC) monodiglyceride, and two propylene glycol (PG) monoesters, caprylic acid and lauryl.

[0259] Vehicle 1: MCT / Polyoxyglyceride base: 20% Corifol RH40 / 14% Pulrololeic CC497 / 33% Labrafil 1944CS / 33% Labrafac Lipofilament WL1349

[0260] Vehicle 2: PG monoester base: 20% Corifol RH40 / 14% Plurol Oleic CC497 / 66% Lauroglycol 90

[0261] Vehicle 3: PG monoester base: 20% Corifol RH40 / 14% Plurol Oleic CC497 / 66% Capmul PG-8

[0262] Vehicle 4: LC monodiglyceride base: 20% corifoll RH40 / 14% pulrololeic CC497 / 66% mycin CC

[0338]

[0263] The solubility of abiraterone decanoate in different vehicles was tested according to the following procedure: Prepare a vehicle weighing 5g. Weigh out approximately 350 mg of the drug into a 4 mL vial, then add 2 mL of the vehicle. All samples are ultrasonically treated, vortex stirred, and then placed in a rotating apparatus at 25°C. At the end of the day, check the sample to ensure the drug is completely dissolved. If it is, use wax paper to transfer the additional drug and record the amount added. After 2-3 days, take approximately 0.5 mL from each sample and filter it using a microcentrifuge. 0.45 μm filter paper can be used. Return the vial to a 25°C incubator for subsequent use. The solubility of the samples was analyzed using HPLC. Results were obtained for samples after 2 and 7 days.

[0339]

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

[0340] [Table 10]

[0341] Example 3. Solubility of abiraterone decanoate in an additional vehicle

[0265] This example tests the solubility of abiraterone decanoate in an additional vehicle.

[0266] The vehicle to be tested has the following composition:

[0267] Vehicle 1 (see Example 2): 20% Corifol RH40 / 14% Pullol Oleic CC497 / 33% Labrafil 1944CS / 33% Labrafac Lipofil WL1349, used as control.

[0268] Vehicle 5:20% Corifol RH 40 / 14% Pullol Oleic CC497 / 33% Mycin CC / 33% Labrafac Lipofil WL1349 *

[0269] Vehicle 6: 20% Corifol RH 40 / 14% Pullol Oleic CC 497 / 16% Labrafil 1944CS / 30% Mycin CC / 20% Labrafac Lipofil WL1349

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

[0271] Vehicle 8: 20% Corifol RH40 / 14% Pulrololeic CC497 / 16% Labrafil 1944CS / 30% Capmul PG-12 / 20% Labrafac Lipofil WL1349

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

[0342]

[0273] The procedure for preparing the sample to be tested and its solubility is similar to that described in Example 2. The results are shown in the table below.

[0343] [Table 11]

[0344]

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

[0345] Example 4. Dispersion of abiraterone decanoate preparation

[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]

[0276] The distributed test was conducted according to the following general procedure: Each formulation is prepared at a concentration of abiraterone decanoate (AbDec) with a solubility of less than 10% in each vehicle; Equilibrate 7.92 mL of 0.1 M HCl in the vial onto a rotating apparatus at 37°C; Add 0.08 mL of the formulation to 0.1 M HCl medium at 37°C and start the rotating apparatus. To distribute 80 μL, draw the dispersant medium into the pipette and release it several times; Filter a total volume of 8 mL through 25 mm 0.45 μm PVDF filter paper over 60 minutes; Each formulation for the assay is prepared by diluting it to a concentration below the standard concentration using IPA (isopropyl alcohol); Perform HPLC assays on formulations, dispersed samples, and standards; Furthermore, a sample of abiraterone is prepared in IPA at a concentration similar to the AbDec highest standard. This sample demonstrates what should be formed during the dispersion test if HPLC can detect free Ab.

[0347]

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

[0348] [Table 12]

[0349]

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

[0350] Example 5. Dispersion of additional abiraterone decanoate preparation

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

[0351]

[0280] The dispersion test was carried out according to the general procedure shown in Example 4. The results are shown in the table below.

[0352] [Table 13]

[0353]

[0281] The results indicate 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(registered trademark) [Crl:CD(registered trademark)(SD)] rats.

[0282] The purpose of this study is to evaluate the relative absorption of two different oral formulations of abiraterone decanoate over 72 hours following a single oral administration of gastric tube nutrition to male rats.

[0355]

[0283] This example also determines the plasma pharmacokinetics of abiraterone and abiraterone decanoate, serum concentrations of luteinizing hormone, and serum concentrations of steroid androstenedione, corticosterone, progesterone, and testosterone in rats following a single oral administration of abiraterone decanoate to two groups of CD(registered trademark)[Crl:CD(registered trademark)(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 a vehicle for Formulation 2 and was used as a control. In addition, tissues were collected from all animals 72 hours after administration to determine the concentrations of abiraterone and abiraterone decanoate.

[0356]

[0284] The following table shows the experimental plan for this embodiment.

[0357] [Table 14]

[0358]

[0285] Details of the test material are as follows: Aviraterone decanoate preparation 1: 40 mg aviraterone decanoate / mL in vehicle 1: 20% corifor RH40 / 14% plurol oleic CC497 / 33% lavrafil 1944CS / 33% lavrafak lipofil WL1349. Aviraterone decanoate preparation 2: Vehicle 2 contains 40 mg of aviraterone decanoate / mL: 20% of corifor RH40 / 14% of plurol oleic CC497 / 66% of lauroglycol 90. The control article is Vehicle 2: 20% Corifol RH40 / 14% Plurol Oleic CC497 / 66% Lauroglycol 90.

[0359]

[0286] Male rats manufactured by Charles River Laboratories, Inc. (CD Corporation [Crl:CD Corporation (SD)]) 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 administration for pharmacokinetic or steroid analysis.

[0361]

[0288] Using the concentrations of abiraterone and abiraterone decanoate in plasma, luteinizing hormone in serum, and steroids in serum, 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] Tissue samples (adrenal gland, brain, femur, liver, lung, mandibular lymph node, mesenteric lymph node, prostate, sternum, and testis) were collected 72 hours after drug administration, and the concentration at that time was presented.

[0364]

[0291] Result:

[0292] Pharmacokinetic parameters derived from plasma concentrations of abiraterone and abiraterone decanoate are shown in Tables 3 and 4, and the plasma profile is shown in Figure 3. The effects of oral administration of formulations 1 and 2 on plasma steroid concentrations are shown graphically in Figures 4A, 4B, 5A, 5B, 6A, 6B, 7A, and 7B. The mean plasma concentration of luteinizing hormone is shown graphically in Figure 8. The mean and individual tissue concentrations of abiraterone and abiraterone decanoate are shown in Tables 5 and 6, and graphically 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 administration of Formulation 1, C against abiraterone max It is 404 ng / mL, T max This is at the 2-hour mark, AUC last The value was 3418 ng.h / mL. Following a single oral administration of formulation 2, C2 was administered to abiraterone. max It is 128 ng / mL, T max The AUC is between 1 and 4 hours. last The value was 1591 ng.h / mL. From this, the relative exposure to abiraterone from the oral dose of formulation 1 was, respectively, C compared to formulation 2. max and AUC lastThese were 3.2 times and 2.1 times higher, respectively. The oral bioavailability of abiraterone based on plasma concentrations for formulations 1 and 2 is approximately 59% and 27%, respectively, 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 a 100 mg / kg dose).

[0370]

[0295] Following a single oral administration of Formulation 1, C against abiraterone decanoate. max The value is 54.4 ng / mL, and T max The AUC is between 1 and 4 hours. last The value was 151 ng.h / mL. Following a single oral administration of formulation 2, C2 was administered to abiraterone decanoate. max It was 2.96 ng / mL, and T max The AUC is between 1 and 4 hours. last The value was 25.5 ng.h / mL. From this, the relative exposure to abiraterone decanoate from the oral dose of formulation 1 was, respectively, C compared to formulation 2. max and AUC last These figures were 18.3 times and 5.92 times higher, respectively.

[0371]

[0296] Tissue concentrations of abiraterone and abiraterone decanoate:

[0297] 72 hours after oral administration of Formulation 1, abiraterone was detected in all tissues except the femur at relatively low levels, with the highest concentrations in the liver (63.6 ng / g) and mesenteric lymph nodes (31.0 ng / g). Following oral administration of Formulation 2, abiraterone concentrations were low or BLQ in all tissues, consistent with the results for Formulation 1, with the highest concentrations in the liver (19.7 ng / g) and mesenteric lymph nodes (14.2 ng / g).

[0372]

[0298] Consideration:

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

[0373]

[0300] Both formulations decreased plasma androstenedione concentrations, increased progesterone concentrations, and decreased testosterone concentrations. There was no effect on corticosterone concentrations. The effects of each formulation were considered similar (less than 2x difference), but the effect of formulation 1 tended to be greater than that of formulation 2, consistent with higher exposure to abiraterone.

[0374]

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

[0375]

[0302] Abiraterone, not abiraterone decanoate, was detected in tissue 72 hours after administration, with peak concentrations in the liver and mesenteric lymph nodes that were higher than those in formulation 1 than in formulation 2.

[0376]

[0303] Each reference made herein is incorporated herein in its entirety.

[0377]

[0304] With respect to the aspects of the Disclosure described as types, each individual type can be considered separately from the separate aspects of the Disclosure. Where an aspect of the Disclosure is described as "including" a feature, the embodiment is also intended to "consist of" or "essentially consist of" the feature.

[0378]

[0305] All the various aspects, embodiments, and options described herein can be combined with any variation.

[0379]

[0306] While several embodiments of the present invention have been described here, it should be obvious to those skilled in the art that the above are merely illustrative, not limiting, and are presented only as examples. Many modifications and other embodiments are within the scope of one of the knowledge of the art and are intended to be included within the scope of the present invention and any equivalent thereof. Modifications of the present invention are readily apparent to those skilled in the art and can be understood as intended to include such substitutions. Furthermore, since many modifications are readily apparent to those skilled in the art, we do not wish to limit the present invention to the exact same structure and operation as illustrated and described, and therefore all suitable modifications and equivalents can be used and are included within the scope of the present invention.

Claims

1. A pharmaceutical composition comprising (a) abiraterone decanoate and (b) a lipid-based drug delivery system, wherein abiraterone decanoate has the following structure: 【Chemistry 1】 It has, The lipid-based drug delivery system comprises (1) triglycerides, monoglycerides, diglycerides, and / or propylene glycol esters, and (2) a surfactant containing polyglyceryl esters and / or polyoxyglycerides. A pharmaceutical composition wherein the aforementioned pharmaceutical composition is formulated for oral delivery of abiraterone decanoate.

2. The pharmaceutical composition according to 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, and optionally the medium-chain triglycerides of caprylic acid (C8) and capric acid (C10).

3. The pharmaceutical composition according to claim 1, wherein the lipid-based drug delivery system comprises a monoglyceride and / or a diglyceride, and optionally the lipid-based drug delivery system comprises glycerol / glyceryl linoleate.

4. The pharmaceutical composition according to 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.

5. (i) The lipid-based drug delivery system comprises a surfactant comprising a polyglycerol ester, optionally comprising a surfactant comprising polyglyceryl oleate, optionally comprising polyglyceryl-3 dioleate, and / or (ii) The pharmaceutical composition according to 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 macrogol glycerol hydroxystearate, oleoyl polyoxyl-6 glyceride, or lauroyl polyoxyl-6 glyceride.

6. The pharmaceutical composition according to claim 1, wherein the abiraterone decanoate is dispersed, for example, uniformly dispersed or dissolved, in the lipid-based drug delivery system at a concentration of about 1 mg / g to about 250 mg / g, optionally in the range of about 20 mg / g to about 150 mg / g.

7. The pharmaceutical composition according to claim 1, which is formulated in the form of a capsule or, optionally, a softgel capsule.

8. The pharmaceutical composition according to claim 1, wherein the abiraterone decanoate is dissolved in the lipid-based drug delivery system at a concentration in the range of about 10 mg / g to about 150 mg / g, and the lipid-based drug delivery system comprises (a) lipids in an amount of about 10 to 80% by weight of the lipid-based drug delivery system; and (b) one or more nonionic surfactants in an amount of about 20 to 90% by weight of the lipid-based drug delivery system.

9. (i) The lipid comprises about 10% to about 50% by weight, for example, about 20 to 40% by weight, of medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) in the lipid-based drug delivery system, and / or (ii) The lipid comprises about 10% to about 50% by weight, for example, about 20% to 40% by weight, of the lipid-based drug delivery system, and / or (iii) The lipid further comprises about 10% to about 50% by weight, for example, about 20% to 40% by weight, of the lipid-based drug delivery system, propylene glycol monocaprylate or propylene glycol monolaurate, and / or (iv) The lipid-based drug delivery system comprises two or more nonionic surfactants, for example, two or three nonionic surfactants, and / or (v) The one or more nonionic surfactants include macrogol glycerol 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) comprising abiraterone decanoate dissolved in the lipid-based drug delivery system at a concentration in the range of approximately 20 mg / g to approximately 120 mg / g, (A) The lipid-based drug delivery system comprises (a) about 20 to 40% by weight of medium-chain triglycerides of caprylic acid (C8) and capric acid (C10) in the lipid-based drug delivery system; (b) about 10 to 30% by weight of macrogol glycerol hydroxystearate in the lipid-based drug delivery system; (c) about 10 to 30% by weight of polyglyceryl oleate in the lipid-based drug delivery system; and (d) about 20 to 40% by weight of oleoyl polyoxyl-6 glyceride in the lipid-based drug delivery system, or (B) 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 to 40% by weight of the lipid-based drug delivery system; (b) macrogol glycerol hydroxystearate in an amount of about 10 to 30% by weight of the lipid-based drug delivery system; (c) polyglyceryl oleate in an amount of about 10 to 30% by weight of the lipid-based drug delivery system; (d) oleoyl polyoxyl-6 glyceride in an amount of about 10 to 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 to 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 acid (C8) and capric acid (C10) in an amount of about 10 to 40% by weight of the lipid-based drug delivery system; (b) macrogol glycerol hydroxystearate in an amount of about 10 to 30% by weight of the lipid-based drug delivery system; (c) polyglyceryl oleate in an amount of about 10 to 30% by weight of the lipid-based drug delivery system; (d) oleoyl polyoxyl-6 glyceride in an amount of about 0 to 40% by weight of the lipid-based drug delivery system; and (e) glycerol / glyceryl linoleate in an amount of about 10 to 40% by weight of the lipid-based drug delivery system, and / or (viiii) The pharmaceutical composition according to claim 8, which is formulated in the form of a capsule or, optionally, a softgel capsule.

10. (i) 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, and / or (ii) The abiraterone decanoate is characterized by having a purity of at least 95% by weight, preferably at least 98%, for example, about 98.5%, about 99%, about 99.5%, or higher, and optionally, (A) Formulas in which the abiraterone decanoate is less than 1% by weight, optionally less than 0.5% by weight, less than 0.3% by weight, less than 0.2% by weight, or less than 0.1% by weight: 【Chemistry 2】 Characterized as having ethyl plasterone decanoate, optionally characterized as not having a detectable amount of ethyl plasterone decanoate, and / or (B) The pharmaceutical composition according to claim 1, wherein the abiraterone decanoate is characterized by having a palladium content of less than 50 ppm, and optionally the abiraterone decanoate is characterized by having a palladium content of less than 10 ppm.

11. It is used in methods for treating or preventing diseases or disorders that require it. 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 cancers, 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, classical or non-classical congenital adrenal hyperplasia, precocious puberty, male-pattern hirsutism, and combinations thereof, and optionally, the disease or disorder is (A) A sex hormone-dependent or androgen receptor-induced cancer, and optionally, the sex hormone-dependent or androgen receptor-induced cancer is androgen receptor-positive salivary duct cancer, or androgen receptor-positive glioblastoma pleomorphoni, or (B) Prostate cancer, and optional, (a) The subject having prostate cancer is characterized by 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, (d) The prostate cancer is a 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, chemotherapy has not yet been clinically indicated for the subject, or (f) The prostate cancer is metastatic castration-resistant prostate cancer (mCRPC), and the disease in question has progressed in or after a taxane-based chemotherapy regimen, for example, docetaxel-based, or (g) The prostate cancer is refractory prostate cancer, and / or (ii) The method further includes the step of treating the subject with radiotherapy or surgery, and / or (iii) The method further comprises administering to the subject one or more other agents selected from anticancer agents, hormone ablation agents, antiandrogens, differentiation agents, antineoplastic agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotics, immunoassay agents, interferon-type agents, insertion agents, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloproteinase inhibitors, genetic therapeutic agents, or combinations thereof, and / or (iv) The method further comprises the step of administering to the subject one or more agents selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone, and / or (v) The method further comprises the step of administering to the subject one or more other agents selected from chemotherapeutic agents, hormone replacement agents, or hormone ablation agents, and / or (vi) The method further comprises the step of treating the subject with androgen deprivation therapy, or (vii) The subject is, (A) Not subject to castration, or (B) The subjects are not treated with a gonadotropin-releasing hormone agonist and / or antagonist in an amount effective in lowering serum testosterone levels, and optionally (a) the subjects are not treated with a drug selected from buserelin, leuprolide, deslorerin, fertilelin, histrelin, gonadrelin, resirelin, goserelin, nafarelin, peforellin and triptorelin, or optionally (b) the subjects are not treated with a drug selected from avalerix, cetrorelix, degarerix, 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 (viiii) The method further comprises the step of 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 proxaltoamide, bicalutamide, flutamide, nylutamide, and topirutamide, and / or (x) The method further comprises the step of administering a second-generation androgen receptor antagonist to the subject, and / or (xi) The method further comprises the step of administering a third-generation androgen receptor antagonist or an androgen receptor degrading molecule to the subject, either alone or in combination with one or more first-generation or second-generation androgen receptor antagonists, and / or (xi) The method further comprises the step of administering a chemotherapeutic agent, for example, a taxane-based chemotherapeutic agent or a platinum-based chemotherapeutic agent, to the subject, and / or (xiii) The method further comprises the step of administering an immunotherapy to the subject, for example, the step of administering cypluce-T, an immune checkpoint inhibitor, or an anti-CTLA-4 antibody, and / or (xiv) The method further comprises the step of administering a bispecific T-cell engager (BiTE) therapy, such as blinatumomab or solitomab, to the subject, and / or (xv) The method further comprises the step of administering to the subject a kinase inhibitor, optionally selected from sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivacertib, onvancertib, ipatasertib, afrecertib, alicertib, apitricib, and opaganib, and / or (xvi) The method further comprises the step of administering to the subject a bone protective agent, optionally selected from denosumab and zoledronic acid, wherein the subject is characterized as having prostate cancer with bone metastases, and / or (xvii) The method further comprises the step of administering to the subject a therapeutic agent selected from 1) an anti-IL23 targeted 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) a further nonsteroidal 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 (xviiii) The method further comprises the step of administering to the subject one or more kinase modulators selected from FLT-3 (FMS-like tyrosine kinase) inhibitors, AXL (Anexselect) inhibitors, 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 (nucleoprotein 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 / or combinations thereof. (xix) The subject has not undergone chemotherapy or hormone therapy before administration of the pharmaceutical composition, and / or (xx) The subject has not undergone prostatectomy, and / or (xxi) The subject has been treated with radiotherapy, and / or (xxii) The subject is administered radium-223, or (xxiii) The disease or disorder described above is (A) Breast cancer, optionally the breast cancer being 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, and optionally further comprising the step of administering an aromatase inhibitor to the subject, (B) Related to 21-hydroxylase deficiency, and / or (xxiv) The pharmaceutical composition is administered orally and / or (xxv) The pharmaceutical composition is administered to the subject at a rate ranging from once a day to once a week, for example, once a day or once every two or three days, and / or (xxvi) The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is administered to the subject with or without a meal.

13. An emulsion comprising (a) abiraterone decanoate; (b) lipids; and (c) a nonionic surfactant, wherein the lipid phase of the emulsion comprises abiraterone decanoate dispersed in the lipids, and the abiraterone decanoate has the following structure: 【Transformation 3】 It has, The lipid is selected from triglycerides, monoglycerides, diglycerides, and / or propylene glycol esters. An emulsion in which the nonionic surfactant is selected from surfactants containing polyglyceryl esters and / or polyoxyglycerides.

14. (i) The lipid comprises medium-chain triglycerides 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 nonionic surfactants, for example, two or three nonionic surfactants, and / or (v) The emulsion according to claim 13, wherein the nonionic surfactant comprises macrogol glycerol hydroxystearate and / or polyglyceryl oleate, for example, polyglyceryl-3 dioleate, and optionally the surfactant further comprises oleoyl polyoxyl-6 glyceride and / or lauroyl polyoxyl-6 glyceride.

15. An emulsion used in methods for treating or preventing a disease or disorder that requires it, The emulsion according to claim 13 or 14, wherein the method comprises the step of 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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