Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Definitions

• the present disclosure relates generally to novel oral formulations of abiraterone prodrugs.
• the disclosure is subject to a wide range of applications, such as for administration to a patient suffering from an androgen or estrogen hormone-dependent benign or malignant disorder or androgen receptor driven cancer, including various cancers (such as prostate cancer, bladder cancer, hepatocellular carcinoma, lung cancer, breast cancer, endometrial cancer, and ovarian cancer, etc.), and for the treatment of non-oncologic syndromes due to the overproduction of androgens (including both classical and nonclassical congenital adrenal hyperplasia, endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc.) or due to the overproduction of glucocorticoids, typically cortisol in conditions such as Cushing’s syndrome or Cushing’s disease.
• various cancers such as prostate cancer, bladder cancer, hepatocellular carcinoma, lung cancer, breast cancer, endometrial cancer, and ova
• Formula: C 24 H 31 NO; Mol. Weight: 349.5 g/mol is an inhibitor of CYP17A1 (which is a member of the cytochrome P450 superfamily of enzymes that catalyze the synthesis of cholesterol, steroids and other lipids and are involved in drug metabolism).
• CYP17A1 has both 17 ⁇ - hydroxylase activity and 17,20-lyase activity.
• Abiraterone potently and selectively inhibits both CYP17A1 17 ⁇ -hydroxylase and 17,20-lyase enzyme activities.
• the 17 ⁇ -hydroxylase activity of CYP17A1 is required for the generation of glucocorticoids such as cortisol.
• CYP17A1 both the hydroxylase and 17,20-lyase activities of CYP17A1 are required for the production of androgenic (e.g., androstenedione, testosterone, and dihyrotestosterone) and estrogenic (estrone, estradiol, estratriol) steroids through the conversion of 17 ⁇ -hydroxypregnenolone to the sex steroid precursor, dehydroepiandrosterone, see FIG. 1.
• abiraterone interferes with the synthesis of androgens and estrogens in the gonads (primarily in the testes and overies) and extra-gonadally (e.g., in the adrenals and in the tumors themselves).
• abiraterone itself is poorly absorbed, it can be administered orally as an abiraterone acetate prodrug.
• Abiraterone acetate is also poorly absorbed, but can be converted to abiraterone in the gut, which is poorly absorbed into the bloodstream following the cleavage of the acetate prodrug.
• Abiraterone acetate ((3 ⁇ )-17-(3-Pyridyl)androsta-5, acetate; CAS #154229- 18-2) is approved in the United States for treatment of castration resistant or castration sensitive prostate cancer under the brand name Zytiga®.
• Abiraterone acetate is now also available globally.
• abiraterone acetate prodrug is not significantly absorbed by the gastrointestinal tract (and little prodrug can be detected in blood plasma). Instead, it has been shown that abiraterone acetate is hydrolyzed to abiraterone in the intraluminal environment resulting in generation of abiraterone supersaturation, which is responsible for creating the strong driving force for abiraterone absorption (Stappaerts et al., Eur. J. Pharmaceutics Biopharmaceutics 90:1, 2015).
• Zytiga® 250 mg tablets
• prednisone for the treatment of patients with metastatic castration resistant prostate cancer (CRPC) and patients with metastatic castration-sensitive prostate cancer (CSPC).
• CRPC metastatic castration resistant prostate cancer
• CSPC metastatic castration-sensitive prostate cancer
• the prescribing information explains that for a daily oral dose of 1,000 mg of Zytiga® in patients with metastatic CRPC, abiraterone* s steady-state Cmu values were 226 ⁇ 178 ng/mL (mean ⁇ SD) and its area under the curve (AUC) values were 1173 ⁇ 690 ng.hr/mL (mean ⁇ SD).
• a single-dose (1,000 mg) cross-over study of Zytiga® in healthy subjects found that systemic exposure of abiraterone was increased when Zytiga® was administered with food.
• abiraterone’ s C max and AUC values were approximately 7- and 5-fold higher, respectively, when Zytiga® was administered with a low-fat meal (7% fat, 300 calories) and approximately 17- and 10-fold higher, respectively, when Zytiga® was administered with a high-fat meal (57% fat, 825 calories).
• the currently approved solid dosage oral form of the prodrug abiraterone acetate has several disadvantages. For example, it has very low bioavailability that necessitates a large daily pill burden for patients (4 x 250 mg tablets once daily). In addition, it causes highly variable blood levels in patients due to the combination of low bioavailability and a large food effect. Further, as abiraterone is rapidly cleared, this approved dosing regimen results in a daily C min of abiraterone, which is believed to be associated with a loss of therapeutic effect in metastatic CRPC patients.
• the present disclosure generally relates to novel oral abiraterone prodrugs formulations, and methods of using the same, for example, in treating a subject having a sex hormone- dependent benign or malignant disorder, an androgen receptor driven cancer, and/or a syndrome due to androgen and/or glucocorticoid excess.
• novel abiraterone prodrugs and formulations therein are suitable for dosing once a week, once a month, once every two months, once every three months, or even less frequently, for treating a subject having a sex hormone-dependent benign or malignant disorder, an androgen receptor driven cancer, a syndrome due to androgen excess and/or a syndrome due to glucocorticoid excess.
• abiraterone decanoate can be orally bioavailable with good to excellent oral bioavailability based on plasma abiraterone concentrations, which can achieve an effective plasma concentration of abiraterone for modulating serum steroid level, such as reduction of serum androgen levels.
• the oral abiraterone decanoate formulations herein can be suited for dosing frequencies ranging from once a day to once a week, such as once a day or once every two or three days.
• a single oral administration of the pharmaceutical composition herein can achieve a sustained inhibition of CYP17A1 for a period of 24 hours or more.
• This disclosure thus provides alternative methods for administering abiraterone prodrugs, such as abiraterone lipophilic esters, in particular, abiraterone decanoate, to treat various diseases or disorders described herein, such as a prostate cancer described herein, which can also be advantageous in comparison with the currently marketed Zytiga® tablets.
• the present disclosure provides the following exemplary embodiments:
• a pharmaceutical composition comprising: (a) abiraterone decanoate; and (b) a lipid- based drug delivery system, wherein abiraterone decanoate has the following structure: abiraterone decanoate, wherein the pharmaceutical composition is formulated for oral delivery of abiraterone decanoate.
• composition of [1], wherein the lipid-based drug delivery system comprises: (1) a triglyceride, monoglyceride, diglyceride, and/or a propylene glycol ester; and (2) a surfactant comprising a polyglyceryl ester and/or polyoxyglyceride.
• [4] The pharmaceutical composition of [1] or [2], wherein the lipid-based drug delivery system comprises a medium-chain triglyceride (e.g., LabrafacTM lipophile WL 1349, or medium-chain triglycerides of caprylic (C8) and capric (C10) acids).
• a medium-chain triglyceride e.g., LabrafacTM lipophile WL 1349, or medium-chain triglycerides of caprylic (C8) and capric (C10) acids.
• lipid-based drag delivery system comprises a glycerol/glyceryl linoleate (e.g., Maisine® CC, mono-, di- and triglycerides of mainly linoleic (C 18:2 ) and oleic (C 18:1 ) acids, the diester fraction being predominant).
• glycerol/glyceryl linoleate e.g., Maisine® CC, mono-, di- and triglycerides of mainly linoleic (C 18:2 ) and oleic (C 18:1 ) acids, the diester fraction being predominant.
• lipid-based drug delivery system comprises propylene glycol monocaprylate (e.g., Capmul PG-8) and/or propylene glycol monolaurate (e.g., Capmul PG-12, or LauroglycolTM 90 ).
• a surfactant comprising polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)).
• a surfactant comprising macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40), oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS) or lauroyl polyoxyl-6 glycerides (e.g., Labrafil 2130).
• a capsule e.g., a soft gel capsule
• 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, wherein the lipid-based drug delivery system comprises (a) a lipid in an amount of about 10-80% by weight of the lipid-based drug delivery system; and (b) one or more non-ionic surfactants in an amount of about 20-90% by weight of the lipid-based drug delivery system, wherein abiraterone decanoate has the following structure: abiraterone decanoate.
• [ 18] The pharmaceutical composition of [ 17] , wherein the lipid comprises medium- chain triglycerides of caprylic (C8) and capric (C10) acids (e.g., LabrafacTM lipophile WL 1349). for example, in an amount of about 10% to about 50% by weight of the lipid-based drug delivery system, such as about 20-40% by weight.
• C8 caprylic
• C10 capric
• composition of [17] or [18], wherein the lipid comprises glycerol/glyceryl linoleate (e.g., Maisine® CC). for example, in an amount of about 10% to about 50% by weight of the lipid-based drug delivery system, such as about 20-40% by weight.
• glycerol/glyceryl linoleate e.g., Maisine® CC
• propylene glycol monocaprylate e.g., Capmul PG-8
• propylene glycol monolaurate e.g., Capmul PG-12, or LauroglycolTM 90
• composition of any of [ 17]-[20] wherein the lipid-based drug delivery system comprises two or more, such as two or three, non-ionic surfactants.
• [22] The pharmaceutical composition of any of [17]-[21], wherein the one or more non-ionic surfactants comprise macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40) and/or polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)).
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• polyglyceryl oleate e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)
• oleoyl polyoxyl-6 glycerides e.g., Labrafil® M 1944 CS
• lauroyl polyoxyl-6 glycerides e.g., Labrafil 2130
• composition of any one of [17]-[27], formulated for oral administration such as in the form of a capsule (e.g., a soft gel capsule).
• a method of treating or preventing a disease or disorder in a subject in need thereof comprising administering to the subject an effective amount of the pharmaceutical composition according to any one of [1]-[37], wherein the disease or disorder is selected from a sex hormone-dependent benign or malignant disorder, an androgen receptor driven cancer, a syndrome due to androgen excess, and a syndrome due to glucocorticoid excess.
• 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 nonclassical congenital adrenal hyperplasia, precocious puberty, hirsutism, and combinations thereof.
• prostate cancer is a localized prostate cancer, e.g., a high risk localized prostate cancer.
• prostate cancer is a metastatic castration- sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer, non- metastatic castration-resistant prostate cancer, or metastatic castration-resistant prostate cancer.
• prostate cancer is a metastatic castration resistant prostate cancer (mCRPC), wherein the subject's disease has progressed on or after a taxane-based such as docetaxel-based chemotherapy regimen.
• mCRPC metastatic castration resistant prostate cancer
• agents selected from anticancer agents, hormone ablation agents, anti-androgen agents, differentiating agents, anti-neoplastic agents, kinase inhibitors, anti-metabolite agents, alkylating agents, antibiotic agents, immunological agents, interferon-type agents, intercalating agents, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitor
• PARP poly ADP ribose polymerase
• [62] The method of any one of [38]-[61], further comprising administering to the subject a l ⁇ -generation androgen receptor antagonist, e.g., proxalutamide, bicalutamide, flutamide, nilutamide, topilutamide.
• a l ⁇ -generation androgen receptor antagonist e.g., proxalutamide, bicalutamide, flutamide, nilutamide, topilutamide.
• [63] The method of any one of [38]-[62], further comprising administering to the subject a 2 nd -generation androgen receptor antagonist (e.g., apalutamide, darolutamide or enzalutamide).
• a 2 nd -generation androgen receptor antagonist e.g., apalutamide, darolutamide or enzalutamide.
• chemotherapeutic agent such as a taxane based chemotherapeutic agent (e.g., docetaxel, cabazitaxel, paclitaxel, etc.) or platinum based chemotherapeutic agent (e.g., cisplatin, carboplatin, oxaliplatin, etc.).
• a chemotherapeutic agent such as a taxane based chemotherapeutic agent (e.g., docetaxel, cabazitaxel, paclitaxel, etc.) or platinum based chemotherapeutic agent (e.g., cisplatin, carboplatin, oxaliplatin, etc.).
• [66] The method of any one of [38] -[65], further comprising administering to the subject an immunotherapy, such as administering Sipuleucel-T, an immune checkpoint inhibitor (e.g., anti-PD-1 antibody such as pembrolizumab or nivolumab, or anti-PD-Ll antibody such as avelumab or atezolizumab), or an anti-CTLA-4 antibody (e.g., ipilimumab), etc.
• an immunotherapy such as administering Sipuleucel-T, an immune checkpoint inhibitor (e.g., anti-PD-1 antibody such as pembrolizumab or nivolumab, or anti-PD-Ll antibody such as avelumab or atezolizumab), or an anti-CTLA-4 antibody (e.g., ipilimumab), etc.
• an immunotherapy such as administering Sipuleucel-T, an immune checkpoint inhibitor (e.g., anti-PD-1
• kinase inhibitor e.g., sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivasertib, onvansertib, ipatasertib, afuresertib, alisertib, apitolisib, opaganib, etc.
• a kinase inhibitor e.g., sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivasertib, onvansertib, ipatasertib, afuresertib, alisertib, apitolisib, opaganib, etc.
• [69] The method of any one of [38] -[68], further comprising administering to the subject a bone protecting agent (e.g., denosumab, zolendronic acid), and wherein the subject is characterized as having prostate cancer (e.g., CRPC) with bone metastasis.
• a bone protecting agent e.g., denosumab, zolendronic acid
• prostate cancer e.g., CRPC
• an HSP90 inhibitor e.g., onalespib (AT13387); 15) an HSP27 inhibitor, e.g., OGX-427; 16) a 5-alpha-reductase inhibitor, e.g., dutasteride; 17) metformin; 18) AMG-386; 19) dextromethorphan; 20) theophylline; 21) hydroxychloroquine; and 22) lenalidomide.
• HSP90 inhibitor e.g., onalespib (AT13387); 15) an HSP27 inhibitor, e.g., OGX-427; 16) a 5-alpha-reductase inhibitor, e.g., dutasteride; 17) metformin; 18) AMG-386; 19) dextromethorphan; 20) theophylline; 21) hydroxychloroquine; and 22) lenalidomide.
• kinase modulators selected from FLT-3 (FMS-like tyrosine kinase) inhibitors, AXL (anexelekto) inhibitors (e.g., Gilteritinib), CDK (cyclin dependent kinase) inhibitors, such as CDK1, 2, 4, 5, 6, 7, or 9 inhibitors, retinoblastoma (Rb) inhibitors, protein kinase B (AKT) inhibitors, SRC inhibitors, IkappaB kinase 1 (IKK1) inhibitors, PIM-1 modulators, Lemur tyrosine kinase 2 (LMTK2) modulators, Lyn inhibitors, Aurora A inhibitors, ANPK (a nuclear protein kinase) inhibitors, extracellular-signal regulated kinase (ERK) modulators, c-jun N- terminal kinase (INK)
• FLT-3 FLT-3
• AXL anexelekto inhibitors
• CDK cyclin dependent
• breast cancer e.g., molecular apocrine HER2-negative breast cancer, metastatic breast cancer, such as ER+ metastatic breast cancer, ER+ and HER2 negative breast cancer, AR+ triple negative breast cancer, etc.
• breast cancer e.g., molecular apocrine HER2-negative breast cancer, metastatic breast cancer, such as ER+ metastatic breast cancer, ER+ and HER2 negative breast cancer, AR+ triple negative breast cancer, etc.
• An emulsion comprising (a) abiraterone decanoate; (b) a lipid; and (c) a non-ionic surfactant, wherein the lipid phase of the emulsion comprises abiraterone decanoate dispersed in the lipid, wherein abiraterone decanoate has the following structure: abiraterone decanoate.
• lipid further comprises propylene glycol monocaprylate (e.g., Capmul PG-8) or propylene glycol monolaurate (e.g., Capmul PG-12, or LauroglvcolTM 90 ).
• propylene glycol monocaprylate e.g., Capmul PG-8
• propylene glycol monolaurate e.g., Capmul PG-12, or LauroglvcolTM 90 .
• non-ionic surfactant comprises macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40) and/or polyglyceryl oleate (e.g., Plural Oleique CC 497 (polyglyceryl-3 dioleate)).
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• polyglyceryl oleate e.g., Plural Oleique CC 497 (polyglyceryl-3 dioleate)
• a method of treating or preventing a disease or disorder in a subject in need thereof comprising administering to the subject an effective amount of the emulsion according to any one of [82] -[90], wherein the disease or disorder is selected from a sex hormone-dependent benign or malignant disorder, an androgen receptor driven cancer, a syndrome due to androgen excess, and a syndrome due to glucocorticoid excess.
• Embodiments of the present disclosure can fulfill a long felt need in the field of sex hormone-dependent disorders and oncology including the treatment of a sex hormone dependent or androgen receptor driven cancer such as prostate cancer. Embodiments of the present disclosure can also fulfill a long felt need in the field of treating syndromes due to androgen excess syndrome and/or due to glucocorticoid excess such as hypercortisolemia.
• Embodiments of the present disclosure can overcome major disadvantages and deficiencies of prior art formulations (including commercially-available oral dosage forms) of abiraterone acetate, by providing novel oral formulations of abiraterone prodrugs, methods of producing the same, methods of treatment using the same, and kits for convenient administration of the formulations to subjects in need of therapy for various disorders including prostate cancer.
• FIG. 1 presents biochemical pathways showing the effects of CYP17A1 inhibition on the synthesis of androgens, estrogens, glucocorticoids, progesterone, and mineralocorticoids.
• FIG. 2A presents a representative X-ray Powder Diffraction (XRPD) spectrum of the abiraterone decanoate (alternatively abbreviated herein as “AbiDec”, “ADEC”, or “AbDec”) solid form prepared in Example 1 A, designated as Form A.
• XRPD X-ray Powder Diffraction
• FIG. 2B shows a representative Differential Scanning Calorimetry (DSC) spectrum of the abiraterone decanoate solid form prepared in Example 1 A, designated as Form A.
• FIG. 2C shows a representative thermogravimetric analysis (TGA) of the abiraterone decanoate solid form prepared in Example 1 A, designated as Form A.
• FIG. 2D presents a representative XRPD spectrum of the abiraterone decanoate in Form B.
• FIG. 2E shows a representative DSC spectrum of the abiraterone decanoate in Form B.
• FIG. 2F shows a representative TGA of the abiraterone decanoate in Form B.
• FIG. 2G presents a representative XRPD spectrum of the abiraterone decanoate in Form C.
• FIG. 2H shows a representative DSC spectrum of the abiraterone decanoate in Form C.
• FIG. 21 shows a representative TGA of the abiraterone decanoate in Form C.
• FIG. 3 presents a graph showing the mean plasma concentrations of abiraterone and abiraterone decanoate in plasma following oral administration of abiraterone decanoate in 2 different formulations.
• the ranking from the highest Cmax to lowest Cmax in absolute values is the following: abiraterone from Group 2 treatment, abiraterone from Group 3 treatment, abiraterone decanoate from Group 2 treatment, and abiraterone decanoate from Group 3 treatment.
• FIG. 4A presents a graph showing the mean plasma concentrations of progesterone ("Prog") following oral administration of vehicle (Group 1 or Grp 1), formulation 1 (Group 2 or Grp 2) and formulation 2 (Group 3 or Grp 3).
• FIG. 4B presents a graph showing the mean plasma concentrations of progesterone ("Prog") following oral administration of formulation 1 (Group 2 or Grp 2) and formulation 2 (Group 3 or Grp 3) relative to that from oral administration of vehicle (Group 1 or Grp 1).
• Prog progesterone
• FIG. 5A presents a graph showing the mean plasma concentrations of corticosterone ("Cortico") following oral administration of vehicle (Group 1 or Grp 1), formulation 1 (Group 2 or Grp 2) and formulation 2 (Group 3 or Grp 3).
• Cortico corticosterone
• FIG. 5B presents a graph showing the mean plasma concentrations of corticosterone ("Cortico") following oral administration of formulation 1 (Group 2 or Grp 2) and formulation 2 (Group 3 or Grp 3) relative to that from oral administration of vehicle (Group 1 or Grp 1).
• Cortico corticosterone
• FIG. 6A presents a graph showing the mean plasma concentrations of androstenedione ("Andro") following oral administration of vehicle (Group 1 or Grp 1), formulation 1 (Group 2 or Grp 2) and formulation 2 (Group 3 or Grp 3).
• FIG. 6B presents a graph showing the mean plasma concentrations of androstenedione ("Andro") following oral administration of formulation 1 (Group 2 or Grp 2) and formulation 2 (Group 3 or Grp 3) relative to that from oral administration of vehicle (Group 1 or Grp 1).
• FIG. 7A presents a graph showing the mean plasma concentrations of testosterone ("T") following oral administration of vehicle (Group 1 or Grp 1), formulation 1 (Group 2 or Grp 2) and formulation 2 (Group 3 or Grp 3).
• FIG. 7B presents a graph showing the mean plasma concentrations of testosterone ("T") following oral administration of formulation 1 (Group 2 or Grp 2) and formulation 2 (Group 3 or Grp 3) relative to that from oral administration of vehicle (Group 1 or Grp 1).
• FIG. 8 presents a graph showing the mean plasma concentrations of luteinizing hormone following oral administration of vehicle (Group 1 or Grp 1), formulation 1 (Group 2 or Grp 2) and formulation 2 (Group 3 or Grp 3).
• the ranking based on the last observed concentraton (at 72 hours) is the following: Group 2>Group 3>Group 1.
• FIG. 9 presents a bar graph showing the mean tissue concentrations of abiraterone in tissues following oral administration of formulation 1 (Group 2 or Grp 2) and formulation 2 (Group 3 or Grp 3).
• the present disclosure relates to novel oral abiraterone prodrug formulations, methods for modulating serum steroid hormone levels in a subject in need thereof and methods for treating or preventing a disease or disorder associated with such steroid hormones.
• abiraterone prodrugs in particular, abiraterone decanoate, can be administered to a subject orally to achieve sustained inhibition of CYP17A1 activities and reduction of serum androgen levels.
• parenteral administration of abiraterone prodrugs such as abiraterone decanoate can be advantageous over existing methods in many aspects, including but not limited to a fast and sustained reduction of serum testosterone, no need for castration, reduced or no liver toxicity compared to methods using oral abiraterone acetate formulations, improved bioavailability, elimination of the food effect associated with oral abiraterone acetate formulation, reduced pill burden, better patient compliance, decreased dosing frequency, sustained stable blood levels of active drug, reduced Cmax, which can reduce associated side effects, etc.
• abiraterone decanoate can be orally bioavailable with good to excellent bioavailability to achieve an effective plasma concentration of abiraterone for modulating serum steroid level, such as reduction of serum androgen levels.
• This provides alternative methods for administering abiraterone prodrugs, such as abiraterone lipophilic esters, in particular, abiraterone decanoate, to treat various diseases or disorders described herein, such as a prostate cancer described herein.
• the present disclosure provides novel oral abiraterone prodrug formulations, methods for modulating serum steroid hormone levels, such as for reducing testosterone levels, and/or novel methods for treating or preventing diseases or disorders mediated by or associated with such steroids, such as sex hormone dependent or androgen receptor driven cancers.
• the present disclosure provides various formulations comprising abiraterone prodrugs, such as abiraterone lipophilic esters, in particular, abiraterone decanoate, which has the following structure: abiraterone decanoate.
• abiraterone prodrugs such as abiraterone lipophilic esters, in particular, abiraterone decanoate, which has the following structure: abiraterone decanoate.
• the pharmaceutical composition herein comprises (a) abiraterone decanoate; and (b) a lipid-based drug delivery system, wherein the pharmaceutical composition is formulated for oral delivery of abiraterone decanoate.
• the lipid-based drug delivery system herein broadly refers to any lipid-based vehicle, which when formulated with abiraterone decanoate, is suitable for oral administration to deliver a sufficient amount of abiraterone decanoate to achieve an effective plasma concentration of abiraterone for inhibiting CYP17A1, for modulation of various steroid hormone levels, such as androgens, estrogens, glucocorticoids, progesterone, and mineralocorticoids, and/or for treating a disease or disorder described herein, such as a prostate cancer described herein.
• various steroid hormone levels such as androgens, estrogens, glucocorticoids, progesterone, and mineralocorticoids
• the lipid-based drug delivery system herein can typically be characterized as a self-dispersing drug delivery system, such as a self-emulsifying drug delivery system or self-microemulsifying drug delivery system.
• abiraterone decanoate is homogeneous dispersed or dissolved in the lipid- based drug delivery system.
• the pharmaceutical composition herein is characterized as being capable of deliverying at least a portion of the abiraterone decanoate through the lymphatic delivery system upon oral administration to a mammal.
• Lymphatic delivery of lipid-based drug delivery system can bypass the first-pass metabolism and therefore can lead to better overall pharmacokinetic profile. See general discussions of lymphatic delivery in, Punjabi etal. Current Pharmaceutical Design, 27; 1992-1998 (2021); Bora et al. Indian Drugs 54(08):5-22 (2017); Pouton et al. Advanced Drug Delivery Reviews 60:625-631 (2008); and Cote et al. Advanced Drug Delivery Reviews 144:16-34 (2019).
• a single administration of exemplary oral formulations herein achieved excellent oral bioavailability in rat pharmacokinetic studies, which also potently reduced circulating androgen levels (androstenedione and testosterone) and increased the levels of progesterone.
• the pharmaceutical composition comprising abiraterone decanoate herein (e.g., any of those described herein, such as [1]-[37] of the Summary section herein) to a mammal, at least a portion of the abiraterone decanoate is absorbed through the lymphatic system.
• the lymphatic delivery is also supported by the tissue study herein which showed that abiraterone was detected in tissues at 72 h post dose, in mandibular and mesenteric lymph nodes.
• the pharmaceutical composition herein is typically formulated in the form of an oral dosage form, such as a capsule (e.g., a soft gel capsule).
• the pharmaceutical composition herein (e.g., any of those described herein, such as [1]- [37] of the Summary section herein) is typically also characterized by one or more of the following: (1) the pharmaceutical composition is storage stable at room temperature; (2) the recovery of abiraterone decanoate is greater than 50% when the pharmaceutical composition is assessed using an in vitro dispersion test; and (3) upon oral administration to a mammal, the pharmaceutical composition is capable of delivering a sufficient amount of abiraterone decanoate to the mammal to achieve a therapeutically effective plasma concentration of abiraterone, e.g., for treating a disease or disorder described herein, such as a prostate cancer described herein.
• the "in vitro dispersion test” should be understood as using a procedure in accordance with the procedures described in Example 4 of this application.
• storage stable it is meant that the pharmaceutical composition, upon storage at a storage condition for a storage period, for example, at room temperature for 1 month or longer (e.g., about 1 month, about 3 months, about 6 months, or longer), has (1) substantially the same amount of abiraterone decanoate, e.g., within 80-125% of the amount at the start of the storage; (2) substantially the same amount of impurities (total and/or individual impurity), e.g., within 80-125% of the amount at the start of the storage; and/or (3) no substantial physical property changes, for example, the appearance and dispersibility in aqueous solution remain substantially the same as the start of the storage.
• the pharmaceutical composition herein e.g., any of those described herein, such as [1]-[37] of the Summary section herein
• Oral bioavailability can be readily determined by those skilled in the art. Exemplary methods for determining rat oral bioavailability are shown in the Examples section herein.
• the lipid-based drug delivery system herein typically includes one or more lipids and one or more surfactants. Suitable lipids and surfactants and their amounts include those that are generally accepted for pharmaceutical uses, such as those described in the inactive ingredient database from the U.S. Food and Drug Administration. Particular lipids and surfactants for the pharmaceutical compositions herein can be typically selected based on the solubility of abiraterone decanoate, stability of the pharmaceutical composition, excipient compatibility, and dispersibility of the pharmaceutical composition in aqueous solution, etc.
• the lipids and surfactants are selected such that the pharmaceutical composition can have abiraterone decanoate dissolved or suspended in the lipid-based drug delivery system at a concentration of about 1 mg/g to about 250 mg/g.
• a concentration of 250 mg/g means that for each gram of a mixture of abiraterone decanoate in the lipid-based drug delivery system, there is 250 mg of abiraterone decanoate. Concentrations of abiraterone decanoate in the lipid-based drug delivery system described elsewhere in this disclosure should be understood similarly.
• the lipids and surfactants are selected such that the pharmaceutical composition can have abiraterone decanoate dissolved in the lipid-based drug delivery system at a concentration of about 20 mg/g to about 150 mg/g.
• the lipids and surfactants are selected such that the pharmaceutical composition is storage stable at room temperature, for example, for 1 month, 3 months, 6 months, or longer.
• the lipids and surfactants are selected such that the pharmaceutical composition comprises a solution (or otherwise a homogenous mixture) of abiraterone decanoate in the lipid-based drug delivery system at room temperature, wherein the solution (or otherwise homogenous mixture) can remain a solution (or otherwise homogenous), i.e., no visible formation of drug and/or excipient crystals/precipitations, after storage at room temperature for 1 month, 3 months, 6 months, or longer.
• the lipids and surfactants are selected such that the recovery of abiraterone decanoate is greater than 50% (e.g., 55%, 60%, 70%, 80%, 90%, or up to 100%, or any range between the recited values) when the pharmaceutical composition is assessed using an in vitro dispersion test.
• the lipids and surfactants are selected such that upon oral administration to a mammal, the pharmaceutical composition is capable of delivering a sufficient amount of abiraterone decanoate to the mammal to achieve a therapeutically effective plasma concentration of abiraterone, e.g., for treating a disease or disorder described herein, such as a prostate cancer described herein.
• the lipids and surfactants are selected such that upon oral administration to a mammal, the pharmaceutical composition is capable of delivering a sufficient amount of abiraterone decanoate to the mammal to achieve an effective plasma concentration of abiraterone, e.g., for inhibiting CYP17A1.
• the lipids and surfactants are selected such that the pharmaceutical composition herein can have an oral bioavailability greater than 30%, e.g., up to 60%, 70% or higher, based on abiraterone plasma concentration profile, when tested in rats.
• the lipid for the lipid-based drug delivery system comprises a triglyceride, monoglyceride, diglyceride, and/or a propylene glycol ester.
• the surfactant for the lipid-based drug delivery system typically comprises one or more non-ionic surfactants.
• the lipid-based drug delivery system herein comprises (1) a lipd comprising a triglyceride, monoglyceride, diglyceride, and/or a propylene glycol ester; and (2) a surfactant, such as a non-ionic surfactant.
• the surfactant can be any of those described herein, for example, the surfactant can comprise a polyglyceryl ester and/or polyoxyglyceride.
• Triglycerides, monoglycerides, and diglycerides as used herein should be understood as mono-, di-, or tri- esters of glycerol of fatty acids
• propylene glycol esters as used herein should be understood as mono or di esters of propylene glycol of fatty acids, wherein the fatty acids can typically be, but not limited to, medium or long-chained fatty acids, which can for example be saturated or unsaturated.
• medium-chained fatty acids include an aliphatic tail of 6-12 carbons
• long-chained fatty acids include an aliphatic tail of 13-21 carbons.
• triglycerides, monoglycerides, diglycerides, or propylene glycol esters may also be viewed as a surfactant.
• the surfactant for the lipid-based drug delivery system herein should be understood as requiring one or more surfactants that are not the triglycerides, monoglycerides, diglycerides, or propylene glycol esters defined herein.
• the weight percentages of the surfactants in the lipid-based drug delivery system or pharmaceutical composition herein only those surfactants that are not the triglycerides, monoglycerides, diglycerides, or propylene glycol esters should be considered, unless otherwise specified or contrary from context.
• the lipid-based drug delivery system herein comprises (1) a triglyceride, monoglyceride, diglyceride, and/or a propylene glycol ester; and (2) a surfactant comprising a polyglyceryl ester and/or polyoxyglyceride.
• the lipid-based drug delivery system herein comprises a triglyceride and the surfactant.
• the lipid-based drug delivery system herein comprises a diglyceride and the surfactant.
• the lipid-based drug delivery system herein comprises a monoglyceride and the surfactant.
• the lipid-based drug delivery system herein comprises (1) a triglyceride, monoglyceride, diglyceride, and propylene glycol ester and (2) the surfactant.
• Suitable triglycerides, monoglycerides, diglycerides, propylene glycol esters, and surfactants include any of those described herein in any combinations.
• the lipid-based drug delivery system herein comprises (1) a medium-chain triglyceride; and (2) a surfactant, such as a non-ionic surfactant.
• the medium- chain triglyceride is not particularly limited.
• the medium- chain triglyceride can be medium-chain triglycerides of caprylic (C8) and capric (C10) acids, such as those commercially available under the tradename: LabrafacTM lipophile WL 1349.
• the surfactant comprises a polyglyceryl ester and/or polyoxyglyceride.
• the lipid-based drug delivery system herein comprises a monoglyceride and/or diglyceride.
• the lipid-based drug delivery system comprises a glycerol/glyceryl linoleate, such as those from a commercial available product under the tradename: Maisine® CC, which is believed to have mono-, di- and triglycerides of mainly linoleic (Cl 8:2) and oleic (C18: 1) acids, with the diester fraction being predominant.
• the lipid-based drug delivery system herein comprises a propylene glycol ester.
• Suitable propylene glycol esters include for example propylene glycol monocaprylate (e.g., sold under the tradename: Capmul PG-8) and/or propylene glycol monolaurate (e.g., sold under the tradename: Capmul PG-12, or LauroglycolTM 90).
• the lipid-based drug delivery system herein comprises medium- chain triglycerides of caprylic (C8) and capric (C10) acids (e.g., LabrafacTM lipophile WL 1349) and a surfactant as described herein.
• the lipid-based drug delivery system herein comprises (1) medium-chain triglycerides of caprylic (C8) and capric (C10) acids (e.g., LabrafacTM lipophile WL 1349): (2) glycerol/glyceryl linoleate (e.g., Maisine® CC, mono-, di- and triglycerides of mainly linoleic (C 18 :2) and oleic (Cig : i) acids, the diester fraction being predominant); and a surfactant as described herein, hi such embodiments (e.g., any of those applicable embodiments described herein, such as [6]-[ 16] and [19]-[37] of the Summary section herein), the weight ratio of medium-chain triglycerides to glycerol/glyceryl linoleate typically ranges from about 5:1 to 1:5, more typically ranges from about 2:1 to about 1:2, such as about
• the lipid-based drug delivery system herein comprises (1) medium-chain triglycerides of caprylic (C8) and capric (C10) acids (e.g., LabrafacTM lipophile WL 1349): (2) propylene glycol monocaprylate (e.g., Capmul PG-8): and a surfactant as described herein.
• the weight ratio of medium-chain triglycerides to propylene glycol monocaprylate typically ranges from about 5:1 to 1:5, more typically ranges from about 2:1 to about 1:2, such as about 1.5:1, about 1:1, about 1:1.5, or about 1:2, or any range between the recited values.
• the surfactant in the lipid-based drug delivery system can comprise a polyglycerol ester.
• Useful polyglycerol esters are not particularly limited, which include esters formed from fatty acids and homopolymers of glycerol, such as trimers, tetramers, etc.
• the surfactant in the lipid-based drug delivery system can comprise polyglyceryl oleate, such as polyglyceryl-3 dioleate, available commercially under the tradename: Plurol Oleique CC 497.
• the surfactant in the lipid-based drug delivery system can comprise a polyoxyglyceride.
• Useful polyoxyglyceride are not particularly limited, which include esters formed from fatty acids and ethoxylated glycerol.
• the surfactant in the lipid-based drug delivery system can comprise macrogolglycerol hydroxystearate, for example, those available commercially under the tradename: Kolliphor RH 40.
• the surfactant in the lipid-based drug delivery system can comprise oleoyl polyoxyl-6 glycerides, for example, those available commercially under the tradename: Labrafil® M 1944 CS.
• Labrafil® M 1944 CS can have mono-, di- and triglycerides and PEG-6 (MW 300) mono- and diesters of oleic (C 18:1 ) acid.
• the surfactant in the lipid-based drug delivery system can comprise lauroyl polyoxyl-6 glycerides, for example, those available commercially under the tradename: Labrafil® 2130 CS.
• Labrafil® 2130 CS can have mono-, di- and triglycerides and PEG-6 (MW 300) mono- and diesters of lauric (C 12 ) and stearic (C 18 ) acids.
• the surfactant for the lipid-based drug delivery system can comprise (1) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40); and (2) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)).
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• polyglyceryl oleate e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)
• the surfactant for the lipid- based drug delivery system herein comprises macrogolglycerol hydroxystearate and polyglyceryl oleate (e.g., any of those applicable embodiments described herein, such as [ 12]-[ 16] and [22]- [37] of the Summary section herein)
• the weight ratio of macrogolglycerol hydroxystearate to polyglyceryl oleate typically ranges from about 5:1 to 1:5, more typically ranges from about 2:1 to about 1:2, such as about 1.5:1, about 1:1, or about 1:1.5, or any range between the recited values.
• the surfactant for the lipid-based drug delivery system can comprise (1) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40); (2) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)); and (3) oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS).
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• polyglyceryl oleate e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)
• oleoyl polyoxyl-6 glycerides e.g., Labrafil® M 1944 CS.
• the weight ratio of macrogolglycerol hydroxystearate to polyglyceryl oleate can range from about 5:1 to 1:5, more typically ranges from about 2:1 to about 1:2, such as about 1.5:1, about 1:1, or about 1:1.5, or any range between the recited values; and the weight ratio of macrogolglycerol hydroxystearate to oleoyl polyoxyl-6 glycerides can also range from about 5:1 to 1:5, more typically ranges from about 2:1 to about 1:2, such as about 1.5:1, about 1:1, or about 1:1.5, or any range between the recited values.
• the lipid-based drug delivery system comprises (a) medium- chain triglycerides of caprylic (C8) and capric (C10) acids; and (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40).
• the lipid-based drug delivery system further comprises one or more lipids selected from triglyceride, monoglyceride, diglyceride, and/or a propylene glycol ester.
• the lipid-based drug delivery system further comprises a propylene glycol ester, such as propylene glycol monocaprylate (e.g., Capmul PG-8).
• the lipid-based drug delivery system further comprises a mono-, di-, and/or triglyceride, such as a glycerol/glyceryl linoleate (e.g., Maisine® CC, mono-, di- and triglycerides of mainly linoleic (C 18:2 ) and oleic (C 18:1 ) acids, the diester fraction being predominant).
• the lipid-based drug delivery system further comprises one or more surfactants described herein.
• the lipid-based drug delivery system further comprises a second polyglyceryl ester, such as a polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)).
• a polyglyceryl oleate e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)
• the lipid-based drug delivery system further comprises a polyoxyglyceride, such as oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS).
• the lipid-based drug delivery system comprises (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids; (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40); and (c) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)).
• the lipid-based drug delivery system further comprises one or more lipids selected from triglyceride, monoglyceride, diglyceride, and/or a propylene glycol ester.
• the lipid-based drug delivery system further comprises a propylene glycol ester, such as propylene glycol monocaprylate (e.g., Capmul PG-8).
• the lipid-based drug delivery system further comprises a mono-, di-, and/or triglyceride, such as a glycerol/glyceryl linoleate (e.g., Maisine® CC, mono-, di- and triglycerides of mainly linoleic (C 18:2 ) and oleic (C 18:1 ) acids, the diester fraction being predominant).
• the lipid-based drug delivery system further comprises one or more surfactants described herein.
• the lipid-based drug delivery system further comprises a polyoxyglyceride, such as oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS).
• the lipid-based drug delivery system comprises (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids; (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40); and (c) propylene glycol monocaprylate (e.g., Capmul PG-8).
• the lipid-based drug delivery system further comprises one or more surfactants described herein.
• the lipid-based drug delivery system further comprises a second polyglyceryl ester, such as a polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)).
• a polyglyceryl oleate e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)
• the lipid-based drug delivery system further comprises a polyoxyglyceride, such as oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS).
• the lipid-based drug delivery system comprises (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids; (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40); and (c) glycerol/glyceryl linoleate (e.g., Maisine® CC, mono-, di- and triglycerides of mainly linoleic (C 18:2 ) and oleic (C 18:1 ) acids, the diester fraction being predominant).
• the lipid-based drug delivery system further comprises one or more surfactants described herein.
• the lipid-based drug delivery system further comprises a second polyglyceryl ester, such as a polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)).
• a polyglyceryl oleate e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)
• the lipid-based drug delivery system further comprises a polyoxyglyceride, such as oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS).
• the lipid-based drug delivery system can comprise (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids; (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40); (c) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)); and (d) oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS).
• the lipid-based drug delivery system can comprise (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids; (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40); (c) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)); (d) oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS): and (e) propylene glycol monocaprylate (e.g., Capmul PG-8).
• C8 and capric (C10) acids e.g., Kolliphor RH 40
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• polyglyceryl oleate e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)
• the lipid-based drug delivery system can comprise (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids; (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40); (c) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)); (d) oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS): and (e) propylene glycol monolaurate (e.g., Capmul PG-12, or LauroglycolTM 90 ).
• C8 and capric (C10) acids e.g., Kolliphor RH 40
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• polyglyceryl oleate e.g., Plurol Oleique CC 497 (polygly
• the lipid-based drug delivery system can comprise (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids; (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40); (c) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)); (d) oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS): and (e) glycerol/glyceryl linoleate (e.g., Maisine® CC, mono-, di- and triglycerides of mainly linoleic (Cis:2) and oleic (C 18 :i) acids, the diester fraction being predominant).
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• the weight percentages of ingredients of the lipid-based drug delivery system are not particularly limited.
• the triglyceride, monoglyceride, diglyceride, and/or a propylene glycol ester can be in an amount of about 10-80% (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, or any range between the recited values) by weight of the lipid-based drug delivery system
• the surfactant is in an amount of about 20- 90% (e.g., about 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%, or any range between the recited values, such as about 50-80% or about 40-60%) by weight of the lipid-based drug delivery system.
• the lipid-based drug delivery system comprises (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 10- 40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value, such as about 20-40% or 10-30% etc.) by weight of the lipid-based drug delivery system; and (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited value) by weight of the lipid-based drug delivery system.
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• the lipid-based drug delivery system further comprises one or more lipids selected from triglyceride, monoglyceride, diglyceride, and/or a propylene glycol ester.
• the lipid-based drug delivery system further comprises a propylene glycol ester, such as propylene glycol monocaprylate (e.g., Capmul PG-8) in an amount of about 10-40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value) by weight of the lipid-based drug delivery system.
• the lipid-based drug delivery system further comprises a mono-, di-, and/or triglyceride, such as a glycerol/glyceryl linoleate (e.g., Maisine® CC, mono-, di- and triglycerides of mainly linoleic (C 18:2 ) and oleic (C 18:1 ) acids, the diester fraction being predominant), in an amount of about 10-40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value) by weight of the lipid-based drug delivery system.
• a glycerol/glyceryl linoleate e.g., Maisine® CC, mono-, di- and triglycerides of mainly linoleic (C 18:2 ) and oleic (C 18:1 ) acids, the diester fraction being predominant
• about 10-40%
• the lipid-based drug delivery system further comprises one or more surfactants described herein.
• the lipid-based drug delivery system further comprises a second polyglyceryl ester, such as a polyglyceryl oleate (e.g., Plural Oleique CC 497 (polyglyceryl-3 dioleate)) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited value) by weight of the lipid-based drug delivery system.
• a polyglyceryl ester such as a polyglyceryl oleate (e.g., Plural Oleique CC 497 (polyglyceryl-3 dioleate)) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited value) by weight of the lipid-based drug delivery system.
• the lipid-based drug delivery system further comprises a polyoxyglyceride, such as oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS), in an amount of about 10-40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value, such as about 20-40% or 10-30% etc.) by weight of the lipid- based drug delivery system.
• a polyoxyglyceride such as oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS)
• about 10-40% e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value, such as about 20-40% or 10-30% etc.
• the lipid-based drug delivery system comprises (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 10- 40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value, such as about 20-40% or 10-30% etc.) by weight of the lipid-based drug delivery system; (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited value) by weight of the lipid-based drag delivery system; and (c) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%
• the lipid-based drag delivery system further comprises one or more lipids selected from triglyceride, monoglyceride, diglyceride, and/or a propylene glycol ester.
• the lipid-based drag delivery system further comprises a propylene glycol ester, such as propylene glycol monocaprylate (e.g., Capmul PG-8) in an amount of about 10- 40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value) by weight of the lipid-based drug delivery system.
• the lipid-based drag delivery system further comprises a mono-, di-, and/or triglyceride, such as a glycerol/glyceryl linoleate (e.g., Maisine® CC. mono-, di- and triglycerides of mainly linoleic (C 18:2 ) and oleic (C 18: 1 ) acids, the diester fraction being predominant), in an amount of about 10-40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value) by weight of the lipid-based drag delivery system.
• a glycerol/glyceryl linoleate e.g., Maisine® CC. mono-, di- and triglycerides of mainly linoleic (C 18:2 ) and oleic (C 18: 1 ) acids, the diester fraction being predominant
• about 10-40%
• the lipid-based drag delivery system further comprises one or more surfactants described herein.
• the lipid-based drag delivery system further comprises a polyoxyglyceride, such as oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS). in an amount of about 10-40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value, such as about 20-40% or 10-30% etc.) by weight of the lipid- based drag delivery system.
• a polyoxyglyceride such as oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS). in an amount of about 10-40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value, such as about 20-40% or 10-30% etc.) by weight of the lipid-
• the lipid-based drag delivery system comprises (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 10- 40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value) by weight of the lipid-based drug delivery system; (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited value) by weight of the lipid-based drug delivery system; and (c) propylene glycol monocaprylate (e.g., Capmul PG-8) in an amount of about 10-40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value) by weight of the
• the lipid-based drug delivery system further comprises one or more surfactants described herein.
• the lipid-based drug delivery system further comprises a second polyglyceryl ester, such as a polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited value) by weight of the lipid-based drug delivery system.
• a polyglyceryl ester such as a polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited value) by weight of the lipid-based drug delivery system.
• the lipid-based drug delivery system further comprises a polyoxyglyceride, such as oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS). in an amount of about 10-40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value, such as about 20-40% or 10-30% etc.) by weight of the lipid-based drug delivery system.
• a polyoxyglyceride such as oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS). in an amount of about 10-40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value, such as about 20-40% or 10-30% etc.) by weight of the lipid-based drug delivery system.
• the lipid-based drug delivery system comprises (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 10- 40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value) by weight of the lipid-based drug delivery system; (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited value) by weight of the lipid-based drug delivery system; and (c) glycerol/glyceryl linoleate (e.g., Maisine® CC, mono-, di- and triglycerides of mainly linoleic (C 18:2 ) and oleic (C 18:1 ) acids, the
• the lipid-based drug delivery system further comprises one or more surfactants described herein.
• the lipid-based drug delivery system further comprises a second polyglyceryl ester, such as a polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited value) by weight of the lipid-based drug delivery system.
• a polyglyceryl ester such as a polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited value) by weight of the lipid-based drug delivery system.
• the lipid-based drug delivery system further comprises a polyoxyglyceride, such as oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS), in an amount of about 10-40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value, such as about 20-40% or 10-30% etc.) by weight of the lipid-based drug delivery system.
• a polyoxyglyceride such as oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS)
• about 10-40% e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value, such as about 20-40% or 10-30% etc.
• the lipid-based drug delivery system can comprise (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 20- 40% (e.g., about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value) by weight of the lipid-based drug delivery system; (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited value) by weight of the lipid-based drug delivery system; (c) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited value) by weight of the lipid-
• the lipid-based drug delivery system can comprise (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 10- 40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value) by weight of the lipid-based drug delivery system; (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited value) by weight of the lipid-based drug delivery system; (c) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range
• the lipid-based drug delivery system can comprise (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 10- 40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value) by weight of the lipid-based drug delivery system; (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited value) by weight of the lipid-based drug delivery system; (c) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range
• the lipid-based drug delivery system can comprise (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 10- 40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value) by weight of the lipid-based drug delivery system; (b) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40) in an amount of about 10-30% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, or any range between the recited value) by weight of the lipid-based drug delivery system; (c) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)) in an amount of about 10-30% by weight of the lipid- based drug delivery system; (d) oleoyl polyoxy
• the lipid-based drug delivery system can include any of the vehicles described in the Examples section.
• the lipid-based drug delivery system can have about 20% Kolliphor RH40, about 14% Plurol Oleique CC 497, about 33% Labrafil 1944 CS, and about 33% Labrafac Lipophile WL 1349, by weight of the lipid-based drug delivery system, wherein "about” refers to within 25% of the stated value. For example, about 20% in such embodiments would mean 15% to 25%.
• the lipid-based drug delivery system can have about 20% Kolliphor RH40, about 14% Plurol Oleique CC 497, and about 66% Lauroglycol 90, by weight of the lipid-based drug delivery system, wherein "about” refers to within 25% of the stated value.
• the lipid-based drug delivery system can have about 20% Kolliphor RH40, about 14% Plurol Oleique CC 497, about 16% Labrafil 1944 CS, about 30% Maisine CC, and about 20% Labrafac Lipophile WL 1349, by weight of the lipid-based drug delivery system, wherein "about” refers to within 25% of the stated value.
• the lipid-based drug delivery system can have about 20% Kolliphor RH40, about 14% Plurol Oleique CC 497, about 16% Labrafil 1944 CS, about 30% Capmul PG-8, and about 20% Labrafac Lipophile WL 1349, by weight of the lipid-based drug delivery system, wherein "about” refers to within 25% of the stated value.
• the pharmaceutical composition herein typically comprises abiraterone decanoate dispersed, such as homogeneously dispersed or dissolved, in the lipid-based drug delivery system herein, with a concentration ranging from about 1 mg/g to about 250 mg/g, about 10 mg/g, about 20 mg/g, about 30 mg/g, about 40 mg/g, about 50 mg/g, about 60 mg/g, about 70 mg/g, about 80 mg/g, about 90 mg/g, about 100 mg/g, about 120 mg/g, about 150 mg/g, about 200 mg/g, about 250 mg/g, or any range between the recited values, e.g., about 10 mg/g to about 150 mg/g, about 20-150 mg/g, about 30-80 mg/g, etc.
• the abiraterone decanoate is dissolved in the lipid-based drug delievery system herein.
• the abiraterone decanoate is typically present in the pharmaceutical composition herein in its basic form and should be understood as such unless otherwise obvious to the contrary from context.
• the pharmaceutical composition herein can comprise abiraterone decanoate in its basic form and/or a pharmaceutically acceptable salt thereof.
• the abiraterone decanoate for the pharmarceutical composition herein is typically a substantially pure form described herein.
• the pharmaceutical composition herein typically can be prepared from mixing the substantially pure abiraterone decanoate with the lipid-based drug delivery system and optional other ingredients.
• the substantially pure abiraterone decanoate is in a crystalline form described herein, preferably, crystalline Form A, and the pharmaceutical composition can be prepared from mixing (e.g., dissolving, suspending, or otherwise forming a mixture) the crystalline form (e.g., Form A) with the lipid-based drug delivery system and optional other ingredients.
• the abiraterone decanoate for the pharmaceutical composition herein is in a substantially pure form, such as having a purity of greater than 80%, preferably greater than 90% (e.g., greater than 95%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%), by weight, by HPLC area, or both.
• the abiraterone decanoate for the pharmaceutical composition herein can be characterized by a purity by weight and/or by HPLC area of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any ranges between the specified values.
• the abiraterone decanoate for the pharmaceutical composition herein can be characterized by a purity by weight of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any ranges between the specified values.
• the abiraterone decanoate for the pharmaceutical composition herein can also be characterized as having a low palladium content, such as less than 150 ppm, less than 100 ppm, less than 50 ppm, or less than 10 ppm.
• the abiraterone decanoate for the pharmaceutical composition herein conforms to the specification shown in Table 1 herein (see Example IB).
• the substantially pure abiraterone decanoate can be in a solid form (e.g., a crystalline form described herein, preferably, Form A, amorphous form, or a combination thereof) or in a solution, suspension, or another form.
• the pharmaceutical composition herein comprising the substantially pure abiraterone decanoate and one or more other ingredients (e.g., the pharmaceutical composition according to [33]-[37] in the Summary Section herein) should be understood as a mixture of the substantially pure abiraterone decanoate herein and the one or more other ingredients, for example, such formulation can be obtained directly or indirectly from mixing (e.g., dissolving, suspending, or otherwise forming a mixture) the substantially pure abiraterone decanoate with the one or more other ingredients, such as the lipid-based drug delivery system described herein.
• the pharmaceutical composition herein comprises a substantially pure abiraterone decanoate, which has the following formula: or a pharmaceutically acceptable salt thereof, which is dispersed or dissolved in a lipid-based drug delivery system herein.
• the pharmaceutical composition comprises the substantially pure abiraterone decanoate in its basic form, which is dispersed or dissolved in the lipid-based drug delivery system.
• the substantially pure abiraterone decanoate has a purity by weight of at least 95%, preferably, at least 98%, such as about 98.5%, about 99%, about 99.5%, or higher.
• the substantially pure abiraterone decanoate can be characterized by a purity by weight and/or by HPLC area of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any ranges between the specified values. In some embodiments, the substantially pure abiraterone decanoate can be characterized by a purity by weight of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any ranges between the specified values. In some embodiments, the substantially pure abiraterone decanoate can also be characterized as having a low palladium content, such as less than 150 ppm, less than 100 ppm, less than 50 ppm, or less than 10 ppm.
• Abiraterone is typically synthesized with a step of palladium catalyzed cross-coupling reaction.
• available abiraterone generally has an undesired level of palladium residue, which may be carried into crude abiraterone decanoate product.
• the present disclosure shows that it is possible to reduce the palladium content of abiraterone decanoate to less than 5 ppm, particularly, 3.7 ppm in Example IB, by using a process of recrystallization with acetone and water as solvents and activated carbon.
• the substantially pure abiraterone decanoate conforms to the specification shown in Table 1 herein (see Example IB).
• the substantially pure abiraterone decanoate comprises an impurity derived from ethyl prasterone.
• the substantially pure abiraterone decanoate comprises ethyl prasterone decanoate having the formula:
• the substantially pure abiraterone decanoate comprises the ethyl prasterone decanoate in an amount of less than 2% by weight, such as less than 1% by weight, less than 0.5% by weight, such as less than 0.3%, less than 0.2%, or less than 0.1% by weight.
• the amount of ethyl prasterone decanoate can be readily determined by HPLC methods, such as those descried herein.
• the substantially pure abiraterone decanoate can also contain no detectable amount of ethyl prasterone decanoate.
• Abiraterone starting material is readily available from commercial sources in high purity.
• Abiraterone starting material obtained from a process using in a cross-coupling reaction to introduce the 3-pyridyl group in abiraterone may contain small amount of impurities which can ultimately be converted into ethyl prasterone.
• the substantially pure abiraterone decanoate can be prepared from an abiraterone starting material which has no detectable amount of ethyl prasterone, e.g., those obtained from processes that do not include a cross-coupling with
• the substantially pure abiraterone decanoate can be in a solid form, such as a crystalline form as described herein.
• the substantially pure abiraterone decanoate can be in a crystalline Form A, which can be characterized by an X-Ray Power Diffraction (XRPD) spectrum having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) of the following peaks: 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6, and 20.8, degrees 2 theta, ⁇ 0.2°; a Differential Scanning Calorimetry (DSC) pattern having an endothermic peak with an onset temperature at about 69.0 °C; or a combination thereof.
• XRPD X-Ray Power Diffraction
• DSC Differential Scanning Calorimetry
• the crystalline Form A can be characterized by an XRPD spectrum substantially the same as shown in FIG.
• the XRPD spectrum shows peaks at the respective diffraction angels (degrees 2 theta, ⁇ 0.2°) corresponding to the peaks as shown in FIG. 2A, regardless of their relative intensities.
• the crystalline Form A can be characterized by a DSC spectrum substantially the same as shown in FIG. 2B.
• the pharmaceutical compositions herein comprising abiraterone decanoate typically are a solution or suspension of the abiraterone decanoate in a suitable vehicle as described herein.
• the solution can be prepared by dissolving or suspending one or more of the solid forms of abiraterone decanoate, such as crystalline Form A, B, and/or C, in a suitable vehicle.
• the pharmaceutical composition can also comprise one or more solid form of abiraterone decanoate.
• the pharmaceutical composition can comprise the crystalline Form A described herein.
• the pharmaceutical composition can comprise the crystalline Form B described herein.
• the pharmaceutical composition can comprise the crystalline Form C described herein.
• the pharmaceutical composition herein can also be prepared from abiraterone decanoate comprising crystalline Form A.
• the pharmaceutical composition herein can be prepared from crystalline Form A of abiraterone decanoate, which is substantially free of Form B and Form C of abiraterone decanoate, e.g., no detectable amount of Form B and Form C by XRPD.
• the pharmaceutical composition herein can be prepared from crystalline Form A of abiraterone decanoate, which is characterized as substantially pure, for example, the crystalline Form A can be characterized as (1) having a Palladium content of less than 50 ppm, such as less than 10 ppm; (2) having a purity by weight of at least 95%, preferably, at least 98%, such as about 98.5%, about 99%, about 99.5%, or higher; (3) having less than 1% (e.g., less than 0.5% by weight, such as less than 0.3%, less than 0.2%, or less than 0.1%) by weight of ethyl prasterone decanoate having the formula:
• the pharmaceutical composition herein can also be prepared from abiraterone decanoate comprising crystalline Form B.
• crystalline Form B can be characterized by an X-Ray Power Diffraction (XRPD) spectrum having one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) of the following peaks: 4.4, 6.6, 14.8, 16.4, 18.1, 21.6, and 22.2, degrees 2 theta, ⁇ 0.2°; a Differential Scanning Calorimetry (DSC) pattern having two endothermic peaks with onset temperatures at about 60.6 °C and about 64.9 °C, respectively; or a combination thereof.
• XRPD X-Ray Power Diffraction
• the crystalline Form B can be characterized by an XRPD spectrum substantially the same as shown in FIG. 2D, for example, the XRPD spectrum shows peaks at the respective diffraction angels (degrees 2 theta, ⁇ 0.2°) corresponding to the peaks as shown in FIG. 2D, regardless of their relative intensities,
• the crystalline Form B can be characterized by a DSC spectrum substantially the same as shown in FIG. 2E.
• Crystalline Form B can be typically prepared by dissolving abiraterone decanoate in a suitable solvent, such as methanol, ethanol, ethyl acetate, dimethyl acetamide (DMA), methyl tert-butyl ether, 2-propanol, or heptane, to form a solution, and cooling the solution, such as to about -10 °C to about -20 °C to form the crystalline form. Exemplary procedures are shown in Example 1C herein.
• a suitable solvent such as methanol, ethanol, ethyl acetate, dimethyl acetamide (DMA), methyl tert-butyl ether, 2-propanol, or heptane
• the pharmaceutical composition herein can also be prepared from abiraterone decanoate comprising crystalline Form C.
• crystalline Form C can be characterized by an X-Ray Power Diffraction (XRPD) spectrum having one or more of the following peaks: 4.9, 6.3, 14.5, and 15.3, degrees 2 theta, ⁇ 0.2°; a Differential Scanning Calorimetry (DSC) pattern having two endothermic peaks with onset temperatures at about 58.7 °C and about 66.6 °C, respectively; or a combination thereof.
• XRPD X-Ray Power Diffraction
• DSC Differential Scanning Calorimetry
• the crystalline Form C can be characterized by an XRPD spectrum substantially the same as shown in FIG.
• the crystalline Form C can be characterized by a DSC spectrum substantially the same as shown in FIG. 2H.
• Crystalline Form C can be typically prepared by dissolving abiraterone decanoate in a suitable solvent, such as 1:1 mixture of ethanol and 2-butanone, and reducing the amount of solvent, such as by evaporation, to form the crystalline form. Exemplary procedures are shown in Example 1C herein.
• compositions comprising non-ionic surfactants
• the pharmaceutical composition herein typically includes abiraterone decanoate dissolved in any of the lipid-based drug delivery system described herein.
• 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, e.g., about 30-80 mg/g or about 30-100 mg/g etc.), wherein the lipid-based drug delivery system comprises (a) a lipid in an amount of about 10-80% by weight of the lipid-based drug delivery system; and (b) one or more non-ionic surfactants in an amount of about 20-90% by weight of the lipid-based drug delivery system, wherein abiraterone decanoate has the following
• the weight ratio of the lipid to the one or more non-ionic surfactants ranges from about 5:1 to 1:5, more typically, from about 2:1 to about 1:2, such as about 2:1, about 1.5:1, about 1:1, about 1:1.5, about 1:2, or any range between the recited values.
• Suitable lipid is not particularly limited and can include any of the triglyceride, monoglyceride, diglyceride, and/or a propylene glycol ester as described herein.
• Suitable non-ionic surfactants are also not particularly limited, which can include any of those described herein.
• the lipid can comprise medium-chain triglycerides of caprylic (C8) and capric (C10) acids (e.g., LabrafacTM lipophile WL 1349).
• the lipid can comprise glycerol/glyceryl linoleate (e.g., Maisine® CC).
• the lipid can comprise propylene glycol monocaprylate (e.g., Capmul PG-8).
• the lipid can comprise propylene glycol monolaurate (e.g., Capmul PG-12, or LauroglycolTM 90 ).
• the lipid can comprise medium-chain triglycerides of caprylic (C8) and capric (C10) acids (e.g., LabrafacTM lipophile WL 1349) and glycerol/glyceryl linoleate (e.g., Maisine® CC).
• the lipid can comprise medium-chain triglycerides of caprylic (C8) and capric (C10) acids (e.g., LabrafacTM lipophile WL 1349) and propylene glycol monocaprylate (e.g., Capmul PG-8).
• Suitable amounts, ratios, or weight percentages of the medium-chain triglycerides of caprylic (C8) and capric (C10) acids, glycerol/glyceryl linoleate, propylene glycol monocaprylate, and propylene glycol monolaurate include any of those described herein in any combinations.
• the lipid-based drug delivery system comprises two or more, such as 2 or 3, non-ionic surfactants.
• the one or more non-ionic surfactants comprise macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40) and/or polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)).
• the one or more non-ionic surfactants comprise (1) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40); and (2) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)).
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• polyglyceryl oleate e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)
• the one or more non-ionic surfactants comprise (1) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40); (2) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)); and (3) oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS).
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• polyglyceryl oleate e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)
• oleoyl polyoxyl-6 glycerides e.g., Labrafil® M 1944 CS.
• the one or more non-ionic surfactants comprise (1) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40); (2) polyglyceryl oleate (e.g., Plurol Qleique CC 497 (polyglyceryl-3 dioleate)); and (3) lauroyl polyoxyl-6 glycerides (e.g., Labrafil 2130).
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• polyglyceryl oleate e.g., Plurol Qleique CC 497 (polyglyceryl-3 dioleate)
• lauroyl polyoxyl-6 glycerides e.g., Labrafil 2130.
• the pharmaceutical composition can comprise abiraterone decanoate dissolved in the lipid-based drug delivery system at a concentration ranging from about 20 mg/g to about 120 mg/g (e.g., about 20 mg/g, about 30 mg/g, about 40 mg/g, about 50 mg/g, about 60 mg/g, about 70 mg/g, about 80 mg/g, about 90 mg/g, about 100 mg/g, about 120 mg/g, or any range between the recited values, e.g., about 30-80 mg/g or about 30-100 mg/g etc.), wherein the lipid-based drug delivery system comprises (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 20-40% (e.g., about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value) by weight of the lipid-based drug delivery system; (b) macrogolglycerol hydroxystearate
• the pharmaceutical composition can comprise abiraterone decanoate dissolved in the lipid-based drug delivery system at a concentration ranging from about 20 mg/g to about 120 mg/g (e.g., about 20 mg/g, about 30 mg/g, about 40 mg/g, about 50 mg/g, about 60 mg/g, about 70 mg/g, about 80 mg/g, about 90 mg/g, about 100 mg/g, about 120 mg/g, or any range between the recited values, e.g., about 30-80 mg/g or about 30-100 mg/g etc.), wherein the lipid-based drug delivery system comprises (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 10-40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value, such as about 20-40% or 10-30% etc.) by weight of the lipid-
• the pharmaceutical composition can comprise abiraterone decanoate dissolved in the lipid-based drug delivery system at a concentration ranging from about 20 mg/g to about 120 mg/g (e.g., about 20 mg/g, about 30 mg/g, about 40 mg/g, about 50 mg/g, about 60 mg/g, about 70 mg/g, about 80 mg/g, about 90 mg/g, about 100 mg/g, about 120 mg/g, or any range between the recited values, e.g., about 30-80 mg/g or about 30-100 mg/g etc.), wherein the lipid-based drug delivery system comprises (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 10-40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value, such as about 20-40% or 10-30% etc.) by weight of the lipid-
• the pharmaceutical composition can comprise abiraterone decanoate dissolved in the lipid-based drug delivery system at a concentration ranging from about 20 mg/g to about 120 mg/g (e.g., about 20 mg/g, about 30 mg/g, about 40 mg/g, about 50 mg/g, about 60 mg/g, about 70 mg/g, about 80 mg/g, about 90 mg/g, about 100 mg/g, about 120 mg/g, or any range between the recited values, e.g., about 30-80 mg/g or about 30-100 mg/g etc.), wherein the lipid-based drug delivery system comprises (a) medium-chain triglycerides of caprylic (C8) and capric (C10) acids in an amount of about 10-40% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value, such as about 20-40% or 10-30% etc.) by weight of the lipid-
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• polyglyceryl oleate e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)
• oleoyl polyoxyl-6 glycerides e.g., Labrafil® M 1944 CS
• oleoyl polyoxyl-6 glycerides e.g., Labrafil® M 1944 CS
• about 0-40% e.g., 0%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or any range between the recited value, such
• the pharmaceutical composition can comprise abiraterone decanoate dissolved in a vehicle described in any of the examples herein, see e.g., Examples 2 and 3.
• the pharmaceutical composition can comprise abiraterone decanoate dissolved in a lipid-based drug delivery system having about 20% Kolliphor RH40, about 14% Plurol Oleique CC 497, about 33% Labrafil 1944 CS, and about 33% Labrafac Lipophile WL 1349, by weight of the lipid-based drug delivery system, wherein "about” refers to within 25% of the stated value.
• the abiraterone decanoate is typically dissolved at a concentration ranging from about 20 mg/g to about 120 mg/g (e.g., about 20 mg/g, about 30 mg/g, about 40 mg/g, about 50 mg/g, about 60 mg/g, about 70 mg/g, about 80 mg/g, about 90 mg/g, about 100 mg/g, about 120 mg/g, or any range between the recited values, e.g., about 30- 80 mg/g or about 30-100 mg/g etc.), up to the maxium solubility of abiraterone decanoate in the lipid-based drug delivery system.
• the pharmaceutical composition can comprise abiraterone decanoate dissolved in a lipid-based drug delivery system having about 20% Kolliphor RH40, about 14% Plurol Oleique CC 497, and about 66% Lauroglycol 90, by weight of the lipid-based drug delivery system, wherein "about” refers to within 25% of the stated value.
• the abiraterone decanoate is typically dissolved at a concentration ranging from about 20 mg/g to about 120 mg/g (e.g., about 20 mg/g, about 30 mg/g, about 40 mg/g, about 50 mg/g, about 60 mg/g, about 70 mg/g, about 80 mg/g, about 90 mg/g, about 100 mg/g, about 120 mg/g, or any range between the recited values, e.g., about 30-80 mg/g or about 30-100 mg/g etc.), up to the maxium solubility of abiraterone decanoate in the lipid-based drug delivery system.
• the pharmaceutical composition can comprise abiraterone decanoate dissolved in a lipid-based drug delivery system having about 20% Kolliphor RH40, about 14% Plurol Oleique CC 497, about 16% Labrafil 1944 CS, about 30% Maisine CC, and about 20% Labrafac Lipophile WL 1349, by weight of the lipid-based drug delivery system, wherein "about” refers to within 25% of the stated value.
• the abiraterone decanoate is typically dissolved at a concentration ranging from about 20 mg/g to about 120 mg/g (e.g., about 20 mg/g, about 30 mg/g, about 40 mg/g, about 50 mg/g, about 60 mg/g, about 70 mg/g, about 80 mg/g, about 90 mg/g, about 100 mg/g, about 120 mg/g, or any range between the recited values, e.g., about 30-80 mg/g or about 30-100 mg/g etc.), up to the maxium solubility of abiraterone decanoate in the lipid-based drug delivery system.
• the pharmaceutical composition can comprise abiraterone decanoate dissolved in a lipid-based drug delivery system having about 20% Kolliphor RH40, about 14% Plurol Oleique CC 497, about 16% Labrafil 1944 CS, about 30% Capmul PG-8, and about 20% Labrafac Lipophile WL 1349, by weight of the lipid-based drug delivery system, wherein "about” refers to within 25% of the stated value.
• the abiraterone decanoate is typically dissolved at a concentration ranging from about 20 mg/g to about 120 mg/g (e.g., about 20 mg/g, about 30 mg/g, about 40 mg/g, about 50 mg/g, about 60 mg/g, about 70 mg/g, about 80 mg/g, about 90 mg/g, about 100 mg/g, about 120 mg/g, or any range between the recited values, e.g., about 30-80 mg/g or about 30-100 mg/g etc.), up to the maxium solubility of abiraterone decanoate in the lipid-based drug delivery system.
• the pharmaceutical composition can be typically formulated for oral administration, such as in the form of a capsule (e.g., a soft gel capsule).
• the pharmaceutical composition herein can also be characterized by one or more of the following: (1) the pharmaceutical composition is storage stable at room temperature; (2) the recovery of abiraterone decanoate is greater than 50% (e.g., 55%, 60%, 70%, 80%, 90%, or up to 100%, or any range between the recited values) when the pharmaceutical composition is assessed using an in vitro dispersion test; and (3) upon oral administration to a mammal, the pharmaceutical composition is capable of delivering a sufficient amount of abiraterone decanoate to the mammal to achieve a therapeutically effective plasma concentration of abiraterone, e.g., for treating a disease or disorder described herein, such as a prostate cancer described herein.
• the pharmaceutical composition is storage stable at room temperature, for example, for 1 month, 3 months, 6 months, or longer.
• the pharmaceutical composition comprises a solution at room temperature wherein the solution can remain a solution, i.e., no visible formation of drug and/or excipient crystals/precipitations, after storage at room temperature for 1 month, 3 months, 6 months, or longer.
• the pharmaceutical composition is characterized in that the recovery of abiraterone decanoate is greater than 50% (e.g., 55%, 60%, 70%, 80%, 90%, or up to 100%, or any range between the recited values) when the pharmaceutical composition is assessed using an in vitro dispersion test.
• the pharmaceutical composition is characterized in that upon oral administration to a mammal, the pharmaceutical composition is capable of delivering a sufficient amount of abiraterone decanoate to the mammal to achieve a therapeutically effective plasma concentration of abiraterone, e.g., for treating a disease or disorder described herein, such as a prostate cancer described herein.
• the pharmaceutical composition is characterized in that upon oral administration to a mammal, the pharmaceutical composition is capable of delivering a sufficient amount of abiraterone decanoate to the mammal to achieve aan effective plasma concentration of abiraterone, e.g., for inhibiting CYP17A1.
• the pharmaceutical composition can also be characterized by an oral bioavailability of greater than 30%, e.g., up to 60%, 70% or more, based on abiraterone plasma concentration profile, when tested in rats.
• the pharmaceutical composition can be a self-dispersing drug delivery system, such as a self-emulsifying drug delivery system or self-microemulsifying drug delivery system.
• the pharmaceutical composition can be characterized in that upon oral administration to a mammal, at least a portion of the abiraterone decanoate is absorbed through the lymphatic system.
• the present disclosure also provides methods of preparing the pharmaceutical compositions comprising the abiraterone decanoate and lipid-based drug delivery system as described herein (e.g., any of those applicable embodiments described herein, such as [1]-[37] of the Summary section herein).
• the method typically comprises mixing, such as dissolving, the 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 the lipid-based drug delivery system (e.g., any of those described herein).
• the particular sequences of mixing is typically not important.
• abiraterone decanoate can be mixed, such as dissolved, with one or more components of the lipid-based drug delivery system before mixing with the 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.
• the present disclosure also provides emulsions comprising abiraterone decanoate.
• the emulsions can also be considered pharmaceutical compositions described herein and can be orally administered to a subject in need.
• the emulsion can comprise (a) abiraterone decanoate; (b) a lipid; and (c) a non-ionic surfactant, wherein the lipid phase of the emulsion comprises abiraterone decanoate dispersed in the lipid, wherein abiraterone decanoate has the following structure: abiraterone decanoate.
• the weight ratio of the lipid to the non-ionic surfactant ranges from about 5:1 to 1:5, more typically, from about 2:1 to about 1:2, such as about 2:1, about 1.5:1, about 1:1, about 1:1.5, about 1:2, or any range between the recited values.
• Suitable lipid is not particularly limited and can include any of the triglyceride, monoglyceride, diglyceride, and/or a propylene glycol ester as described herein.
• Suitable non-ionic surfactants are also not particularly limited, which can include any of those described herein.
• the lipid can comprise medium-chain triglycerides of caprylic (C8) and capric (C10) acids (e.g., LabrafacTM lipophile WL 1349).
• the lipid can comprise glycerol/glyceryl linoleate (e.g., Maisine® CC).
• the lipid can comprise propylene glycol monocaprylate (e.g., Capmul PG-8).
• the lipid can comprise propylene glycol monolaurate (e.g., Capmul PG-12, or LauroglycolTM 90 ).
• the lipid can comprise medium-chain triglycerides of caprylic (C8) and capric (C10) acids (e.g., LabrafacTM lipophile WL 1349) and glycerol/glyceryl linoleate (e.g., Maisine® CC).
• the lipid can comprise medium-chain triglycerides of caprylic (C8) and capric (C10) acids (e.g., LabrafacTM lipophile WL 1349) and propylene glycol monocaprylate (e.g., Capmul PG-8).
• Suitable amounts, ratios, or weight percentages of the medium-chain triglycerides of caprylic (C8) and capric (C10) acids, glycerol/glyceryl linoleate, propylene glycol monocaprylate, and propylene glycol monolaurate include any of those described herein in any combinations.
• the emulsion comprises two or more, such as 2 or 3, non-ionic surfactants.
• the non-ionic surfactant comprises macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40) and/or polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)).
• the non-ionic surfactant comprises (1) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40); and (2) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)).
• the non-ionic surfactant comprises (1) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40); (2) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)); and (3) oleoyl polyoxyl-6 glycerides (e.g., Labrafil® M 1944 CS).
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• polyglyceryl oleate e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)
• oleoyl polyoxyl-6 glycerides e.g., Labrafil® M 1944 CS.
• the non-ionic surfactant comprises (1) macrogolglycerol hydroxystearate (e.g., Kolliphor RH 40); (2) polyglyceryl oleate (e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)); and (3) lauroyl polyoxyl-6 glycerides (e.g., Labrafil 2130).
• macrogolglycerol hydroxystearate e.g., Kolliphor RH 40
• polyglyceryl oleate e.g., Plurol Oleique CC 497 (polyglyceryl-3 dioleate)
• lauroyl polyoxyl-6 glycerides e.g., Labrafil 2130.
• the present disclosure also provides an emulsion produced by mixing the pharmaceutical composition comprising the abiraterone decanoate and lipid-based drug delivery system herein (e.g., any of those described herein, such as [ 1 ]-[37] shown in the Summary section herein) with water.
• the present disclosure also provides an emulsion produced by administering the pharmaceutical composition comprising the abiraterone decanoate and lipid- based drug delivery system herein (e.g., any of those described herein, such as [1]-[37] shown in the Summary section herein) to a mammal.
• the pharmaceutical composition comprising the abiraterone decanoate and lipid- based drug delivery system herein (e.g., any of those described herein, such as [1]-[37] shown in the Summary section herein) to a mammal.
• compositions Comprising Abiraterone Prodrugs
• abiraterone decanoate While many of the embodiments herein are directed specifically to abiraterone decanoate, the present disclosure also contemplate oral formulations of abiraterone prodrugs (including abiraterone decanoate) in the lipid-based drug delivery system herein.
• the oral abiraterone prodrug formulation can include an abiraterone lipophilic ester, such as an acetate, a propionate, a butanoate, a (vaterate) pentanoate, an isocaproate, a buciclate, a cyclohexanecarboxylate, a phenyl propionate, caproate (hexanoate), an enanthate (heptanoate), a cypionate, an octanoate, a nonanoate, a decanoate, an undecanoate, a dodecanoate, a tridecanoate, a tetradecanoate, a pentadecanoates, or a hexadecanoate of abiraterone in the lipid-based drug delivery system herein.
• an abiraterone lipophilic ester such as an acetate, a propionate, a butan
• Suitable abiraterone prodrugs include any of those described in U.S. Patent No. 10,792,292 B2 and U.S. Provisional Application No. 63/073,502 and 63/149,550, the content of each of which is herein incorporated by reference in its entirety.
• the pharmaceutical composition can include an abiraterone prodrug of Formula I, or a pharmaceutically acceptable salt thereof:
• R 1 is R 10 , 0-R 10 , or NHR 10 , wherein R 10 is selected from: a C 7-30 alkyl; C 7-30 alkenyl; C 7- 30 alkynyl; an alkyl substituted with a cycloalkyl, which typically has a total number of carbons between 5 and 16; an alkyl substituted with a phenyl, which typically has a total number of carbons between 7 and 16; a cycloalkyl optionally substituted with one or more alkyl, which typically has a total number of carbons between 5 and 16; and a branched C 5 or C 6 alkyl such as
• R 10 is a C 7-30 alkyl. As used herein, unless expressly stated to be substituted, an alkyl should be understood as unsubstituted. However, an alkyl can be either linear or branched. In some embodiments, R 10 can be a linear C 7-30 alkyl. In some embodiments, R 10 can be a branched C 7-30 alkyl. In some embodiments, R 10 is a linear C7-16 alkyl, for example, R 10 can have a formula -(CH 2 ) n -CH 3 , wherein n is an integer between 6 and 15 (e.g., between 6 and 12, such as 6, 7, 8, 9, 10, 11, or 12). In some embodiments, R 10 can be a branched C 7-16 alkyl.
• R 10 can also be an alkyl substituted with a cycloalkyl.
• R 10 has a total number of carbons between 5 and 16, i.e., the total number of carbons from the alkyl moiety and the cycloalkyl moiety are between 5 and 16.
• the cycloalkyl typically is unsubstituted.
• the cycloalkyl can be optionally substituted, e.g., with one or two lower alkyl (e.g, a C 1-4 alkyl).
• R 10 can be an alkyl substituted with a C 3-6 cycloalkyl, which typically has a total number of carbons between 6 and 12.
• R 10 can be a linear alkyl substituted with a C 3-6 cycloalkyl, for example, R 10 can have a formula -(CH 2 ) n -Cy, wherein n is an integer of 1-6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is a C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
• R 10 can have a formula -(CH 2 ) n - Cy, wherein n is 1 or 2, and Cy is cyclopentyl or cyclohexyl.
• R 10 can also be a branched alkyl (e.g., branched C 2-6 ) substituted with a C 3-6 cycloalkyl.
• a branched C 2 alkyl should be understood as a 1,1-disubstitued ethyl group, for example, - CH(CH 3 )-Cy.
• R 10 can also be an alkyl substituted with a phenyl.
• R 10 has a total number of carbons between 7 and 16, i.e., the total number of carbons from the alkyl moiety and the phenyl moiety are between 5 and 16.
• R 10 can be a linear alkyl substituted with a phenyl, for example, R 10 can have a formula -(CH 2 ) n -Cy, wherein n is an integer of 1-6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is a phenyl.
• R 10 can have a formula -(CH 2 ) n -Cy, wherein n is 1 or 2, and Cy is phenyl.
• R 10 can also be a branched alkyl (e.g., branched C 2-6 ) substituted with a phenyl. The phenyl typically is unsubstituted. However, in some embodiments, the phenyl can be optionally substituted, e.g., with one or two lower alkyl (e.g, a C 1-4 alkyl).
• R 10 can be a cycloalkyl optionally substituted with one or more alkyl. In such embodiments, R 10 typically has a total number of carbons between 5 and 16, i.e., the total number of carbons of the cycloalkyl and its optional substituents are between 5 and 16. In some embodiments, R 10 can be a C 3-6 cycloalkyl, either unsubstituted or substituted with a C 1-4 alkyl. In some specific embodiments, R 10 can be [0133] In some embodiments, R 10 can be a branched C5 or C6 alkyl. In some embodiments, R 10 can be Other branched C5 or C6 alkyls are also suitable.
• R 10 can be an unsaturated aliphatic group such as a C 7-30 alkenyl or a C 7-30 alkynyl.
• the compound of Formula I is an ester of abiraterone, e.g., R 1 is R 10 , wherein R 10 is defined herein.
• R 1 in Formula I can be a C7-16 alkyl, e.g., an alkyl having a formula of -(CH2) n -CH3, wherein n is an integer between 6 and 12 (e.g., 6, 7, 8, 9, 10, 11, or 12).
• R 1 in Formula I can be represented by the formula -(CH 2 ) n -Cy, wherein n is an integer of 1-6, and Cy is a 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.
• R 1 in Formula I can be In some specific embodiments, R 1 in Formula I can be Other suitable groups for R 1 include any of the R 10 defined herein.
• R 1 in Formula I can also be O-R 10 or NHR 10 , wherein R 10 is defined herein.
• the pharmaceutical composition can comprise a compound of Formula n, or a pharmaceutically acceptable salt thereof. wherein R 2 is defined herein.
• R 2 can be selected such that the compound of Formula II is an ester, a carbamate, or a carbonate of abiraterone.
• R 2 is R 20 , O-R 20 , or NHR 20 , and R 20 is selected from: a C 1-30 alkyl; a C 2-30 alkenyl; a C 2-30 alkynyl; an alkyl substituted with a cycloalkyl, which typically has a total number of carbons between 4 and 30; an alkyl substituted with a phenyl, which typically has a total number of carbons between 7 and 30; and a cycloalkyl optionally substituted with one or more alkyl, which typically has a total number of carbons between 3 and 30.
• R 20 is a C 1-16 alkyl. In some embodiments, R 20 can be a linear C 1-16 alkyl. In some embodiments, R 20 can be a branched C 3-16 alkyl. In some embodiments, R 20 can be a branched C5 or C6 alkyl. In some embodiments, R 20 can be In some embodiments, R 20 can have a formula -(CH 2 ) n -CH 3 , wherein n is an integer between 0 and 12 (e.g., between 6 and 12, such as 6, 7, 8, 9, 10, 11, or 12).
• R 20 can also be an alkyl substituted with a cycloalkyl.
• R 20 has a total number of carbons between 4 and 30, such as between 5 and 16 (i.e., the total number of carbons from the alkyl moiety and the cycloalkyl moiety are between 5 and 16).
• the cycloalkyl typically is unsubstituted.
• the cycloalkyl can be optionally substituted, e.g., with one or two lower alkyl (e.g, a C 1-4 alkyl).
• R 20 can be an alkyl substituted with a C 3-6 cycloalkyl, which typically has a total number of carbons between 6 and 12.
• R 20 can be a linear alkyl substituted with a C 3-6 cycloalkyl, for example, R 20 can have a formula -(CH 2 ) n -Cy, wherein n is an integer of 1-6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is a C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
• R 20 can have a formula -(CH 2 ) n - Cy, wherein n is 1 or 2, and Cy is cyclopentyl or cyclohexyl.
• R 20 can also be a branched alkyl (e.g., branched C 2-6 ) substituted with a C 3-6 cycloalkyl.
• R 20 can also be an alkyl substituted with a phenyl.
• R 20 has a total number of carbons between 7 and 30, e.g., between 7 and 16 (i.e., the total number of carbons from the alkyl moiety and the phenyl moiety are between 7 and 16).
• R 20 can be a linear alkyl substituted with a phenyl, for example, R 20 can have a formula -(CH 2 ) n -Cy, wherein n is an integer of 1-6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is a phenyl.
• R 20 can have a formula -(CH 2 ) n -Cy, wherein n is 1 or 2, and Cy is phenyl.
• R 20 can also be a branched alkyl (e.g., branched C 2-16 ) substituted with a phenyl. The phenyl typically is unsubstituted. However, in some embodiments, the phenyl can be optionally substituted, e.g., with one or two lower alkyl (e.g, a C 1-4 alkyl).
• R 20 can be a cycloalkyl optionally substituted with one or more alkyl.
• R 20 typically has a total number of carbons between 3 and 30, e.g., 5 and 16 (i.e., the total number of carbons of the cycloalkyl and its optional substituents are between 5 and 16).
• R 20 can be a C 3-6 cycloalkyl, either unsubstituted or substituted with a C 1-4 alkyl. In some specific embodiments, R 20 can be .
• R 20 can be an unsaturated aliphatic group such as a C2-30 alkenyl or a C2-3oalkynyl.
• the compound of Formula II is an abiraterone ester, e.g., R 2 is R 20 , wherein R 20 is defined herein.
• R 2 in Formula II can be a C1-16 alkyl, e.g., an alkyl having a formula of -(CHaVCHs, wherein n is an integer between 0 and 12.
• the abiraterone ester can be an acetate, a propionate, a butanoate, a (vaterate) pentanoate, an isocaproate, a buciclate, a cyclohexanecarboxylate, a phenyl propionate, caproate (hexanoate), a enanthate (heptanoate), a cypionate, an octanoate, a noncanoate, a decanoate, an undecanoate, a dodecanoate, a tridecanoate, a tetradecanoate, a pentadecanoates, or a hexadecanoate of abiraterone.
• the abiraterone ester can be abiraterone acetate, abiraterone propionate, and abiraterone decanoate.
• the abiraterone ester can be abiraterone pentanoate, abiraterone hexanoate, abiraterone heptanoate, abiraterone decanoate, abiraterone isocaproate, or abiraterone cypionate.
• R 2 in Formula II can also be O-R 20 or NHR 20 , wherein R 20 is defined herein.
• compounds of Formula I or II can be present in a formulation in the basic form.
• pharmaceutically acceptable salts of compounds of Formula I or II are also useful. Unless specifically referred to as in its salt form or otherwise contradictory from context, the compound of Formula I or II can be in its basic form in the pharmaceutical compositions described herein. In some embodiments, the compound of Formula I or II can be in a substantially pure form.
• the present disclosure provides a method of treating a disease or disorder described herein in a subject in need thereof.
• the method typically comprises orally administering to the subject a therapeutically effective amount of pharmaceutical composition herein (e.g., any of those described herein, such as [1]-[37] shown in the Summary section herein) or an emulsion described herein (e.g., any of those described herein, such as [82]-[90] shown in the Summary section herein).
• the oral administration delivers a sufficient amount of abiraterone decanoate to the subject to achieve an effective inhibition of CYP17A1 and/or modulation of various steroid hormone levels in the subject, such as androgens, estrogens, glucocorticoids, progesterone, and mineralocorticoids.
• U.S. Patent No. 10,792,292 B2, and U.S. Provisional Application Nos. 63/073,502 and 63/149,550 show various advantages of parenteral administration of abiraterone prodrugs, such as abiraterone decanoate, such as sustained inhibition of CYP17A1, sustained PD effects such as increase of progesterone level and reduction of cortisol, dihydrotestosterone and testosterone levels for up to 70 days or more, sustained reduction of testosterone within a few days following the first administration of the prodrug without the need for castration or another drug that is effective in lowering testosterone levels, and generally well tolerated, for example, no liver toxicity observed from intramuscular administration of abiraterone decanoate at the tested doses.
• abiraterone prodrugs such as abiraterone decanoate
• sustained PD effects such as increase of progesterone level and reduction of cortisol, dihydrotesto
• the prolonged PD effects observed may in part due to the slow-, tight-binding of CYP17A1 by abiraterone, which may have effectively achieved irreversible inhibition of CYP17A1, see e.g., Cheong EJ.Y., etal. J. Pharmacol. Exp. Ther. 574.-438-451 (2020).
• abiraterone prodrug resulted in both a sustained effective blood plasma levels of abiraterone and favorable tissue distribution of abiraterone and abiraterone prodrug, such as to the testes, which may contribute to the observed effects on serum steroids that are not achieved by oral abiraterone acetate formulations (e.g., Zytiga®).
• oral administration of exemplary lipid-based formulations of abiraterone decanoate similarly achieved inhibition of CYP17A1 as evidenced by the increase of progesterone level and reduction of testosterone levels for at least 24 hours or more.
• oral administration can achieve similar pharmacodynamics effects as observed in Applicant's earlier intramuscular administration, albeit at a different dosing regimen.
• the methods herein would not rely on castration to achieve a desired testosterone level, thus can also be advantageously used at least for treating subjects who do not wish to be castrated and/or who are sensitive to or otherwise intolerant with gonadal testosterone suppressing drugs.
• oral administration of abiraterone decanoate would be generally well tolerated, and can be used to treat subjects suffering from hepatic impairment, such as moderate to severe hepatic impairment (Child-Pugh Class B or C), prior to the administering of abiraterone decanoate.
• the oral formulations herein can be advantageously used for inhibiting CYP17A1 activity, reducing glucocorticoids levels, such as cortisol levels, reducing sex hormone levels such as androgen and/or estrogen levels, and/or treating disorders associated with high glucocorticoids levels, such as cortisol levels, and/or treating disorders due to high sex hormone levels such as androgen and/or estrogen levels.
• the present disclosure provides a method of treating a disease or disorder described herein in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition herein (e.g., any of those described herein, such as [1]-[37] of the Summary section).
• the present disclosure provides a method of treating a disease or disorder described herein in a subject in need thereof, the method comprising administering to the subject an effective amount of an emulsion described herein (e.g., any of those described herein, such as [82]-[90] shown in the Summary section herein).
• the disease or disorder can be a sex hormone-dependent benign or malignant disorder, an androgen receptor drive cancer, a syndrome due to androgen excess, and a syndrome due to glucocorticoid excess, such as a disease or disorder 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 nonclassical congenital adrenal hyperplasia, precocious puberty, hirsutism, and combmations thereof.
• a disease or disorder 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 nonclassical congenital adrenal hyperplasia, precocious puberty, hirsut
• the hormone-dependent benign or malignant disorders can be androgen-dependent disorders and/or estrogen-dependent disorders such as androgen or estrogen-dependent cancers.
• the sex hormone-dependent benign or malignant disorder can be prostate cancer or breast cancer.
• the sex hormone-dependent benign or malignant disorder is CRPC or CSPC.
• the sex hormone-dependent benign or malignant disorder can be metastatic CRPC or metastatic CSPC.
• the sex hormone-dependent benign or malignant disorder can also be endometrial cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, or lung cancer.
• Various non-oncologic syndromes due to androgen excess and/or due to glucocorticoid excess such as hypercortisolemia can also be treated with the methods herein, for example, syndromes due to androgen excess such as endometriosis, polycystic ovary syndrome, classical or nonclassical congenital adrenal hyperplasia, precocious puberty, hirsutism, etc., and/or syndromes due to cortisole excess such as Cushing’s syndrome, Cushing’s disease, etc.
• the methods herein are for treating a sex hormone dependent or androgen receptor driven cancer.
• the sex hormone dependent or androgen receptor driven cancer can be androgen receptor positive salivary duct carcinoma, or androgen receptor positive glioblastoma multiforme.
• the sex hormone dependent or androgen receptor driven cancer is prostate cancer (e.g., any of those described herein).
• Prostate cancer suitable to be treated with the methods herein is not particularly limited and include without limitation any of those prostate cancer for which abiraterone or its derivatives (particularly abiraterone acetate) has been approved for marketing (e.g., in the U.S. or Europe) or for which abiraterone or its derivatives (e.g., abiraterone acetate) is or has been in a clinical trial, such as those trials registered in the website clinicaltrials.gov as of the filing date of this application.
• the prostate cancer can be primary/localized prostate cancer (newly diagnosed or early stage), advanced prostate cancer (e.g., after castration for recurrent prostate cancer, locally advanced prostate cancer, etc.), recurrent prostate cancer (e.g., prostate cancer which was not responsive to a primary therapy), non-metastatic castration-resistant prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer (CRPC), or hormone-sensitive prostate cancer.
• the prostate cancer is a localized prostate cancer, e.g., a high risk localized prostate cancer.
• the subject having prostate cancer is characterized as having a rising amount of prostate specific antigen, e.g., following radical prostatectomy.
• the prostate cancer is a metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer, non-metastatic castration- resistant prostate cancer, or metastatic castration-resistant prostate cancer.
• the prostate cancer is a newly diagnosed high risk metastatic hormone sensitive prostate cancer, hi some embodiments, the prostate cancer is a metastatic CRPC (mCRPC), wherein the subject is asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated.
• mCRPC metastatic CRPC
• the prostate cancer is a metastatic CRPC (mCRPC), wherein the subject's disease has progressed on or after a taxane-based chemotherapy regimen, such as docetaxel-based or cabazitaxel-based chemotherapy regimen.
• the prostate cancer is a refractory prostate cancer.
• the phrase “refractory prostate cancer” means prostate cancer that is not responding to an anti-cancer treatment or prostate cancer that is not responding sufficiently to an anti-cancer treatment.
• Refractory prostate cancer can also include recurring or relapsing prostate cancer.
• the phrase “relapsing prostate cancer*’ means prostate cancer that was at one time responsive to an anti-cancer treatment but has become no longer responsive to such treatment or is no longer responding sufficiently to such treatment.
• the phrase “recurring (or recurrent) prostate cancer*’ means prostate cancer that has returned after a patient has been earlier diagnosed with prostate cancer, undergone treatment or had been previously diagnosed as cancer-free.
• the methods herein can also be used for treating breast cancer.
• Breast cancer suitable to be treated with the methods herein is not particularly limited.
• the breast cancer can be molecular apocrine HER2-negative breast cancer, metastatic breast cancer, such as ER+ metastatic breast cancer, ER+ and HER2 negative breast cancer, AR+ triple negative breast cancer, etc.
• a disease or disorder is associated with 21 -hydroxylase deficiency can also be treated with the methods herein.
• the methods herein can be used for treating subjects having a cancer, such as prostate cancer, breast cancer, adrenal cancer, leukemia, lymphoma, myeloma, Waldenstrom's macroglobulinemia, monoclonal gammopathy, benign monoclonal gammopathy, heavy chain disease, bone and connective tissue sarcoma, brain tumors, thyroid cancer, pancreatic cancer, pituitary cancer, eye cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, cholangiocarcinoma, lung cancer, testicular cancer, penal cancer, oral cancer, skin cancer, kidney cancers, Wilms' tumor and bladder cancer.
• a cancer such as prostate cancer, breast cancer, adrenal cancer, leukemia, lympho
• the method herein can include treating the subject with one or more additional therapies.
• the subject is further treated a radiation therapy.
• the method is for treating prostate cancer and includes a combination therapy, which further comprises administering to the subject one or more additional therapies, e.g., as described herein under the section titled Combmation Treatment for Prostate Cancer as described herein below.
• additional therapies also include any of those described in [50]-[54] and [61]-[71], [73]-[75], and [77] in the Summary section herein.
• Subjects suitable to be treated by the methods herein are not particularly limited, which include subjects at various stages of diseases or treatments and other characteristics.
• the subject can be a non-castrated subject.
• the subject can be a castrated subject.
• the methods herein can also administer the pharmaceutical composition herein (e.g., any of [1]-[37] of the Summary section herein) to the subject without regard to whether the subject is castrated or not.
• the subject has not undergone a prostatectomy.
• the subject can be characterized as suffering from hepatic impairment, such as moderate to severe hepatic impairment (Child-Pugh Class B or C), prior to the administering of the abiraterone prodrug.
• the subject can be characterized as being sensitive to or otherwise intolerant with a gonadotropin-releasing hormone antagonist and/or agonist.
• the subject can be characterized as chemotherapy naive or hormone therapy naive prior to being administered the pharmaceutical composition herein.
• the subject can also be treated with chemotherapy or hormone therapy prior to being administered the pharmaceutical composition herein.
• the subject can have a disease or disorder (e.g., prostate cancer) that has progressed on or after the chemotherapy and/or hormone therapy, such as a taxane-based chemotherapy regimen, for example, docetaxel- based or cabazitaxel-based chemotherapy.
• a disease or disorder e.g., prostate cancer
• hormone therapy such as a taxane-based chemotherapy regimen, for example, docetaxel- based or cabazitaxel-based chemotherapy.
• the subject can be a human subject.
• Suitable pharmaceutical compositions for the methods herein are not particularly limited and include any of those described herein, such as any of the abiraterone decanoate formulations described herein, e.g., any of those described in the Summary section.
• the pharmaceutical composition can be formulated to deliver a therapeutically effective plasma levels of abiraterone over an extended period of time (e.g., at least 1 day, at least 2 days, at least 3 days, etc.) in the subject, following a single oral administration.
• the therapeutically effective plasma concentration of abiraterone can be a concentration of at least 1 ng/ml, e.g., at least 2 ng/ml, at least 4 ng/ml, at least 8 ng/ml. In some embodiments, the therapeutically effective blood plasma concentration of abiraterone can also be about 0.5 ng/ml or higher. In some embodiments, the therapeutically effective blood plasma concentration of abiraterone can also be about 0.1 ng/ml or higher.
• the pharmaceutical composition can be administered to the subject with or without food.
• Dosing amounts and frequencies for the methods herein are also not particularly limited and include any of those described herein.
• the pharmaceutical composition is administered to the subject ranging from once a day to once a week, such as once a day or once every two or three days.
• the dosing amounts of the abiraterone decanoate for each administration can vary, typically ranging from 0.5 mg/kg to 200 mg/kg, such as about 0.5 mg/kg to about 200 mg/kg of body weight of a subject.
• Some embodiments of the present disclosure are directed to methods of reducing serum steroid hormone level in a subject in need thereof.
• the present disclosure provides a method of reducing serum testosterone level in a subject in need thereof, the method comprising orally administering to the subject a pharmaceutical composition herein (e.g., any of those described herein, such as [1]-[37] of the Summary section herein) or an emulsion described herein (e.g., any of those described herein, such as [82]-[90] shown in the Summary section herein).
• a pharmaceutical composition herein e.g., any of those described herein, such as [1]-[37] of the Summary section herein
• an emulsion described herein e.g., any of those described herein, such as [82]-[90] shown in the Summary section herein.
• Subjects suitable to be treated with the methods herein for reducing serum testosterone levels are not particularly limited.
• the subject can be a non- castrated subject.
• the subject can be a castrated subject.
• the methods herein can also administer the pharmaceutical composition herein (e.g., any of those described herein, such as [1 ]-[37] of the Summary section herein) to the subject without regard to whether the subject is castrated or not.
• another drug that is effective in lowering serum and/or gonadal testosterone level is not administered to the subject concurrently with the administration of the abiraterone prodrug, during the treatment with the abiraterone prodrug, or otherwise interfering with the treatment with the abiraterone prodrug.
• the subject is not treated with a gonadal testosterone suppressing drug, other than the administered abiraterone prodrug, in an amount effective to reduce serum testosterone level in the subject.
• the subject is not treated with a gonadotropin-releasing hormone antagonist and/or agonist in an amount effective to reduce serum testosterone level in the subject.
• 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, deslorelin, fertirelin, histrelin, gonadorelin, lecirelin, goserelin, nafarelin, peforelin and triptorelin.
• the subject is not treated with a drug selected from abarelix, cetrorelix, degarelix, ganirelix, elagolix, linzagolixa, and relugolix.
• the subject can be sensitive to or otherwise intolerant with a gonadotropin-releasing hormone antagonist and/or agonist.
• the subject can also be treated with a gonadotropin-releasing hormone antagonist and/or agonist, e.g., described herein.
• the subject in need of reduction of testosterone typically suffers from one or more diseases or disorders mediated or associated with androgens.
• the subject is characterized as having a sex hormone dependent cancer or androgen receptor driven cancer, e.g., any of those described herein.
• the subject is characterized as having androgen receptor positive salivary duct carcinoma, or androgen receptor positive glioblastoma multiforme.
• the subject is characterized as having prostate cancer (e.g., any of those described herein).
• the prostate cancer is a localized prostate cancer, e.g., a high risk localized prostate cancer.
• the subject has not undergone a prostatectomy.
• the subject is further treated with a radiation therapy.
• the present disclosure also provides a method of inhibiting CYP17A1 activity such as inhibiting 17 ⁇ -hydroxylase activity and 17,20-lyase activity, the method comprising administering to a subject in need thereof any of the pharmaceutical composition herein (e.g., any of [1]-[37] of the Summary section herein).
• the present disclosure provides a method of inhibiting CYP17A1 activity such as inhibiting 17 ⁇ - hydroxylase activity and 17,20-lyase activity, the method comprising administering to a subject in need thereof an emulsion described herein (e.g., any of those described herein, such as [82]- [90] shown in the Summary section herein).
• the subject suffers from a sex hormone-dependent benign or malignant disorder, e.g., as described herein.
• the subject suffers from a syndrome due to androgen excess and/or a syndrome due to glucocorticoid excess such as hypercortisolemia, e.g., as described herein.
• the subject suffers from a sex hormone dependent cancer or androgen receptor driven cancer described herein.
• Suitable pharmaceutical compositions, subjects, dosing regimen, and routes of administrations for the method include any of those described herein in any combination, such as any of those described in connection with the methods shown in the Summary section herein.
• the present disclosure provides a method of reducing the level of glucocorticoids (e.g., cortisol) in a subject in need thereof, the method comprising administering to the subject any of the pharmaceutical composition herein (e.g., any of [1]-[37] of the Summary section herein).
• the present disclosure provides a method of reducing the level of glucocorticoids (e.g., cortisol) in a subject in need thereof, the method comprising administering to the subject an emulsion described herein (e.g., any of those described herein, such as [82]-[90] shown in the Summary section herein).
• the subject suffers from a syndrome due to glucocorticoid excess such as hypercortisolemia as described herein, such as Cushing’s syndrome or Cushing’s disease.
• a syndrome due to glucocorticoid excess such as hypercortisolemia as described herein, such as Cushing’s syndrome or Cushing’s disease.
• Suitable pharmaceutical compositions, subjects, dosing regimen, and routes of administrations for the method include any of those described herein in any combination, such as any of those described in connection with the methods shown in the Summary section herein.
• the present disclosure provides a method of reducing the level of androgens (e.g., testosterone) and/or estrogens in a subject in need thereof, the method comprising administering to the subject any of the pharmaceutical composition herein (e.g., any of [1]-[37] of the Summary section herein).
• the present disclosure provides a method of reducing the level of androgens (e.g., testosterone) and/or estrogens in a subject in need thereof, the method comprising administering to the subject an emulsion described herein (e.g., any of those described herein, such as [82]-[90] shown in the Summary section herein).
• the subject suffers from an androgen receptor driven cancer.
• the subject suffers from a syndrome due to androgen excess, such as congenital adrenal hyperplasia (e.g., classical or nonclassical congenital adrenal hyperplasia), endometriosis, polycystic ovary syndrome precocious puberty, hirsutism, etc.
• the subject suffers from an androgen and/or estrogen associated cancer, such as prostate cancer or breast cancer.
• the subject suffers from a sex hormone dependent cancer described herein.
• Suitable pharmaceutical compositions, subjects, dosing regimen, and routes of administrations for the method include any of those described herein in any combination, such as any of those described in connection with the methods shown in the Summary section herein.
• the abiraterone decanoate in the pharmaceutical composition or emulsion is typically included in a therapeutically effective amount for treating a disease or disorder described herein, such as prostate cancer.
• the abiraterone decanoate can be present in the pharmaceutical composition or emulsion in an amount suitable for a dosing frequency ranging from once a day to once a week, such as once a day or once every two or three days, for oral administration to a subject having a sex hormone-dependent benign or malignant disorder, an androgen receptor driven cancer, a syndrome due to androgen excess, and/or a syndrome due to glucocorticoid excess such as hypercortisolemia.
• the methods herein can comprise administering one or more other drug or agent (for example, another cancer chemotherapeutic drug, hormone replacement drug, or hormone ablation drug) to the subject, either concurrently or sequentially, through the same route or a different route of administration.
• the other drug or agent can be a steroid, such as prednisone, prednisolone, and/or methylprednisolone.
• the other drug or agent can be a chemotherapy drug, such as paclitaxel, mitoxantrone, and/or docetaxel.
• the other agent or drug can be a GnRH agonist, such as Leuprolide, deslorelin, goserelin, or triptorelin, e.g., leuprolide acetate (e.g., a long-acting IM injectable formulation).
• the other agent or drug can be seocalcitol, bicalutamide, flutamide, a glucocorticoid including, but not limited to, hydrocortisone, prednisone, prednisolone, or dexamethasone.
• the amount of the other drugs or agents to be administered can vary, typically can be an amount that is effective in treating the respective disease or disorder (e.g., prostate cancer) either alone or in combination with the pharmaceutical composition herein (e.g., any of [1]-[37] of the Summary section herein).
• the respective disease or disorder e.g., prostate cancer
• the pharmaceutical composition herein e.g., any of [1]-[37] of the Summary section herein).
• useful other drugs or agents include, but are not limited to, anticancer agents, hormone ablation agents, anti-androgen agents, differentiating agents, anti-neoplastic agents, kinase inhibitors, anti-metabolite agents, alkylating agents, antibiotic agents, immunological agents, interferon- type agents, intercalating agents, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloprotease inhibitors, genetic therapeutics, and anti-androgens.
• suitable anti-cancer agents including but not limited to, acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, amsacrine, anagrelide, anastrozole, ancestim, bexarotene, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, daclizumab, dexrazoxane, dilazep, docosanol, doxifluridine, bromocriptine, carmustine, cytarabine, diclofenac, edelfosine, edrecolomab, eflomithine, emitefur, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemus
• Suitable anti-androgen agents include but are not limited to bicalutamide, flutamide and nilutamide.
• Suitable differentiating agents include, but are not limited to, polyamine inhibitors; vitamin D and its analogs, such as, calcitriol, doxercalciferol and seocalcitol; metabolites of vitamin A, such as, ATRA, retinoic acid, retinoids; short-chain fatty acids; phenylbutyrate; and nonsteroidal anti-inflammatory agents, anti-neoplastic agent, including, but not limited to, tubulin interacting agents, topoisomerase inhibitors and agents, acitretin, alstonine, amonafide, amphethinile, amsacrine, ankinomycin, anti-neoplaston, aphidicolin glycinate, asparaginase, baccharin, batracylin, benfluron, benzotript, bromofosfamide, caracemid
• a kinase inhibitor including p38 inhibitors and CDK inhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP), COX-2 inhibitors including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, SOD mimics or ⁇ v ⁇ 3 inhibitors.
• Suitable anti-metabolite agents may be selected from, but not limited to, 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, dezaguanine, dideoxycytidine, dideoxyguanosme, didox, doxifluridine, camrabme, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2'-furanidyl)-5-fluorouracil, isopropyl pyrrolizine, methobenzaprim, methotrexate, norspermidine, pentostatm, piritrexim, plicamycin, thioguanine, tiazofurin, trimetrexate, tyrosine kinase inhibitors, and uricytin.
• Suitable alkylating agents may be selected from, but not limited to, aldo-phosphamide analogues, altretamine, anaxirone, bestrabucil, budotitane, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cyplatate, diphenylspiromustine, diplatinum cytostatic, elmustine, estramustine phosphate sodium, fotemustine, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, oxaliplatin, prednimustine, ranimustine, semustine, spiromustine, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol.
• Suitable antibiotic agents may be selected from, but not limited to, aclarubicin, actinomycin D, actinoplanone, adriamycin, aeroplysinin derivative, amrubicin, anthracycline, azino-mycin-A, bisucaberin, bleomycin sulfate, bryostatin-1, calichemycin, chromoximycin, dactinomycin, daunorubicin, ditrisarubicin B, dexamethasone, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-Al, esperamicin-Alb, fostriecin, glidobactm, gregatin-A, grincamycin, herbimycin, corticosteroids such as hydrocortisone, idarubicin, ilhidins,
• Prostate cancer treatments often involve multiple therapies, including for example, radiotherapy, surgery, androgen deprivation therapy, hormone therapy, chemotherapy, immunotherapy, and various drug combinations.
• a search in the website clinicaltrials.gov identified more than 250 clinical trials with abiraterone/abiraterone acetate listed as an intervention agent, and many of such clinical trials include a combination therapy for treating prostate cancer.
• the pharmaceutical compositions herein e.g., any of those described herein, such as any of [1]-[37] of the Summary section herein
• the methods herein can include the combmation treatment that does not treat the subject with a gonadal testosterone suppressing drug, other than the administered abiraterone prodrug, in an amount effective to reduce serum testosterone level in the subject.
• the methods herein can include the combination treatment that does not treat the subject with any GnRH angonist and antagonist.
• the present disclosure provides a method of treating prostate cancer (e.g., any of those described herein) in a subject in need thereof, with a combination therapy, which comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition herein (e.g., any of those described herein, such as any of [1]-[37] of the Summary section herein), and one or more additional therapies.
• the one or more additional therapies can be administered to the subject concurrently or sequentially in any order with administering the pharmaceutical composition herein, which can be via the same or different route of administration.
• the method herein comprises treating the subject with a radiotherapy or surgery.
• the method comprises administering to the subject one or more other agents selected from anticancer agents, hormone ablation agents, anti-androgen agents, differentiating agents, anti-neoplastic agents, kinase inhibitors, anti- metabolite agents, alkylating agents, antibiotic agents, immunological agents, interferon-type agents, intercalating agents, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloprotease inhibitors, genetic therapeutics, or combinations thereof.
• the method comprises administering to the subject one or more other agents selected from a chemotherapeutic drug, hormone replacement drug, or hormone ablation drug.
• the method comprises treating the subject with an androgen deprivation therapy. While many of the combination therapies below are described as in connection with various treatments for prostate cancer, the present disclosure is not so limited. And in some embodiments, the combination therapies described below can also be used in the treatment of other diseases or disorders described herein, such as other cancers described herein.
• the combination therapy typically includes administering to the subject a glucocorticoid.
• the method comprises administering to the subject one or more agents selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone.
• a glucococorticoid replacement therapy e.g., administering a glucocorticoid, such as hydrocortisone, prednisone, prednisolone, methylprednisolone, or dexamethasone is not desired.
• a glucocorticoid may be contraindicated for the subject, who may have an underlying condition, such as diabetics.
• the method can also be characterized in that the subject is not treated with a glucocorticoid replacement therapy.
• the subject is not treated with an agent selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone.
• the method can comprise administering to the subject a mineralocorticoid receptor antagonist, such as eplerenone.
• the method can comprise administering to the subject a mineralocorticoid receptor antagonist, such as eplerenone.
• the combination therapy for the methods herein can also include an androgen deprivation therapy, such as through administering to the subject a gonadotropin-releasing hormone (GnRH) analog.
• GnRH gonadotropin-releasing hormone
• suitable GnRH analogs for the combination therapy are not particularly limited and include both GnRH agonists and GnRH antagonists.
• the method can comprise administering to the subject a gonadotropin-releasing hormone (GnRH) agonist, such as buserelin, leuprolide, deslorelin, fertirelin, histrelin, gonadorelin, lecirelin, goserelin, nafarelin, peforelin or triptorelin, and/or a GnRH antagonist, such as abarelix, cetrorelix, degarelix, ganirelix, elagolix, linzagolixa, or relugolix.
• the subject is not administered any of the GnRH agonists and GnRH antagonists described herein.
• the combination therapy includes treating the subject to reduce androgen receptor (AR) activities, such as an AR antagonist or an agent otherwise downregulating or inhibiting AR activities.
• AR androgen receptor
• the method can include administering to the subject an androgen receptor (AR) antagonist.
• AR androgen receptor
• Various AR antagonists are known in the art, which include without limitation 1“ and 2 nd -generations AR antagonists, see e.g., Rice, M.A., et al. Front Oncol. 9/801 (2019), and third-generation AR antagonists, such as an N-terminal domain inhibitor.
• the method comprises administering to the subject a 1 “ generation androgen receptor antagonist, which includes without limitation, proxalutamide, bicalutamide, flutamide, nilutamide, topilutamide, etc.
• the method comprises administering to the subject a 2 nd "generation androgen receptor antagonist, which includes without limitation, for example, apalutamide, darolutamide or enzalutamide. In some embodiments, the method comprises administering to the subject apalutamide. In some embodiments, the method comprises administering to the subject enzalutamide. In some embodiments, the method comprises administering to the subject a S ⁇ generation androgen receptor antagonist, such as an N-terminal domain inhibitor. N-terminal domain inhibitors are known in the art. Non-limiting useful examples include any of those described in U.S. Application Publication No.
• an AR antagonist is administered, one or more such antagonists can be administered, which can be selected from 1 st , 2 nd , or 3 rd AR antagonists alone, or in any combination.
• the combination therapy can include administering to the subject one or more upstream kinase modulators, the activation or inhibition of which can reduce AR activities.
• upstream kinases are known in the art, for example, as described in Shah, K. and Bradbury, N. A., Cancer cell microenviron.
• the method comprises administering to the subject 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, such as CDK1, 2, 4, 5, 6, 7, or 9 inhibitors, retinoblastoma (Rb) inhibitors, protein kinase B (AKT) inhibitors, SRC inhibitors, IkappaB kinase 1 (IKK1) inhibitors, PIM-1 modulators, Lemur tyrosine kinase 2 (LMTK2) modulators, Lyn inhibitors, Aurora A inhibitors, ANPK (a nuclear protein kinase) inhibitors, extracellular-
• FLT-3 FLT-3
• AXL anexelekto inhibitors
• CDK cyclin dependent kinase
• CDK1 cyclin dependent kinase
• the combination therapy can include administering to the subject an agent that downregulates AR or otherwise inhibits AR activities.
• AR activities can be affected on the genomic and/or the transcription level of AR itself, or the genomic and/or the transcription level of those upstream targets of AR that play a role in regulating AR activities and those downstream targets that are regulated by AR, using a variety of molecules which interfere with transcription and/or translation (e.g., RNA silencing agents (e.g., antisense, siRNA, shRNA, micro-RNA), Ribozyme and DNAzyme), or on the protein level using e.g., antagonists, enzymes that cleave the polypeptide, small molecules that interfere with the protein's activity (e.g., competitive ligands) and the like.
• RNA silencing agents e.g., antisense, siRNA, shRNA, micro-RNA
• RNA silencing refers to a group of regulatory mechanisms (e.g., RNA interference (RNAi), transcriptional gene silencing (TGS), post-transcriptional gene silencing (PTGS), quelling, co-suppression, and translational repression) mediated by RNA molecules which result in the inhibition or “silencing” of the expression of a corresponding protein-coding gene.
• RNA silencing has been observed in many types of organisms, including plants, animals, and fungi.
• RNA silencing agent refers to an RNA which is capable of specifically inhibiting or “silencing” the expression of a target gene.
• the RNA silencing agent is capable of preventing complete processing (e.g., the full translation and/or expression) of an mRNA molecule through a post-transcriptional silencing mechanism.
• RNA silencing agents include noncoding RNA molecules, for example, RNA duplexes comprising paired strands, as well as precursor RNAs from which such small non-coding RNAs can be generated.
• RNA silencing agents include double-stranded RNAs (dsRNAs) such as short interfering RNAs (siRNAs), miRNAs and shRNAs.
• dsRNAs double-stranded RNAs
• siRNAs short interfering RNAs
• miRNAs miRNAs
• shRNAs shRNAs
• the RNA silencing agent is capable of inducing RNA interference.
• the RNA silencing agent is capable of mediating translational repression.
• the strands of a double-stranded interfering RNA e.g., an siRNA
• shRNA short hairpin RNA
• RNA silencing agent of some embodiments of the present disclosure need not be limited to those molecules containing only RNA, but further encompasses chemically modified nucleotides and non-nucleotides.
• the RNA silencing agent provided herein can be functionally associated with a cell-penetrating peptide.
• a “cell-penetrating peptide” is a peptide that comprises a short (about 12-30 residues) amino acid sequence or functional motif that confers the energy-independent (i.e., non-endocytotic) translocation properties associated with transport of the membrane-permeable complex across the plasma and/or nuclear membranes of a cell.
• the RNA silencing agent may be a miRNA or a mimic thereof.
• miRNA miRNA
• miR miRNA receptor
• miRNAs are found in a wide range of organisms and have been shown to play a role in development, homeostasis, and disease etiology.
• microRNA mimic refers to synthetic non-coding RNAs that are capable of entering the RNAi pathway and regulating gene expression. miRNA mimics imitate the function of endogenous microRNAs (miRNAs) and can be designed as mature, double stranded molecules or mimic precursors (e.g., or pre-miRNAs).
• Downregulation of AR or inhibition of AR activities can also be achieved by gene editing of a target gene (e.g., AR or suitable upstream and downstream targets of AR as described herein, etc.).
• Gene editing can be performed, for example, with a clustered regularly interspaced short palindromic repeats CRISPR-CAS9 system.
• CRISPR-CAS9 systems have been described in the literature and can include, for example, CAS9 and a guide RNA.
• Other gene editing techniques have also been described in the literature and can also be used.
• Another agent capable of downregulating a target is a DNAzyme molecule capable of specifically cleaving an mRNA transcript or DNA sequence of the target.
• DNAzymes are single- stranded polynucleotides which are capable of cleaving both single and double stranded target sequences.
• DNAzymes have a catalytic domain of 15 deoxyribonucleotides, flanked by two substrate-recognition domains of seven to nine deoxyribonucleotides each. This type of DNAzyme can effectively cleave its substrate RNA at purine:pyrimidine junctions. (Santoro et al., Khachigian, Curr. Opin. Mol. Ther. 2002; 4:119-121.)
• Downregulation of a target can also be affected by using an antisense polynucleotide capable of specifically hybridizing with an mRNA transcript encoding the target.
• Another agent capable of downregulating a target is a ribozyme molecule capable of specifically cleaving an mRNA transcript encoding a target. Ribozymes are being increasingly used for the sequence-specific inhibition of gene expression by the cleavage of mRNAs encoding proteins of interest. (Welch et al., Curr. Opin. Biotechnol. 1998; 9:486-96.)
• Another agent capable of downregulating a target is any molecule which binds to and/or cleaves the target.
• Such molecules can be antagonists of the target, or inhibitory peptides of the target.
• Another agent which can be used along with some embodiments of the present disclosure to downregulate a target is a molecule which prevents target activation and/or substrate binding.
• Another agent which can be used along with some embodiments of the present disclosure to downregulate AR or inhibit AR's activities is an androgen receptor degrader, such as those based on PROteolysis TArgeting Chimeric (PROTAC) technology. See, e.g., Kregel, S. et al. Neoplasia 22(2);111-119 (2020).
• PROTAC PROteolysis TArgeting Chimeric
• Another agent which can be used along with some embodiments of the present disclosure to downregulate a target is to repress or downregulate the activation of the target's transcriptional activity, more particularly, AR's transcriptional activities.
• such agent can interfere with the nuclear translocation of AR, downregulate the protein level of AR, decrease hormone binding to AR, interfere with recruitment of transcriptional cofactors (e.g., steroid receptor coactivator 1 (SRC1) and transcriptional intermediary factor 2 (TIF2)), interefer with with AR- DNA-binding, e.g., the binding to specific DNA response elements (AREs or, androgen response elements), inhibit AR recruitment to an AR target gene enhancer, and/or inhibit AR-chromatin binding etc. or otherwise inhibit the DNA-binding-dependent or non-DNA-binding-dependent AR signaling pathways.
• transcriptional cofactors e.g., steroid receptor coactivator 1 (SRC1) and transcriptional intermediary factor 2 (TIF2)
• SRC1 steroid receptor coactivator 1
• TRF2 transcriptional intermediary factor 2
• Suitable agents that can inhibit or interfere with AR transcriptional activities include any of those known in the art and any of those agents exemplified herein that are capable of inhibiting or interfering with such activities.
• certain AR antagonists such as the 1 st generation AR antagonists (e.g., bicalutamide) are known to inhibit AR transcriptional activities by inhibiting nuclear translocation of AR.
• Other agents such as arsenic compounds (e.g., arsenic trioxide), were also known to inhibit AR transcriptional activity. See e.g., Rosenblatt A.E., et al, Mol. Endocrinol. 23(3 ):412-421 (2009).
• the combination therapy can include administering to the subject one or more chemotherapeutic agents.
• Suitable chemotherapeutic agents include any of those known in the art.
• the method comprises administering to the subject a taxane based chemotherapeutic agent (e.g., docetaxel, cabazitaxel, paclitaxel, etc.) and/or platinum based chemotherapeutic agent (e.g., cisplatin, carboplatin, oxaliplatin, etc.).
• the combination therapy can include treating the subject with a radiotherapy.
• Suitable radiotherapy includes any of those known in the art.
• the method comprises treating the subject with stereotactic body radiotherapy or neutron radiation.
• the combination therapy can include treating the subject with Radium-223, e.g., Xofigo (Radium-223 dichloride) injection.
• Radium-223 e.g., Xofigo (Radium-223 dichloride) injection.
• the combination therapy can include administering to the subject one or more immunotherapies. Suitable immunotherapies include any of those known in the art.
• the method comprises administering to the subject Sipuleucel-T.
• the method comprises administering to the subject an immune checkpoint inhibitor.
• the method comprises administering to the subject an anti-PD-1 antibody, such as pembrolizumab or nivolumab, and/or an anti-PD-Ll antibody, such as avelumab or atezolizumab.
• the method comprises administering to the subject an anti-CTLA-4 antibody, such as ipilimumab.
• the combination therapy can include administering to the subject a bispecific T-cell engager (BiTE) therapy, such as blinatumomab or solitomab.
• BiTE bispecific T-cell engager
• the combination therapy can include administering to the subject one or more poly ADP ribose polymerase (PARP) inhibitors.
• PARP poly ADP ribose polymerase
• the subject having prostate cancer also has DNA repair defects.
• the subject having prostate cancer does not have DNA repair defects.
• Suitable PARP inhibitors include any of those known in the art.
• the method comprises administering to the subject a PARP inhibitor selected from niraparib, rucaparib, olaparib, talazoparib, veliparib, and fluzoparib.
• the combination therapy can include administering to the subject one or more kinase inhibitors, fa some embodiments, the subject is characterized as having an abnormal level of the respective kinase, fa some embodiments, the kinase inhibitor can reduce the activity of androgen receptor or otherwise beneficial to cancer treatment.
• Suitable kinase inhibitors include any of those known in the art.
• the method comprises administering to the subject a kinase inhibitor selected from sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivasertib, onvansertib, ipatasertib, afuresertib, alisertib, apitolisib, and opaganib.
• a kinase inhibitor selected from sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivasertib, onvansertib, ipatasertib, afuresertib, alisertib, apitolisib, and opaganib.
• the combination therapy can include administering to the subject one or more bone protecting agents, fa such embodiments, typically, the subject is characterized as having prostate cancer (e.g., CRPC) with bone metastasis.
• Suitable bone protecting agents include any of those known in the art.
• the method comprises administering to the subject a bone protecting agent selected from denosumab and zolendronic acid.
• the combination therapy can include administering to the subject one or more additional agents that are useful for treating prostate cancer, by itself or in combination with an abiraterone medication such as the abiraterone prodrugs herein.
• additional agents are not particularly limited.
• the method comprises administering to the subject a therapeutic agent selected from 1) an anti-IL23 targeting monoclonal antibody, e.g., tildrakizumab; 2) a selenium, such as 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, alobresib, ZEN-3694, or molibresib (GSK525762); 7) an anti-CD105 antibody, e.g., TRC105 or carotuximab; 8) niclosamide; 9) an A2A receptor antagonist, e.g., AZD4635; 10)
• a therapeutic agent selected from
• an antiprogestogen e.g., onapristone; 13) navitoclax; 14) an HSP90 inhibitor, e.g., onalespib (AT13387); 15) an HSP27 inhibitor, e.g., OGX-427; 16) a 5-alpha-reductase inhibitor, e.g., dutasteride; 17) metformin; 18) AMG-386; 19) dextromethorphan; 20) theophylline; 21) hydroxychloroquine; and 22) lenalidomide.
• the combination therapy can include administering to the subject one or more 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, such as CDK1, 2, 4, 5, 6, 7, or 9 inhibitors, retinoblastoma (Rb) inhibitors, protein kinase B (AKT) inhibitors, SRC inhibitors, IkappaB kinase 1 (IKK1) inhibitors, PIM-1 modulators, Lemur tyrosine kinase 2 (LMTK2) modulators, Lyn inhibitors, Aurora A inhibitors, ANPK (a nuclear protein kinase) inhibitors, extracellular- signal regulated kinase (ERK) modulators, c-jun N-terminal kinase (INK) modulators, Big MAP kina
• the combination therapy can include administering to the subject one or more agents selected from 1) a poly (ADP-ribose) polymerase (PARP) inhibitor including but not limited to olaparib, niraparib, rucaparib, talazoparib; 2) an androgen receptor ligand binding domain inhibitor including but not limited to enzalutamide, apalutamide, darolutamide, bicalutamide, nilutamide, flutamide, ODM-204, TAS3681; 3) an additional inhibitor of CYP17 including but not limited to galeterone, abiraterone, abiraterone acetate; 4) a microtubule inhibitor including but not limited to docetaxel, paclitaxel, cabazitaxel (XRP-6258); 5) a modulator of PD-1 or PD-L1 including but not limited to pembrolizumab, durvalumab, nivoluma
• PARP poly (ADP
• the combination therapy herein is not particularly limited to any specific numbers of additional therapies.
• the combination therapy typically can include additional 1, 2, 3, 4, 5, 6, or more therapies described herein.
• the combination therapy can include one additional therapy, e.g., any one of those described herein, for example, a GnRH agonist, a GnRH antagonist, an androgen receptor antagonist, a chemotherapy, a PARP inhibitor, a kinase inhibitor, an immunotherapy, a radiation therapy, surgery, an androgen deprivation therapy, etc.
• the combination therapy can include two or more additional therapies described herein.
• the combination therapy can include administering to the subject a PARP inhibitor and an androgen deprivation therapy.
• the combination therapy can include administering to the subject a GnRH agonist and a radiation therapy.
• the combination therapy can include administering to the subject a GnRH agonist, a chemotherapeutic agent, and a radiation therapy.
• the combination therapy can include administering to the subject an androgen receptor antagonist (e.g., 1 st , 2 nd , and/or 3 rd generation AR antagonist), a GnRH agonist, and optionally a radiation therapy, a chemotherapeutic agent, indomethacin, or 5-alpha reductase inhibitor, hi some embodiments, the combination therapy can include administering to the subject an androgen receptor antagonist (e.g., 1 st , 2 nd , and/or 3 rd generation AR antagonist) and a radiation therapy.
• an androgen receptor antagonist e.g., 1 st , 2 nd , and/or 3 rd generation AR antagonist
• the combination therapy can include administering to the subject an androgen receptor antagonist (e.g., 1 st , 2 nd , and/or 3 rd generation AR antagonist) and a chemotherapeutic agent.
• the combmation therapy can include administering to the subject an androgen receptor antagonist (e.g., 1 st , 2 nd , and/or 3 rd generation AR antagonist) and an anti-CTLA4 antibody. It should be understood that these combinations discussed are examples of useful combinations, which are in no way limiting, and other combinations of the additional therapies described herein are allowed.
• the method of treating prostate cancer is not in conjunction with a combination therapy.
• the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition herein, without the one or more additional therapies described herein.
• the pharmaceutical composition herein can be administered to a subject in need thereof as the only source of abiraterone. However, in some embodiments, other abiraterone medications/formulations are not excluded.
• the administering herein can be combined, either concurrently or sequentially in any order, with an oral administration of abiraterone acetate, such as the Zytiga® formulation.
• the subject can use the pharmaceutical composition herein as a supplement to an existing abiraterone therapy.
• formulations, methods, and kits for treating a subject with a sex hormone-dependent benign or malignant disorder such as prostate cancer.
• a sex hormone- dependent benign or malignant disorder such as prostate cancer
• an androgen receptor driven cancer such as prostate cancer
• a syndrome due to androgen excess such as prostate cancer
• glucocorticoid excess such as hypercortisolemia
• subject means, but is not limited to, an animal or human in need of or capable of receiving chemotherapy for a sex hormone-dependent benign or malignant disorder such as, for example, an androgen-dependent disorder or an estrogen-dependent disorder (including prostate cancer and breast cancer), an androgen receptor driven cancer, an animal or human in need of or capable of receiving therapy for non-oncologic syndromes due to androgen excess, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classical or nonclassical congenital adrenal hyperplasia), precocious puberty, hirsutism, etc., and/or due to glucocorticoid excess such as hypercortisolemia, such as Cushing’s syndrome or Cushing’s disease.
• a sex hormone-dependent benign or malignant disorder such as, for example, an androgen-dependent disorder or an estrogen-dependent disorder (including prostate cancer and breast cancer), an androgen receptor driven cancer, an animal or human
• the subject is a human subject.
• other drug or agent as used herein (when, for example, referring to prior, simultaneous, and post-administration of at least one other drug or agent with at least one abiraterone prodrug formulation) means at least one other compound, formulation, molecule, biologic, or the like, capable of enhancing the efficacy of the formulation(s), decreasing an undesirable side effect(s) of the formulation(s), or improving the treatment of the particular disorder. Any suitable routes of administration of such “other drug or agent” can be used, for example, oral administration, parenteral administration, etc.
• a person skilled in the art of treating a subject having a sex hormone-dependent benign or malignant disorder such as an androgen-dependent disorder or an estrogen-dependent disorder
• a sex hormone-dependent benign or malignant disorder such as an androgen-dependent disorder or an estrogen-dependent disorder
• an androgen receptor driven cancer such as an androgen-dependent disorder or an estrogen-dependent disorder
• syndromes due to androgen excess syndrome such as hypercortisolemia
• the formulations can optionally be administered via a modified-release device or method.
• modified-release as used herein should be understood as encompassing delayed release, prolonged or extended release, sustained release, or a targeted release, etc.
• the modified release device or method can further prolong the release of abiraterone of the prodrugs and formulations of the present disclosure.
• the modified release device or method can also include any device or method capable of releasing an agent or product (for example, a drug or a biologic) at a time later than immediately following its administration (and can include, for example, implants).
• agent or product for example, a drug or a biologic
• Various modified release devices have been described (Stubbe et al., Pharm. Res. 21:1732, 2004) and could be applicable to the representative embodiments. Modified-release devices and methods can be identified and employed without undue experimentation by a person skilled in the art after consideration of all criteria and use of best judgment on the subject’s behalf.
• the formulations and agents of the embodiments are administered in a pharmacologically or physiologically acceptable and effective amount to reduce or eliminate the presence, for example, of prostate tumor tissue and abnormal or malignant prostate cells in a subject presenting with prostate cancer.
• the formulations and agents of the embodiments are administered alone or in combination with other therapeutic agents or therapeutic modalities (for example, radiotherapy and surgery) in prophylactically or therapeutically effective amounts, which are to be understood as amounts meeting the intended prophylactic or therapeutic objectives and providing the benefits available from administration of such formulations and agents.
• an “effective amount,” “effective dose,” and “therapeutic blood plasma concentration” as used herein mean, but are not limited to, an amount, dose, or concentration capable of treating, delaying, slowing, inhibiting, or eliminating the onset, existence or progression of a disorder, disease or condition.
• an “effective amount,” “effective dose,” or “therapeutic blood plasma concentration” is capable of reducing or eliminating the presence of prostate tumor tissue and abnormal or malignant prostate cells in a subject presenting with prostate cancer, which is sufficient to cure (partly or completely) illness or prevent the onset or further spread of disorder, disease or condition.
• an effective amount of formulation refers to the amount administered alone or in combination with other therapeutic agents or therapeutic modalities (for example, radiotherapy and surgery) to achieve clinically significant reduction in tumor burden.
• therapeutic agents or therapeutic modalities for example, radiotherapy and surgery
• a person skilled in the art would understand when a clinically significant reduction in tumor burden (or improvement of a sex hormone-dependent benign or malignant disorder or another disorder or syndrome described herein) has occurred following administration of a formulation.
• An “effective amount,” “effective dose,” or “therapeutic blood plasma concentration” is understood to be an amount, dose, or concentration not critically harmful to the subject and, in any case, where any harmful side effects are outweighed by benefits.
• an effective amount or dose of an abiraterone decanoate formulation means an amount capable of attaining blood plasma concentrations of at least 1 ng/ml, e.g., at least 1 ng/ml, at least 2 ng/ml, at least 4 ng/ml, or at least 8 ng/ml, of abiraterone in the subject following oral administration of the pharmaceutical composition herein, and the efficacious blood plasma concentrations are attained for 12 hours or more, preferably, 24 hours or more following administration.
• the dosage ranges for administration of the formulation according to the present disclosure are those that produce the desired effects).
• the useful dosage to be administered will vary depending on the age, weight, and health of the subject treated, the mode, route, and schedule of administration, the response of the individual subject, and the type or staging of prostate cancer (or severity of a sex hormone-dependent benign or malignant disorder or another symdrome or disorder described herein) against which treatment with the formulation is sought.
• the dosage will also vary with the nature or the severity of the primary tumor and other underlying conditions, with epidemiologic conditions, with the concomitant use of other active compounds, and the route of administration.
• the dosage will be determined by the existence of any adverse side effects such as local hypersensitivity, systemic adverse effects, and immune tolerance.
• an effective dose of the formulations (and other agent(s)) can be determined without undue experimentation (for example, by pharmacokinetic studies) by a person skilled in the art after consideration of all criteria and use of best judgment on the patient’s behalf (and will most often be contingent upon the particular formulation utilized).
• the dosage to be administered will depend upon the particular case, but in any event, it is the amount sufficient to induce clinical benefit against, or improvement of, a sex hormone-dependent benign or malignant disorder (such as prostate cancer), an androgen receptor driven cancer, a syndrome due to androgen excess, and/or a syndrome due to glucocorticoid excess such as hypercortisolemia.
• the formulations and agents of the embodiments can, optionally, be administered in combination with (or can include) one or more pharmaceutically acceptable carriers, diluents, or excipients.
• pharmaceutically acceptable carriers, diluents, or excipients are known in the art and are described, for example, in “Remington: The Science and Practice of Pharmacy” (formerly “Remington’s Pharmaceutical Sciences,” University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia, Pa. (2005)), the disclosure of which is hereby incorporated by reference.
• Headings and subheadings are used for convenience and/or formal compliance only, do not limit the subject technology, and are not referred to in connection with the interpretation of the description of the subject technology.
• Features described under one heading or one subheading of the subject disclosure may be combined, in various embodiments, with features described under other headings or subheadings. Further it is not necessarily the case that all features under a single heading or a single subheading are used together in embodiments.
• the term “about” modifying an amount related to the disclosure refers to variation in the numerical quantity that can occur, for example, through routine testing and handling; through error in such testing and handling; through differences in the manufacture, source, or purity of ingredients/materials employed in the disclosure; and the like.
• “about” a specific value also includes the specific value, for example, about 10% includes 10%. Whether or not modified by the term “about”, the claims include equivalents of the recited quantities. In one embodiment, the term “about” means within 25% of the reported numerical value.
• variable moiety herein may be the same or different as another specific embodiment having the same identifier.
• alkyl refers to a straight- or branched-chain saturated aliphatic hydrocarbon.
• the alkyl can include one to thirty carbon atoms (i.e., C 1-30 alkyl or alternatively expressed as C 1 -C 30 alkyl) or the number of carbon atoms designated (i.e., a C 1 alkyl such as methyl, a C 2 alkyl such as ethyl, a C 3 alkyl such as propyl or isopropyl, etc.).
• the alkyl group is a straight chain C 1-16 alkyl group.
• the alkyl group is a branched chain C 3-16 alkyl group.
• the alkyl group is a branched chain C 3-16 alkyl group.
• C 7-16 herein encompasses, C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 7-16 , C 7-15 , C 7-14 , C 1-13 , C 7-12 , C 7-11 , C 7-10 , C 7-9 , C 7-8 , C 8-16 , C 8-15 , C 8-14 , C8-13 , 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
• cycloalkyl refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms (i.e., C 3-12 cycloalkyl) or the number of carbons designated.
• the cycloalkyl group has two rings.
• the cycloalkyl group has one ring.
• the cycloalkyl group is a C 3-8 cycloalkyl group.
• the cycloalkyl group is a C 3- 6 cycloalkyl group.
• Cycloalkyl also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system.
• Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbomyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl.
• alkenyl as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one or more (e.g., 1, 2, or 3) carbon-to-carbon double bonds. In one embodiment, the alkenyl group is a C 2-16 alkenyl group.
• alkynyl as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one or more (e.g., 1, 2, or 3) carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is a C 2-16 alkynyl group.
• abiraterone prodrug(s) includes any of the compounds described herein according to Formula I or II, a lipophilic ester of abiraterone, isotopically labeled compound(s) thereof (e.g., deuterium enriched compounds), possible stereoisomers thereof (including diastereoisomers, enantiomers, and racemic mixtures), tautomers thereof, conformational isomers thereof, and/or pharmaceutically acceptable salts thereof (e.g., acid addition salt such as HC1 salt). Hydrates and solvates of the prodrugs are considered compositions of the present disclosure, wherein the prodrug(s) is in association with water or solvent, respectively.
• prodrugs can also exist in various polymorphic forms or amorphous forms.
• the abiraterone prodrugs described herein also include those compounds that readily undergo chemical changes under physiological conditions to provide active abiraterone. Additionally, prodrugs can be converted by chemical or biochemical methods in an ex vivo environment. In any of the embodiments described herein, unless otherwise specified or contrary from context, the abiraterone prodrug can be abiraterone decanoate.
• the abiraterone prodrugs described herein can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature.
• Isotopes can be radioactive or non- radioactive isotopes.
• Isotopes of atoms such as hydrogen, carbon, oxygen, and nitrogen, include, but are not limited to 2 H, 3 H, 13 C, 14 C, 15 N, and 18 O. Compounds that contain other isotopes of these and/or other atoms are within the scope of this disclosure.
• the abiraterone decanoate obtained in this example was determined to have a purity of 99.7% by weight using a HPLC method.
• HPLC analysis abiraterone decanoate samples were prepared in methanol at a concentration of 0.05 mg/mL (for assay analysis) or 5 mg/mL (for impurity analysis).
• HPLC conditions are the following: HPLC column: Halo C8 (2.7 um, 100 x 3.0 mm); injection volume: 5 uL; 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: starting with 65/35 MPA/MPB, in 35 minutes, reaching to 100% MPB, hold at 100% MPB until 40 minutes, at 40.10 minute, back to 65/35 MPA/MPB, and hold at 65/35 MPA/MPB until end at 45 minutes.
• HPLC column Halo C8 (2.7 um, 100 x 3.0 mm)
• injection volume 5 uL
• Column Temperature 40°C
• Sample Temperature ambient
• Detection 210 nm
• Mobile Phase 25 mM Ammonium Acetate, pH 8.0 (MPA
• the white solid obtained in this example was also characterized by X-Ray Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC).
• XRPD was conducted with Broker’s D8 Discover X-ray diffractometer, with Theta ⁇ theta vertical goniometer, using Vantec- 500 as detector. Standard conditions: voltage 40kV, current 40 mA, radiation, Cu, temperature, ambient, X-ray source exit slit size, 0.5 mm pinhole, snout collimator, 0.5 mm, sample holder, ground quartz plate.
• thermogravimetric analysis was also performed on this sample.
• TGA was performed with TA Instruments TGA Q500 (Thermal Advantage V5.2.5 - qualified), with a sample size of 5-20 mg, heating range from 25°C to 150°C at a heating rate of 10 °C/min.
• a representative TGA trace is shown in FIG. 2C.
• This example shows a process of purifying abiraterone decanoate to remove residue palladium.
• Abiraterone decanoate used for this Example was prepared using similar procedures as shown in Example 1 A.
• Ethylprasterone Decanoate may be an impurity, which is believed to have the following structure:
• Separation is performed with an Advanced Materials Technology Halo C8 reversed phase column using dimensions of 3.0 x 100 mm and a particle size of 2.7 ⁇ m.
• a linear gradient program (20 minutes) is used with mobile phases consisting of a 25 mM aqueous ammonium acetate buffer and a mixture of methanol and acetonitrile (see gradient profile below in Table 2).
• Working standard and sample solutions are prepared in a methanol diluent.
• the typical injection volume is 5 ⁇ L and the detection wavelength is 210 nm.
• the crude abiraterone decanoate contained 130 ppm Pd. Recrystalization from just acetone/water lowered the Pd level to 120 ppm. However, by using the process described in this example, the final abiraterone decanoate can be purified to have a Pd content of only 3.7 ppm.
• EXAMPLE 1C POLYMORPH SCREENING OF ABIRATERONE DECANOATE
• a polymorph screening study was also carried out for abiraterone decanoate.
• Form A As shown in Example 1 A, two other polymorphs of abiraterone decanoate were identified, namely Form B and Form C.
• Non-competitive slurry experiments The non-competitive slurry experiments were performed by exposing abiraterone decanoate in Form A to solvents and agitating the resulting suspensions for one week at ambient temperature. The solids were filtered and analyzed by XRD to determine the resulting form(s).
• the solvents used in this study include: water, acetonitrile, isopropyl ether/acetonitrile (1:4), 2-butanol/water (1:1), 1-propanol/water (1:1), t-butanol/water (1:1), ethanol/water (1:1), THF/water (1:1), acetone/water (1:1), dioxane/water (1:1), 2- butanone/water (1:1), methanol, DMF/water (1:1), ethyl acetate/water (1:1), and heptane. Based on their X-ray scattering behavior, all of the non-competitive slurry experiments resulted in no change from the starting material.
• each form was studied to determine if other properties of the forms could be differentiated.
• the characterization of each form began by comparing the diffraction data representative of each form with that from the other forms. This was generally followed by NMR, DSC, and TGA.
• the initial material used in this study was Form A, which is consistent with the representative characterization data shown in Example 1 A, see also summary table E7 below.
• Form B was obtained in a variety of crystallization experiments, particularly those carried out at low temperature (-10 to -20 °C). The characteristic diffraction behavior of this form is shown in a representative XRPD spectrum, FIG. 2D.
• the 1 H NMR spectrum of Form B shows no organic impurities and is consistent with the expected structure of ADEC.
• Representative DSC and TGA spectra of Form B are shown in FIGs. 2E and 2F.
• Form C was obtained by evaporation from a 1:1 mixture of ethanol and 2-butanone.
• the characteristic diffraction behavior of this form is shown in a representative XRPD spectrum, FIG. 2G. It should be noted that the diffractogram obtained for the one “pure” Form C sample shows significant overlap with Form A at higher diffraction angles and therefore may contain some Form A.
• the 1 H NMR spectrum of Form C shows no organic impurities and is consistent with the expected structure of ADEC. Representative DSC and TGA spectra of Form C are shown in FIGs. 2H and 21.
• Table E7 summarizes representative analysis of abiraterone decanoate Forms A, B, and C.
• solubility of abiraterone decanoate in the following four vehicles were tested.
• Each vehicle has a distinctive base, namely, medium chain trigylceride (MCT)/polyoxylglyceride, long chain (LC) monodiglyceride, and two propylene glycol (PG) monoesters, caprylic and lauryl.
• MCT medium chain trigylceride
• LC long chain
• PG propylene glycol
• Vehicle 1 MCT/Polyoxylglyceride based: 20% Kolliphor RH40/14% Plurol Oleique CC 497/33% Labrafil 1944 CS/33% Labrafac Lipophile WL 1349
• Vehicle 2 PG Monoester based: 20%Kolliphor RH 40/14% Plurol Oleique CC 497/66% Lauroglycol 90
• Vehicle 3 PG Monoester based: 20% Kolliphor RH40/14% Plurol Oleique CC 497/66% Capmul PG-8
• Vehicle 4 LC Monodiglyceride based: 20% Kolliphor RH40/14% Plurol Oleique CC 497/66% Maisine CC
• the vehicles being tested have the following compositions:
• Vehicle 1 (see Example 2): 20% Kolliphor RH40/14% Plurol Oleique CC 497/33% Labrafil 1944 CS/33% Labrafac Lipophile WL 1349, used as a control.
• Vehicle 5 20% Kolliphor RH40/14% Plurol Oleique CC 497/33% Maisine CC/33%
• Vehicle 6 20% Kolliphor RH40/14% Plurol Oleique CC 497/16% Labrafil 1944
• Vehicle 7 20% Kolliphor RH40/14% Plurol Oleique CC 497/16% Labrafil 1944
• Vehicle 8 20% Kolliphor RH40/14% Plurol Oleique CC 497/16% Labrafil 1944 CS/30%
• Vehicle 9 20% Kolliphor RH40/14% Plurol Oleique CC 497/16% Labrafil 1944 CS/30% Labrafil M 2130 CS/20% Labrafac Lipophile WL 1349
• This example tests dispersibility of abiraterone decanoate formulations in different vehicles.
• the formulations were prepared using Vehicles 1-4 (shown in Example 2) and Vehicle 9 (Capmul PG-8).
• This example tests further abiraterone decanoate formulations in different vehicles.
• the formulations were prepared using Vehicles 1 (Example 2) and 5-8 (shown in Example 3).
• the objective of this study is to evaluate the relative absorption of two different oral formulations of abiraterone decanoate over 72 hours after a single oral gavage dose to male rats.
• This Example also determines the plasma pharmacokinetics of abiraterone and abiraterone decanoate, serum concentrations of luteinizing hormone and serum concentrations of the steroids androstenedione, corticosterone, progesterone and testosterone in the rat following a single oral administration of abiraterone decanoate to 2 groups of CD ® [Crl:CD ® (SD)] rats (Group 2, Formulation 1 at 100 mg/kg; Group 3, Formulation 2 at 100 mg/kg). An additional group of animals (Group 1) received the vehicle for formulation 2 and acted as control. In addition tissues were collected from all animals at 72 h post dose and the concentration of abiraterone and abiraterone decanoate determined.
• test material The details of the test material are the following:
• Abiraterone decanoate Formulation 1 40 mg abiraterone decanoate/mL in Vehicle 1: 20% Kolliphor RH40/14% Plurol Oleique CC497/33% Labrafil 1944CS/33% Labrafac Lipophile WL1349.
• Abiraterone decanoate Formulation 2 40 mg abiraterone decanoate/mL in Vehicle 2: 20% Kolliphor RH40/14% Plurol Oleique CC497/66% Lauroglycol 90.
• Control Article is Vehicle 2: 20% Kolliphor RH40/14% Plurol Oleique CC497/66% Lauroglycol 90.
• Plasma and serum samples were collected at 0 min, 1 h, 2 h, 4 h, 24 h, 48 h and 72 h (terminal) postdose for pharmacokinetic or steroid analysis.
• the pharmacokinetic parameters derived from the plasma concentrations of abiraterone and abiraterone decanoate are shown in Tables 3 and 4 and the plasma profile shown in FIG. 3.
• the effects of oral administration of formulations 1 and 2 on steroid concentrations in plasma are shown graphically in FIGs. 4A, 4B, 5A, 5B, 6A, 6B, 7 A, and 7B.
• the mean plasma concentrations of luteinizing hormone are shown graphically in FIG. 8.
• the mean and individual tissue concentrations of abiraterone and abiraterone decanoate are shown in Table 5 and Table 6 and shown graphically in FIG. 9.
• Table 5 Tissue concentrations of abiraterone following oral administration of abiraterone decanoate in 2 different formulations
• Table 6 Tissue concentrations of abiraterone decanoate following oral K adiimiiTiTniRisjtration of abiraterone decanoate in 2
• the C max for abiraterone decanoate was 54.4 ng/mL, TTM, was at 1 to 4 h and the AUC last was 151 ng.h/mL.
• the C max of abiraterone decanoate was 2.96 ng/mL, T max was between 1 to 4 h and the AUC last was 25.5 ng.h/mL. From this, the relative exposure of abiraterone decanoate from an oral dose of Formulation 1 was 18.3-fold and 5.92-fold higher for C max and AUC last , respectively than for Formulation 2.
• abiraterone was detected in all tissues except for femur with levels tending to be relatively low, with the highest concentration in liver (63.6 ng/g) and mesenteric lymph node (31.0 ng/g).
• concentrations of abiraterone were lower or BLQ in all tissues, with the highest concentrations in liver (19.7 ng/g) and mesenteric lymph node (14.2 ng/g), consistent with the results for Formulation 1.

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