Abiraterone prodrug

Abstract

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

Description

[Technical Field]

[0001] This disclosure generally relates to novel prodrugs of abiraterone and long-acting depot-based parenteral formulations of abiraterone prodrugs. This disclosure is intended for a wide range of uses, including intramuscular (IM) injection into patients with androgen or estrogen-dependent benign or malignant diseases, including various cancers (such as prostate cancer, bladder cancer, hepatocellular carcinoma, lung cancer, breast cancer, and ovarian cancer), and for the treatment of non-neoplastic syndromes resulting from androgen overproduction (including classical and non-classical congenital adrenal hyperplasia, endometriosis, polycystic ovary syndrome with precocious puberty, hirsutism, etc.), or conditions such as Cushing's syndrome or Cushing's disease resulting from glucocorticoid, typically cortisol overproduction. [Background technology]

[0002] Abiraterone ((3β)-17-(pyridine-3-yl)androsta-5,16-dien-3-ol; CAS number 154229-19-3); Chemical formula: C 24 H 31NO (molar mass: 349.5 g / mol) is an inhibitor of CYP17A1 (a member of the cytochrome P450 superfamily of enzymes that catalyze the synthesis of cholesterol, steroids, and other lipids and are involved in drug metabolism). CYP17A1 possesses both 17α-hydroxylase activity and 17,20-lyase activity. Abiraterone potently and selectively inhibits both CYP17A1 17α-hydroxylase and 17,20-lyase enzyme activity. The 17α-hydroxylase activity of CYP17A1 is required for the production of glucocorticoids such as cortisol. However, both the hydroxylase and 17,20-lyase activities of CYP17A1 are necessary for the production of androgenic steroids (e.g., androstenedione, testosterone, and dihydrotestosterone) and estrogen steroids (estrone, estradiol, and estriol) through the conversion of 17α-hydroxypregnenolone to the sex steroid precursor, dehydroepiandrosterone (see Figure 14D). Therefore, abiraterone inhibits the synthesis of androgens and estrogens in the gonads (mainly the testes and ovaries) and extragonads (adrenal glands and their tumors).

[0003] Although abiraterone itself is poorly absorbed, it can be administered orally as an abiraterone acetate prodrug. While abiraterone acetate is also poorly absorbed, it can be converted to abiraterone in the intestines, which reduces its absorption into the bloodstream after cleavage of the acetate prodrug. Abiraterone acetate ((3β)-17-(3-pyridyl)androsta-5, acetate; CAS number 154229-18-2) is approved in the United States under the trademark Zytiga® for the treatment of castration-resistant or castration-sensitive prostate cancer. Abiraterone acetate is currently available worldwide.

[0004] Orally administered abiraterone acetate is known not to be absorbed in the gastrointestinal tract (and not detected in plasma). Instead, it has been shown that abiraterone acetate is hydrolyzed in the lumen environment to abiraterone, resulting in abiraterone supersaturation, which plays a role in generating a strong propulsion for abiraterone absorption (Stappaerts et al., Eur.J.Pharmaceutics Biopharmaceutics 90:1, 2015).

[0005] Because abiraterone interferes with the normal physiological production of steroids by the adrenal glands, its prodrug formulations are generally prescribed with low-dose steroids to prevent adrenal insufficiency. In fact, Zytiga® tablets (250 mg) are approved in the United States in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer. The prescribing information for Zytiga® recommends a daily oral dose of 1000 mg (4 x 250 mg tablets) in combination with oral prednisone (5 mg) twice daily for patients with castration-resistant prostate cancer, or once daily for patients with castration-sensitive prostate cancer. In Europe, the use of Zytiga® is approved in combination with either prednisone or prednisolone.

[0006] Administering abiraterone acetate with food increases its absorption (and therefore can lead to increased exposure and greater variability in exposure, potentially causing various side effects such as cardiovascular and / or hepatotoxicity); therefore, prodrugs should be taken on an empty stomach at least one hour or two hours before a meal. In fact, the prescribing information for Zytiga® states that it must be taken on an empty stomach and that no food should be consumed at least two hours before oral administration and at least one hour after oral administration.

[0007] The prescribing information states that for daily oral administration of 1,000 mg of Zytiga® to patients with metastatic castration-resistant prostate cancer, the steady-state C of abiraterone is max The value was described as 226 ± 178 ng / mL (mean ± standard deviation), and the area under the curve (AUC) value was 1173 ± 690 ng·hr / mL (mean ± standard deviation). A single-dose (1,000 mg) crossover study of healthy subjects with Zytiga® confirmed that systemic exposure to abiraterone increased when Zytiga® was administered with food. Specifically, abiraterone C max The values ​​and AUC values ​​were approximately 7 times and 5 times higher, respectively, when Zytiga® was administered with a low-fat diet (7% fat, 300 calories), and approximately 17 times and 10 times higher, respectively, when Zytiga® was administered with a high-fat diet (57% fat, 825 calories).

[0008] The currently approved oral solid dosage form of the prodrug abiraterone acetate has several drawbacks. For example, its bioavailability is very low, forcing patients to take a large daily dose (4 x 250 mg tablets once daily). In addition, the combination of low bioavailability and high susceptibility to food intake results in significant variability in blood levels among patients. Furthermore, because abiraterone is rapidly excreted, the approved dosage and administration are based on a daily dose of C min This is associated with abiraterone, which is thought to be linked to the loss of therapeutic effect in patients with metastatic castration-resistant prostate cancer.

[0009] Parenteral administration (e.g., via parenteral routes) has been investigated for other drug classifications. However, to date, there is no sustained-release injectable prodrug formulation of abiraterone. [Overview of the prefecture]

[0010] In various embodiments, this disclosure provides novel abiraterone prodrugs, long-acting abiraterone prodrug formulations, and methods of using such agents in the treatment of patients with, for example, sex hormone-dependent benign or malignant diseases and / or syndromes resulting from androgen and / or glucocorticoid excess. Certain aspects of this disclosure claim the benefit of U.S. Patent Application No. 16 / 808,912 filed March 4, 2020, U.S. Provisional Patent Application No. 62 / 814,568 filed March 6, 2019, and U.S. Provisional Patent Application No. 62 / 849,259 filed May 17, 2019, the entire contents of which are incorporated herein by reference.

[0011] Typically, the novel abiraterone prodrugs described herein may be fatty acid esters of abiraterone, which release abiraterone and a safe and biodegradable fatty acid component upon cleavage. As detailed herein, compared to oral abiraterone acetate formulations, the novel abiraterone prodrugs and formulations disclosed herein offer improved bioavailability, elimination of food influence, reduced burden on administration, decreased frequency of administration, and sustained effective plasma levels of abiraterone, for example, the daily C12C levels observed with oral administration of abiraterone acetate. min This is groundbreaking in that it provides a level of continuous plasma exposure exceeding that of other formulations, for example, at least one week, typically at least two weeks, and up to 10 weeks or more, after administration of an abiraterone prodrug formulation. Furthermore, pharmacokinetic and pharmacodynamic studies of representative abiraterone prodrugs as described herein, such as abiraterone decanoate or abiraterone isocaproate, demonstrate that the novel abiraterone prodrugs and formulations disclosed herein for the treatment of patients with sex hormone-dependent benign or malignant diseases, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess are suitable for administration at weekly, monthly, every two months, every three months, or even less frequently. This characteristic represents a very significant improvement over currently marketed Zytiga® tablets, which require a large daily dosage burden on the patient (one 4 x 250 mg tablet daily).

[0012] Some embodiments of this disclosure aim to provide novel abiraterone prodrugs. In some embodiments, the abiraterone prodrug is a compound of formula I or a pharmaceutically acceptable salt thereof. [ka] R in the formula 1 The terms are defined herein. In some embodiments, the compound of formula I may be in a substantially pure form.

[0013] In one representative embodiment, an abiraterone prodrug formulation for parenteral administration to patients having sex hormone-dependent benign or malignant diseases, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid (e.g., cortisol) excess is provided. In one embodiment, the formulation comprises a lipophilic ester form of abiraterone and one or more pharmaceutically acceptable carriers, diluents, or excipients (for example, such that the prodrug formulation exists as a solution or suspension of a pharmaceutically acceptable oil, such as a synthetic oil containing plant-derived oils or synthetic monoglycerides or diglycerides of fatty acids; for example, such that the prodrug formulation exists as a solution or suspension of a vegetable oil and other cosolvents and excipients). In certain representative embodiments, the lipophilic ester form of abiraterone may be an acetate, propionic acid, butanoic acid, valeric acid, caproic acid, enanthic acid, cypionic acid, isocaproic acid, buciclate, cyclohexanecarboxylic acid, phenylpropionic acid, decanoic acid, or undecanoic acid. In some embodiments, the abiraterone prodrug formulation may contain a compound of formula II or a pharmaceutically acceptable salt thereof. [ka] R in the formula 2The terms are defined herein. In some embodiments, the compound of formula II may be in a substantially pure form. In some embodiments, the abiraterone prodrug formulation can be formulated for intramuscular, intradermal, or subcutaneous injection. In some embodiments, the compound of formula II or a pharmaceutically acceptable salt thereof may be present in the formulation at concentrations of about 25 mg / ml to about 500 mg / ml.

[0014] Typically, upon administration of the formulation (e.g., the abiraterone prodrug formulation described herein), a therapeutic plasma concentration of abiraterone is achieved and persists for at least one week, e.g., at least two weeks, and up to four weeks or more, e.g., up to ten weeks or more. In one embodiment, the therapeutic plasma concentration of abiraterone after parenteral administration of the prodrug formulation is at least 1 ng / ml, e.g., at least 1 ng / ml, at least 2 ng / ml, at least 4 ng / ml, or at least 8 ng / ml. In some embodiments, the therapeutic plasma concentration of abiraterone may be about 0.5 ng / ml or more. Parenteral administration may be via IM injection, intradermal injection, or subcutaneous injection. In one embodiment, the formulation is suitable for the treatment of sex hormone-dependent benign or malignant diseases such as androgen-dependent cancers and estrogen-dependent diseases. Examples of sex hormone-dependent benign or malignant diseases include prostate cancer and breast cancer. Examples of prostate cancer include castration-resistant prostate cancer and castration-sensitive prostate cancer. In some embodiments, sex hormone-dependent benign or malignant diseases include various cancers such as ovarian cancer, bladder cancer, hepatocellular carcinoma, and lung cancer. Inhibition of CYP17A1 is expected to reduce the overproduction of androgens and glucocorticoids (e.g., cortisol). The abiraterone prodrug formulations herein are not limited to the treatment of neoplastic conditions described herein, but may also be used to treat non-neoplastic syndromes caused by excess androgens and glucocorticoids (e.g., cortisol). In one embodiment, the formulations are suitable for the treatment of non-neoplastic syndromes caused by excess androgens, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), precocious puberty, and hirsutism, and / or syndromes caused by excess glucocorticoids (e.g., cortisol), such as Cushing's syndrome or Cushing's disease.

[0015] Parenteral formulations address long-unmet needs by providing an alternative to oral formulations that suffer from (1) low bioavailability, (2) interactions with ingested food, (3) delivery of unchanged drugs with significantly variable blood levels that may reduce efficacy and increase side effects, (4) the need for daily administration and high burden of taking medication, and (5) reduced patient adherence due to the need for daily administration of supplemental prednisone or prednisolone taken with meals due to food abstinence within hours of administration, high burden of taking medication, and conflicting administration schedules.

[0016] One object of this disclosure is to provide a method for inhibiting CYP17A1 activity, such as inhibiting 17α-hydroxylase activity and 17,20-lyase activity by parenterally administering at least one effective dose of abiraterone prodrug formulation to a patient in need. In some embodiments, the patient suffers from a sex hormone-dependent benign or malignant disease as described herein, a syndrome caused by androgen excess, and / or a syndrome caused by glucocorticoid excess, such as hypercortisolemia.

[0017] One object of this disclosure is to provide a method for reducing glucocorticoid (e.g., cortisol) levels by parenterally administering at least one effective dose of abiraterone prodrug formulation to a patient in need. In some embodiments, the patient suffers from a syndrome resulting from glucocorticoid excess, such as hypercortisolemia as described herein. In some embodiments, the patient suffers from Cushing's syndrome or Cushing's disease.

[0018] One object of this disclosure is to provide a method for reducing androgen (e.g., testosterone and / or dihydrotestosterone) and / or estrogen levels by parenterally administering at least one effective dose of an abiraterone prodrug formulation to a patient in need. In some embodiments, the patient suffers from a syndrome resulting from androgen excess, such as classical or non-classical congenital adrenal hyperplasia, endometriosis, polycystic ovary syndrome, precocious puberty, or hirsutism. In some embodiments, the patient suffers from an androgen and / or estrogen-related cancer, such as prostate cancer or breast cancer.

[0019] Another objective is to provide a method for treating sex hormone-dependent benign or malignant diseases, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia, by parenterally administering at least one abiraterone prodrug formulation in an effective dose to patients requiring such treatment. In one representative embodiment, the method is for treating sex hormone-dependent benign or malignant diseases such as androgen-dependent cancer or estrogen-dependent cancer, or estrogen-dependent diseases. Examples of sex hormone-dependent benign or malignant diseases include prostate cancer or breast cancer. Examples of prostate cancer include castration-resistant prostate cancer and castration-sensitive prostate cancer. In some embodiments, examples of sex hormone-dependent benign or malignant diseases include ovarian cancer, bladder cancer, hepatocellular carcinoma, lung cancer, and the like. In one representative embodiment, the method is for treating non-neoplastic syndromes resulting from androgen excess, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), precocious puberty, hirsutism, and / or syndromes resulting from glucocorticoid (e.g., cortisol) excess, such as Cushing's syndrome or Cushing's disease.

[0020] In some embodiments, the abiraterone prodrug formulation may include at least one compound of formula I or II or a pharmaceutically acceptable salt thereof, for example, a substantially pure basic form of the compound of formula I or II. In one embodiment, the formulation comprises a lipophilic ester form of abiraterone and one or more pharmaceutically acceptable carriers, diluents, or excipients. In certain representative embodiments, the lipophilic ester form of abiraterone may be, for example, an acetate, propionate, butanoate, valerate, caproate, enanthate, cypionate, isocaproate, bucicrate, cyclohexanecarboxylic acid, phenylpropionate, decanoate, or undecanoate. Upon administration of the formulation to a patient requiring it, a therapeutic plasma concentration of abiraterone is achieved and lasts for at least one week, e.g., at least two weeks, and up to four weeks or more, e.g., ten weeks or more. In one embodiment, the therapeutic plasma concentration of abiraterone after parenteral administration of the prodrug formulation is at least 1 ng / ml, e.g., at least 1 ng / ml, at least 2 ng / ml, at least 4 ng / ml, or at least 8 ng / ml. In some embodiments, the therapeutic plasma concentration of abiraterone may be about 0.5 ng / ml or greater. Parenteral administration may be via IM injection, intradermal injection, or subcutaneous injection. In certain embodiments, the method may include monthly administration of at least one abiraterone prodrug formulation. In certain embodiments, the method may include administration of at least one abiraterone prodrug formulation at a frequency ranging from once a month to once every few months, e.g., once every two months or once every three months. In one embodiment, at least one abiraterone prodrug formulation may be administered in divided doses. In another representative embodiment, at least one abiraterone prodrug formulation may be administered concurrently with one or more different prodrug formulations and / or at least one other drug or agent (e.g., another cancer chemotherapy agent, hormone replacement agent, or hormone removal agent). In certain embodiments, at least one abiraterone prodrug formulation may be administered before at least one other drug or agent.Alternatively, at least one abiraterone prodrug formulation may be administered after at least one other drug or agent. In other representative embodiments, two or more administrations of one or more formulations may be performed over several days, weeks, months, or years to provide initial and continuous treatment for sex hormone-dependent benign or malignant diseases (e.g., prostate cancer), syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia. In other representative embodiments, at least one abiraterone prodrug formulation may contain at least two different lipophilic ester forms of abiraterone, and the formulation may be administered concurrently with one or more different prodrug formulations and / or at least one other drug or agent (e.g., another cancer chemotherapy agent, hormone replacement, or hormone removal agent). In certain embodiments, at least one abiraterone prodrug formulation may contain at least two different lipophilic ester forms of abiraterone, and the formulation may be administered before at least one other drug or agent. Alternatively, at least one abiraterone prodrug formulation may contain at least two different lipophilic ester forms of abiraterone, and the formulation may be administered after at least one other drug or agent. In other representative embodiments, two or more administrations of one or more formulations containing at least two different lipophilic ester forms of abiraterone may be performed over several days, weeks, months, or years to provide initial and continuous treatment for sex hormone-dependent benign or malignant diseases (e.g., prostate cancer), syndromes caused by excess androgen, and / or syndromes caused by excess glucocorticoids such as hypercortisolemia. The lipophilic ester forms of abiraterone may be selected from, for example, acetate, propionate, butanoate, valerate, caproate, enanthate, cypionate, isocaproate, bucicrate, cyclohexanecarboxylic acid, phenylpropionate, decanoate, or undecanoate.

[0021] Another objective is to provide a kit for treating patients with sex hormone-dependent benign or malignant diseases (e.g., prostate cancer), syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia. In a typical embodiment, the kit includes a container such as a vial, ampoule, or pre-equipped syringe containing one or more formulations. In another typical embodiment, the kit includes a container such as a vial, ampoule, or pre-equipped syringe containing one or more formulations and at least one other drug or agent that can enhance the efficacy of the formulation(s) or reduce the undesirable side effects(s) of the formulation(s). In yet another typical embodiment, the kit includes a container such as a vial, ampoule, or pre-equipped syringe containing one or more formulations and at least one other drug or agent that can enhance the efficacy of the formulation(s) or reduce the undesirable side effects(s) of the formulation(s). It is understood that the formulations may contain one lipophilic ester form of abiraterone or two or more different lipophilic ester forms of abiraterone. Those skilled in the art will understand that kits and packages may be prepared comprising a formulation, diluent, buffer, adjuvant, pharmaceutically acceptable carrier, and at least one other drug or agent, all of them, or any combination thereof, which can enhance the efficacy of the formulation or reduce undesirable side effects of the formulation.

[0022] Another objective is to provide a method for preparing abiraterone decanoate formulations suitable for parenteral administration to patients with sex hormone-dependent benign or malignant diseases, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia.

[0023] These and other objectives can be achieved in certain embodiments.

[0024] Embodiments of this disclosure can meet long-standing needs in the field of sex hormone-dependent diseases and oncology, including the treatment of prostate cancer. Embodiments of this disclosure can also meet long-standing needs in the field of treatment for syndromes caused by androgen excess and / or syndromes caused by glucocorticoid excess, such as hypercortisolemia. Embodiments of this disclosure can overcome the major shortcomings and deficiencies of prior art formulations of abiraterone acetate (including commercially available oral formulations) by providing a long-acting, sustained-release depot-based parenteral formulation of abiraterone prodrug, a method for manufacturing the same, a therapeutic method using the same, and a kit for convenient administration of the formulation to patients requiring treatment of various diseases, including prostate cancer.

[0025] To provide a better understanding of the details described below, and to provide a better understanding of this contribution to the relevant technical field, the features have been outlined in a broader sense. Naturally, additional features will be described further below. In fact, both the general description above and the detailed description below should be understood as illustrative and explanatory, and intended to provide further explanation of this disclosure.

[0026] In this regard, before describing at least one embodiment in detail, it should be understood that the present invention is not limited in its application to the configuration details and configuration arrangements described in the following description or shown in the following drawings. Other embodiments of the present invention are possible and can be carried out or performed in various ways. Furthermore, it should be understood that the expressions and terms used herein are for illustrative purposes only and should not be considered limiting.

[0027] Accordingly, those skilled in the art will understand that the underlying concepts of this disclosure can be readily used as a basis for designing other formulations, methods, systems, kits, and compositions to accomplish some of the purposes of this disclosure. Therefore, it is important that equivalent structures, within the scope of this disclosure and without departing from the spirit and scope of this disclosure, be included.

[0028] The accompanying drawings are included to provide a further understanding, are incorporated into and constitute part of the present invention, illustrate several embodiments, and are provided together with the description to illustrate the principles thereof. [Brief explanation of the drawing]

[0029] [Figure 1] This figure shows the mean plasma concentrations (ng / ml) of abiraterone in rats at different time intervals after IM administration of various abiraterone or abiraterone acetate preparations. Figure 1 shows the profiles obtained with castor oil solution of abiraterone acetate (70 mg / ml), abiraterone acetate in sodium phosphate buffer, 0.1% Tween suspension (70 mg / ml), abiraterone in castor oil suspension (62.5 mg / ml), and abiraterone in sodium phosphate buffer, 0.1% Tween suspension (62.5 mg / ml). [Figure 2] Figure 2 shows the mean plasma concentrations (ng / ml) of abiraterone in dogs at different time intervals after administration of various abiraterone acetate preparations via intravenous injection (IM) or intravenous (IV). Figure 2 shows the profiles obtained after IV administration of abiraterone acetate solution (33% HP-β-cyclodextrin aqueous solution) at a dose of 10 mg / kg, the profile obtained after IM administration of abiraterone acetate castor oil solution (66 mg / ml) at a dose of 21 mg / kg, the profile obtained after IM administration of abiraterone acetate castor oil solution containing 10% benzyl alcohol (91 mg / ml) at a dose of 30 mg / kg, and the profile obtained after IM administration of abiraterone acetate castor oil solution containing 50% benzyl benzoate (124 mg / ml) at a dose of 42 mg / kg. [Figure 3] The mean plasma concentrations (ng / ml) of abiraterone (upper line) and abiraterone acetate (lower line) in dogs at different time intervals after intravenous administration of abiraterone acetate (administered as a solution of 33% HP-β-cyclodextrin aqueous solution at a dose of 10.3 mg / ml). [Figure 4] The mean plasma concentrations (ng / ml) of abiraterone (upper line) and abiraterone acetate (lower line) in dogs over different periods (days) after administration of castor oil solution containing 10% benzyl alcohol of abiraterone acetate (91 mg / ml) at a dose of 30 mg / kg. [Figure 5] This graph shows the time course of mean plasma concentrations of abiraterone and abiraterone decanoate after intravenous administration of 1.2 mg / kg abiraterone decanoate to dogs. Error bars represent the standard deviation. [Figure 6] This graph shows the time course of mean plasma concentrations of abiraterone and abiraterone propionate after intravenous administration of 1 mg / kg abiraterone propionate to dogs. Error bars represent the standard deviation. [Figure 7] This graph shows the time course of mean plasma concentrations of abiraterone and abiraterone decanoate after administering 50 mg / kg of abiraterone decanoate (90% castor oil / 10% benzyl alcohol) to dogs using intramuscular immobilization (IM). Error bars represent the standard deviation. [Figure 8] This graph shows the time course of mean plasma concentrations of abiraterone and abiraterone decanoate after administering 50 mg / kg of abiraterone decanoate (90% corn oil / 10% benzyl alcohol) to dogs using intracellular immobilization (IM). Error bars represent the standard deviation. [Figure 9] This shows the time course of mean plasma concentrations of abiraterone and abiraterone propionate after administering IM (implant-mediated) abiraterone propionate at a dose of 41 mg / kg to dogs (90% castor oil / 10% benzyl alcohol). Error bars represent the standard deviation. [Figure 10] This shows the time course of mean plasma concentrations of abiraterone and abiraterone propionate after administering IM (implant-mediated) abiraterone (41 mg / kg) to dogs (90% corn oil / 10% benzyl alcohol). Error bars represent the standard deviation. [Figure 11A]This shows exemplary predicted human abiraterone plasma concentrations after intramuscular administration of abiraterone decanoate, based on computer modeling of humans using an input half-life assumed to be the same as that observed in dogs. The computer modeling predictions are shown after 120 mg of abiraterone decanoate administered via IM every two weeks. The horizontal line represents the target Cmin value of abiraterone at approximately 8 ng / ml. [Figure 11B] This shows exemplary predicted human abiraterone plasma concentrations after intramuscular administration of abiraterone decanoate, based on computer modeling of humans using an input half-life assumed to be the same as that observed in dogs. The computer modeling predictions are shown after IM administration of 350 mg of abiraterone decanoate every 4 weeks. The horizontal line represents the target Cmin value of abiraterone at approximately 8 ng / ml. [Figure 11C] This shows exemplary predicted human abiraterone plasma concentrations after intramuscular administration of abiraterone decanoate, based on computer modeling of humans using an input half-life assumed to be the same as that observed in dogs. The computer modeling predictions are shown after 1000 mg of abiraterone decanoate administered via IM every 6 weeks. The horizontal line represents the target Cmin value of abiraterone at approximately 8 ng / ml. [Figure 11D] This shows exemplary predicted human abiraterone plasma concentrations after intramuscular administration of abiraterone decanoate, based on computer modeling of humans using an input half-life assumed to be the same as that observed in dogs. It shows computer modeling predictions after 1700 mg of abiraterone decanoate administered via IM every two months. The horizontal line represents the target Cmin value of abiraterone at approximately 8 ng / ml. [Figure 12A] The typical X-ray powder diffraction (XRPD) spectrum of abiraterone decanoate solid prepared in Example 6A is shown. [Figure 12B] The differential scanning calorimetry (DSC) spectrum of abiraterone decanoate solid prepared in Example 6A is shown. [Figure 12C] The thermogravimetric analysis (TGA) of abiraterone decanoate solid prepared in Example 6A is shown. [Figure 13A] The solubility of aviraterone decanoate in corn oil in the presence of various amounts of benzyl alcohol and benzyl benzoate is plotted. [Figure 13B] Contour plots of the solubility of aviraterone decanoate in corn oil in the presence of various amounts of benzyl alcohol and benzyl benzoate are shown. [Figure 13C] This indicates the viscosity (Pa*s) of an oily solvent without additives, an oily solvent containing 10% benzyl alcohol, an oily solvent containing 20% ​​benzyl benzoate, or an oily solvent containing a combination of 10% benzyl alcohol and 20% benzyl benzoate. [Figure 13D] The glide force (N) is shown for oily solvents without additives, oily solvents containing 10% benzyl alcohol, oily solvents containing 20% ​​benzyl benzoate, or oily solvents containing a combination of 10% benzyl alcohol and 20% benzyl benzoate, tested with a 23-gauge needle in a 5 ml syringe. [Figure 13E] The glide force (N) is shown for oily solvents without additives, oily solvents containing 10% benzyl alcohol, oily solvents containing 20% ​​benzyl benzoate, or oily solvents containing a combination of 10% benzyl alcohol and 20% benzyl benzoate, tested using a 27-gauge needle with a 5 ml syringe. [Figure 14A] The following shows the time course of mean plasma concentrations of abiraterone and abiraterone decanoate after intravenous administration of 1.2 mg / kg abiraterone decanoate (0.4 mg / ml solution in 40% HP-β-cyclodextrin 25 mM sodium phosphate buffer (pH 7.4)) to male cynomolgus monkeys (n=3). [Figure 14B] This shows the time course of mean plasma concentrations of abiraterone and abiraterone decanoate after a single IM administration of abiraterone decanoate at a dose of 90 mg / kg to male cynomolgus monkeys (n=3) using an abiraterone decanoate preparation (90% corn oil, 10% benzyl alcohol, 192 mg / ml abiraterone decanoate). [Figure 14C]The time-course data of observed steroid levels (progesterone, cortisol, and testosterone levels) after this single IM administration are shown. As shown in Figure 14C, long-term CYP17A1 inhibition was achieved after a single IM injection, as evidenced by the maintenance of elevated progesterone levels and the decrease in glucocorticoid (cortisol) and sex hormone (testosterone) levels. [Figure 14D] This diagram illustrates the biochemical pathways that demonstrate the effects of CYP17A1 inhibition on the synthesis of androgens, estrogens, glucocorticoids, progesterone, and mineralocorticoids. As shown in Figure 14D, inhibition of CYP17A1 17α-hydroxylase and C17,20-lyase activity results in (1) an increase in progesterone and mineralocorticoid levels, (2) a decrease in glucocorticoid levels such as cortisol, and (3) a decrease in sex hormone levels, such as androgens including testosterone and dihydrotestosterone, and estrogens including estradiol. [Figure 14E] This shows the time course of mean plasma concentrations of abiraterone and abiraterone decanoate after repeated administration of an abiraterone decanoate preparation (90% corn oil, 10% benzyl alcohol, 192 mg / ml abiraterone decanoate) to male cynomolgus monkeys (n=3) via intracellular injection (IM) on days 0, 7, and 35. Each dose of abiraterone decanoate was 90 mg / kg. [Figure 14F] The following shows the time course of mean plasma abiraterone concentration after repeated administration of either abiraterone decanoate preparation 1 (90% corn oil, 10% benzyl alcohol, 207 mg / ml abiraterone decanoate) or preparation 2 (70% corn oil, 10% benzyl alcohol, 20% benzyl benzoate, 209 mg / ml abiraterone decanoate) to a male cynomolgus monkey (n=1) via intramuscular injection (IM) on days 0, 7, and 14. Each dose of abiraterone decanoate was 100 mg / kg. [Figure 15A]The following shows the time course of mean plasma concentrations of abiraterone and abiraterone decanoate after intravenous administration of 1.2 mg / kg abiraterone decanoate (0.4 mg / ml solution in 40% HP-β-cyclodextrin 25 mM sodium phosphate buffer (pH 7.4)) to male rats (n=5). [Figure 15B] The following shows the time course of mean plasma concentrations of abiraterone and abiraterone decanoate after a single IM administration of abiraterone decanoate at a dose of 90 mg / kg to male rats (n=5) with an abiraterone decanoate preparation (90% corn oil, 10% benzyl alcohol, 172 mg / ml abiraterone decanoate). [Figure 15C] This shows the time course of mean plasma concentrations of abiraterone and abiraterone decanoate after repeated administration of an abiraterone decanoate preparation (90% corn oil, 10% benzyl alcohol, 172 mg / ml abiraterone decanoate) to male rats (n=5) via intracellular injection (IM) on days 0, 7, and 35. Each dose of abiraterone decanoate was 90 mg / kg. [Figure 16A] This shows the relative growth scaling of the predicted volume of distribution (Vss) of abiraterone in rats, dogs, monkeys, and, in the case of humans. [Figure 16B] This shows the predicted plasma profile of abiraterone in humans after a single intramuscular administration of 1 mg of abiraterone, based on a 56% bioavailability. [Figure 16C] This shows the predicted plasma profile of abiraterone in humans after repeated intramuscular administration of 1000 mg of abiraterone decanoate every four weeks, based on a 56% bioavailability. [Figure 16D] This shows the predicted plasma profile of abiraterone in humans after repeated intramuscular administration of 1000 mg of abiraterone decanoate every 4 weeks, assuming complete bioavailability. [Figure 17A]This graph shows the time course of mean plasma concentrations of abiraterone and abiraterone isocaproate after intravenous administration of 1.0 mg / kg abiraterone isocaproate to dogs. Error bars represent the standard deviation. [Figure 17B] This graph shows the time course of mean plasma concentrations of abiraterone and abiraterone isocaproate after IM administration of abiraterone isocaproate to dogs. Error bars represent the standard deviation. [Figure 17C] This graph shows the time course of mean plasma concentrations of abiraterone and abiraterone decanoate after IM administration of abiraterone decanoate to dogs. Error bars represent the standard deviation. [Figure 17D] This shows the time course of mean plasma concentrations of abiraterone after IM administration of abiraterone isocaproate or abiraterone decanoate to dogs. Error bars represent the standard deviation. [Figure 18] This shows a representative analysis of a batch of high-purity abiraterone decanoate. [Figure 19A] This shows the time course of mean plasma abiraterone concentrations in chemically castrated, sexually mature male cynomolgus monkeys after a single oral administration of abiraterone acetate (5 mg / kg, 15 mg / kg, and 45 mg / kg) on ​​day 29 and a single intramuscular injection of abiraterone decanoate (10 mg / kg, 30 mg / kg, and 100 mg / kg) on ​​day 43. [Figure 19B] This shows the time course of mean plasma concentrations of abiraterone (10 mg / kg, 30 mg / kg, and 100 mg / kg) after a single IM injection in chemically castrated, sexually mature male cynomolgus monkeys, up to 70 days later. [Figure 20A] The graph shows the time course of dihydrotestosterone levels (DHT, shown in the figure) up to 70 days after a single IM injection of abiraterone decanoate (10 mg / kg, 30 mg / kg, and 100 mg / kg) in chemically castrated, sexually mature male cynomolgus monkeys. [Figure 20B]After single IM injection of abiraterone decanoate (10 mg / kg, 30 mg / kg, and 100 mg / kg) into chemically castrated and sexually mature male cynomolgus monkeys, the time-course data of testosterone levels (indicated as T in the drawings) up to a maximum of 70 days are shown. [Figure 20C] After single IM injection of abiraterone decanoate (10 mg / kg, 30 mg / kg, and 100 mg / kg) into chemically castrated and sexually mature male cynomolgus monkeys, the time-course data of cortisol levels (indicated as Cort in the drawings) up to a maximum of 70 days are shown. [Figure 20D] After single IM injection of abiraterone decanoate (10 mg / kg, 30 mg / kg, and 100 mg / kg) into chemically castrated and sexually mature male cynomolgus monkeys, the time-course data of progesterone levels (indicated as Prog in the drawings) up to a maximum of 70 days are shown.

Mode for Carrying Out the Invention

[0030] The present disclosure relates to compounds and compositions that deliver therapeutic plasma levels of the potent drug abiraterone to patients over a long period of time. In an initial experiment in rats, it was found that even when a suspension of the potent drug abiraterone was injected intramuscularly, the desired therapeutic plasma levels could not be achieved. However, as detailed herein, when representative novel abiraterone prodrugs and formulations are administered parenterally (e.g., intramuscularly), it has been found that the desired therapeutic plasma levels can be achieved over a long period of time, e.g., for up to 10 weeks or more.

[0031] Thus, various embodiments of the present disclosure are directed to novel abiraterone prodrugs and formulations that have various advantages over existing abiraterone formulations such as commercially available oral abiraterone acetate formulations. Such advantages include improved bioavailability, elimination of the effect of food associated with oral abiraterone acetate formulations, reduced dosing burden, improved patient compliance, reduced dosing frequency, maintenance of stable plasma levels of the potent drug, and reduction of associated side effects. maxExamples include, but are not limited to, a decrease in [specific factor]. In some embodiments, methods are also provided for using novel abiraterone prodrugs and formulations to treat, for example, sex hormone-dependent benign or malignant diseases (e.g., prostate cancer), syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia.

[0032] Compound of formula I In some embodiments, the disclosure provides novel abiraterone prodrugs. In some embodiments, the novel abiraterone prodrug is a compound of formula I or a pharmaceutically acceptable salt thereof. [ka]

[0033] Various groups, R in formula I 1 It is suitable as. In some embodiments, R 1 The compound of formula I may be selected to be an ester (e.g., a lipophilic ester), a carbamate ester, or a carbonate ester of abiraterone. In some embodiments, R 1 R 10 , OR 10 or NHR 10 And here, R 10 C 7-30 Alkyl; C 7-30 Alkenil; C 7-30 Alkynyl; alkyl typically substituted with cycloalkyl groups having a total of 5 to 16 carbon atoms; alkyl typically substituted with phenyl groups having a total of 7 to 16 carbon atoms; cycloalkyl groups optionally substituted with one or more alkyl groups having a total of 5 to 16 carbon atoms; and [ka] Selected from branched C5 or C6 alkyl groups such as the following.

[0034] In some preferred embodiments, R 10 C7-30 It is alkyl. Where used herein, alkyl should be understood to be unsubstituted unless explicitly stated otherwise. However, alkyl may be either linear or branched. In some embodiments, R 10 is a linear C 7-30 It may be alkyl. In some embodiments, R 10 is a branched chain C 7-30 It may be alkyl. In some embodiments, R 10 is a linear C 7-16 It is alkyl, for example, R 10 This is the formula -(CH2) n -CH3 may be present, where 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 is a branched chain C 7-16 It may be alkyl.

[0035] In some embodiments, R 10 R may also be an alkyl substituted with a cycloalkyl. Typically, in such embodiments, R 10 It has a total of 5 to 16 carbon atoms, in other words, the total number of carbon atoms in the alkyl and cycloalkyl parts is 5 to 16. Cycloalkyls are typically unsubstituted. However, in some embodiments, the cycloalkyl is, for example, one or two lower alkyl groups (e.g., C 1-4 It may be optionally substituted with alkyl. In some embodiments, R 10 These are typically C atoms with a total of 6 to 12 carbon atoms. 3-6 It is an alkyl group substituted with a cycloalkyl group. In some embodiments, R 10 C 3-6 A linear alkyl group substituted with a cycloalkyl group, for example, R 10 This is the formula -(CH2) n -Cy may be present, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is C 3-6It is a cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, R 10 This is the formula -(CH2) n -Cy may be present, where n is 1 or 2 and Cy is cyclopentyl or cyclohexyl. In some embodiments, R 10 Also, C 3-6 Branched alkyl groups substituted with cycloalkyl groups (e.g., branched C 2-6 ) may be. When used herein, the branched C2 alkyl should be understood to be a 1,1-disubstituted ethyl group, for example, CH(CH3)-Cy.

[0036] In some embodiments, R 10 R may also be a phenyl-substituted alkyl. Typically, in such embodiments, R 10 It has a total of 7 to 16 carbon atoms, in other words, the total number of carbon atoms in the alkyl and phenyl portions is 5 to 16. In some embodiments, R 10 R is a linear alkyl group substituted with phenyl, for example, 10 This is the formula -(CH2) n -Cy may be present in the formula, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is phenyl. In some embodiments, R 10 This is the formula -(CH2) n -Cy may be present, where n is 1 or 2 and Cy is phenyl. In some embodiments, R 10 Also, phenyl-substituted branched alkyl groups (e.g., branched C) 2-6 ) may also be phenyl is typically unsubstituted. However, in some embodiments, phenyl may be, for example, one or two lower alkyl groups (e.g., C 1-4 It may be optionally substituted with alkyl.

[0037] In some embodiments, R 10 R may be a cycloalkyl group optionally substituted with one or more alkyl groups. In such embodiments, R 10Typically, it has a total of 5 to 16 carbon atoms, in other words, the total number of carbon atoms of the cycloalkyl and any substituent is 5 to 16. In some embodiments, R 10 is unsubstituted or C 1-4 C substituted with alkyl 3-6 It may be cycloalkyl. In some specific embodiments, R 10 teeth, [ka] That's fine.

[0038] In some embodiments, R 10 R may be a branched C5 or C6 alkyl group. In some embodiments, R 10 teeth, [ka] This may be the case. Other branched C5 or C6 alkyl groups are also preferred.

[0039] In some embodiments, R 10 C 7-30 Alkenyl or C 7-30 It may be an unsaturated aliphatic group such as an alkynyl group.

[0040] In some preferred embodiments, the compound of formula I is an ester of abiraterone, for example, R 1 R 10 And R 10 The terms are defined herein. In some embodiments, R in formula I 1 C 7-16 It may be alkyl, for example, alkyl is -(CH2) n -CH3 has the formula -CH3, where n is an integer between 6 and 12 (e.g., 6, 7, 8, 9, 10, 11, or 12). In some embodiments, R in formula I 1 This is the formula -(CH2) n It can be expressed as -Cy, where n is an integer from 1 to 6, and Cy is C 3-6It is a cycloalkyl or phenyl compound, and in more specific embodiments, for example, n may be 1 or 2, and Cy may be cyclopentyl, cyclohexyl, or phenyl. In some specific embodiments, R in formula I 1 teeth [ka] It may be so. In some specific embodiments, R in formula I 1 teeth [ka] That's fine. 1 Other suitable groups are R as defined herein. 10 Includes any of the following.

[0041] In some embodiments, R in formula I 1 Also, OR 10 or NHR 10 It is fine if R 10 This is defined herein.

[0042] Typically, the compound of formula I may be present in a formulation in a basic form, for example, in a non-aqueous formulation. However, in some embodiments, pharmaceutically acceptable salts of the compound of formula I are also useful. Unless otherwise specifically mentioned as its salt form, or unless inconsistent with the context, the compound of formula I may be in its basic form in the abiraterone prodrug formulations described herein. In some embodiments, the compound of formula I may be in a substantially pure form.

[0043] Compounds of formula I can be readily synthesized by those skilled in the art in view of this disclosure. Exemplary synthesis of representative compounds is described in the Examples section. For example, typically, esters of formula I can be prepared by reacting abiraterone with the corresponding carboxylic acid or with its own activated form, such as the corresponding acyl chloride or anhydride. Exemplary reaction conditions using activated forms such as acyl chloride are shown in the Examples section.

[0044] Abiraterone prodrug formulation The abiraterone prodrugs of this specification, comprising compounds of Formula I, are useful for delivering abiraterone to patients in need, for example, patients with sex hormone-dependent benign or malignant diseases as defined herein, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia. Typically, abiraterone prodrugs are formulated as parenteral formulations, such as intramuscular, intradermal, or subcutaneous formulations, and in some embodiments, they can be formulated to deliver therapeutically effective plasma concentrations of abiraterone over extended periods, for example, at least one week, at least two weeks, at least three weeks, at least four weeks, and up to six or eight weeks or more, for example, up to ten weeks or more.

[0045] Various abiraterone prodrugs, such as abiraterone esters, carbamates, and carbonates, are suitable for the compositions and methods of this disclosure. In some embodiments, this disclosure provides pharmaceutical compositions (or, as may be referred to herein as abiraterone prodrug formulations) comprising a compound of formula I (e.g., any one or more as defined herein) or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions can be formulated for parenteral administration, such as intramuscular injection, intradermal injection, or subcutaneous injection. The pharmaceutical compositions typically comprise a pharmaceutically acceptable carrier. Suitable carriers include those known in the art, such as those listed in "Remington: The Science and Practice of Pharmacy" (formerly "Remington's Pharmaceutical Sciences," University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia, Pa. (2005)) and the FDA's Center for Drug Evaluation and Research's database of inactive ingredients in FDA-approved drugs. In some embodiments, the pharmaceutically acceptable carrier may be a carrier approved for use by the FDA for intramuscular, intradermal, or subcutaneous pharmaceuticals, e.g., one listed in the FDA's Inactive Ingredients Database. In some embodiments, the pharmaceutically acceptable carrier may be any suitable non-aqueous solvent suitable for injection, such as those listed in the United States Pharmacopeia. In some embodiments, the pharmaceutically acceptable carrier may be a pharmaceutically acceptable oil, e.g., vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil. In some embodiments, the pharmaceutically acceptable oil may be an oil suitable as a solvent for injection (e.g., as described herein), e.g., one that meets the criteria described in the corresponding sections of the United States Pharmacopeia. In some embodiments, the pharmaceutically acceptable oil may be a plant-derived oil suitable as a solvent for injection.In some embodiments, the pharmaceutically acceptable oil may be a synthetic oil suitable as an injectable solvent, such as a synthetic monoglyceride or diglyceride of fatty acids, for example, a liquid that remains a clear liquid when cooled to 10°C and has an iodine value of 140 or less. In some embodiments, the pharmaceutically acceptable oil may be a natural oil, a synthetic oil, or a semi-synthetic oil such as fractionated coconut oil and a medium-chain triglyceride, such as those sold under the trademark Miglyol. In some embodiments, the pharmaceutically acceptable carrier comprises triglycerides derived from fatty acids. In some embodiments, the pharmaceutically acceptable carrier comprises triglycerides derived from long-chain and / or medium-chain fatty acids, which may independently be polyunsaturated, monounsaturated, or saturated. In some embodiments, two or more different pharmaceutically acceptable oils may be used. In some embodiments, the pharmaceutical composition is a non-aqueous solution or suspension. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable solvent such as benzyl alcohol, benzyl benzoate, or a combination thereof. In some embodiments, compounds of formula I or pharmaceutically acceptable salts thereof may be present in the pharmaceutical composition at concentrations of about 25 mg / ml to about 500 mg / ml (e.g., about 25 mg / ml, about 50 mg / ml, about 100 mg / ml, about 150 mg / ml, about 200 mg / ml, about 250 mg / ml, about 300 mg / ml, about 400 mg / ml, about 500 mg / ml, or any of the listed ranges).

[0046] In some embodiments, the disclosure also provides pharmaceutical compositions (or, as may be referred herein, to abiraterone prodrug formulations) comprising compounds of formula II or pharmaceutically acceptable salts thereof. [ka] R in the formula 2It is defined in this specification. In some embodiments, the pharmaceutical composition can be formulated for intramuscular injection, intradermal injection, or subcutaneous injection. In some embodiments, the compound of formula II or their pharmaceutically acceptable salts can be present in the pharmaceutical composition at a concentration of about 25 mg / ml to about 500 mg / ml (e.g., about 25 mg / ml, about 50 mg / ml, about 100 mg / ml, about 150 mg / ml, about 200 mg / ml, about 250 mg / ml, about 300 mg / ml, about 400 mg / ml, about 500 mg / ml or any value within the recited range). In some embodiments, the pharmaceutical composition is a non-aqueous solution or suspension. In some embodiments, the compound of formula II or their pharmaceutically acceptable salts are dissolved or suspended in a pharmaceutically acceptable oil such as vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil (e.g., as described herein). In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable solvent such as benzyl alcohol, benzyl benzoate, or a combination thereof.

[0047] Various groups are R in formula II 2 and are suitable as. In some embodiments, R 2 can be selected such that the compound of formula II is an ester, carbamate, or carbonate ester of abiraterone. In some embodiments, R 2 is R 20 , O-R 20 or NHR 20 and R 20 is selected from C 1-30 alkyl; C 2-30 alkenyl; C 2-30 alkynyl; typically alkyl substituted with cycloalkyl having 4 to 30 total carbon atoms; typically alkyl substituted with phenyl having 7 to 30 total carbon atoms; and typically cycloalkyl optionally substituted with one or more alkyl having 3 to 30 total carbon atoms.

[0048] In some preferred embodiments, R 20 is C 1-16It is alkyl. In some embodiments, R 20 is a linear C 1-16 It may be alkyl. In some embodiments, R 20 is a branched chain C 3-16 It may be alkyl. In some embodiments, R 20 R may be a branched C5 or C6 alkyl group. In some embodiments, R 20 teeth, [ka] It may be R 20 This is the formula -(CH2) n -CH3 may be present, where n is an integer between 0 and 12 (e.g., between 6 and 12 such as 6, 7, 8, 9, 10, 11, or 12).

[0049] In some embodiments, R 20 R may also be an alkyl substituted with a cycloalkyl. Typically, in such embodiments, R 20 It has a total of 4 to 30 carbon atoms, for example, a total of 5 to 16 carbon atoms (in other words, the total number of carbon atoms in the alkyl and cycloalkyl parts is 5 to 16). Cycloalkyls are typically unsubstituted. However, in some embodiments, the cycloalkyl is, for example, one or two lower alkyl groups (e.g., C 1-4 It may be optionally substituted with alkyl. In some embodiments, R 20 These are typically C atoms with a total of 6 to 12 carbon atoms. 3-6 It is an alkyl group substituted with a cycloalkyl group. In some embodiments, R 20 C 3-6 A linear alkyl group substituted with a cycloalkyl group, for example, R 20 This is the formula -(CH2) n -Cy may be present, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is C 3-6 It is a cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, R20 This is the formula -(CH2) n -Cy may be present, where n is 1 or 2 and Cy is cyclopentyl or cyclohexyl. In some embodiments, R 20 Also, C 3-6 Branched alkyl groups substituted with cycloalkyl groups (e.g., branched C 2-6 ) is acceptable.

[0050] In some embodiments, R 20 R may also be a phenyl-substituted alkyl. Typically, in such embodiments, R 20 It has a total of 7 to 30 carbon atoms, for example, a total of 7 to 16 carbon atoms (in other words, the total number of carbon atoms in the alkyl and phenyl portions is 7 to 16). In some embodiments, R 20 R is a linear alkyl group substituted with phenyl, for example, 20 This is the formula -(CH2) n -Cy may be present in the formula, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is phenyl. In some embodiments, R 20 This is the formula -(CH2) n -Cy may be present, where n is 1 or 2 and Cy is phenyl. In some embodiments, R 20 Also, phenyl-substituted branched alkyl groups (e.g., branched C) 2-6 ) may also be phenyl is typically unsubstituted. However, in some embodiments, phenyl may be, for example, one or two lower alkyl groups (e.g., C 1-4 It may be optionally substituted with alkyl.

[0051] In some embodiments, R 20 R may be a cycloalkyl group optionally substituted with one or more alkyl groups. In such embodiments, R 20 It typically has a total of 3 to 30 carbon atoms, for example, a total of 5 to 16 carbon atoms (in other words, the total number of carbon atoms of the cycloalkyl and any substituent is 5 to 16). In some embodiments, R 20 is unsubstituted or C1-4 C substituted with alkyl 3-6 It may be cycloalkyl. In some specific embodiments, R 20 teeth, [ka] That's fine.

[0052] In some embodiments, R 20 C 2-30 Alkenyl or C 2-30 It may be an unsaturated aliphatic group such as an alkynyl group.

[0053] In some preferred embodiments, the compound of formula II is an abiraterone ester, for example, R 2 R 20 And R 20 The terms are defined herein. In some embodiments, R in formula II 2 C 1-16 It may be alkyl, for example, alkyl is -(CH2) n The formula has the form -CH3, where n is an integer from 0 to 12. In some embodiments, R in formula II 2 This is the formula -(CH2) n It can be expressed as -Cy, where n is an integer from 1 to 6, and Cy is C 3-6 It is a cycloalkyl or phenyl compound, and in more specific embodiments, for example, n may be 1 or 2, and Cy may be cyclopentyl, cyclohexyl, or phenyl. In some specific embodiments, R in formula II 2 teeth, [ka] That's fine. 2 Other suitable groups are R as defined herein. 20It includes any of the following. In some embodiments, the abiraterone ester may be abiraterone acetate, propionate, butanoate, (vaterate)pentanoate, isocaproate, bucicrate, cyclohexanecarboxylic acid, phenylpropionate, caproate (hexanoate), enanthate (heptanoate), cypionic acid, octanoate, noncanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate, or hexadecanate. In some embodiments, the abiraterone ester may be abiraterone acetate, abiraterone propionate, and abiraterone decanoate. In some specific embodiments, the abiraterone ester may be abiraterone pentanoate, abiraterone hexanoate, abiraterone heptanoate, abiraterone decanoate, abiraterone isocaproate, or abiraterone cypionicate.

[0054] In some embodiments, R in formula II 2 Also, OR 20 or NHR 20 It is fine if R 20 This is defined herein.

[0055] Typically, the compound of formula II may be present in the formulation in a basic form, for example, in a non-aqueous formulation. However, in some embodiments, pharmaceutically acceptable salts of the compound of formula II are also useful. Unless otherwise specifically mentioned as its salt form, or unless inconsistent with the context, the compound of formula II may be in its basic form in the abiraterone prodrug formulations described herein. In some embodiments, the compound of formula II may be in a substantially pure form.

[0056] Compounds of formula II can be readily synthesized by those skilled in the art in view of this disclosure. Exemplary synthesis of representative compounds is described in the Examples section. For example, typically, esters of formula II can be prepared by reacting abiraterone with the corresponding carboxylic acid or with its own activated form, such as the corresponding acyl chloride or anhydride. Exemplary reaction conditions using activated forms such as acyl chloride are shown in the Examples section.

[0057] Typically, the abiraterone prodrugs of this disclosure are formulated as non-aqueous solutions or suspensions. In some embodiments, non-aqueous solutions or suspensions provide higher concentrations of abiraterone in plasma for a longer period compared to aqueous solutions or suspensions. For example, as detailed herein, IM injections of aqueous suspensions and vegetable oil solutions of abiraterone acetate prodrugs were evaluated in rats. Surprisingly, the vegetable oil solution (not the aqueous suspension) of abiraterone acetate prodrugs was found to result in the highest plasma levels and the longest exposure to the potent drug abiraterone (see Figure 1). Thus, in some embodiments, the abiraterone prodrug formulations of this disclosure may include the abiraterone prodrug of this disclosure (e.g., a compound of formula I or II) dissolved or dispersed in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier may be any suitable non-aqueous solvent suitable for injection, such as those listed in the United States Pharmacopeia. In some embodiments, the pharmaceutically acceptable carrier may be a pharmaceutically acceptable oil, such as vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil. In some embodiments, the pharmaceutically acceptable oil may be an oil suitable as a solvent for injection (e.g., as described herein), meeting the criteria such as those described in the corresponding sections of the United States Pharmacopeia. In some embodiments, the pharmaceutically acceptable oil may be a plant-derived oil suitable as a solvent for injection. In some embodiments, the pharmaceutically acceptable oil may be a synthetic oil suitable as a solvent for injection, such as a synthetic monoglyceride or diglyceride of fatty acids, for example, a liquid that remains a clear liquid when cooled to 10°C and has an iodine value of 140 or less. In some embodiments, the pharmaceutically acceptable oil may be a natural oil, a synthetic oil, or a semi-synthetic oil such as fractionated coconut oil and a medium-chain triglyceride, such as those sold under the trademark Miglyol. In some embodiments, the pharmaceutically acceptable carrier comprises triglycerides derived from fatty acids.In some embodiments, the pharmaceutically acceptable carrier may independently be polyunsaturated, monounsaturated, or saturated triglycerides derived from long-chain and / or medium-chain fatty acids. In some embodiments, the pharmaceutically acceptable oil may be any oil approved for use by the FDA for intramuscular, intradermal, or subcutaneous pharmaceuticals, e.g., any oil listed in the FDA's Inactive Ingredients Database. In some specific embodiments, the pharmaceutically acceptable oil may be castor oil or corn oil. In some embodiments, two or more different pharmaceutically acceptable oils may be used.

[0058] Other components may also be optionally included in the abiraterone prodrug formulations herein. In some embodiments, the abiraterone prodrug formulations may further contain pharmaceutically acceptable solvents such as benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid, and ethyl acetate. Additives / cosolvents, benzyl alcohol and benzyl benzoate, have been found to not only increase the solubility of the prodrug but also to reduce the viscosity and / or glide force of the solution (see Figures 13A-13E and Tables 2A-2D), thereby resulting in higher concentration solutions that are easier to inject with a gauge needle acceptable for IM injection (e.g., 20-27 gauge, e.g., 22-25 gauge). Cosolvents may be selected based on their ability to reduce the viscosity of the solvent, thereby enabling injection through a suitable injection needle or cannula. Benzyl alcohol as an additive for IM or subcutaneous injection has the advantage of acting as a local anesthetic at the injection site (Wilson et al. Ann. Emer. Med. 33(5), 495, 1999). In some embodiments, abiraterone prodrug formulations further contain benzyl alcohol. In some embodiments, co-solvents may be included, if present, in a level that does not cause irritation at the injection site (i.e., minimal or tolerable irritation) (e.g., about 0-50% of the solvent, e.g., 10%).

[0059] In some embodiments, the abiraterone prodrug formulation may contain benzyl benzoate as a co-solvent, for example, in an amount of about 0-50%, typically 0-35%, or 0-30%, or about 20% of the solvent. In some embodiments, the abiraterone prodrug formulation may contain a combination of benzyl alcohol and benzyl benzoate as a co-solvent. In some embodiments, benzyl alcohol may be present in an amount of about 0-20% of the solvent (e.g., 0-15% or 0-10%, e.g., about 10%), and benzyl benzoate may be present in an amount of about 0-50% of the solvent (e.g., 0-35%, or 0-30%, e.g., about 20%), and the remainder of the solvent may be any one or more of the pharmaceutically acceptable oils described herein, such as corn oil, castor oil, sesame oil, peanut oil, cottonseed oil, and / or Miglyol 812. As will be discussed in more detail in the Examples section, the inclusion of benzyl benzoate in various oily solvents proved advantageous in several ways. See, for example, Figures 13A-13E and Tables 2A-2D. For instance, the combination of benzyl alcohol and benzyl benzoate demonstrated lower viscosity and lower glide force compared to using benzyl alcohol alone or benzyl benzoate alone. Furthermore, unexpectedly, a representative abiraterone prodrug (abiraterone decanoate) formulation containing oil (70% corn oil), benzyl alcohol (10%), and benzyl benzoate (20%) was found to achieve a higher abiraterone plasma exposure in monkeys compared to a formulation containing the same oily solvent without benzyl benzoate, i.e., 90% corn oil and 10% benzyl alcohol, with substantially the same concentration of abiraterone decanoate and administered at the same dose.

[0060] The oily solvents described herein are typically used for the abiraterone prodrugs of this disclosure, but the potential use of such oily solvents for the formulation of other active ingredients should also be considered. In some embodiments, this disclosure also provides oily solvents comprising about 0 to 20% (e.g., 0 to 15% or 0 to 10%, e.g., about 10%) of the oily solvent benzyl alcohol and about 0 to 50% (e.g., 0 to 35% or 0 to 30%, e.g., about 20%) of the oily solvent benzyl benzoate, the remainder of the oily solvent may be any one or more of the pharmaceutically acceptable oils described herein, such as corn oil, castor oil, sesame oil, peanut oil, cottonseed oil, and / or Miglyol 812.

[0061] The solubility of abiraterone ester may be affected when a co-solvent is added to a vegetable oil solvent. In some embodiments, abiraterone ester is completely dissolved in the composition, while in other embodiments, it is partially dispersed in the composition. In one embodiment, abiraterone ester is completely dissolved in the solvent.

[0062] Abiraterone prodrug formulations may also contain pharmaceutically acceptable preservatives, polymers, antioxidants, antimicrobial agents, chelating agents, and other excipients, such as citric acid, dextrose, ascorbic acid, benzalkonium chloride, benzoic acid, sodium betadex sulfobutyl ether, calcium chloride, sodium carbomethoxycellulose, chlorobutanol, creatine, croscarmellose, dibasic potassium phosphate, sodium doxate, sodium edetate, glycerin, sodium hyaluronate, hydroxypropyl betadex, lactic acid, lactose, lecithin, maleic acid, mannitol, meglumine, methylcellulose, methylparaben, microcrystalline cellulose, and miripitium chloride. Examples include chloride, monothioglycerol, phenol, poloxamer 188, polyglactin, polysorbate 20, polysorbate 40, polysorbate 80, propylparaben, sodium acetate, sodium benzoate, sodium citrate, sorbitan monolaurate, sorbitol, sucrose, tartaric acid, trisodium citrate, tromantadine, tromethamine, and urea.

[0063] The abiraterone prodrug formulation may be sterilized by methods known to those skilled in the art (e.g., gamma irradiation, micron filtration, and autoclave).

[0064] Long-lasting release of abiraterone The abiraterone prodrugs and abiraterone prodrug formulations of this disclosure (e.g., formulations containing compounds of formula I or II as described herein) are typically formulated to provide long-acting, long-release abiraterone, preferably as parenteral formulations such as intramuscular, intradermal, or subcutaneous formulations, to patients in need, for example, those with sex hormone-dependent benign or malignant diseases, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia. In some embodiments, the abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure (e.g., formulations containing compounds of formula I or II as described herein) can be formulated to deliver therapeutic plasma levels of abiraterone over a long period of time (e.g., at least one week, e.g., at least two weeks, at least three weeks, at least four weeks, and up to six or eight weeks or more, e.g., up to ten weeks or more) after a single administration to patients having hormone-dependent benign or malignant diseases, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia. In some embodiments, the therapeutic plasma concentration of abiraterone may be at least 1 ng / ml, e.g., at least 2 ng / ml, at least 4 ng / ml, or at least 8 ng / ml. In some embodiments, the therapeutic plasma concentration of abiraterone may be about 0.5 ng / ml or higher.

[0065] As described herein, abiraterone acetate vegetable oil IM injection was evaluated in dogs. Solutions of abiraterone acetate in castor oil, co-solvent benzyl alcohol, and benzyl benzoate were prepared at various concentrations (66–124 mg / ml) and administered intramuscularly to dogs, and plasma levels of the parent abiraterone drug were measured over 3 weeks (see Figure 2). Data from the canine study showed that when abiraterone acetate was administered as a solution in castor oil (with or without benzyl alcohol), measurable blood levels were obtained up to 504 hours. The absolute bioavailability results for these formulations ranged from 61.7% to 86.2%. This firstly demonstrates that a single injection can deliver abiraterone to patients over a long period, thus enabling less frequent administration, such as once a week to once every few weeks, for example, once a week to once every few months, or once a week to once every eight weeks or once a week to once every three months.

[0066] While we do not wish to be bound by theory, the duration of action of a prodrug is considered to depend on the selection of the prodrug (e.g., the ester portion) and the oily solvent, as it is controlled by both the rate of release of the prodrug from the oily solvent to the aqueous tissue and the rate of bioconversion of the ester prodrug to unchanged abiraterone. Unlike the case where abiraterone acetate is administered orally and bioconversion occurs before the drug is absorbed (and therefore the prodrug is not observed in plasma), when abiraterone prodrugs are administered parenterally to dogs (either IV or IM), the prodrug is converted to unchanged abiraterone and observed in plasma (see Figures 3-10). Therefore, aspects of this disclosure involve the selection of an ester prodrug and a vegetable oil / cosolvent solvent, taking into account the appropriate solubility of the ester prodrug in the solvent to enable injection, controlled release of the ester prodrug from the oily depot (depending on the distribution coefficient of the drug between the oil and aqueous phases), and subsequent bioconversion of the ester prodrug to unchanged abiraterone. Selected abiraterone prodrugs (acetic acid, propionic acid, butano acid, pentano acid, hexano acid, heptano acid, isocapro acid, cypionic acid, and decano acid) were prepared, and their solubility in several vegetable oils and co-solvents was measured (see Table 2).

[0067] Unit formulation In some embodiments, the abiraterone prodrugs and abiraterone prodrug formulations of this disclosure (e.g., formulations containing compounds of formula I or II as described herein) can be formulated as unit formulations. In some embodiments, the unit formulation may contain a sufficient amount of the corresponding prodrug to provide a therapeutically effective plasma concentration of abiraterone in a patient over a period such as at least two weeks, e.g., at least three weeks, at least four weeks, at least five weeks, and up to six or eight weeks or more, e.g., up to ten weeks or more, after a single administration (e.g., intramuscular injection) to a patient having, for example, a sex hormone-dependent benign or malignant disease (e.g., metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer), a syndrome caused by androgen excess, and / or a syndrome caused by glucocorticoid excess such as hypercortisolemia. In some embodiments, the therapeutic range plasma concentration of abiraterone may be at least 1 ng / ml, e.g., at least 2 ng / ml, at least 4 ng / ml, or at least 8 ng / ml. In some embodiments, the therapeutic plasma concentration of abiraterone may be approximately 0.5 ng / ml or greater. In some embodiments, the unit formulation is a parenteral formulation, such as an intramuscular, intradermal, or subcutaneous formulation. In some embodiments, the unit formulation is a non-aqueous solution or suspension. In some embodiments, the unit formulation comprises an abiraterone prodrug (compound of formula I or II) dissolved or suspended in a pharmaceutically acceptable oil, such as a vegetable oil, e.g., castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil. In some embodiments, two or more different pharmaceutically acceptable oils may be used in the unit formulation. In some embodiments, the unit formulation may further contain a pharmaceutically acceptable solvent, such as an alcohol, ester, and / or acid, e.g., benzyl alcohol, benzyl benzoate, or a combination thereof. Other components suitable for the unit formulation include those described herein.

[0068] The abiraterone prodrug (e.g., compound of formula I or II) is typically present in a unit formulation at concentrations ranging from approximately 25 mg / ml to approximately 500 mg / ml (e.g., approximately 25 mg / ml, approximately 50 mg / ml, approximately 100 mg / ml, approximately 150 mg / ml, approximately 200 mg / ml, approximately 250 mg / ml, approximately 300 mg / ml, approximately 400 mg / ml, approximately 500 mg / ml, or any range of the values ​​listed). The amount of abiraterone prodrug in a unit formulation can be varied depending on various factors, including the clearance rate of the corresponding abiraterone prodrug, the desired administration frequency, and the desired plasma level. Typically, the amount of abiraterone prodrug may range from approximately 50 mg to approximately 2000 mg, and when expressed as equivalent to abiraterone, it may usually range from approximately 25 mg to approximately 1750 mg. In some embodiments, to achieve a lower dosing frequency, such as once a month, once every two months, or once every three months, the prodrug can be included in the unit formulation at the highest possible concentration while remaining within a safe tolerance range for the target user. Typically, the unit formulation is formulated to have a viscosity suitable for parenteral injection, such as intramuscular, intradermal, or subcutaneous injection.

[0069] In some embodiments, a unit formulation can be formulated to obtain a certain pharmacokinetic (PK) profile, for example, a PK profile in which the curve becomes substantially flat after an initial rise. Typically, after administration of a unit formulation to a patient, the plasma concentration of abiraterone in the patient may rise for the first few hours to several weeks (e.g., 5 days or 1 week) post-administration, and then gradually level off (see, for example, Figures 2-4). In some embodiments, after this initial rise, the plasma concentration of abiraterone in the patient may level off and remain substantially constant for a long period, for example, at least several days (e.g., 2, 3, 4, 5, or 6 days) or at least 1 week, at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, etc.

[0070] In some embodiments, the unit formulation is suitable for administration once a month (or once every few months, e.g., once every two months or once every three months), and after a single dose (e.g., intramuscularly) to a patient requiring it, the unit formulation achieves a PK profile characterized by one or more of the following (a) to (f): (a) The unit formulation provides a therapeutically effective plasma concentration of abiraterone in the patient for at least four weeks, e.g., up to six weeks, or up to eight weeks, or up to ten weeks or more; (b) C of a single dose of abiraterone of approximately 10 ng / ml to approximately 400 ng / ml (e.g., approximately 50 ng / ml to approximately 100 ng / ml, or approximately 15 ng / ml to approximately 160 ng / ml). max (c) No effect of food; (d) Abiraterone C observed at steady state after oral administration of 1000 mg of Zytiga (registered trademark) once daily without food. max Compared to that, the C of a single dose of abiraterone is at least 30% lower. max (e) C of a single dose of abiraterone, approximately 1 ng / ml to approximately 8 ng / ml, or greater than approximately 8 ng / ml, on day 28 after administration. min (f) The plasma concentration of abiraterone remains substantially constant after administration for, for example, at least one week, for example, one to three weeks, one to ten weeks, or two to eight weeks. In some embodiments, substantially constant over a period of time may mean that the highest concentration observed on any given day (i.e., 24 hours) during that period is no more than four times, for example, twice, the lowest concentration observed on the same day. No effect of food should generally be understood as no significant difference in PK observed when the unit formulation is administered to patients regardless of food intake, for example, in some embodiments, no effect of food means that the C of abiraterone is not observed between patients administered after a meal or on an empty stomach. max This may mean that the AUC is substantially the same (e.g., 80% to 125%). When used in the present invention, a single dose of C maxThis refers to the C150% achieved after a single dose in untreated patients (generally meaning patients who have not received any abiraterone drug therapy for at least 3 days prior to administration, e.g., at least 1 week, and who do not have observable abiraterone in their plasma prior to administration). max It should be understood that the single dose of C used herein min This refers to the minimum concentration observed on a specified day after a single dose in an untreated patient, for example, on day 28 after administration.

[0071] In some embodiments, the unit formulation is suitable for administration once a month (or once every few months, e.g., once every two months or once every three months), and after administering the unit formulation (e.g., intramuscularly) once a month (or once every few months, e.g., once every two months or once every three months) to patients requiring it, the unit formulation achieves the following (a) to (g): (a) Steady-state C of abiraterone of approximately 10 ng / ml to approximately 400 ng / ml (e.g., approximately 50 ng / ml to approximately 100 ng / ml, or approximately 15 ng / ml to approximately 160 ng / ml). max (b) No effect of food; (c) Steady-state aviraterone C when 1000 mg of Zytiga® is administered orally once daily without food. max Compared to this, the steady state of abiraterone is at least 30% lower. max (d) Steady-state C of abiraterone, approximately 1 ng / ml to approximately 8 ng / ml, or greater than approximately 8 ng / ml min (g) The plasma concentration of abiraterone remains substantially constant after each administration for, for example, at least 1 week, for example, 1 to 3 weeks, 1 to 10 weeks, or 2 to 8 weeks. When used in the present invention, steady state C max or C min This typically refers to C, which is observed after several doses to the patient and after reaching a steady state. max or C min It should be understood that this is the case.

[0072] In some embodiments, the unit formulations may be packaged in containers such as vials or ampoules. In some embodiments, the unit formulations may be contained in a kit with syringes such as pre-filled syringes or disposable syringes. Other packages and / or containers known to those skilled in the art are also useful. In some embodiments, kits containing multiple unit formulations described herein are also provided. In some embodiments, the kit may further include syringes. Typically, one or more (e.g., one) unit formulations are used to satisfy a desired single dose. In some embodiments, the disclosure provides abiraterone prodrug formulations that enable multiple single-use doses. In some embodiments, the disclosure also provides abiraterone prodrug formulations that are divisible into multiple unit formulations.

[0073] Specific prescription examples In some embodiments, the Disclosure also provides several specific abiraterone prodrug formulations, which in some embodiments may be a single formulation or multiple unit formulations. For example, the following tables (Tables A and B) show several representative abiraterone ester prodrug formulations in oily solvents. All numerical values ​​in the tables should be understood as being preceded by the term “approximately”. The concentration of the abiraterone prodrug is expressed as the amount of abiraterone prodrug in mg per ml of the final formulation, which may be a solution or a suspension. The amounts of oil (primary solvent) and co-solvent in the tables are expressed as volume percentages of the solvent containing both the oil and the co-solvent. Suitable oils include any pharmaceutically acceptable oil as described herein. Suitable co-solvents also include any alcohol, ester and / or acid, such as benzyl alcohol, benzyl benzoate, or a combination thereof (see, for example, Table B). An example of a suitable co-solvent is benzyl alcohol. A suitable co-solvent is a combination of benzyl alcohol and benzyl benzoate. In some embodiments, the co-solvent is not included in the formulation. In some embodiments, the co-solvent does not include benzyl benzoate. Other optional components are also described herein. [Table 1]

[0074] As shown in Figures 13A–13E and the Examples section, benzyl alcohol and / or benzyl benzoate can improve the solubility of the abiraterone prodrug of this disclosure in oily solvents such as corn oil, and can reduce the viscosity and glide force of various oily solvents, including corn oil, sesame oil, peanut oil, cottonseed oil, and Miglyol 812 (a medium-chain triglyceride, mainly a mixture of caprylic / capric triglycerides). In some embodiments, this disclosure provides abiraterone prodrug formulations comprising an abiraterone prodrug and a pharmaceutically acceptable carrier, where the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil (e.g., as described herein), benzyl alcohol, and benzyl benzoate. In some embodiments, the abiraterone prodrug may be abiraterone decanoate. In some embodiments, the abiraterone prodrug may be abiraterone isocaproate. pharmaceutically acceptable oils typically contain triglycerides derived from fatty acids. In some embodiments, pharmaceutically acceptable oils may be natural oils, synthetic oils, or semi-synthetic oils such as fractionated coconut oil and medium-chain triglycerides, such as those marketed under the trademark Miglyol. In some embodiments, pharmaceutically acceptable oils may be selected from vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil. In some embodiments, the present disclosure provides certain exemplary formulations shown in Table B. [Table 2]

[0075] In some embodiments, the disclosure also provides a castor oil solution of abiraterone acetate at a concentration of about 50 mg / mL to about 200 mg / mL (e.g., 70 mg / mL); a 10% v / v benzyl alcohol / 90% v / v castor oil solution of abiraterone acetate at a concentration of about 50 mg / mL to about 200 mg / mL (e.g., 90 mg / mL); a 50% v / v benzyl benzoate / 50% v / v castor oil solution of abiraterone acetate at a concentration of about 50 mg / mL to about 200 mg / mL (e.g., 125 mg / mL); and about 50 mg g / mL to approximately 300 mg / mL (e.g., 200 mg / mL) concentration of abiraterone propionate in a 10% v / v benzyl alcohol / 90% v / v castor oil solution; approximately 50 mg / mL to approximately 300 mg / mL (e.g., 168 mg / mL) concentration of abiraterone propionate in a 10% v / v benzyl alcohol / 90% v / v corn oil solution; approximately 100 mg / mL to approximately 300 mg / mL (e.g., 160 mg / mL or 170 mg / mL) concentration of abiraterone decanoate in a castor oil solution; approximately 100 mg Corn oil solution of aviraterone decanoate at a concentration of approximately 300 mg / mL (e.g., 160 mg / mL or 170 mg / mL); 10% v / v benzyl alcohol / 90% v / v castor oil solution of aviraterone decanoate at a concentration of approximately 100 mg / mL to approximately 300 mg / mL (e.g., 160 mg / mL or 170 mg / mL); 10% v / v benzyl alcohol / The disclosure provides certain formulations such as a 90% v / v corn oil solution; a 70% v / v corn oil, 10% v / v benzyl alcohol, and 20% v / v benzyl benzoate solution of abiraterone decanoate at a concentration of about 150 mg / mL to about 300 mg / mL (e.g., 200 mg / mL or 240 mg / mL); and a 90% v / v corn oil, 10% v / v benzyl alcohol solution of abiraterone isocaproate at a concentration of about 120 mg / mL to about 200 mg / mL (e.g., 150 mg / mL or 160 mg / mL). In some embodiments, the disclosure also provides any of the specific formulations prepared herein, such as Examples 3A-3J and 9. In some embodiments, the disclosure also provides the formulation described herein in Example 1.Where used herein, if the solvent system of an abiraterone prodrug formulation contains two or more solvents (including oils), the abiraterone prodrug formulation may be expressed at a specific concentration as a solution of abiraterone prodrug in a solvent system of x% oil and y% co-solvent (e.g., 90% corn oil and 10% benzyl alcohol). In such expressions, x% and y% should be understood to be based on volume percentages, whether followed by "v / v" or not, unless otherwise specifically stated or clearly contrary to the context.

[0076] Formulations containing substantially pure abiraterone prodrug In some embodiments, the disclosure also provides pharmaceutical compositions comprising substantially pure abiraterone prodrugs. For example, in some embodiments, the pharmaceutical composition comprises substantially pure compounds of formula I or II described herein, or pharmaceutically acceptable salts thereof, dispersed or dissolved in a pharmaceutically acceptable carrier.

[0077] In some embodiments, the pharmaceutical composition comprises a substantially pure compound of formula I in a free base form dispersed or dissolved in a pharmaceutically acceptable carrier. [ka] R in the formula 1 R 10 , OR 10 or NHR 10 And, In the formula, R 10 C 7-30 Alkyl; C 7-30 Alkenil; C 7-30 Alkynyl; alkyl groups substituted with cycloalkyl groups having a total of 5 to 16 carbon atoms; alkyl groups substituted with phenyl groups having a total of 7 to 16 carbon atoms; cycloalkyl groups optionally substituted with one or more alkyl groups having a total of 5 to 16 carbon atoms; and [ka] Selected from.

[0078] To avoid misunderstanding, a pharmaceutical composition containing a substantially pure compound of formula I and one or more other components should be understood as a mixture of the substantially pure compound of formula I and one or more other components, for example, such a pharmaceutical composition can be obtained directly or indirectly by mixing (e.g., dissolving, suspending, or otherwise forming a mixture) a substantially pure compound of formula I with one or more other components such as pharmaceutically acceptable oils, solvents, etc. Also, to avoid misunderstanding, when a range of carbon numbers is enumerated, as will be understood by those skilled in the art, the carbon number includes each individual integer within that range and subranges of such integers. For example, "C" in this specification 7-16 " is C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 7-16 , C 7-15 , C 7-14 , C 7-13 , C 7-12 , C 7-11 , C 7-10 , C 7-9 , C 7-8 , C 8-16 , C 8-15 , C 8-14 , C 8-13 , C 8-12 , C 8-11 , C 8-10 , C 8-9 , C 9-16 , C 9-15 , C 9-14 , C 9-13 , C 9-12 , C 9-11 , C 9-10 , C 10-16 , C 10-15 , C 10-14 , C 10-13 , C 10-12 , C 10-11 , C 11-16 , C 11-15 , C 11-14 , C 11-13 , C 11-12 , C12-16 , C 12-15 , C 12-14 , C 12-13 , C 13-16 , C 13-15 , C 13-14 , C 14-16 , C 14-15 , and C 15-16 This includes [specific ranges]. It should be understood that the same applies to other ranges described herein, such as "5 to 16 carbon atoms."

[0079] A substantially pure compound of formula I may typically be characterized by having a purity of at least 95%, preferably at least 98%, for example, about 98.5%, about 99%, or about 99.5% or higher relative to weight. In some embodiments, a substantially pure compound of formula I may be characterized by a purity of about 95%, about 97%, about 99%, about 99%, about 99.5%, about 99.9%, or any range of specified values ​​relative to weight and / or HPLC area. In some embodiments, a substantially pure compound of formula I may be characterized by a purity of about 95%, about 97%, about 99%, about 99%, about 99.5%, about 99.9%, or any range of specified values ​​relative to weight. Methods for measuring the purity of a compound relative to weight are known in the art and are illustrated herein. For example, such purity relative to weight can be measured by HPLC using an appropriate criterion. In any of the embodiments described herein, unless otherwise specifically stated or clearly contrary to the context, purity relative to weight may be measured by HPLC, for example, the purity relative to weight of abiraterone decanoate may be measured using HPLC method 1 as described herein.

[0080] In some embodiments, the compounds of formula I described herein are prepared from abiraterone starting materials containing ethyl plasterone as an impurity. Since ethyl plasterone, like abiraterone, can also form ester, carbamate, or carbonate ester forms, in some embodiments, the compounds of formula I prepared herein may contain a certain amount of impurities derived from ethyl plasterone. In some embodiments, substantially pure compounds of formula I may be characterized by having less than 2% by weight of such impurities derived from ethyl plasterone, for example, the corresponding ethyl plasterone derivative having formula III-1. [ka] R in the formula 1 The term "corresponding ethyl plasterone derivative" means, for a given substantially pure compound of formula I, R in formula III-1. 1 The group is R of a compound of formula I that is practically pure. 1 It should be understood as being equivalent to the base. Typically, the ethyl plasterone derivative of formula III-1, if present, can be purified to a level of less than 1% by weight, for example, less than 0.5%, less than 0.3%, less than 0.2%, or less than 0.1% by weight. The amount of the ethyl plasterone derivative can be readily measured by HPLC methods such as those described herein. In some embodiments, the compound of formula I may be further prepared from abiraterone starting materials that do not contain ethyl plasterone, resulting in a product that is completely free of impurities derived from ethyl plasterone.

[0081] In some embodiments, the pharmaceutical composition comprises a substantially pure compound of formula II (e.g., as defined herein) in a free base form dispersed or dissolved in a pharmaceutically acceptable carrier. In some embodiments, the compound of formula II herein is prepared from an abiraterone starting material containing ethyl plasterone as an impurity. Since ethyl plasterone, like abiraterone, can also form ester, carbamate, or carbonate forms, in some embodiments the compound of formula II prepared herein may contain a certain amount of impurities derived from ethyl plasterone. In some embodiments, a substantially pure compound of formula II may be characterized by having less than 2% by weight of such impurities derived from ethyl plasterone, e.g., the corresponding ethyl plasterone derivative having formula III-2. [ka] R in the formula 2 The term is defined above in this specification. Similarly, the phrase "corresponding ethyl plasterone derivative" means, for a given substantially pure compound of formula II, R in formula III-2. 2 The group is R of a compound of formula II that is practically pure. 2 It should be understood as being equivalent to the base. Typically, the ethyl plasterone derivative of formula III-2, if present, can be purified to a level of less than 1% by weight, for example, less than 0.5%, less than 0.3%, less than 0.2%, or less than 0.1% by weight. The amount of the ethyl plasterone derivative can be easily measured by HPLC methods such as those described herein. In some embodiments, the compound of formula II may be further prepared from abiraterone starting materials that do not contain ethyl plasterone, resulting in a product that is completely free of impurities derived from ethyl plasterone.

[0082] A pharmaceutically acceptable carrier suitable for a pharmaceutical composition comprising a substantially pure compound of formula I or II (e.g., abiraterone decanoate) includes any of the carriers described herein. Typically, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable oil (e.g., as described herein) and optionally, a further pharmaceutically acceptable solvent (e.g., as described herein). For example, in some embodiments, the pharmaceutically acceptable oil includes triglycerides (e.g., long-chain and / or medium-chain triglycerides), and the further pharmaceutically acceptable solvent, if present, includes alcohols, esters and / or acidic solvents. In some embodiments, the pharmaceutically acceptable oil is selected from vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil, and the further pharmaceutically acceptable solvent, if present, includes benzyl alcohol, benzyl benzoate, or a combination thereof. In some embodiments, pharmaceutically acceptable carriers include corn oil, benzyl alcohol, and benzyl benzoate. The pharmaceutical composition typically contains a compound of formula I or II at a concentration of about 25 mg / ml to about 500 mg / ml (e.g., about 25 mg / ml, about 50 mg / ml, about 100 mg / ml, about 150 mg / ml, about 200 mg / ml, about 250 mg / ml, about 300 mg / ml, about 400 mg / ml, about 500 mg / ml, or any range of the values ​​described, e.g., about 100 mg / ml to about 300 mg / ml).

[0083] Pharmaceutical compositions comprising substantially pure compounds of formula I or II (e.g., abiraterone decanoate) are typically formulated for parenteral administration. For example, in some embodiments, the pharmaceutical composition is formulated for intramuscular, intradermal, or subcutaneous injection with, for example, a desired viscosity, glide force, particulate count, endotoxin, etc. In some embodiments, the pharmaceutical composition is (1) 0.1 Pa * Less than s, for example, about 0.05 Ps *(2) Viscosity of s or less; (2) Glide force of approximately 5 to 15 N when measured using a 23 gauge (or 23 G) and 1.5 inch needle, and / or glide force of approximately 30 to 150 N when measured using a 27 G and 1.5 inch needle; (3) USP <788> and / or <789> When measured according to (4) USP <85> It is characterized by having bacterial endotoxins of less than 100 EU / ml, for example, less than 25 EU / ml, as measured according to the USP method. Methods for measuring viscosity and glide force are known in the art and are exemplified herein in Example 9. <788> , <789> and <85> This should be understood as the current version of the method, as known to those skilled in the art.

[0084] Treatment methods Some embodiments of this disclosure relate to methods for delivering abiraterone to patients who need it. In various embodiments, this disclosure also provides methods for treating or preventing diseases or conditions in which the administration of abiraterone is beneficial.

[0085] In some embodiments, the Disclosure provides a method for delivering abiraterone to a patient in need thereof, the method comprising administering to the patient either an abiraterone prodrug or an abiraterone prodrug formulation of the Disclosure. In some embodiments, the patient suffers from a sex hormone-dependent benign or malignant disease, such as an androgen-dependent or estrogen-dependent disease, as described herein. In some embodiments, the patient suffers from a syndrome resulting from androgen excess and / or a syndrome resulting from glucocorticoid excess, such as hypercortisolemia, as described herein. In any of the embodiments described herein, the patient may be a human subject, such as a human patient having a hormone-dependent benign or malignant disease, a syndrome resulting from androgen excess, and / or a syndrome resulting from glucocorticoid excess, such as hypercortisolemia, unless directly contradictory. When used in the present invention, hormone-dependent benign or malignant disease should be understood as a sex hormone-dependent benign or malignant disease, such as an androgen-dependent or estrogen-dependent disease, whether or not the term “sex” precedes it.

[0086] As detailed herein, PK studies in monkeys have shown that a single intramuscular injection of the representative abiraterone prodrug, abiraterone decanoate, can achieve long-term CYP17A1 inhibition accompanied by sustained elevated progesterone levels for up to 8 weeks, as well as decreased cortisol and testosterone levels. As shown in Figure 14D, inhibition of CYP17A1 17α-hydroxylase and C17,20-lyase activity is expected to result in (1) elevated progesterone and mineralocorticoid levels; (2) decreased glucocorticoid levels such as cortisol; and (3) decreased levels of sex hormones, such as androgens including testosterone and dihydrotestosterone, and estrogens such as estradiol. Further confirmation of these initial findings in PK / PD studies in chemically castrated monkeys revealed that a single dose of representative abiraterone prodrugs, abiraterone decanoate, at doses of 10 mg / kg, 30 mg / kg, or 100 mg / kg resulted in sustained CYP17A1 inhibition, as evidenced by sustained elevated progesterone levels for up to 70 days or more, and decreased cortisol, dihydrotestosterone, and testosterone levels. It was also observed that the PD effect persisted even after plasma abiraterone concentrations fell to less than 1 ng / mL in the 10 mg / kg dose group. While we do not wish to be constrained by theory, the observed persistence of these PD effects may be partly due to the slow and strong binding of abiraterone to CYP17A1, which may effectively achieve irreversible inhibition of CYP17A1. For example, see Cheong EJY, et al. J. Pharmacol. Exp. Ther. 374:438-451 (2020).Thus, the abiraterone prodrugs and prodrug formulations of the present disclosure can be advantageously used for the treatment of diseases associated with inhibition of CYP17A1 activity, reduction of glucocorticoid levels such as cortisol levels, reduction of sex hormone levels such as androgen and estrogen levels, and / or diseases associated with high glucocorticoid levels such as cortisol levels, and / or diseases caused by high sex hormone levels such as androgen and estrogen levels.

[0087] In some embodiments, the present disclosure provides a method of inhibiting CYP17A1 activity, such as inhibiting 17α-hydroxylase activity and 17,20-lyase activity, the method comprising administering to a patient either an abiraterone prodrug of the present disclosure or an abiraterone prodrug formulation. In some embodiments, the patient has, for example, a sex hormone-dependent benign or malignant disease as described herein. In some embodiments, the patient has, for example, a syndrome caused by androgen excess and / or a syndrome caused by glucocorticoid excess such as hypercortisolism as described herein.

[0088] In some embodiments, the present disclosure provides a method of reducing the level of a glucocorticoid (e.g., cortisol) in a patient who needs it, the method comprising administering to the patient either an abiraterone prodrug of the present disclosure or an abiraterone prodrug formulation. In some embodiments, the patient has a syndrome caused by glucocorticoid excess such as hypercortisolism as described herein, such as Cushing's syndrome or Cushing's disease.

[0089] In some embodiments, the present disclosure provides a method of reducing the level of androgen (e.g., testosterone and / or dihydrotestosterone) and / or estrogen in a patient who needs it, the method comprising administering to the patient either an abiraterone prodrug of the present disclosure or an abiraterone prodrug formulation. In some embodiments, the patient suffers from syndromes caused by androgen excess, such as congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), endometriosis, polycystic ovary syndrome with premature puberty, hirsutism, etc. In some embodiments, the patient suffers from androgen- and / or estrogen-related cancers, such as prostate cancer or breast cancer.

[0090] In some embodiments, methods of treating sex hormone-dependent benign or malignant diseases, syndromes caused by androgen excess, and / or syndromes caused by glucocorticoid excess, such as hypercortisolism, are provided. Typically, the method comprises administering to a patient who needs it either a therapeutically effective amount of an abiraterone prodrug of the present disclosure or an abiraterone prodrug formulation. In any of the embodiments described herein, unless directly contradictory, the patient can be a human subject, e.g., a human patient having a hormone-dependent benign or malignant disease, a syndrome caused by androgen excess, and / or a syndrome caused by glucocorticoid excess, such as hypercortisolism, as described herein.

[0091] In some embodiments, the patient may be untreated with chemotherapy or hormone therapy before being administered the pharmaceutical composition herein. However, in some embodiments, the patient may also be treated with chemotherapy or hormone therapy before being administered the pharmaceutical composition herein. For example, in some embodiments, the patient may suffer from a disease or disorder (e.g., prostate cancer) that has progressed during or after chemotherapy and / or hormone therapy, such as docetaxel-based chemotherapy.

[0092] The administration method described herein is not limited to any particular route. However, in some preferred embodiments, the administration may be parenteral, such as intramuscular, intradermal, or subcutaneous injection. Parenteral administration may be advantageous in some embodiments. For example, in some embodiments, the administration may be parenteral, such as intramuscular injection, which can be performed regardless of whether the patient has eaten, and therefore, in some embodiments, the abiraterone prodrug or abiraterone prodrug formulation of this disclosure can be administered to the patient regardless of meals. In other words, it is not important whether the patient has eaten or is hungry. This eliminates the restriction of currently marketed Zytiga® formulations, which state that the drug "must be taken with water at least one hour before a meal or two hours after a meal on an empty stomach." Thus, among other advantages, the method described herein can also improve patient adherence to medication.

[0093] The usage and dosage of the methods described herein are not particularly limited and include any of those described herein. Typically, the methods described herein involve administering the abiraterone prodrug or abiraterone prodrug formulations herein at a frequency ranging from once a week to once every few months. As described in detail herein, a single dose of representative abiraterone prodrugs, abiraterone decanoate, at doses of 10 mg / kg, 30 mg / kg, or 100 mg / kg resulted in sustained CYP17A1 inhibition for up to 70 days or more in chemically castrated monkeys. This result further supports the less frequent dosing schedules described herein. In some specific embodiments, the methods described herein involve administering the abiraterone prodrug or abiraterone prodrug formulations herein at a frequency ranging from once a month to once every few months, for example, once a month, once every two months, once every three months, or less. The dose of the abiraterone prodrug specified herein (e.g., abiraterone decanoate) per administration is typically variable within the range of 0.5 mg / kg to 200 mg / kg of the patient's body weight, for example, about 0.5 mg to about 100 mg / kg (e.g., about 0.5 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 50 mg / kg, about 90 mg / kg, about 100 mg / kg, or any range of the values ​​described). In some embodiments, the administration results in (a) a plasma concentration of abiraterone greater than 1.0 ng / ml over a period of at least 2 weeks from a single dose (e.g., up to 10 weeks or more); and (b) a single dose of abiraterone at about 10 ng / ml to about 400 ng / ml or a steady state C max ; or any of the pharmacokinetic profiles described herein, such as (c)(a) and (b).

[0094] Various sex hormone-dependent benign or malignant diseases can be treated by the methods described herein. In some embodiments, the hormone-dependent benign or malignant disease may be androgen-dependent and estrogen-dependent diseases, such as androgen or estrogen-dependent cancers. In some embodiments, the sex hormone-dependent benign or malignant disease may be prostate cancer or breast cancer. In some embodiments, the sex hormone-dependent benign or malignant disease may be castration-resistant or castration-sensitive prostate cancer. In some embodiments, the sex hormone-dependent benign or malignant disease may be metastatic castration-resistant or metastatic castration-sensitive prostate cancer. In some embodiments, the sex hormone-dependent benign or malignant disease may also be ovarian cancer, bladder cancer, hepatocellular carcinoma, or lung cancer. For example, various non-tumor syndromes resulting from androgen excess and / or glucocorticoid excess, such as hypercortisolemia, including syndromes caused by androgen excess such as endometriosis, polycystic ovary syndrome, classical or non-classical congenital adrenal hyperplasia, precocious puberty, and hirsutism, and / or syndromes caused by cortisol excess such as Cushing's syndrome and Cushing's disease, can also be treated by the methods of this specification.

[0095] In some specific embodiments, the methods described herein are for the treatment of prostate cancer. Prostate cancers suitable for treatment by the methods described herein are not particularly limited, but include any prostate cancer in which the manufacture and sale of abiraterone or its derivatives (e.g., abiraterone acetate) has been approved (e.g., in the United States or Europe), or which is in or after a clinical trial in which abiraterone or its derivatives (e.g., abiraterone acetate) is registered on the website clinicaltrials.gov at the time of filing of this application. For example, in some embodiments, prostate cancer may be primary / localized prostate cancer (newly diagnosed or early), advanced prostate cancer (e.g., recurrent prostate cancer, post-castration such as locally advanced prostate cancer), recurrent prostate cancer (e.g., prostate cancer that did not respond to first-line therapy), non-metastatic castration-resistant prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer (CRPC), or hormone-sensitive prostate cancer. In some embodiments, prostate cancer may be localized prostate cancer, e.g., high-risk localized prostate cancer. In some embodiments, patients with prostate cancer are characterized by an increased amount of prostate-specific antigen, for example, after radical prostatectomy. In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer, non-metastatic castration-resistant prostate cancer, or metastatic castration-resistant prostate cancer. In some embodiments, the prostate cancer is newly diagnosed high-risk metastatic hormone-sensitive prostate cancer. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC), where the patient is asymptomatic or mildly symptomatic after failure of androgen deprivation therapy, for which there is no clinical need for chemotherapy. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC), where the patient's disease progresses during or after a docetaxel-based chemotherapy regimen. In some embodiments, the prostate cancer is refractory prostate cancer. As used herein, and unless otherwise specified, the term “refractory prostate cancer” means prostate cancer that does not respond to or does not respond adequately to anticancer therapies. Refractory prostate cancer may also include recurrent or recurrent prostate cancer.As used herein and unless otherwise specified, the term “recurrent prostate cancer” means prostate cancer that has responded to anticancer treatment once but has become unresponsive to such treatment or is no longer responding adequately to such treatment. As used herein and unless otherwise specified, the term “recurrent (or recurrent) prostate cancer” means prostate cancer that has recurred after a patient has been previously diagnosed with and treated for prostate cancer, or after being previously diagnosed as not having cancer.

[0096] In some embodiments, the methods described herein are for treating breast cancer. The types of breast cancer suitable for treatment by the methods described herein are not particularly limited. For example, in some embodiments, the breast cancer may be molecular apocrine HER2-negative breast cancer, metastatic breast cancer, such as ER+ metastatic breast cancer, ER+ and HER2-negative breast cancer, or AR+ triple-negative breast cancer.

[0097] In some embodiments, the disease or disorder is related to 21-hydroxylase deficiency and can be treated by the methods described herein.

[0098] In some embodiments, the methods described herein are for treating patients with cancers such as prostate cancer, breast cancer, adrenal cancer, leukemia, lymphoma, myeloma, Waldenström macroglobulinemia, monoclonal gammaglobulinemia, benign monoclonal gammaglobulinemia, heavy chain disease, bone and connective tissue sarcoma, brain tumor, thyroid cancer, pancreatic cancer, pituitary cancer, eye cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, bile duct cancer, lung cancer, testicular cancer, penile cancer, oral cancer, skin cancer, kidney cancer, Wilms' tumor, and bladder cancer.

[0099] The methods described herein can be used in combination with one or more additional therapies for the corresponding disease or disorder. For example, the label on Zytiga® (abiraterone acetate) states that patients taking Zytiga® must also be taking a gonadotropin-releasing hormone (GnRH) analog or have already undergone bilateral orchiectomy. Accordingly, in some embodiments of the methods of this disclosure, the patient may be treated with a gonadotropin-releasing hormone analog and / or bilateral orchiectomy. In some embodiments, the method also includes administering an effective amount of prednisone or prednisolone to the patient simultaneously or sequentially. However, in some embodiments, the methods described herein can also achieve the desired therapeutic effect without causing adrenal insufficiency, thereby avoiding the simultaneous administration of prednisone or prednisolone. In some embodiments, the patient is not treated with a gonadotropin-releasing hormone analog and / or bilateral orchiectomy. In some embodiments, the patient is not treated with prednisone or prednisolone.

[0100] In some embodiments, the methods described herein, for example, for treating breast cancer, may further include administering an aromatase inhibitor, such as exemestane, to the patient.

[0101] In some embodiments, the method may involve administering one or more other drugs or agents (e.g., another cancer chemotherapy agent, hormone replacement agent, or hormone removal agent) to the patient simultaneously or sequentially via the same or different routes of administration. In some embodiments, the other drugs or agents may be steroids such as prednisone, prednisolone, and / or methylprednisolone. In some embodiments, the other drugs or agents may be chemotherapy agents such as paclitaxel, mitoxantrone, and / or docetaxel. In some embodiments, the other drugs or agents may be GnRH agonists such as leuprolide, deslorerin, goserelin, or triptorelin, e.g., leuprolide acetate (e.g., long-acting IM injection formulation). In some embodiments, the other drugs or agents may be glucocorticoids including theocalcitol, bicalutamide, flutamide, but not limited to hydrocortisone, prednisone, prednisolone, or dexamethasone. The amount of other drugs or medications administered may be modified and may typically be an effective amount to treat the corresponding disease or condition (e.g., prostate cancer) either alone or in combination with the abiraterone prodrug or abiraterone prodrug formulations of this disclosure.

[0102] Other suitable drugs or agents include, but are not limited to, those described herein. For example, other useful drugs or agents include, anticancer agents, hormone scavengers, antiandrogens, differentiation agents, antitumor agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotics, immunotherapies, interferon-type agents, inserts, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloproteinase inhibitors, gene therapies, and antiandrogens.

[0103] For example, suitable anticancer agents include acemannan, acralubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, amsacrin, anagrelide, anastrozole, ancestim, bexarotene, proxuridine, capecitabine, cermoleukin, cetrorelix, cladribine, clotrimazole, daclizumab, dexrazoxane, dilazep, docosanol, doxifluridine, bromocriptine, carmustine, cytarabine, and diclofena. Edelfosine, Edrecolomab, Efronitine, Emitefur, Exemestane, Exislind, Fadrozol, Filgrastim, Finasteride, Fludarabine Phosphate, Formestan, Fotemustine, Gallium Nitrate, Gemcitabine, Glycopine, Heptaplatin, Ibandronate, Imiquimod, Yobenguan, Irinotecan, Ilsogladine, Lanreotide, Leflunomide, Lenograstim, Lentinan Sulfate, Letrozole, Rialozol, Lovaplatin, Ronidamin, Masoproco Melalsoprole, Metoclopramide, Mifepristone, Miltefosine, Millimostim, Mitoguazone, Mitractol, Morglamostim, Nafarelin, Naltograstim, Nedaplatin, Nilutamide, Noscapine, Oprelbequin, Osateron, Oxaliplatin, Pamidronic acid, Pegasparagase, Pentosan sodium polysulfate, Pentostatin, Picibanil, Pirarubicin, Porfimer sodium, Raloxifene, Larcitrexed, Rasburicase, Rituximab Examples of suitable antiandrogens include, but are not limited to, lomultide, salglamostim, schizophyllan, sobuzoxane, sonelmin, suramin, tasonelmin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfacin, thyrotropin alfa, topotecan, toremifene, trastuzumab, treosulfan, tretinoin, trilostane, trimethrexate, ubenimex, barrubicin, verteporfin, and vinorelbine. Suitable antiandrogens include, but are not limited to, bicalutamide, flutamide, and nilutamide.Suitable differentiation agents include, but are not limited to, polyamine inhibitors; vitamin D and its analogues such as calcitriol, doxelcalciferol, and theocalcitol; vitamin A metabolites such as ATRA, retinoic acid, and retinoids; short-chain fatty acids; phenylbutyrate; and nonsteroidal anti-inflammatory drugs.Antitumor agents include tubulin interaction agents, topoisomerase inhibitors and drugs, acitretin, alstonin, amonafide, amfetinil, amsacrin, ankinomycin, antineoplaston, aphydicolin glycinate, asparaginase, baccharin, batracillin, benflurone, benzotrypto, bromophosphamide, chalasemide, carmethizol hydrochloride, chlorsulfaquinoxalone, cranfenuol, claviridenon, cristatol, claderm, cytarabine, cytocytin, dacarbazine, dateliptinium, dihematoporphyrin ether, dihydrolenperone, dinarin, distamycin, docetaxel, and eripravin. , erliptinium acetate, epotilon, ergotamine, etoposide, etretinate, fenretinide, gallium nitrate, genquadahunin, hexadecylphosphocholine, homohalingtonin, hydroxyurea, ylmofosin, isoglutamine, isotretinoin, leucolegurin, ronidamin, melbaron, merocyanine derivatives, methylanilinoacridine, minactibin, mitonafid, mitokidone, mitoxantrone, mopidamol, motoretinide, N-(retinoyl) amino acids, N-acylated dehydroalanine, naphazatrom, nocodazole derivatives, ocreotide, oxanosine, paclitaxel, pancratistatin, pazeriptin, pyroxantrone, polyhematoporphyrin, polyprenic acid Examples of kinase inhibitors include, but are not limited to, p38 inhibitors and CDK inhibitors, TNF inhibitors, metal matrix protease inhibitors (MMPs), COX-2 inhibitors (including celecoxib, rofecoxib, parecoxib, vardecoxib, and etoricoxib), SOD mockuids, or α. vExamples include β3 inhibitors. Suitable antimetabolites may be selected from, but are not limited to, 5-FU-fibrinogen, acanthiolic acid, aminothiadiazole, brackinal sodium, carmofur, cyclopentylcytosine, cytarabine stearate phosphate, cytarabine complex, dezaguanine, dideoxycytidine, dideoxyguanosine, zidox, doxifluridine, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2′-flanidyl)-5-fluorouracil, isopropylpyrrolidine, metobenzaprim, methotrexate, norspermidine, pentostatin, pyritrexime, plicamycin, thioguanine, thiazophrine, trimethrexate, tyrosine kinase inhibitors, and uricitine. Suitable alkylating agents may be selected from, but are not limited to, aldofsphamide analogs, altoretamine, anaxylone, bestrabusil, budotitan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, ciplatate, diphenylspiromustine, cell proliferation inhibitory diplatinum (diplatinum cytostatic), ermustine, estramustine sodium phosphate, fotemustine, hepsulfame, ifosfamide, iproplatin, lomustine, maphosphamide, mitractol, oxaliplatin, prednimustine, ranimustine, semustine, spiromustine, tauromustine, temozolomide, teroxylone, tetraplatin, and trimelamol.Suitable antibiotics include acralubicin, actinomycin D, actinoplanon, adriamycin, aeropricinin derivatives, amrubicin, anthracyclines, azinomycin A, viscabelin, bleomycin sulfate, bryostatin-1, calikemycin, chromoximycin, dactinomycin, daunorubicin, ditrisarubicin B, dexamethasone, doxorubicin, doxorubicin-fibrinogen, erusamycin-A, epirubicin, erbustatin, esorubicin, esperamycin-A1, esperamycin-A1b, fostoliesin, glidobactin, glegatin-A. Corticosteroids such as glinkamycin, herbimycin, and hydrocortisone, idarubicin, ilidine, kazusamycin, kesarirosin, menogalil, mitomycin, neoenactin, oxalisin, oxaunomycin, peplomycin, pyratin, pirarubicin, polosuramycin, prednisone, prednisolone, pirindanisin A, rapamycin, rhizoxin, rhodorubicin, sibanomycin, siwenmycin, solandisin-A, sparsomycin, tarisomycin, terpentesin, soladine, triclozarin A, and zolubicin may be selected, but are not limited to these. Non-limiting examples of preferred steroids include hydrocortisone, prednisone, prednisolone, or dexamethasone.

[0104] Combination therapy for prostate cancer Treatment for prostate cancer often involves multiple therapies, such as radiotherapy, surgery, androgen deprivation therapy, hormone therapy, chemotherapy, immunotherapy, and various combination formulations. A search of the website clinicaltrials.gov reveals over 250 clinical trials with abiraterone / abiraterone acetate listed as the intervention, the vast majority of which involve combination therapy for the treatment of prostate cancer. As discussed herein, compared to oral abiraterone acetate formulations, the abiraterone prodrugs herein can result in improved bioavailability, elimination of the effects of food, reduced burden of administration, decreased frequency of administration, and sustained effective plasma levels of abiraterone, as well as the maintenance of elevated progesterone levels for up to 70 days or more after administration of the abiraterone prodrug formulation, and long-term CYP17A1 inhibition accompanied by decreased cortisol, dihydrotestosterone, and testosterone levels. These excellent pharmacokinetic and / or pharmacodynamic profiles make the abiraterone prodrugs described herein advantageous for use in a variety of combination therapies to replace or complement oral administration of abiraterone acetate.

[0105] In some embodiments, the Disclosure provides a method for treating prostate cancer (e.g., any of those described herein) in a patient in need of such treatment using combination therapy, the method comprising administering to the patient a therapeutically effective amount of the abiraterone prodrug (e.g., abiraterone decanoate) or abiraterone prodrug formulation herein, and one or more additional therapeutic agents. The one or more additional therapeutic agents may be administered to the patient simultaneously or sequentially in any order with the administration of the abiraterone prodrug or abiraterone prodrug formulation herein, via the same or different routes of administration. In some embodiments, the method herein comprises treating the patient with radiotherapy or surgery. In some embodiments, the method involves administering to a patient one or more other agents selected from anticancer agents, hormone depletion agents, antiandrogens, differentiation agents, antitumor agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotics, immunotherapies, interferon-type agents, inserts, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloproteinase inhibitors, gene therapies, or combinations thereof. In some embodiments, the method involves administering to a patient one or more other agents selected from chemotherapeutic agents, hormone replacement agents, or hormone depletion agents. In some embodiments, the method involves treating a patient with androgen depletion therapy. Many of the following combination therapies are described in relation to various treatments for prostate cancer, but the disclosure is not limited thereto. In some embodiments, the combination therapies described below may also be used to treat other diseases or disorders described herein, such as other cancers described herein.

[0106] In many specific embodiments, combination therapy typically involves administering glucocorticoids to the patient. For example, in some embodiments, the method involves administering one or more agents selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone to the patient.

[0107] Combination therapy may typically include androgen deprivation therapy, such as the administration of gonadotropin-releasing hormone (GnRH) analogs to the patient. Suitable GnRH analogs for combination therapy are not particularly limited and include both GnRH agonists and GnRH antagonists. For example, in some embodiments, the method may include administering to the patient a gonadotropin-releasing hormone (GnRH) agonist such as buserelin, leuprolide, deslorerin, fertilelin, histrelin, gonadrelin, recirelin, goserelin, nafarelin, peforelin, or triptorelin, and / or a GnRH antagonist such as abarelix, cetrorelinx, degarelix, ganirelix, elagolix, linzagolixa, or relugolix.

[0108] Inhibition of androgen receptor activity In some embodiments, combination therapy involves treating the patient to reduce androgen receptor (AR) activity, such as by using an AR antagonist or by downregulating or inhibiting AR activity.

[0109] In some embodiments, the method may include administering an androgen receptor (AR) antagonist to a patient. Various AR antagonists are known in the art and include, but are not limited to, first- and second-generation AR antagonists (see, e.g., Rice, M.A., et al. Front Oncol. 9:801 (2019)), and third-generation AR antagonists such as N-terminal domain inhibitors. In some embodiments, the method includes administering to the patient a first-generation androgen receptor antagonist including, but not limited to, proxalutamide, bicalutamide, flutamide, nilutamide, topralutamide, and the like. In some embodiments, the method includes administering to the patient a second-generation androgen receptor antagonist including, but not limited to, apalutamide, darolutamide, or enzalutamide, for example. In some embodiments, the method includes administering apalutamide to the patient. In some embodiments, the method includes administering enzalutamide to the patient. In some embodiments, the method includes administering to the patient a third-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. Patent Application Publication No. 2020 / 0123117, the contents of which are incorporated herein by reference. It should be noted that in embodiments where an AR antagonist is administered, one or more such antagonists selected from first, second, and third AR antagonists may be administered alone or in any combination.

[0110] In addition to agents that directly target androgen receptors, other methods and / or agents that modulate androgen receptor activity, including, for example, the modulation of upstream kinase activity and / or androgen receptor transcriptional activity, can also be used in the combination therapies described herein. For example, in some embodiments, the combination therapy may involve administering one or more upstream kinase modulators to the patient, which can reduce AR activity by activation or inhibition. Such upstream kinases are known in the art and are described, for example, in Shah, K. and Bradbury, NA, Cancer cell microenviron. 2(4):doi:10.14800 / ccm.1023 (2015), and Koul HK et al. Genes & Cancer 4(9-10):342-359 (2013). In some embodiments, the method involves administering to a patient 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, Ikappa B kinase 1 (IKK1) inhibitors, PIM-1 modulators, Lemur tyrosine kinase 2 (LMTK2) modulators, Lyn inhibitors, Aurora A inhibitors, ANPK (nucleoprotein A) inhibitors, extracellular signal-regulated kinase (ERK) modulators, c-jun N-terminal kinase (JNK) modulators, Big MAP kinase (BMK) modulators, p38 mitogen-activated protein kinase (MAPK) modulators, and combinations thereof. Suitable kinase modulators / inhibitors are not particularly limited and include any known ones such as monoclonal antibodies or their antigen-binding fragments, small molecule drugs, polypeptides including antibodies, RNA or DNA-based drugs, etc.

[0111] In some embodiments, combination therapy may involve administering to the patient a drug that downregulates AR or inhibits AR activity in other ways. While we do not wish to be bound by theory, AR activity may be affected at the genomic and / or transcriptional level of AR itself, or at the genomic and / or transcriptional level of upstream targets of AR and downstream targets regulated by AR, through the use of various molecules that interfere with transcription and / or translation (e.g., RNA silencing agents (e.g., antisense, siRNA, shRNA, microRNA), ribozymes, and DNAzymes), or at the protein level, through the use of, for example, antagonists, polypeptide-cleaving enzymes, or small molecules that interfere with protein activity (e.g., competitive ligands).

[0112] In some embodiments, downregulation of AR or inhibition of AR activity can be achieved via RNA silencing of target genes (e.g., AR or appropriate upstream and downstream targets of AR as described herein). As used herein, the term “RNA silencing” refers to a group of regulatory mechanisms mediated by RNA molecules that result in inhibition or “silencing” of the expression of the corresponding protein-coding gene (e.g., RNA interference (RNAi), transcriptional gene silencing (TGS), post-transcriptional gene silencing (PTGS), querying, co-repression, and translational repression). RNA silencing has been observed in many types of organisms, including plants, animals, and fungi.

[0113] As used herein, the term “RNA silencing agent” refers to RNA capable of specifically inhibiting or “silencing” the expression of a target gene. In some embodiments, RNA silencing agents can prevent the complete processing of mRNA molecules (e.g., complete translation and / or expression) via a post-transcriptional silencing mechanism. RNA silencing agents include non-coding RNA molecules, such as double-stranded RNAs containing paired strands, as well as precursor RNAs capable of producing such small non-coding RNAs. Exemplary RNA silencing agents include double-stranded RNAs (dsRNAs) such as small interfering RNAs (siRNAs), miRNAs, and shRNAs. In one embodiment, RNA silencing agents can induce RNA interference. In another embodiment, RNA silencing agents can mediate translational repression. The strands of double-stranded interfering RNA (e.g., siRNAs) may be ligated to form hairpin or stem-loop structures (e.g., shRNAs or sh-RNAs). Thus, as described, RNA silencing agents in some embodiments of this disclosure may also be short hairpin RNAs (shRNAs).

[0114] It will be understood that the RNA silencing agents in some embodiments of this disclosure are not limited to molecules containing only RNA, but also include chemically modified nucleotides and non-nucleotides.

[0115] In some embodiments, the RNA silencing agents provided herein may be functionally related to cell-permeable peptides. As used herein, “cell-permeable peptide” is a peptide comprising a short amino acid sequence (approximately 12–30 residues) or a functional motif that provides energy-independent (i.e., non-endocytosis) translocation properties related to the transport of membrane-permeable complexes across the plasma and / or nuclear membrane of cells.

[0116] In another embodiment, the RNA silencing agent may be a miRNA or a mimetic thereof. The terms “microRNA,” “miRNA,” and “miR” are synonymous and refer to a collection of non-coding single-stranded RNA molecules, approximately 19–28 nucleotides in length, that regulate gene expression. miRNAs are found in a wide range of organisms and have been shown to be involved in development, homeostasis, and disease pathogenesis. The term “microRNA mimetic” refers to synthetic non-coding RNA that can enter the RNAi pathway and regulate gene expression. miRNA mimetics may be designed to mimic the function of endogenous microRNAs (miRNAs) and may be designed as mature double-stranded molecules or mimetic precursors (e.g., pre-miRNAs).

[0117] Downregulation of AR or inhibition of AR activity can also be achieved by gene editing of target genes (e.g., AR or appropriate upstream and downstream targets of AR as described herein). Gene editing may be carried out, for example, using a clustered, regularly spaced short palindromic repeat CRISPR-CAS9 system. CRISPR-CAS9 systems have been described in the literature and may include, for example, CAS9 and guide RNA. Other gene editing techniques have also been described in the literature and may be used.

[0118] Another agent capable of downcontrolling a target (e.g., AR or appropriate upstream and downstream targets of AR as described herein) is a DNAzyme molecule capable of specifically cleaving the target mRNA transcript or DNA sequence. A DNAzyme is a single-stranded polynucleotide capable of cleaving both single-stranded and double-stranded target sequences (Breaker et al., Chemistry and Biology 1995;2:655; Santoro et al., Proc. Natl. Acad. Sci. USA 1997;943:4262). A common model of DNAzymes ("10-23" model) has been proposed. The "10-23" DNAzyme has a catalytic region of 15 deoxyribonucleotides flanked by two substrate recognition domains, each consisting of 7-9 deoxyribonucleotides. This type of DNAzyme can effectively cleave its substrate RNA at the purine:pyrimidine junction (Santoro et al., Khachigian, Curr. Opin. Mol. Ther. 2002;4:119-121).

[0119] Downcontrol of targets (e.g., ARs or appropriate upstream and downstream targets of ARs as described herein) may also be affected by using antisense polynucleotides that can specifically hybridize with mRNA transcripts encoding the target.

[0120] Another type of agent that can downcontrol a target (e.g., AR or appropriate upstream and downstream targets of AR as described herein) is a ribozyme molecule that can specifically cleave the mRNA transcript encoding the target. Ribozymes are increasingly being used for sequence-specific inhibition of gene expression by cleaving the protein encoding the mRNA of interest (Welch et al., Curr. Opin. Biotechnol. 1998;9:486-96).

[0121] Another agent that can downcontrol a target (e.g., AR or appropriate upstream and downstream targets of AR as described herein) is any molecule that binds to and / or cleaves the target. Such molecules may be antagonists of the target or inhibitory peptides of the target.

[0122] Another agent that may be used in accordance with some embodiments of this disclosure to downcontrol a target (e.g., an AR or appropriate upstream and downstream target of an AR as described herein) is a molecule that prevents target activation and / or substrate binding.

[0123] Another agent that may be used in accordance with some embodiments of this disclosure to downregulate AR or inhibit AR activity is androgen receptor degradation inducers, such as those based on proteolytic chimeric molecule (PROTAC) technology. See, for example, Kregel, S. et al. Neoplasia 22(2):111-119 (2020).

[0124] Another agent that may be used in accordance with some embodiments of this disclosure to downcontrol a target (e.g., AR or suitable upstream and downstream targets of AR as described herein) is for suppressing or downcontrolling the activation of the transcriptional activity of the target, more specifically the transcriptional activity of AR. For example, such an agent may interfere with the nuclear translocation of AR, downcontrol the protein level of AR, reduce hormone binding to AR, interfere with the recruitment of transcriptional cofactors (e.g., steroid receptor coactivator 1 (SRC1) and transcription mediator 2 (TIF2)), interfere with AR-DNA binding, e.g., binding to specific DNA response elements (ARE, or androgen response elements), inhibit the recruitment of AR to AR target gene enhancers, and / or inhibit AR-chromatin binding, etc., or otherwise inhibit DNA-binding-dependent or non-DNA-binding-dependent AR signaling pathways. Suitable agents that can inhibit or interfere with AR transcriptional activity include any of those known in the art that can inhibit or interfere with such activity, and any of the agents exemplified herein. For example, certain AR antagonists, such as first-generation AR antagonists (e.g., bicalutamide), are known to inhibit AR transcriptional activity by inhibiting AR nuclear translocation. Other drugs, such as arsenic compounds (e.g., arsenic trioxide), are also known to inhibit AR transcriptional activity. See, for example, Rosenblatt AE, et al, Mol. Endocrinol. 23(3):412-421 (2009).

[0125] In some embodiments, combination therapy may involve administering one or more chemotherapeutic agents to a patient. Suitable chemotherapeutic agents include any of those known in the art. In some embodiments, the method involves administering a taxane-based chemotherapeutic agent (e.g., docetaxel, cabazitaxel, paclitaxel, etc.) and / or a platinum-based chemotherapeutic agent (e.g., cisplatin, carboplatin, oxaliplatin, etc.) to a patient.

[0126] In some embodiments, the combination therapy may include treating the patient with radiotherapy. Appropriate radiotherapy includes any of those known in the art. In some embodiments, the method includes treating the patient with stereotactic body radiotherapy or neutron radiation.

[0127] In some embodiments, combination therapy may involve treating the patient with radium-223, for example, Xofigo (radium-223 dichloride) injections.

[0128] In some embodiments, combination therapy may involve administering one or more immunotherapeutic agents to the patient. Appropriate immunotherapies include any of those known in the art. In some embodiments, the method involves administering Sipuleucel-T to the patient. In some embodiments, the method involves administering an immune checkpoint inhibitor to the patient. For example, in some embodiments, the method involves administering an anti-PD-1 antibody such as pembrolizumab or nivolumab, and / or an anti-PD-L1 antibody such as avelumab or atezolizumab to the patient. In some embodiments, the method involves administering an anti-CTLA-4 antibody such as ipilimumab to the patient.

[0129] In some embodiments, combination therapy may involve administering one or more poly-ADP-ribose polymerase (PARP) inhibitors to the patient. In some embodiments, patients with prostate cancer also have DNA repair defects. In some embodiments, patients with prostate cancer do not have DNA repair defects. Suitable PARP inhibitors include any of those known in the art. For example, in some embodiments, the method involves administering a PARP inhibitor selected from niraparib, rucaparib, olaparib, talazoparib, veliparib, and fluzoparib to the patient.

[0130] In some embodiments, the combination therapy may involve administering one or more kinase inhibitors to the patient. In some embodiments, the patient is characterized by having abnormal levels of the corresponding kinase. In some embodiments, the kinase inhibitor can reduce the activity of the androgen receptor or is beneficial for cancer treatment. Suitable kinase inhibitors include any of those known in the art. For example, in some embodiments, the method involves administering to the patient a kinase inhibitor selected from sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivacertib, onvancertib, ipatasertib, afrecertib, alicertib, apitricib, and opaganib.

[0131] In some embodiments, combination therapy may involve administering one or more osteoprotective agents to the patient. In such embodiments, the patient is typically characterized by having prostate cancer with bone metastases (e.g., castration-resistant prostate cancer). Suitable osteoprotective agents include any of those known in the art. For example, in some embodiments, the method involves administering to the patient an osteoprotective agent selected from denosumab and zolendronic acid.

[0132] In some embodiments, combination therapy may involve administering to the patient one or more additional agents useful for the treatment of prostate cancer, either alone or in combination with abiraterone drugs such as the abiraterone prodrugs herein. Such additional agents are not particularly limited. For example, in some embodiments, the method includes: 1) an anti-IL23 targeted monoclonal antibody, e.g., tildrakizumab; 2) selenium 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 extraterminal domain (BET) inhibitor, e.g., CCS1477, INCB057643, alloblecib, ZEN-3694, or molyblecib (GSK525762); 7) an anti-CD105 antibody, e.g., TRC105 or carotuximab; 8) niclosamide; 9) an A2A receptor antagonist, e.g., A The treatment comprises administering to the patient a therapeutic agent selected from ZD4635; 10) phosphoinositide 3 kinase (PI3K) inhibitors, e.g., AZD-8186, buparisib, or dactrisib; 11) further nonsteroidal CYP17A1 inhibitors, e.g., ceviteronel; 12) antiprogestogens, e.g., onapristone; 13) navitoclax; 14) HSP90 inhibitors, e.g., onarespib (AT13387); 15) HSP27 inhibitors, e.g., OGX-427; 16) 5α-reductase inhibitors, e.g., dutasteride; 17) metformin; 18) AMG-386; 19) dextromethorphan; 20) theophylline; 21) hydroxychloroquine; and 22) lenalidomide.In some embodiments, combination therapy may involve administering to a patient 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, Ikappa B kinase 1 (IKK1) inhibitors, PIM-1 modulators, Lemur tyrosine kinase 2 (LMTK2) modulators, Lyn inhibitors, Aurora A inhibitors, ANPK (nucleoprotein kinase A) inhibitors, extracellular signal-regulated kinase (ERK) modulators, c-jun N-terminal kinase (JNK) modulators, Big MAP kinase (BMK) modulators, p38 mitogen-activated protein kinase (MAPK) modulators, and combinations thereof. In some embodiments, cell therapies, such as T cell-mediated cell therapy including central memory T cells, may be part of a combination therapy.

[0133] In some embodiments, the combination therapy includes: 1) poly(ADP-ribose) polymerase (PARP) inhibitors, including but not limited to olaparib, niraparib, lucaparib, and talazoparib; 2) androgen receptor ligand-binding domain inhibitors, including but not limited to enzalutamide, apalutamide, darolutamide, bicalutamide, nilutamide, flutamide, ODM-204, and TAS3681; 3) additional CYP17 inhibitors, including but not limited to galeterone, abiraterone, and abiraterone acetate; and 4) docetaxy Microtubule inhibitors, including but not limited to cell, paclitaxel, and cabazitaxel (XRP-6258); 5) PD-1 or PD-L1 modifiers, including but not limited to pembrolizumab, durvalumab, nivolumab, and atezolizumab; 6) Gonadotropin-releasing hormone agonists, including but not limited to cyproterone acetate and leuprolide; 7) Finasteride, dutasteride, tulosteride, bexrosteride, izonsteride, FCE28260, SKF105,111, and others. 5α-reductase inhibitors; 8) Vascular endothelial growth factor inhibitors, including but not limited to bevacizumab (Avastin); 9) Histone deacetylase inhibitors, including but not limited to OSU-HDAC42; 10) Integrin α-v-β3 inhibitors, including but not limited to vitaxin; 11) Receptor tyrosine kinase inhibitors, including but not limited to sunitumib; 12) Phosphodiyl tyrosine kinase inhibitors, including but not limited to alpelisib, buparisib, and idealisib. Nocitide 3 kinase inhibitors; 13) Anaplastic lymphoma kinase (ALK) inhibitors, including but not limited to crizotinib and alectinib; 14) Endothelin receptor A antagonists, including but not limited to ZD-4054; 15) Anti-CTLA4 inhibitors, including but not limited to MDX-010 (ipilimumab); 16) Heat shock protein 27 (HSP27) inhibitors, including but not limited to OGX427; 17) Androgen receptor degradation inducers, including but not limited to ARV-330 and ARV-110;18) Androgen receptor DNA-binding domain inhibitors, including but not limited to VPC-14449; 19) Bromodomain and extra-terminal motif (BET) inhibitors, including but not limited to BI-894999, GSK525762, and GS-5829; 20) Androgen receptor N-terminal domain inhibitors, including but not limited to syntocamide; 21) Radiotherapeutic agents that emit alpha particles, including but not limited to radium-233 or salts thereof; 22) Closamide; or related compositions; 23) Selective estrogen receptor modulators (SERMs) including but not limited to tamoxifen, raloxifen, toremifene, aldoxifen, bazedoxifen, pipindoxifen, rasofoxifen, and enclomifene; 24) Selective estrogen receptor modulators including but not limited to fulvestrant, ZB716, OP-1074, elacestrant, AZD9496, GDC0810, GDC0927, GW5638, and GW7604. 25) Aromitase inhibitors, including but not limited to anastrozole, exemestane, and letrozole; 26) Selective progesterone receptor modulators (SPRMs), including but not limited to mifepristone, lonaprison, onapristone, asoprisnil, lonaprisnil, ulipristal, and terapristone; 27) Mifepristone, COR108297, This may include administering to the patient one or more drugs selected from the following: 28) glucocorticoid receptor inhibitors, including but not limited to COR125281, ORIC-101, and PT150; 29) CDK4 / 6 inhibitors, including palbociclib, abemaciclib, and ribociclib; 20) HER2 receptor antagonists, including but not limited to trastuzumab and neratinib; and 31) rapamycin's mammalian target (mTOR) inhibitors, including but not limited to everolimus and temsirolimus.

[0134] The combination therapies described herein are not particularly limited to any particular number of additional therapies. For example, in addition to administering the abiraterone prodrug or abiraterone prodrug formulations described herein, as well as glucocorticoids such as hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone, the combination therapy may typically include one, two, three, four, five, six or more additional therapies described herein. For example, in some embodiments, the combination therapy may include one additional therapy, for example, any one of those described herein, such as a GnRH agonist, a GnRH antagonist, an androgen receptor antagonist, chemotherapy, a PARP inhibitor, a kinase inhibitor, immunotherapy, radiotherapy, surgery, or androgen deprivation therapy. In some embodiments, the combination therapy may include two or more additional therapies described herein. For example, in some specific embodiments, the combination therapy may include administering a PARP inhibitor and an androgen deprivation therapy agent to the patient. In some embodiments, the combination therapy may include administering a GnRH agonist and a radiotherapy agent to the patient. In some embodiments, combination therapy may involve administering a GnRH agonist, a chemotherapeutic agent, and a radiotherapeutic agent to the patient. In some embodiments, combination therapy may involve administering an androgen receptor antagonist (e.g., a first, second, and / or third-generation AR antagonist), a GnRH agonist, and optionally, a radiotherapeutic agent, a chemotherapeutic agent, indomethacin, or a 5α-reductase inhibitor to the patient. In some embodiments, combination therapy may involve administering an androgen receptor antagonist (e.g., a first, second, and / or third-generation AR antagonist) and a radiotherapeutic agent to the patient. In some embodiments, combination therapy may involve administering an androgen receptor antagonist (e.g., a first, second, and / or third-generation AR antagonist) and a chemotherapeutic agent to the patient. In some embodiments, combination therapy may involve administering an androgen receptor antagonist (e.g., a first, second, and / or third-generation AR antagonist) and an anti-CTLA4 antibody to the patient.The combinations discussed are examples of useful combinations, not limiting ones, and it should be understood that other combinations of additional therapies described herein are also possible.

[0135] In any of the combination therapies described herein, unless otherwise specifically stated or clearly contrary to the context, the method may include administering abiraterone decanoate as described herein, or a pharmaceutical composition containing abiraterone decanoate as described herein, in combination with one or more additional therapeutic agents.

[0136] It should be noted that in some embodiments, the methods for treating prostate cancer as described herein (e.g., any of those described herein) are not used in combination with combination therapies. For example, the method includes administering to a patient a therapeutically effective amount of abiraterone prodrug (e.g., abiraterone decanoate) or an abiraterone prodrug formulation as described herein, without the use of one or more additional therapeutic agents described herein.

[0137] Usage / Dosage The abiraterone prodrugs and formulations of this disclosure can generally provide the target user with a long-acting release of abiraterone. This long-acting release profile allows for administration of abiraterone to the target user at a lower frequency, such as once a week, once a month, once every two months, once every three months, or less, thereby improving patient adherence to medication and reducing the burden of taking medication.

[0138] In some embodiments, the methods described herein may involve a dosage regimen of once a week or once every few weeks. Typically, the frequency of administration can range from once a week to once every few months, for example, once a week to once every eight weeks, or once a week to once every three months, for example, once a month, once every two months, or once every three months. In some embodiments, the dose per administration is about 50 mg to about 2000 mg of abiraterone prodrug (e.g., about 500 mg, about 1000 mg, about 1500 mg, or any range of the values ​​described). In some embodiments, the dose of abiraterone prodrug per administration is approximately 0.5 mg / kg to approximately 100 mg / kg of the patient's body weight (e.g., approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 50 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, or any range of the values ​​listed). In some embodiments, the methods herein may involve administering the abiraterone prodrug or abiraterone prodrug formulation of the herein to a patient in need, once a week or once every few weeks, for example, once every two weeks or once a month, where such administration results in a therapeutically effective plasma concentration of abiraterone in the patient over a long period, for example, more than one week, more than two weeks, more than three weeks, more than four weeks, and up to six or eight weeks or more, for example up to ten weeks or more (e.g., 0.5 ng / ml or more, 1 ng / ml or more, 8 ng / ml or more, or 8.4 ng / ml or more, as described herein). In some embodiments, such administration results in a C100 ng / ml to about 400 ng / ml (e.g., about 50 ng / ml to about 100 ng / ml, or about 15 ng / ml to about 160 ng / ml) of abiraterone as a single dose. max This may result in a steady-state C of abiraterone of approximately 10 ng / ml to approximately 400 ng / ml (e.g., approximately 50 ng / ml to approximately 100 ng / ml, or approximately 15 ng / ml to approximately 160 ng / ml). In some embodiments, this administration may result in a steady-state C of abiraterone of approximately 10 ng / ml to approximately 400 ng / ml (e.g., approximately 50 ng / ml to approximately 100 ng / ml, or approximately 15 ng / ml to approximately 160 ng / ml). maxThis may result in a C1c of approximately 1 ng / ml to approximately 8 ng / ml, or greater than approximately 8 ng / ml, for example greater than 8.4 ng / ml, on each day from day 1 to 7, day 1 to 14, day 1 to 21, day 1 to 28, day 1 to 70, or day 7 to 70 after administration. min This may result. In some embodiments, this administration can lead to a steady-state C of abiraterone of approximately 1 ng / ml to approximately 8 ng / ml, or greater than approximately 8 ng / ml, for example greater than 8.4 ng / ml. min This could result.

[0139] Abiraterone prodrugs suitable for use in the above-described weekly or weekly dosing regimen include those described herein. In some embodiments, the abiraterone prodrug may be a lipophilic ester of abiraterone as described herein, for example, acetate, propionate, butanoate, (vaterate)pentanoate, isocaproate, bucicrate, cyclohexanecarboxylic acid, phenylpropionate, caproate (hexanoate), enanthate (heptanoate), cypionic acid, octanoate, non-canoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate, and hexadecanate. In some preferred embodiments, the abiraterone prodrug may be a compound of formula I, for example, in the formula of a compound of formula I, R 1 C 7-16 Alkyl, for example, -(CH2) n - An alkyl group having the formula CH3, where n is an integer between 6 and 12 (for example, n is 6, 7, 8, 9, 10); R 1 This is the formula -(CH2) n It can be expressed as -Cy, where n is an integer from 1 to 6, and Cy is C 3-6R is cycloalkyl or phenyl, but in a more specific embodiment, for example, n may be 1 or 2, and Cy may be cyclopentyl, cyclohexyl, or phenyl; 1 teeth, [ka] Is it; or, R 1 teeth, [ka] In some embodiments, the abiraterone prodrug may be a compound of formula II, for example, in formula II, R 2 C 1-16 Alkyl, for example, -(CH2) n - An alkyl having the formula CH3, where n is an integer between 0 and 12; R in formula II 2 This is the formula -(CH2) n It can be expressed as -Cy, where n is an integer from 1 to 6, and Cy is C 3-6 R in formula II is cycloalkyl or phenyl, but in a more specific embodiment, for example, n may be 1 or 2, and Cy may be cyclopentyl, cyclohexyl, or phenyl; 2 teeth, [ka] In some embodiments, the abiraterone prodrug may also be abiraterone acetate or one of Examples 2A-2H. In some embodiments, the abiraterone prodrug may be abiraterone acetate, abiraterone propionate, or abiraterone decanoate. In some specific embodiments, the abiraterone ester may be abiraterone pentanoate, abiraterone hexanoate, abiraterone heptanoate, abiraterone decanoate, abiraterone isocaproate, or abiraterone cypionicate. In any of the embodiments described herein, unless otherwise specified or directly inconsistent with the context, the abiraterone prodrug may be abiraterone decanoate.

[0140] In some embodiments, administration is preferred at a frequency of once a month or once every few months, for example, once a month to once every few months, or once a month to once every two months, or once a month to once every three months. In such embodiments, the abiraterone prodrug needs to release abiraterone not only slowly but also at a sufficient plasma concentration to be beneficial to the target user. Administration at a frequency of once a month or once every few months is typically parenteral, such as intramuscular, intradermal, or subcutaneous. In any embodiment of this specification, administration may be intramuscular, unless directly contradictory.

[0141] As detailed herein, a single intramuscular administration of abiraterone acetate was found to result in a prolonged release of abiraterone. However, in canine PK studies, similar administrations of abiraterone propionate did not show improvement over the prolonged release of abiraterone acetate; in fact, the abiraterone release observed with the propionate ester was lower than that observed with the acetate ester at all time points measured. Furthermore, unexpectedly, the extension of the alkyl chain to abiraterone butanoate was found to lead to a sharp decrease in solubility in various oily solvents. Despite this unexpected trend, the inventors have found that certain abiraterone prodrugs or abiraterone prodrug formulations of the present disclosure, such as compounds of formula I, including abiraterone decanoate, may be superior to the acetate ester, propionate ester, or butanoate ester for use in monthly or every few months administration. Certain abiraterone prodrugs or abiraterone prodrug formulations of the present disclosure, such as compounds of formula I, including abiraterone decanoate. 1 / 2 It was also found that the PK profiles of these compounds did not change significantly even when different oily solvents were used. In contrast, as detailed in Example 5B, some variability in the PK profile of abiraterone propionate was observed depending on whether it was formulated with castor oil or corn oil.

[0142] In some specific embodiments, the Disclosure provides a method for treating, in patients in need, sex hormone-dependent benign or malignant diseases (as described herein), syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia, the method comprising parenterally administering to the patient a therapeutically effective amount of a compound of formula I (as described herein), or a pharmaceutical composition containing a compound of formula I (as described herein), once a month or once every few months, for example, once every two months or once every three months. In some embodiments, the parenteral administration is intramuscular, intradermal, or subcutaneous. In some preferred embodiments, in the compound of formula I, R 1C 7-16 Alkyl, for example, -(CH2) n - An alkyl group having the formula CH3, where n is an integer between 6 and 12 (for example, n is 6, 7, 8, 9, or 10); R 1 This is the formula -(CH2) n -Cy is expressed as -Cy, where n is an integer from 1 to 6, and Cy is C 3-6 R is cycloalkyl or phenyl, but in a more specific embodiment, for example, n may be 1 or 2, and Cy may be cyclopentyl, cyclohexyl, or phenyl; 1 teeth, [ka] Is it; or, R 1 teeth, [ka] In some embodiments, this administration results in a therapeutically effective plasma concentration of abiraterone in the patient for a period of at least 4 weeks, e.g., at least 5 weeks, and up to 6 or 8 weeks or more, e.g., up to 10 weeks or more. In some embodiments, the therapeutic range plasma concentration of abiraterone may be at least 1 ng / ml, e.g., at least 2 ng / ml, at least 4 ng / ml, or at least 8 ng / ml. In some embodiments, the therapeutically effective plasma concentration of abiraterone may also be about 0.5 ng / ml or more. In some embodiments, this administration results in a single dose of abiraterone of approximately 10 ng / ml to about 400 ng / ml (e.g., about 50 ng / ml to about 100 ng / ml, or about 15 ng / ml to about 160 ng / ml) C max This may result in a steady-state C of abiraterone of approximately 10 ng / ml to approximately 400 ng / ml (e.g., approximately 50 ng / ml to approximately 100 ng / ml, or approximately 15 ng / ml to approximately 160 ng / ml). In some embodiments, this administration may result in a steady-state C of abiraterone of approximately 10 ng / ml to approximately 400 ng / ml (e.g., approximately 50 ng / ml to approximately 100 ng / ml, or approximately 15 ng / ml to approximately 160 ng / ml). maxThis may result in a C1c of approximately 1 ng / ml to approximately 8 ng / ml, or greater than approximately 8 ng / ml, for example greater than 8.4 ng / ml, of a single dose of abiraterone on day 28 or 70 after administration. min This may result. In some embodiments, this administration can lead to a steady-state C of abiraterone of approximately 1 ng / ml to approximately 8 ng / ml, or greater than approximately 8 ng / ml, for example, greater than approximately 8.4 ng / ml. min This may result. In some embodiments, the plasma concentration of abiraterone in the patient may remain substantially constant for at least one week after administration, for example, 1 to 3 weeks, 1 to 10 weeks, or 2 to 8 weeks. In some embodiments, administration is performed regardless of whether the patient eats. In some embodiments, this administration may result in a steady-state C of abiraterone compared to the C of 1000 mg of Zytiga® administered orally once daily without food. max Compared to that, the C of a single dose of abiraterone is at least 30% lower. max This is leaked. In some embodiments, the C of abiraterone observed at steady state after oral administration of 1000 mg of Zytiga (registered trademark) once daily without food was observed with this administration. max Compared to this, the steady state of abiraterone is at least 30% lower. max In some embodiments, pharmaceutical compositions comprising the compound of formula I may be formulated as unit formulations as described herein. Suitable carriers, oily solvents, and excipients for such pharmaceutical compositions include those described herein.

[0143] The abiraterone prodrugs and abiraterone prodrug formulations of this disclosure can be administered to patients in need as the sole source of abiraterone. However, in some embodiments, other abiraterone drugs / formulations are not excluded. For example, in some embodiments, the administrations of this specification can be combined with oral administration of abiraterone acetate, such as Zytiga® formulations, simultaneously or sequentially in any order. In some embodiments, patients can use abiraterone prodrugs and abiraterone prodrug formulations as a supplement to existing abiraterone therapy. Furthermore, the administrations of this specification are not limited to the administration of a single abiraterone prodrug or abiraterone prodrug formulation of this disclosure. In some embodiments, two or more abiraterone prodrugs and abiraterone prodrug formulations of this disclosure may be administered to a patient.

[0144] In some embodiments, the method herein may include an initial treatment period with a higher administration frequency, such as weekly or bi-weekly administration, prior to monthly or semi-monthly administration. The initial treatment period may include administration of different abiraterone drugs, such as the same abiraterone prodrug or different abiraterone prodrugs. Typically, the initial treatment period may be used to achieve a plasma concentration of abiraterone of approximately 1 ng / ml to approximately 8 ng / ml or greater than approximately 8 ng / ml prior to the monthly or semi-monthly administration described herein. However, in some embodiments, the method herein does not include such an initial treatment period.

[0145] As discussed herein, the abiraterone prodrugs and abiraterone prodrug formulations of this disclosure offer many advantages over currently marketed Zytiga® products. For example, administration of the abiraterone prodrugs and abiraterone prodrug formulations of this disclosure to a patient typically results in the C157 aviraterone max A decrease in abiraterone (for example, the steady state observed when 1000 mg of Zytiga® was orally administered once daily without food) maxThis results in a value that is at least 30% lower compared to [the previous method].

[0146] Therefore, in some embodiments, the present disclosure relates to, for example, aviraterone C maxThis invention provides a method for treating patients with adverse effects associated with high abiraterone exposure, including adverse effects related to the abiraterone prodrug and abiraterone prodrug formulations of this disclosure, the method comprising administering the abiraterone prodrug and abiraterone prodrug formulations to the patient, the administration of which reduces adverse effects compared to oral administration of 1000 mg of Zytiga® once daily without food. Preferred routes of administration, dosages, and frequencies include those described herein. Various adverse effects or adverse effects are described in the FDA-approved Zytiga® prescribing information (see, for example, the February 2018 or June 2019 editions). In some embodiments, the Disclosure provides a method for treating a patient who is also administered a substrate drug of CYP2D6 and / or CYP2C8, whose metabolism is inhibited by abiraterone, the method comprising administering to the patient an abiraterone prodrug and an abiraterone prodrug formulation of the Disclosure, the administration of which reduces the inhibition of drug metabolism compared to oral administration of 1000 mg of Zytiga® once daily without food. In some embodiments, the Disclosure provides a method for treating patients who have, or are likely to have, hypertension, hypokalemia, or fluid retention due to mineralocorticoid excess, the method comprising administering to the patient the abiraterone prodrug and abiraterone prodrug formulations of the Disclosure, the administration of which reduces hypertension, hypokalemia, and fluid retention, or the likelihood of having hypertension, hypokalemia, and fluid retention, compared to oral administration of 1000 mg of Zytiga® once daily without food. In some embodiments, the Disclosure provides a method for treating patients who have, or are likely to have, adrenal insufficiency, the method comprising administering to the patient the abiraterone prodrug and abiraterone prodrug formulations of the Disclosure, the administration of which reduces adrenal insufficiency or the likelihood of having adrenal insufficiency, compared to oral administration of 1000 mg of Zytiga® once daily without food.In some embodiments, the Disclosure provides a method for treating patients with severe or fatal hepatotoxicity following administration of Zytiga®, the method comprising administering the abiraterone prodrug and abiraterone prodrug formulations of the Disclosure to the patient, thereby reducing hepatotoxicity. While not wishing to be bound by theory, administration of the abiraterone prodrug and abiraterone prodrug formulations of the Disclosure typically results in a reduced but effective abiraterone exposure, and is therefore considered beneficial for patients requiring low doses of abiraterone, as described above. Preferred uses, dosages, and routes of administration include those described herein.

[0147] Abiraterone decanoate Some embodiments of this disclosure focus particularly on abiraterone decanoate. As will be discussed in more detail in the Examples section, pharmacokinetic studies have shown that intramuscular injection of abiraterone decanoate formulations can deliver therapeutically effective plasma abiraterone levels over a long period in various animal models. In monkey PK studies, it was further shown that a single intramuscular injection of abiraterone decanoate formulations can achieve long-term CYP17A1 inhibition accompanied by sustained elevated progesterone levels, as well as decreased cortisol and testosterone levels. Furthermore, based on rat, dog, and monkey PK studies, human PK predictions were made based on relative growth scaling. As shown in Figure 16C, based on relative growth scaling, intramuscular administration of approximately 1000 mg of abiraterone decanoate to humans once every four weeks, followed by C min It was predicted that the steady state would be 5 ng / mL. In addition, as detailed in the Examples section and Figure 14F, compared to abiraterone decanoate formulations with the same dosage in 90% v / v corn oil and 10% v / v benzyl alcohol, which have substantially the same abiraterone decanoate concentration, abiraterone decanoate formulations containing certain combinations of oil and solvent were found to unexpectedly achieve significantly higher abiraterone plasma concentrations in monkeys after IM injection. Therefore, the C predicted to be 5 ng / mL at steady state was not expected.min It is possible to reduce the dosage of abiraterone decanoate required to achieve this. Alternatively, the steady state C min This can be increased to levels exceeding the predicted 5 ng / mL. These initial results were further confirmed in further PK / PD studies in chemically castrated monkeys. As discussed in detail herein, a single dose of representative abiraterone decanoate formulations at doses of 10 mg / kg, 30 mg / kg, or 100 mg / kg (approximately 200 mg / ml in a combination of corn oil, benzyl alcohol, and benzyl benzoate) resulted in sustained CYP17A1 inhibition for up to 70 days or more in chemically castrated monkeys, as evidenced by the maintenance of elevated progesterone levels and the decrease in cortisol, dihydrotestosterone, and testosterone levels. These disclosures demonstrate that abiraterone can be delivered to patients (e.g., human subjects) in therapeutically effective doses by injecting abiraterone prodrugs, such as abiraterone lipophilic ester prodrugs, or more specifically, by injecting abiraterone decanoate at a frequency less than once a week, e.g., once every two weeks, once a month, or once every few months, e.g., once every two months or once every three months. Typically, the dosing frequency can range from once a week to once every few months, e.g., once a week to once every eight weeks, or once a week to once every three months, e.g., once a month, once every eight weeks, once every twelve weeks, etc.

[0148] In some specific embodiments, the present disclosure relates to abiraterone decanoate having the following formula, [ka] Alternatively, compounds that are pharmaceutically acceptable salts thereof are provided. In some embodiments, abiraterone decanoate may be its basic form. In some embodiments, abiraterone decanoate may be a pharmaceutically acceptable salt such as an oxalate, hydrochloride, benzenesulfonate, p-toluenesulfonate, or phosphate. In some embodiments, salts of abiraterone decanoate may be used as synthetic intermediates for the preparation and purification of abiraterone decanoate in its basic form. As discussed herein, abiraterone decanoate is typically present in the abiraterone prodrug formulations herein in its basic form. Unless otherwise specifically mentioned as a salt form or unless inconsistent with the context, abiraterone decanoate should be understood as its basic form.

[0149] Abiraterone decanoate and its pharmaceutically acceptable salts can be readily prepared by those skilled in the art in view of this disclosure. Several representative synthesis methods are described herein. In some embodiments, this disclosure provides a method for synthesizing abiraterone decanoate, which involves reacting abiraterone with decanoic acid or its activated form, such as a corresponding acyl chloride or an anhydride (e.g., a mixed anhydride). The reaction can typically be carried out in the presence of a coupling agent such as a carbodiimide. As shown in the Examples section, the bonding of abiraterone and decanoic acid can be carried out in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, a base (such as triethylamine), and a catalytic amount of DMAP. Salts of abiraterone decanoate can typically be prepared by reacting abiraterone decanoate with a suitable acid such as oxalic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, or phosphoric acid in an organic solvent such as isopropyl acetate or ethyl acetate.

[0150] In some embodiments, abiraterone decanoate may exist in solid forms such as crystalline, amorphous, or a combination thereof. For example, in some embodiments, the disclosure provides abiraterone decanoate in crystalline form. In some embodiments, the crystalline form may be characterized by an X-ray powder diffraction (XRPD) spectrum having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) 2Θ (±0.2°) peaks at 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6, and 20.8 degrees; a differential scanning calorimetry (DSC) pattern having an endothermic peak at a starting temperature of about 69.0°C; or a combination thereof. In some embodiments, the crystalline form may be characterized by substantially the same XRPD spectrum as shown in Figure 12A, for example, the XRPD spectrum showing peaks at each diffraction angle (angle 2Θ, ±0.2°) corresponding to the peaks shown in Figure 12A, regardless of their relative intensities. In some embodiments, the crystalline form may be characterized by substantially the same DSC spectrum as shown in Figure 12B.

[0151] In some embodiments, the disclosure also provides a method for preparing the crystalline form of abiraterone decanoate. In some embodiments, the method may involve recrystallizing abiraterone decanoate in a suitable solvent such as acetone and water. In a typical method, abiraterone decanoate can first be dissolved in a first solvent such as acetone at room temperature or under heating (e.g., about 40°C) to form a solution; then the solution can be cooled to form a suspension, which can optionally be subsequently diluted with a second solvent such as water (typically a poor solvent in which abiraterone decanoate has low solubility) and stirred for a certain period of time (e.g., about 12 hours) to form the crystalline form. The amount, concentration, etc., of the solvent can be adjusted by those skilled in the art in view of the disclosure. An exemplary procedure is also shown in Example 6A.

[0152] Abiraterone decanoate is typically prepared in a highly purified form suitable for pharmaceutically acceptable use. In some embodiments, this disclosure provides substantially pure forms of abiraterone decanoate having a purity of over 80%, preferably over 90% (e.g., over 95%, over 97%, over 98%, over 99%, over 99.5%) relative to, for example, weight, HPLC area, or both. In some embodiments, abiraterone decanoate may be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any range of values ​​specified, relative to weight and / or HPLC area. For example, in some embodiments, abiraterone decanoate may be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any range of values ​​specified, relative to weight. Exemplary procedures for preparing substantially pure abiraterone decanoate are shown in the Examples section. Suitable HPLC methods for measuring the purity of abiraterone decanoate are also described in the Examples section. Substantially pure abiraterone decanoate may be in solid form (e.g., crystalline, amorphous, or a combination thereof as described herein), or in solution, suspension, or other form. To avoid misunderstanding, abiraterone prodrug formulations relating to substantially pure abiraterone decanoate and one or more other components relating to this specification should be understood as mixtures of substantially pure abiraterone decanoate and one or more other components relating to this specification, for example, such formulations can be obtained directly or indirectly by mixing substantially pure abiraterone decanoate with one or more other components such as pharmaceutically acceptable oils, solvents, etc. (e.g., by dissolving, suspending, or otherwise forming a mixture).

[0153] In some specific embodiments, the present disclosure relates to abiraterone decanoate having the following formula, [ka] Alternatively, a pharmaceutical composition comprising pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier is provided. Abiraterone decanoate is typically present in the pharmaceutical composition in its basic form and should be understood as such unless it is evident that this is contrary to the context. In some embodiments, aviraterone decanoate may be the substantially pure form described herein. For example, a pharmaceutical composition may be prepared by mixing substantially pure aviraterone decanoate with a pharmaceutically acceptable carrier and any other component. In some specific embodiments, substantially pure aviraterone decanoate is the crystalline form described herein, and the pharmaceutical composition may be prepared by mixing the crystalline form with a pharmaceutically acceptable carrier and any other component (e.g., by dissolving, suspending, or otherwise forming a mixture).

[0154] Typically, pharmaceutical compositions are formulated for parenteral administration. For example, in some embodiments, pharmaceutical compositions may be formulated for intramuscular, intradermal, or subcutaneous injection.

[0155] Pharmaceutical compositions are generally non-aqueous formulations, such as oil-based formulations, and include a non-aqueous pharmaceutically acceptable carrier (such as those described herein). For example, in some embodiments, the pharmaceutically acceptable carrier includes a pharmaceutically acceptable oil, such as a plant-derived oil or a pharmaceutically acceptable oil for injection containing synthetic monoglycerides or diglycerides of fatty acids. In some embodiments, the pharmaceutically acceptable oil may be a natural oil, a synthetic oil, or a semi-synthetic oil such as fractionated coconut oil and medium-chain triglycerides, such as those marketed under the trademark Miglyol. In some embodiments, the pharmaceutically acceptable carrier includes triglycerides derived from fatty acids. In some embodiments, the pharmaceutically acceptable carrier includes triglycerides derived from long-chain and / or medium-chain fatty acids, which may independently be polyunsaturated, monounsaturated, or saturated. As will be understood by those skilled in the art, medium-chain fatty acids contain 6 to 12 carbon atoms, such as caproic acid, caprylic acid, capric acid, and lauric acid; short-chain fatty acids typically have fewer than 6 carbon atoms; and long-chain fatty acids typically contain 13 to 21 carbon atoms. In some embodiments, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable oil, such as vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil. In some specific embodiments, a pharmaceutically acceptable carrier may include corn oil containing triglycerides whose fatty acid components are mainly linoleic acid, oleic acid, palmitic acid, and stearic acid.

[0156] In some embodiments, in addition to a pharmaceutically acceptable oil, the pharmaceutically acceptable carrier may further include a pharmaceutically acceptable solvent (or co-solvent, if the oil is considered a solvent) such as an alcohol, ester, or acid. In some embodiments, the pharmaceutically acceptable solvent may include benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid, and / or ethyl acetate. In some embodiments, the pharmaceutically acceptable solvent may be benzyl alcohol and / or benzyl benzoate. In some embodiments, the pharmaceutically acceptable solvent may be benzyl alcohol. In some embodiments, the pharmaceutically acceptable solvent may be a combination of benzyl alcohol and benzyl benzoate. As discussed herein, the combination of benzyl alcohol and benzyl benzoate can significantly improve the solubility of avirateron decanoate in a pharmaceutically acceptable oil.

[0157] In some specific embodiments, the Disclosure provides pharmaceutical compositions comprising abiraterone decanoate, a pharmaceutically acceptable oil (such as as described herein), benzyl alcohol, and benzyl benzoate. In some embodiments, the pharmaceutically acceptable oil is corn oil. In some embodiments, the total amount of benzyl alcohol, benzyl benzoate, and corn oil is 100%, with benzyl alcohol present in an amount of about 5–10% by volume, benzyl benzoate in an amount of about 10–20% by volume, and corn oil in an amount of about 70–85% by volume.

[0158] The pharmaceutical composition typically contains abiraterone decanoate at concentrations ranging from about 25 mg / ml to about 500 mg / ml. In some embodiments, abiraterone decanoate may be present at concentrations ranging from about 50 mg / ml, about 100 mg / ml, about 150 mg / ml, about 200 mg / ml, about 250 mg / ml, about 300 mg / ml, about 350 mg / ml, about 400 mg / ml, about 500 mg / ml, or any range of the values ​​listed. In some embodiments, abiraterone decanoate may be present at concentrations ranging from about 100 mg / ml to about 300 mg / ml, for example, about 150 mg / ml to about 250 mg / ml, about 200 mg / ml to about 300 mg / ml, etc.

[0159] A preparation containing substantially pure abiraterone decanoate. In some embodiments, the Disclosure relates to substantially pure abiraterone decanoate having the following formula, dispersed or dissolved in a pharmaceutically acceptable carrier. [ka] Alternatively, a pharmaceutical composition comprising pharmaceutically acceptable salts thereof is provided. In some embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate in a basic form dispersed or dissolved in a pharmaceutically acceptable carrier. In some embodiments, the substantially pure abiraterone decanoate has a purity of at least 95%, preferably at least 98%, for example, about 98.5%, about 99%, or about 99.5% or higher, relative to weight. In some embodiments, the substantially pure abiraterone decanoate may be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any range of specified values ​​relative to weight and / or HPLC area. In some embodiments, the substantially pure abiraterone decanoate may be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any range of specified values ​​relative to weight. In some embodiments, the substantially pure abiraterone decanoate contains impurities derived from ethyl plasterone. For example, in some embodiments, substantially pure avirateron decanoate comprises ethyl plasterone decanoate having the following formula. [ka] Typically, substantially pure abiraterone decanoate contains, if present, less than 2% by weight, e.g., less than 1% by weight, less than 0.5% by weight, e.g., less than 0.3%, less than 0.2%, or less than 0.1% by weight of ethyl plasterone decanoate. The amount of ethyl plasterone decanoate can be readily measured by HPLC methods such as those described herein. In some embodiments, substantially pure abiraterone decanoate may also not contain any detectable amount of ethyl plasterone decanoate. High-purity abiraterone starting materials are readily available from the market. In cross-coupling reactions... [ka] The abiraterone starting material obtained from the process of introducing a 3-pyridine group into abiraterone using may contain small amounts of impurities that can ultimately be converted to ethyl plasterone. In some embodiments, substantially pure decanoic acid abiraterone is an abiraterone starting material that does not contain any detectable amount of ethyl plasterone, for example, [ka] It can be prepared from abiraterone starting materials obtained by a cross-coupling-free process using [a specific method]. Substantially pure abiraterone decanoate may be in solid form, such as the crystalline form described herein. For example, in some embodiments, substantially pure abiraterone decanoate may be in crystalline form characterized by an X-ray powder diffraction (XRPD) spectrum having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) 2Θ (±0.2°) peaks at 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6, and 20.8 degrees; a differential scanning calorimetry (DSC) pattern having an endothermic peak at a starting temperature of about 69.0°C; or a combination thereof. In some embodiments, the crystalline form may be characterized by substantially the same XRPD spectrum as shown in Figure 12A, for example, the XRPD spectrum showing peaks at each diffraction angle (angle 2Θ, ±0.2°) corresponding to the peaks shown in Figure 12A, regardless of their relative intensities. In some embodiments, the crystalline form may be characterized by substantially the same DSC spectrum as shown in Figure 12B.

[0160] In some embodiments, the pharmaceutical composition comprises a substantially pure abiraterone decanoate in a basic form dispersed or dissolved in a pharmaceutically acceptable carrier containing a pharmaceutically acceptable oil (e.g., as described herein) and optionally a further pharmaceutically acceptable solvent (e.g., as described herein). In some embodiments, the pharmaceutically acceptable oil comprises triglycerides (e.g., long-chain and / or medium-chain triglycerides), and the further pharmaceutically acceptable solvent, if present, comprises alcohols, esters and / or acidic solvents. In some embodiments, the pharmaceutically acceptable oil is selected from vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil, and the further pharmaceutically acceptable solvent, if present, comprises benzyl alcohol, benzyl benzoate, or a combination thereof. In some embodiments, the pharmaceutically acceptable solvent comprises corn oil, benzyl alcohol, and benzyl benzoate.

[0161] In some specific embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable oil (such as those described herein), benzyl alcohol, and substantially pure abiraterone decanoate in a basic form dissolved in benzyl benzoate. In some embodiments, the pharmaceutical composition comprises (a) substantially pure abiraterone decanoate in basic form at a concentration of about 25 mg / ml to about 500 mg / ml (e.g., about 25 mg / ml, about 50 mg / ml, about 100 mg / ml, about 150 mg / ml, about 200 mg / ml, about 250 mg / ml, about 300 mg / ml, about 400 mg / ml, about 500 mg / ml, or any range of the values ​​described, e.g., about 100 mg / ml to about 300 mg / ml); (b) about 50 mg to about 150 mg / mL of benzyl alcohol; (c) about 100 mg to about 300 mg / mL of benzyl benzoate; and (d) a pharmaceutically acceptable oil (e.g., as described herein), in particular, for example, an appropriate amount of corn oil relative to the volume of the pharmaceutical composition. In some specific embodiments, the pharmaceutical composition contains, per milliliter, (a) about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg, or any range of the values ​​described) of substantially pure abiraterone decanoate in its basic form; (b) about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg, or any range of the values ​​described) of benzyl alcohol; (c) about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg, or any range of the values ​​described) of benzyl benzoate; and (d) an appropriate amount of corn oil per milliliter. In some embodiments, the pharmaceutical composition can be prepared by mixing (e.g., dissolving) substantially pure abiraterone decanoate with a pharmaceutically acceptable carrier.For example, in some embodiments, the pharmaceutical composition can be prepared by mixing (e.g., dissolving) substantially pure abiraterone decanoate in its basic form with corn oil, benzyl alcohol, and benzyl benzoate.

[0162] Pharmaceutical compositions containing substantially pure abiraterone decanoate are typically formulated for parenteral administration. For example, in some embodiments, the pharmaceutical composition is formulated for intramuscular, intradermal, or subcutaneous injection, for example, with a desired viscosity, glide force, particulate count, endotoxin, etc. In some embodiments, the pharmaceutical composition is (1) 0.1 Pa * Less than s, for example, about 0.05 Ps * (2) Viscosity of s or less; (2) Glide force of approximately 5 to 15 N when measured using a 23 gauge (or 23 G) and 1.5 inch needle, and / or glide force of approximately 30 to 150 N when measured using a 27 G and 1.5 inch needle; (3) USP <788> and / or <789> When measured according to (4) USP <85> It is characterized by having bacterial endotoxins of less than 100 EU / ml, for example, less than 25 EU / ml, as measured according to the USP method. Methods for measuring viscosity and glide force are known in the art and are exemplified herein in Example 9. <788> , <789> and <85> This should be understood as the current version of the method, as known to those skilled in the art.

[0163] In any of the embodiments described herein, unless otherwise specifically stated or clearly contrary to the context, the pharmaceutical composition comprising abiraterone decanoate (sometimes also called an abiraterone prodrug formulation) may be any substantially pure pharmaceutical composition comprising abiraterone decanoate as described herein.

[0164] Abiraterone decanoate is typically included in a pharmaceutical composition in an amount therapeutically effective for treating diseases or conditions described herein, such as prostate cancer. In some embodiments, abiraterone decanoate may be present in a pharmaceutical composition in an amount sufficient to provide therapeutically effective plasma concentrations of abiraterone for a period of at least one week, e.g., at least two weeks, at least four weeks, and up to six or eight weeks or more, e.g., up to ten weeks or more, after a single administration to a patient having a sex hormone-dependent benign or malignant disease, a syndrome caused by androgen excess, and / or a syndrome caused by glucocorticoid excess, such as hypercortisolemia. In some embodiments, abiraterone decanoate may be present in the pharmaceutical composition in an amount sufficient to provide therapeutically effective plasma concentrations of abiraterone, such as about 1 ng / ml or more, for example, about 2 ng / ml or more, about 4 ng / ml or more, about 5 ng / ml or more, or about 8 ng / ml or more, for a period of at least 1 week, for example, at least 2 weeks, at least 4 weeks, and up to 6 or 8 weeks or more, for example, up to 10 weeks or more, after a single administration to patients having sex hormone-dependent benign or malignant diseases, syndromes caused by androgen excess, and / or syndromes caused by glucocorticoid excess such as hypercortisolemia. In some embodiments, abiraterone decanoate may be present in the pharmaceutical composition in an amount sufficient to provide a therapeutically effective plasma concentration of approximately 0.5 ng / ml or more for a period of at least 4 weeks, e.g., at least 6 weeks and up to 8 weeks or more, e.g., up to 10 weeks or more, after a single administration to patients with sex hormone-dependent benign or malignant diseases, syndromes caused by androgen excess, and / or syndromes caused by glucocorticoid excess, such as hypercortisolemia.

[0165] In some specific embodiments, the Disclosure relates to a therapeutically effective amount of abiraterone decanoate having the following formula: [ka] The present invention provides a pharmaceutical composition, for example, a unit formulation, comprising a pharmaceutically acceptable oil and a pharmaceutically acceptable solvent, wherein the abiraterone decanoate is present in its basic form at concentrations ranging from about 25 mg / ml to about 500 mg / ml, for example, about 50 mg / ml, about 100 mg / ml, about 150 mg / ml, about 200 mg / ml, about 250 mg / ml, about 300 mg / ml, about 350 mg / ml, about 400 mg / ml, about 500 mg / ml, or any range of the values ​​described, and the pharmaceutical composition, for example, a unit formulation, is formulated for parenteral injection, such as intramuscular injection, intradermal injection, or subcutaneous injection, and the pharmaceutical composition, for example, a unit formulation, contains an amount of abiraterone decanoate ranging from about 50 mg to about 2,000 mg, for example, about 100 mg, about 350 mg, about 500 mg, about 1,000 mg, about 1,500 mg, about 2,000 mg, or any range of the values ​​described. In some embodiments, the pharmaceutical composition may be a unit formulation. Typically, one or more unit formulations (e.g., one) may be administered to a patient in need, depending on the dosage. For example, a pharmaceutically acceptable oil in a pharmaceutical composition that is a unit formulation may be any of those described herein. For example, in some embodiments, the pharmaceutically acceptable oil is a pharmaceutically acceptable oil for injection, comprising plant-derived oils or synthetic monoglycerides or diglycerides of fatty acids. In some embodiments, the pharmaceutically acceptable oil may be a natural oil, a synthetic oil, or a semi-synthetic oil such as fractionated coconut oil and medium-chain triglycerides, such as those marketed under the trademark Miglyol. In some embodiments, the pharmaceutically acceptable oil may include triglycerides derived from fatty acids. In some embodiments, the pharmaceutically acceptable oil may include triglycerides derived from long-chain and / or medium-chain fatty acids, which may independently be polyunsaturated, monounsaturated, or saturated. In some embodiments, pharmaceutically acceptable oils can be selected from vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil. In some specific embodiments, pharmaceutically acceptable oils may include corn oil containing triglycerides whose fatty acid components are mainly linoleic acid, oleic acid, palmitic acid, and stearic acid.Furthermore, a pharmaceutically acceptable solvent in a pharmaceutical composition, for example, a unit formulation, may include any of those described herein. In some embodiments, the pharmaceutically acceptable solvent (or co-solvent, if an oil is considered a solvent) is an alcohol, an ester, an acid, etc. In some embodiments, the pharmaceutically acceptable solvent may include benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid, and / or ethyl acetate. In some embodiments, the pharmaceutically acceptable solvent may be benzyl alcohol and / or benzyl benzoate. In some embodiments, a pharmaceutical composition, for example, a unit formulation, may include abiraterone decanoate, a pharmaceutically acceptable oil (such as one described herein), benzyl alcohol, and benzyl benzoate. In some embodiments, the pharmaceutically acceptable oil is corn oil. In some embodiments, the total amount of benzyl alcohol, benzyl benzoate, and corn oil is 100%, with benzyl alcohol present in an amount of about 5–10% by volume, benzyl benzoate in an amount of about 10–20% by volume, and corn oil in an amount of about 70–85% by volume. In some embodiments, abiraterone decanoate is in a substantially pure form as described herein. In some specific embodiments, the pharmaceutical composition comprises (a) abiraterone decanoate, such as substantially pure abiraterone decanoate as described herein, in a basic form at a concentration of about 25 mg / ml to about 500 mg / ml (e.g., about 25 mg / ml, about 50 mg / ml, about 100 mg / ml, about 150 mg / ml, about 200 mg / ml, about 250 mg / ml, about 300 mg / ml, about 400 mg / ml, about 500 mg / ml, or any range of the values ​​described herein, e.g., about 100 mg / ml to about 300 mg / ml); (b) benzyl alcohol in an amount of about 50 mg to about 150 mg / mL; (c) benzyl benzoate in an amount of about 100 mg to about 300 mg / mL; and (d) a pharmaceutically acceptable oil (e.g., as described herein), in particular, an appropriate amount of corn oil relative to the volume of the pharmaceutical composition.In some specific embodiments, the pharmaceutical composition comprises, per milliliter, (a) about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg) of abiraterone decanoate, such as substantially pure abiraterone decanoate as described herein, in a basic form; (b) about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg, or any range of the values ​​described) of benzyl alcohol; (c) about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg, or any range of the values ​​described) of benzyl benzoate; and (d) an appropriate amount of corn oil per milliliter. In some specific embodiments, the pharmaceutical composition comprises abiraterone decanoate, benzyl alcohol, benzyl benzoate, and corn oil in substantially the same corresponding amounts (mg per milliliter) as shown in Table 14A of this disclosure.

[0166] In some embodiments, the Disclosure provides exemplary abiraterone decanoate formulations as shown in Table C. All numerical values ​​in the table should be understood as being preceded by the term “approximately”. The concentration of abiraterone decanoate is expressed as the amount of abiraterone decanoate in mg per ml of the final formulation, which may be a solution or a suspension. The amounts of oil (primary solvent) and co-solvent (benzyl alcohol and / or benzyl benzoate) in the table are expressed as volume percentages of the solvent, including both the oil and the co-solvent. Preferred oils include any pharmaceutically acceptable oils as described herein, such as corn oil. Any additional components are not shown in Table C. Examples 3F–3H of this Specification illustrate the procedure for preparing representative abiraterone decanoate formulations of Table C. [Table 3]

[0167] The pharmaceutical compositions or unit formulations of this specification can be prepared by those skilled in the art in view of the methods disclosed herein. In some embodiments, this disclosure provides methods for preparing abiraterone decanoate formulations suitable for parenteral administration to patients having sex hormone-dependent benign or malignant diseases, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia. In some embodiments, the method involves mixing (e.g., dissolving or suspending) abiraterone decanoate having the following formula in a pharmaceutically acceptable carrier, [ka] The method includes forming a mixture (e.g., a solution or suspension). In some embodiments, abiraterone decanoate is in a substantially pure form as described herein. In some embodiments, the method further includes sterilizing the mixture (e.g., a solution or suspension). In some embodiments, dissolving or suspending may include mixing (e.g., dissolving or suspending) the crystalline form of abiraterone decanoate as described herein in a pharmaceutically acceptable carrier. In some embodiments, mixing (e.g., dissolving or suspending) may include mixing (e.g., dissolving or suspending) the substantially pure abiraterone decanoate as described herein in a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers and amounts, amounts of abiraterone decanoate, and concentrations of abiraterone decanoate include any of those described herein. For example, in some embodiments, the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil and a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable oil includes vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil, and the pharmaceutically acceptable solvent comprises benzyl alcohol and / or benzyl benzoate, and the abiraterone decanoate is present at a concentration of about 50 mg / mL to about 300 mg / mL, for example, about 100 mg / mL to about 300 mg / mL.

[0168] In some specific embodiments, the Disclosure also provides methods for treating sex hormone-dependent benign or malignant diseases, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia, the methods comprising administering a therapeutically effective amount of a pharmaceutical composition (e.g., a unit formulation as described herein) containing abiraterone decanoate as described herein to a patient in need. The administration is not limited to any particular route. However, abiraterone decanoate is typically administered parenterally, for example, by intramuscular, intradermal, or subcutaneous injection. In some embodiments, the administration is by intramuscular injection. Unlike the oral administration of abiraterone acetate, the pharmaceutical composition (e.g., a unit formulation as described herein) containing abiraterone decanoate as described herein can be administered to a patient in need regardless of diet.

[0169] The sex hormone-dependent benign or malignant diseases that can be treated by this method include any of those described herein. In some embodiments, the sex hormone-dependent benign or malignant disease may be selected from androgen-dependent and estrogen-dependent diseases, such as androgen-dependent cancer or estrogen-dependent cancer. In some embodiments, the sex hormone-dependent benign or malignant disease may be selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, and lung cancer, among others. In some embodiments, the sex hormone-dependent benign or malignant disease may be prostate cancer or breast cancer. In some embodiments, the sex hormone-dependent benign or malignant disease may be castration-resistant prostate cancer or castration-sensitive prostate cancer. In some embodiments, the sex hormone-dependent benign or malignant disease may be metastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer. The androgen-induced syndromes and / or glucocorticoid-induced syndromes, such as hypercortisolemia, that can be treated by this method include any of those described herein. In some embodiments, the methods herein may be methods for treating non-neoplastic syndromes in patients resulting from androgen excess, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), precocious puberty, and hirsutism. In some embodiments, the methods herein may be methods for treating non-neoplastic syndromes resulting from glucocorticoid (e.g., cortisol) excess, such as Cushing's syndrome or Cushing's disease.

[0170] The methods described herein can be used in combination with one or more additional therapies for the corresponding disease or disorder. For example, the methods may include administering one or more other drugs or agents (e.g., other cancer chemotherapy agents, hormone replacement agents, or hormone removal agents, as described herein) to the patient simultaneously or sequentially, via the same or different routes of administration. In some embodiments, the patient may also be treated with gonadotropin-releasing hormone analogs and / or bilateral orchiectomy.

[0171] As discussed herein, abiraterone is a 17α-hydroxylase / C17,20-lyase (CYP17) inhibitor that may result in reduced androgen (e.g., testosterone) biosynthesis, reduced glucocorticoid (e.g., cortisol) levels, and mineralocorticoid excess (e.g., increased progesterone). Adrenal insufficiency is also known to be associated with abiraterone therapy, such as Zytiga®. Intramuscular administration of the pharmaceutical composition comprising abiraterone decanoate described herein has been shown to provide effective plasma levels of abiraterone and long-term in vivo inhibition of CYP17A1, along with increased progesterone levels and decreased cortisol levels.

[0172] In some embodiments, the methods of this specification (e.g., treating prostate cancer or classical or non-classical congenital adrenal hyperplasia) may include administering to the patient an agent that counteracts the reduction of glucocorticoids associated with the administration of abiraterone decanoate as described herein. In some embodiments, the methods may include administering to the patient an agent effective in treating one or more symptoms associated with adrenal insufficiency, such as acute stress or fatigue. In some specific embodiments, the methods may include administering to the patient a steroid, such as a corticosteroid. In some embodiments, the methods may include administering to the patient glucocorticoids. In some specific embodiments, the methods may also include administering to the patient prednisone, prednisolone, and / or methylprednisolone. In some embodiments, the methods may also include administering to the patient an agent effective in treating cortisol deficiency, such as hydrocortisone, prednisone, prednisolone, methylprednisolone, and / or dexamethasone. In any such embodiment, the drugs may be administered to the patient simultaneously or sequentially in any order, via the same or different routes of administration. In some embodiments, the method is for the treatment of prostate cancer and includes combination therapy further comprising administering to the patient one or more additional therapeutic agents, such as those described in the "Combination Therapies for Prostate Cancer" chapter of this specification.

[0173] In some embodiments, the methods of this specification may be characterized by a dosing frequency of once a week or less. Typically, the dosing frequency can range from once a week to once every few months, for example, once a week to once every three months, or once a week to once every eight weeks, for example, once a month, once every two months, or once every three months. In some embodiments, the method includes administering a pharmaceutical composition containing abiraterone decanoate (e.g., a unit formulation as described herein) to a patient once a week, once every two weeks, once every three weeks, once a month, or once every few months, for example, once every two months, or once every three months. In some embodiments, the method includes administering a pharmaceutical composition containing abiraterone decanoate (e.g., a unit formulation as described herein) to a patient once every two weeks, once a month, or once every few months, for example, once every two months, or once every three months. In some embodiments, the dose per administration is approximately 50 mg to approximately 2000 mg of abiraterone decanoate (e.g., approximately 100 mg, approximately 350 mg, approximately 500 mg, approximately 1000 mg, approximately 1500 mg, or any range of the values ​​described). In some embodiments, the dose of abiraterone decanoate per administration is approximately 0.5 mg / kg to approximately 100 mg / kg of the patient's body weight (e.g., approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 50 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, or any range of the values ​​described). In some embodiments, administration is via intramuscular injection. In some embodiments, a single dose provides therapeutically effective plasma concentrations of abiraterone for a period of at least one week, for example, at least two weeks, for example, at least three weeks, at least four weeks, and up to six or eight weeks or more, for example, up to ten weeks or more.In some embodiments, a single dose administration results in a plasma concentration of abiraterone greater than 1.0 ng / ml (e.g., approximately 1 ng / ml to approximately 8 ng / ml, or approximately 2 ng / ml or more, approximately 4 ng / ml or more, approximately 5 ng / ml or more, or approximately 8 ng / ml or more) over a period of at least 1 week, e.g., at least 2 weeks, e.g., at least 3 weeks, at least 4 weeks, and up to 6 or 8 weeks or more, e.g., up to 10 weeks or more. In some embodiments, this administration results in a steady-state C of abiraterone greater than 1.0 ng / ml (e.g., approximately 1 ng / ml to approximately 8 ng / ml, approximately 2 ng / ml or more, approximately 4 ng / ml or more, approximately 5 ng / ml or more, or approximately 8 ng / ml or more). min This results in a single dose of abiraterone or steady-state C14 in any range of values ​​listed, such as approximately 10 ng / ml to approximately 400 ng / ml, for example, approximately 10 ng / ml, approximately 15 ng / ml, approximately 20 ng / ml, approximately 30 ng / ml, approximately 50 ng / ml, approximately 60 ng / ml, approximately 100 ng / ml, approximately 150 ng / ml, approximately 160 ng / ml, or for example, approximately 10-30 ng / ml, approximately 20-60 ng / ml, approximately 15-160 ng / ml, or approximately 50-100 ng / ml. max This is achieved. In some embodiments, abiraterone decanoate preparations can be administered to patients who need it as the sole source of abiraterone. However, in some embodiments, abiraterone decanoate preparations can also be administered to patients who need it as a supplement to another abiraterone therapy.

[0174] In some specific examples, the Disclosure provides a method for treating prostate cancer, the method comprising administering abiraterone decanoate (e.g., substantially pure abiraterone decanoate as herein) to a patient in need, via intramuscular, intradermal, or subcutaneous injection, at doses of approximately 50 mg to approximately 2000 mg (e.g., approximately 100 mg, approximately 350 mg, approximately 500 mg, approximately 1000 mg, approximately 1500 mg, or any range of the values ​​described) once a week or once every few weeks, for example, once a month or once every few months, for example, once every two months or once every three months. In some embodiments, abiraterone decanoate is administered via intramuscular injection. In some embodiments, the prostate cancer is castration-resistant or castration-sensitive. In some embodiments, the prostate cancer is metastatic castration-resistant or metastatic castration-sensitive. Suitable prostate cancers that can be treated by this method include any of those described herein. In some embodiments, the method for treating prostate cancer includes combination therapy, which further includes administering to the patient one or more additional therapeutic agents, such as those described in the chapter “Combination Therapies for Prostate Cancer” herein.

[0175] In some specific cases, the Disclosure provides a method for treating prostate cancer in which each dose of abiraterone decanoate is approximately 50 mg to approximately 2000 mg (e.g., approximately 100 mg, approximately 350 mg, approximately 500 mg, approximately 1000 mg, approximately 1500 mg, or any range of values ​​described) or each dose of abiraterone decanoate is approximately 0.5 mg / kg to approximately 100 mg / kg of the patient's body weight (e.g., approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately The method involves administering a pharmaceutical composition (e.g., a unit formulation as described herein) containing abiraterone decanoate as described herein (e.g., substantially pure abiraterone decanoate as described herein) to a patient in need, via intramuscular, intradermal, or subcutaneous injection, once a week or once every few weeks, for example, once a month or once every few months, for example, once every two months or once every three months, at a dose of 30 mg / kg, approximately 50 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, or any range of the values ​​described herein. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the prostate cancer is castration-resistant or castration-sensitive prostate cancer. In some embodiments, the prostate cancer is metastatic castration-resistant or metastatic castration-sensitive prostate cancer. Suitable prostate cancers that can be treated by this method also include any of those described herein. In some embodiments, a method for treating prostate cancer includes a combination therapy that further comprises administering to the patient one or more additional therapeutic agents, such as those described in the "Combination Therapies for Prostate Cancer" chapter of this specification.

[0176] In some specific cases, the Disclosure provides a method for treating prostate cancer in which each dose of abiraterone decanoate is approximately 50 mg to approximately 2000 mg (e.g., approximately 100 mg, approximately 350 mg, approximately 500 mg, approximately 1000 mg, approximately 1500 mg, or any range of the values ​​described) or approximately 0.5 mg / kg to approximately 100 mg / kg of the patient's body weight (e.g., approximately 0.5 mg / kg, approximately 1 mg / kg) The method involves administering the unit formulations described herein to a patient in need of it, via intramuscular, intradermal, or subcutaneous injection, at doses of approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 50 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, or any range of the values ​​described herein, once a week or once every few weeks, for example, once a month or once every few months, for example, once every two months or once every three months. In some embodiments, the unit formulations are administered via intramuscular injection. In some embodiments, the prostate cancer is castration-resistant or castration-sensitive prostate cancer. In some embodiments, the prostate cancer is metastatic castration-resistant or metastatic castration-sensitive prostate cancer. Suitable prostate cancers that can be treated by this method also include any of those described herein. In some embodiments, the method for treating prostate cancer includes combination therapy, further comprising administering one or more additional therapeutic agents to the patient, for example, as described in the chapter “Combination Therapies for Prostate Cancer” herein.

[0177] In some specific embodiments, the Disclosure also provides a method for treating breast cancer in a patient in need thereof, wherein each dose of abiraterone decanoate is approximately 50 mg to approximately 2000 mg (e.g., approximately 100 mg, approximately 350 mg, approximately 500 mg, approximately 1000 mg, approximately 1500 mg, or any range of the values ​​described) or approximately 0.5 mg / kg to approximately 100 mg / kg of the patient's body weight (e.g., approximately 0.5 mg / kg, approximately 1 mg / kg) The method involves administering to a patient a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit formulation as described herein) via intramuscular, intradermal, or subcutaneous injection at a dose of approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 50 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, or any range of the values ​​described herein, once a week or once every few weeks, for example, once a month or once every few months, for example, once every two months or once every three months. In some embodiments, the breast cancer may be molecular apocrine HER2-negative breast cancer, metastatic breast cancer, for example, ER+ metastatic breast cancer, ER+ and HER2-negative breast cancer, AR+ triple-negative breast cancer, etc. In some embodiments, the method further involves administering to the patient an aromatase inhibitor, for example, exemestane.

[0178] In some specific embodiments, the Disclosure also provides a method for treating 21-hydroxylase deficiency in a patient in need thereof, wherein each dose of abiraterone decanoate is approximately 50 mg to approximately 2000 mg (e.g., approximately 100 mg, approximately 350 mg, approximately 500 mg, approximately 1000 mg, approximately 1500 mg, or any range of the values ​​described) or approximately 0.5 mg / kg to approximately 100 mg / kg of the patient's body weight (e.g., approximately 0.5 mg / kg, approximately The treatment involves administering to a patient a pharmaceutical composition containing abiraterone decanoate as described herein (e.g., a unit formulation as described herein) via intramuscular, intradermal, or subcutaneous injection at a dose of 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 50 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, or any range of the values ​​described herein, once a week or once every few weeks, for example, once a month or once every few months, for example, once every two months or once every three months.

[0179] In some specific embodiments, the Disclosure also provides a method for delivering abiraterone to a patient in need thereof, wherein each dose of abiraterone decanoate is approximately 50 mg to approximately 2000 mg (e.g., approximately 100 mg, approximately 350 mg, approximately 500 mg, approximately 1000 mg, approximately 1500 mg, or any range of the values ​​described) or approximately 0.5 mg / kg to approximately 100 mg / kg of the patient's body weight (e.g., approximately 0.5 mg / kg, approximately 1 mg / kg, approximately The treatment involves administering a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit formulation as described herein) to a patient via intramuscular, intradermal, or subcutaneous injection at doses of 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 50 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, or any range of the values ​​described herein, once a week or once every few weeks, for example, once a month or once every few months, for example, once every two months or once every three months. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the patient suffers from, for example, a hormone-dependent benign or malignant disease, a syndrome resulting from androgen excess, and / or a syndrome resulting from glucocorticoid excess, such as hypercortisolemia, as described herein.

[0180] In some specific embodiments, the Disclosure also provides a method for inhibiting CYP17A1 activity in patients requiring it, wherein each dose of abiraterone decanoate is approximately 50 mg to approximately 2000 mg (e.g., approximately 100 mg, approximately 350 mg, approximately 500 mg, approximately 1000 mg, approximately 1500 mg, or any range of the values ​​described) or approximately 0.5 mg / kg to approximately 100 mg / kg of the patient's body weight (e.g., approximately 0.5 mg / kg, approximately 1 mg / kg) The method involves administering a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit formulation as described herein) to a patient via intramuscular, intradermal, or subcutaneous injection at a dose of approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 50 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, or any range of the values ​​described herein, once a week or once every few weeks, for example, once a month or once every few months, for example, once every two months or once every three months. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the patient suffers from a sex hormone-dependent benign or malignant disease, for example, as described herein. In some embodiments, the patient suffers from a syndrome caused by excess androgens and / or a syndrome caused by excess glucocorticoids, such as hypercortisolemia, for example, as described herein.

[0181] In some specific embodiments, the Disclosure also provides a method for reducing glucocorticoid (e.g., cortisol) levels in patients in need, wherein each dose of abiraterone decanoate is approximately 50 mg to approximately 2000 mg (e.g., approximately 100 mg, approximately 350 mg, approximately 500 mg, approximately 1000 mg, approximately 1500 mg, or any range of the values ​​described), or each dose of abiraterone decanoate is approximately 0.5 mg / kg to approximately 100 mg / kg of the patient's body weight (e.g., approximately 0.5 mg / kg). The treatment involves administering a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit formulation as described herein) to a patient via intramuscular, intradermal, or subcutaneous injection at doses of approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 50 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, or any range of the values ​​described herein, once a week or once every few weeks, for example, once a month or once every few months, for example, once every two months or once every three months. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the patient suffers from hypercortisolemia as described herein, such as Cushing's syndrome or Cushing's disease.

[0182] In some specific embodiments, the Disclosure also provides a method for reducing androgen (e.g., testosterone and / or dihydrotestosterone) and / or estrogen levels in patients in need thereof, wherein each dose of abiraterone decanoate is approximately 50 mg to approximately 2000 mg (e.g., approximately 100 mg, approximately 350 mg, approximately 500 mg, approximately 1000 mg, approximately 1500 mg, or any range of the values ​​described), or each dose of abiraterone decanoate is approximately 0.5 mg / kg to approximately 100 mg / kg of the patient's body weight. The treatment involves administering a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit formulation as described herein) to a patient via intramuscular, intradermal, or subcutaneous injection at a dose once a week or once every few weeks, for example, once a month or once every few months, for example, once every two months or once every three months. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the patient suffers from a syndrome resulting from androgen excess, such as congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), endometriosis, polycystic ovary syndrome, precocious puberty, or hirsutism. In some embodiments, the patient has an androgen and / or estrogen-related cancer, such as prostate cancer or breast cancer.

[0183] Other abiraterone prodrugs While this disclosure describes embodiments relating to abiraterone decanoate in more detail, those skilled in the art will understand that similar embodiments are also applicable to other abiraterone prodrugs of this disclosure in view of this specification. For example, pharmacokinetic studies have shown that intramuscular injection of abiraterone isocaproate formulations can result in therapeutically effective plasma abiraterone over a long period, as with abiraterone decanoate. Therefore, the embodiments described herein, particularly for abiraterone decanoate formulations and methods of treatment, are also applicable to abiraterone isocaproate by substituting abiraterone decanoate with abiraterone isocaproate.

[0184] For example, in some embodiments, the Disclosure also provides methods for treating sex hormone-dependent benign or malignant diseases, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia, the methods comprising administering a therapeutically effective amount of a pharmaceutical composition (e.g., a unit formulation as described herein) containing abiraterone isocaproate as described herein to a patient in need. In some embodiments, the pharmaceutical composition (e.g., a unit formulation as described herein) containing abiraterone isocaproate as described herein can be administered to a patient in need regardless of diet. Appropriate sex hormone-dependent benign or malignant diseases, syndromes resulting from androgen excess, syndromes resulting from glucocorticoid excess such as hypercortisolemia, dosage and administration, concomitant therapies, etc., include, for example, those described herein relating to abiraterone decanoate.

[0185] In some specific cases, the Disclosure provides a method for treating prostate cancer in which each dose of abiraterone isocaproate is approximately 50 mg to approximately 2000 mg (e.g., approximately 100 mg, approximately 350 mg, approximately 500 mg, approximately 1000 mg, approximately 1500 mg, or any range of the values ​​described) or each dose of abiraterone isocaproate is approximately 0.5 mg / kg to approximately 100 mg / kg of the patient's body weight (e.g., approximately 0.5 mg / kg) The method involves administering a pharmaceutical composition comprising abiraterone isocaproate as described herein to a patient in need, via intramuscular, intradermal, or subcutaneous injection, once a week or once every few weeks, for example, once a month or once every few months, in doses of approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 50 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, or any range of the values ​​described herein. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the prostate cancer is castration-resistant or castration-sensitive. In some embodiments, the prostate cancer is metastatic castration-resistant or metastatic castration-sensitive.

[0186] In some specific cases, the Disclosure provides a method for treating prostate cancer in which each dose of abiraterone isocaproate is approximately 50 mg to approximately 2000 mg (e.g., approximately 100 mg, approximately 350 mg, approximately 500 mg, approximately 1000 mg, approximately 1500 mg, or any range of the values ​​described) or each dose of abiraterone isocaproate is approximately 0.5 mg / kg to approximately 100 mg / kg of the patient's body weight (e.g., approximately 0.5 mg / kg) The method involves administering a unit formulation containing abiraterone isocaproate as described herein to a patient in need, via intramuscular, intradermal, or subcutaneous injection, once a week or once every few weeks, for example, once a month or once every few months, in a dose of approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 50 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, or any range of the values ​​described herein. In some embodiments, the unit formulation is administered via intramuscular injection. In some embodiments, the prostate cancer is castration-resistant or castration-sensitive. In some embodiments, the prostate cancer is metastatic castration-resistant or metastatic castration-sensitive.

[0187] In some specific embodiments, the Disclosure also provides a method for delivering abiraterone to a patient in need thereof, wherein each dose of abiraterone isocaproate is about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of the values ​​described) or each dose of abiraterone isocaproate is about 0.5 mg / kg to about 100 mg / kg of the patient's body weight (e.g., about 0.5 mg The treatment involves administering a pharmaceutical composition containing abiraterone isocaproate as described herein (e.g., a unit formulation as described herein) to a patient via intramuscular, intradermal, or subcutaneous injection at a dose of approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 50 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, or any range of the values ​​described herein, once a week or once every few weeks, for example, once a month or once every few months. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the patient suffers from, for example, a hormone-dependent benign or malignant disease, a syndrome resulting from androgen excess, and / or a syndrome resulting from glucocorticoid excess, such as hypercortisolemia, as described herein.

[0188] In some specific embodiments, the Disclosure also provides a method for inhibiting CYP17A1 activity in patients requiring it, wherein each dose of abiraterone isocaproate is about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of the values ​​described), or each dose of abiraterone isocaproate is about 0.5 mg / kg to about 100 mg / kg of the patient's body weight (e.g., about 0. The method involves administering to a patient a pharmaceutical composition comprising abiraterone isocaproate as described herein (e.g., a unit formulation as described herein) via intramuscular, intradermal, or subcutaneous injection once a week or once every few weeks, for example, once a month or once every few months, in a dose of 5 mg / kg, approximately 1 mg / kg, approximately 5 mg / kg, approximately 1 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 50 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, or any range of the values ​​described herein. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the patient suffers from a sex hormone-dependent benign or malignant disease, for example, as described herein. In some embodiments, the patient suffers from a syndrome caused by excess androgens and / or a syndrome caused by excess glucocorticoids, such as hypercortisolemia, for example, as described herein.

[0189] In some specific embodiments, the Disclosure also provides a method for reducing glucocorticoid (e.g., cortisol) levels in patients in need thereof, wherein each dose of abiraterone isocaproate is about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of the values ​​described), or each dose of abiraterone is about 0.5 mg / kg to about 100 mg / kg of the patient's body weight. For example, the administration of a pharmaceutical composition containing abiraterone isocaproate as described herein (e.g., a unit formulation as described herein) to a patient via intramuscular, intradermal, or subcutaneous injection once a week or once every few weeks, for example once a month or once every few months, in a dose of approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 50 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, or any range of the values ​​described herein. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the patient suffers from hypercortisolemia as described herein, such as Cushing's syndrome or Cushing's disease.

[0190] In some specific embodiments, the Disclosure also provides a method for reducing androgen (e.g., testosterone and / or dihydrotestosterone) and / or estrogen levels in a patient in need thereof, wherein each dose of abiraterone isocaproate is about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any range of the values ​​described), or each dose of abiraterone isocaproate is about 0.5 mg of the patient's body weight. The treatment involves administering a pharmaceutical composition containing abiraterone isocaproate as described herein (e.g., a unit formulation as described herein) to a patient via intramuscular, intradermal, or subcutaneous injection at a dose of approximately 100 mg / kg (e.g., approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 30 mg / kg, approximately 50 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, or any range of the values ​​described herein) once a week or once every few weeks, for example, once a month or once every few months. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the patient suffers from a syndrome resulting from excess androgens, such as congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), endometriosis, polycystic ovary syndrome, precocious puberty, or hirsutism. In some embodiments, the patient has an androgen and / or estrogen-related cancer, such as prostate cancer or breast cancer.

[0191] This specification provides formulations, methods, and kits for treating patients with sex hormone-dependent benign or malignant diseases, such as prostate cancer. Methods for preparing formulations useful for treating patients with sex hormone-dependent benign or malignant diseases (e.g., prostate cancer), syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia, are also provided. Reference numerals are assigned to details of representative embodiments, examples of which are shown in the accompanying drawings.

[0192] The term “patient” as used in this invention means, but is not limited to, an animal or human who needs or can receive chemotherapy for a sex hormone-dependent benign or malignant disease, e.g., androgen-dependent or estrogen-dependent disease (including prostate cancer and breast cancer), or an animal or human who needs or can receive treatment for a non-tumor syndrome resulting from excess androgen, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), precocious puberty, hirsutism, and / or a non-tumor syndrome resulting from excess glucocorticoids, such as hypercortisolemia, such as Cushing’s syndrome or Cushing’s disease. In preferred embodiments, the patient is a human subject.

[0193] The term “other drugs or agents” means at least one other compound, formulation, molecule, biological agent, etc., that, when used in the present invention (for example, when at least one other drug or agent is administered before, simultaneously with, and after at least one abiraterone prodrug formulation), can enhance the efficacy of the formulation(s), reduce the undesirable side effects(s) of the formulation(s), or improve the treatment of a particular disease. Any preferred route of administration of such “other drugs or agents” can be used, for example, by oral administration, parenteral administration, etc. A person skilled in the art treating patients with sex hormone-dependent benign or malignant diseases (e.g., androgen-dependent or estrogen-dependent diseases), syndromes resulting from androgen excess syndromes and / or syndromes resulting from glucocorticoid excess such as hypercortisolemia will recognize and understand how to select and use such “other drugs or agents” for the intended purpose(s).

[0194] The formulations may be administered via an improved sustained-release device or method, at the option of choice. The term “improved sustained-release,” as used herein, should be understood to encompass delayed release, prolonged or long-duration release, sustained release, or target release, etc. For example, in some embodiments, an improved sustained-release device or method can further extend the release of abiraterone of the prodrugs and formulations of this disclosure. In some embodiments, an improved sustained-release device or method may also include any device or method that can release a drug or product (e.g., a drug or biological formulation) at a later time than immediately after its administration (and, for example, infusion). Various improved sustained-release devices have been described previously (Stubbe et al., Pharm. Res. 21:1732, 2004), and such devices may be applicable to representative embodiments. Improved sustained-release devices and methods can be recognized and utilized by those skilled in the art without requiring excessive experimentation, after considering all criteria and making the best judgment on behalf of the patient.

[0195] The formulations and agents of the embodiments are administered in pharmacologically or physiologically acceptable and effective amounts, for example, to reduce or eliminate the presence of prostate tumor tissue and abnormal or malignant prostate cells in a patient exhibiting prostate cancer. Similarly, the formulations and agents of the embodiments are administered alone or in combination with other therapeutic agents or treatments (e.g., radiotherapy and surgery) in prophylactic or therapeutically effective amounts, such amounts should be understood as amounts that satisfy the intended prophylactic or therapeutic objective and provide the benefits derived from the administration of such formulations and agents.

[0196] The terms “effective dose,” “effective dosage,” and “therapeutic plasma concentration,” as used herein, mean, but not limited to, a quantity, dose, or concentration that can treat, delay, slow, inhibit, or eliminate the onset, presence, or progression of a disease, disorder, or condition. For example, “effective dose,” “effective dosage,” or “therapeutic plasma concentration” is a quantity, dose, or concentration sufficient to reduce or eliminate the presence of prostate tumor tissue and abnormal or malignant prostate cells in a patient exhibiting prostate cancer, that is, to cure the disease (partially or completely) or to prevent the onset or further progression of a disease, disorder, or condition. As a further example, an effective dose of a formulation means the amount administered, alone or in combination with other therapeutic agents or treatments (e.g., radiotherapy and surgery), to clinically significantly reduce tumor load. Those skilled in the art will understand when, after administration of a formulation, a clinically significant reduction in tumor load (or improvement of a sex hormone-dependent benign or malignant disease or another disease or syndrome as described herein) occurs. An "effective amount," "effective dose," or "therapeutic plasma concentration" is defined as an amount, dose, or concentration that does not cause significant harm to the patient, and in all cases, it is understood that any adverse side effects are more important than the benefits. As just one example, an effective amount or dose of an abiraterone prodrug formulation means an amount that can achieve a plasma concentration of at least 1 ng / ml of abiraterone in the patient after parenteral administration of the prodrug formulation, e.g., at least 1 ng / ml, at least 2 ng / ml, at least 4 ng / ml, or at least 8 ng / ml, and an effective plasma concentration is a concentration achieved for at least one week after administration, e.g., at least two weeks (e.g., 4, 6, or 8 weeks or more).

[0197] In general, the dose range for the formulations described herein is that which will produce the desired effect(s). The useful dose will vary depending on the age, weight and health status of the patient being treated, the mode, route and schedule of administration, the individual patient's response, and the type or stage of prostate cancer (or the severity of any sex hormone-dependent benign or malignant disease or other syndrome or disease) to which treatment with the formulation is required. The dose will also vary depending on the nature or severity of the primary tumor and other underlying conditions, the epidemiological context, concomitant use of other active compounds, and the route of administration. In addition, the dose will be determined by the presence of adverse side effects such as local hypersensitivity, systemic adverse effects, and immune resistance.

[0198] The effective dose of a formulation (and other drugs) can be determined without requiring experiments by those skilled in the art (e.g., pharmacokinetic studies) after considering all criteria and making the best judgment on behalf of the patient (and in most cases, it is determined by the specific formulation used). The dosage will vary depending on the specific case, but in any case, it will be sufficient to produce a clinical effect or improvement for sex hormone-dependent benign or malignant diseases (e.g., prostate cancer), syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess, such as hypercortisolemia.

[0199] The formulations and agents of the embodiments may, optionally, be administered in combination with (or include) one or more pharmaceutically acceptable carriers, diluents, or excipients. Formulations, administration techniques, pharmaceutical compositions, methods for preparing pharmaceutical compositions, and pharmaceutically acceptable carriers, diluents, and excipients are known in the art, for example, described in "Remington: The Science and Practice of Pharmacy" (formerly "Remington's Pharmaceutical Sciences," University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia, Pa. (2005)), the disclosure of which is incorporated herein by reference. Those skilled in the art may use known physiologically acceptable sterile solutions for injection. Isotonic aqueous solutions, such as physiological saline, phosphate-buffered saline (PBS), or corresponding plasma protein solutions are readily available for preparing ready-to-use solutions for parenteral injection or infusion. The formulation may exist as a lyophilized preparation or a dry preparation, for example, as a kit of parts, which can be dissolved in a known injectable solution immediately before use under sterile conditions. In addition, the formulation may contain one or more acceptable carriers, such as solvents, dispersions, coatings, adjuvants, stabilizers, diluents, preservatives, antimicrobial and antifungal agents, isotonic agents, absorption modifiers, etc. Diluents may include water, physiological saline, phosphate-buffered saline (PBS), dextrose, ethanol, glycerol, etc. Isotonic agents may include sodium chloride, dextrose, mannitol, sorbitol, and lactose, etc. Stabilizers may include albumin and alkali salts of ethylenediaminetetraacetic acid, etc.

[0200] Any preferred route of administration may be used to deliver an effective amount / dose of formulation and drug to the patient, according to a representative embodiment. The preferred route of administration can be readily determined without excessive experimentation by those skilled in the art, such as pharmacology, immunology, medicine, and oncology. However, the formulation is expected to be primarily suitable for parenteral administration, such as by IM injection, intradermal injection, or subcutaneous injection.

[0201] The abbreviations used herein have their conventional meanings within the fields of chemistry and biology.

[0202] It should also be understood that certain embodiments, which are variable parts of this specification, may be the same as or different from other particular embodiments using the same designation.

[0203] The definitions of specific functional groups and chemical terms are explained in more detail below. For chemical elements, refer to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th Identified by the inside cover of the Ed, and for specific functional groups, generally defined as described herein. Furthermore, for general principles of organic chemistry, as well as specific functional parts and reactivity, see Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley&Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rdThis is described in Edition, Cambridge University Press, Cambridge, 1987. This disclosure is not intended to be limited in any way by the exemplary list of substituents described herein.

[0204] As used herein, the term “alkyl,” either by itself or as part of another group, refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon. In some embodiments, alkyl groups contain 1 to 30 carbon atoms (i.e., C 1-30 Alkyl, or C1-C 30 It may be represented as alkyl, or it may contain a specified number of carbon atoms (i.e., C1 alkyl such as methyl, C2 alkyl such as ethyl, C3 alkyl such as propyl or isopropyl, etc.). In one embodiment, the alkyl group is a linear C 1-16 It is an alkyl group. In another embodiment, the alkyl group is a branched chain C 3-16 It is an alkyl group.

[0205] As used herein, the term “cycloalkyl,” used by itself or as part of another group, refers to a group having 3 to 12 carbon atoms (i.e., C 3-12 This refers to saturated and partially unsaturated (e.g., including one or two double bonds) cyclic aliphatic hydrocarbons (cycloalkyl) or cycloalkyl groups containing 1 to 3 rings having a specified number of carbon atoms. In one embodiment, the cycloalkyl group has two rings. In one embodiment, the cycloalkyl group has one ring. In another embodiment, the cycloalkyl group has C 3-8 It is a cycloalkyl group. In another embodiment, the cycloalkyl group is C 3-6These are cycloalkyl groups. "Cycloalkyl" also includes a ring system in which a cycloalkyl ring is fused with one or more aryl or heteroaryl groups, as described above, where the bonding site is on the cycloalkyl ring, and in such examples, the carbon number still refers to the carbon number of the cycloalkyl ring system. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl.

[0206] As used herein, the term “alkenyl,” used by itself or as part of another group, means a linear or branched aliphatic hydrocarbon containing one or more (e.g., 1, 2, or 3) carbon-to-carbon double bonds. In one embodiment, the alkenyl group is C 2-16 It is an alkenyl group.

[0207] As used herein, the term “alkynyl,” used by itself or as part of another group, means a linear or branched aliphatic hydrocarbon containing one or more (e.g., one, two, or three) carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is C 2-16 It is an alkynyl group.

[0208] As used herein, the term “abiraterone prodrugs of the Disclosure” means any of the compounds of formula I or II described herein, any of the lipophilic esters of abiraterone prodrugs, or Examples 2A-2H, their isotopically labeled compounds (e.g., deuterium-enriched compounds), their possible stereoisomers (diastereoisomers, enantiomers, and racemic mixtures), their tautomers, their conformational isomers, and / or pharmaceutically acceptable salts thereof (e.g., acid addition salts such as HCl salts). Hydrates and solvates of the prodrugs of the Disclosure are considered compositions of the Disclosure, where the prodrug(s) is associated with water or a solvent, respectively. Some of the prodrugs of the Disclosure may also exist in various pleomorphic or amorphous forms. The prodrugs described herein include compounds that readily undergo chemical transformation under physiological conditions to provide active abiraterone. Furthermore, prodrugs may be converted by chemical or biochemical methods in an ex vivo environment. As used herein, the term “Abiraterone Prodrug Formulations of the Disclosure” means any pharmaceutical composition or formulation comprising one or more of the abiraterone prodrugs of the Disclosure, for example, any of the formulations prepared in Examples 3A to 3J and 9. In any of the embodiments described herein, unless directly inconsistent with the context, the abiraterone prodrug of the Disclosure may be abiraterone decanoate. In any of the embodiments described herein, unless directly inconsistent with the context, the abiraterone prodrug formulation of the Disclosure may be any pharmaceutical composition comprising abiraterone decanoate as described herein. In any of the embodiments described herein, unless directly inconsistent with the context, the abiraterone prodrug formulation of the Disclosure may also be abiraterone isocaproate. In any of the embodiments described herein, unless directly inconsistent with the context, the abiraterone prodrug formulation of the Disclosure may also be any pharmaceutical composition comprising abiraterone isocaproate as described herein.

[0209] The abiraterone prodrugs of this disclosure may exist in isotopic-labeled or isotopic-enriched forms containing one or more atoms having atomic masses or mass numbers different from those most commonly found in nature. The isotopes may be radioactive or non-radioactive. Examples of atomic isotopes include hydrogen, carbon, oxygen, and nitrogen. 2 H, 3 H, 13 C, 14 C, 15 N, and 18 Examples include, but are not limited to, O. Compounds containing other isotopes of these and / or other atoms are within the scope of this disclosure.

[0210] The wedge-shaped bonds shown by the solid and dashed lines represent stereochemistry that is conventional in this art. [Examples]

[0211] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claimed subject matter.

[0212] Example 1. Long-acting injectable formulation of abiraterone prodrug The formulations include long-acting injectable oil-based formulations of lipophilic abiraterone prodrugs such as (1) abiraterone 3β-alkanoate and (2) linear, branched, cyclic, and aromatic alkanoates (i.e., aliphatic and aromatic esters consisting of 2 to 16 carbon atoms). Examples of abiraterone esters include acetate, propionate, butanoate, (vaterate)pentanoate, isocaproate, bucicrate, cyclohexanecarboxylic acid, phenylpropionate, caproate (hexanoate), enanthate (heptanoate), cypionic acid, octanoate, non-canoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate, and hexadecanate. In typical embodiments, the abiraterone esters are abiraterone acetate, abiraterone propionic acid, and abiraterone decanoate.

[0213] The formulation may include a solution or suspension of the abiraterone prodrug for injection in a pharmaceutically acceptable oil, such as a plant-derived oil or a pharmaceutically acceptable oil containing synthetic monoglycerides or diglycerides of fatty acids. In some embodiments, the pharmaceutically acceptable oil may contain triglycerides consisting of (polyunsaturated, monounsaturated, and saturated) fatty acids, such as vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil. Vegetable oils were selected based on the solubility of the prodrug in the oil. It was determined that abiraterone acetate is most soluble in castor oil, which contains triglycerides whose fatty acid component is mainly rich in oleic acid (hydroxylated monounsaturated fatty acid). Conversely, more lipophilic prodrugs (abiraterone propionate and abiraterone decanoate) were found to be more soluble in corn oil containing triglycerides whose fatty acid components are mainly linoleic acid (non-hydroxylated polyunsaturated fatty acid), oleic acid (non-hydroxylated unsaturated fatty acid), palmitic acid (non-hydroxylated saturated fatty acid), and stearic acid (non-hydroxylated saturated fatty acid). Surprisingly, abiraterone butanoate was found to have lower solubility in both castor oil and corn oil than acetate, propionate, or decanoate ester prodrugs. We also noted an inverse correlation between the melting point and solubility of prodrugs in vegetable oils. The melting points of the various abiraterone prodrugs shown in Table 1 were measured by differential scanning calorimetry.

[0214] [Table 4]

[0215] The formulation may contain pharmaceutically acceptable excipients such as benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid, and co-solvents (i.e., solubilizers) such as ethyl acetate. Additives / co-solvents benzyl alcohol and benzyl benzoate have been found to not only increase the solubility of the prodrug but also to reduce the viscosity and glide force of the solution (see Figures 13A-13E and Tables 2A-2D), thereby resulting in higher concentration solutions that are easier to inject with needles of acceptable gauge for IM injection (e.g., 20-27 gauge, e.g., 22-25 gauge). In practice, co-solvents are selected based on their ability to reduce the viscosity of the solvent, enabling injection through a suitable needle or cannula. Benzyl alcohol as an additive for IM or subcutaneous injection has the advantage of acting as a local anesthetic at the injection site (Wilson et al. Ann. Emer. Med. 33(5), 495, 1999).

[0216] The solubility of abiraterone ester may be affected when a co-solvent is added to a vegetable oil solvent. Therefore, in some embodiments, abiraterone ester is completely dissolved in the composition, while in other embodiments, it is partially dispersed in the composition. In one embodiment, abiraterone ester is completely dissolved in the solvent.

[0217] The formulation may also contain pharmaceutically acceptable preservatives, polymers, antioxidants, antimicrobial agents, chelating agents, and other excipients, such as citric acid, dextrose, ascorbic acid, benzalkonium chloride, benzoic acid, sodium betadex sulfobutyl ether, calcium chloride, sodium carbomethoxycellulose, chlorobutanol, creatine, croscarmellose, dibasic potassium phosphate, sodium doxate, sodium edetate, glycerin, sodium hyaluronate, hydroxypropyl betadex, lactic acid, lactose, lecithin, maleic acid, mannitol, meglumine, methylcellulose, methylparaben, microcrystalline cellulose, and miripitium chloride. Examples include chloride, monothioglycerol, phenol, poloxamer 188, polyglactin, polysorbate 20, polysorbate 40, polysorbate 80, propylparaben, sodium acetate, sodium benzoate, sodium citrate, sorbitan monolaurate, sorbitol, sucrose, tartaric acid, trisodium citrate, tromantadine, tromethamine, and urea.

[0218] The formulation may be sterilized by methods known to those skilled in the art (e.g., gamma irradiation, micron filtration, and autoclave).

[0219] Abiraterone prodrug formulations can be prepared at various concentrations, such as 25 mg / ml to 500 mg / ml. In typical embodiments, the concentration is 50 mg / ml to 300 mg / ml.

[0220] The formulation releases an effective amount of abiraterone for at least one week, and up to two, three, four weeks or longer, after IM or subcutaneous injection. The therapeutic range plasma level of abiraterone achieved after administration of the abiraterone prodrug formulation may be, for example, 6–15 ng / ml for 14–28 days after parenteral administration. In a typical embodiment, the therapeutic range level is 8–12 ng / ml for 14–28 days after parenteral administration. minIt has been demonstrated that this is associated with a favorable prostate-specific antigen response and may be a very important predictor of progression-free survival in patients with castration-resistant prostate cancer (Carton et al., Eur.J.Cancer, 72:54, 2017).

[0221] Example 2. Synthesis of abiraterone prodrug Abiraterone acetate Abiratherone acetate was obtained from Hetero Labs Limited, India.

[0222] Other abiraterone esters generally use abiraterone R 2 COOH or R 2 It can be synthesized by reacting it with its appropriate activated form, such as COCl. The reaction is typically carried out in an aprotic solvent such as CHCl3, along with a suitable base such as triethylamine. Examples of the preparation of abiraterone propionate, abiraterone butanoate, abiraterone pentanoate, abiraterone hexanoate, abiraterone heptanoate, abiraterone isocaproate, abiraterone cypionicate, and abiraterone decanoate are shown below. [ka]

[0223] Example 2A. Preparation of abiraterone propionate Abiraterone propionate was prepared as follows.

[0224] 15.0 g (42.9 mmol) of abiraterone was added to a 500 ml round-bottom flask, followed by 450 ml of chloroform and 11.96 ml (85.8 mmol, 2.0 equivalents) of triethylamine. The flask was purged with nitrogen, and the mixture was cooled to 0°C in an ice bath. After stirring the mixture for 15 minutes, 4.12 ml (47.2 mmol, 1.1 equivalents) of propanoyl chloride was added dropwise, followed by a further 6.57 ml (47.2 mmol, 1.1 equivalents) of triethylamine. The ice bath was removed, and the solution was stirred for a further 2 hours. The reaction mixture was cooled again to 0°C, and a further 4.12 ml of propanoyl chloride and 6.57 ml of triethylamine were slowly added. The ice bath was removed again, and the reaction mixture was stirred for a further 16 hours. The solution was then washed twice with 300 ml of water and once with 300 ml of brine. The organic phase was dried over sodium sulfate, concentrated under vacuum, and packed onto silica. The crude compound was purified by flash chromatography using an ethyl acetate / hexane solvent system. The desired compound was eluted with approximately 30% ethyl acetate. The pure fractions were mixed and concentrated under vacuum to obtain 8.2 g of abiraterone propionate as a yellow solid. This was 97.8% pure according to HPLC analysis. Other chemical properties were LCMS m / z 406.3 (M+H); 1 ¹H NMR (CDCl3, 200 MHz): δH values ​​were 1.096 (11H, m), 1.625 (11H, m), 1.846 (3H, m), 2.067 (3H, m), 2.323 (5H, m), 4.627 (1H, m), 5.415 (1H, d, J = 5 Hz), 5.992 (1H, q, J = 5 Hz), 7.215 (1H, ddd, J = 1,5,8 Hz), 7.677 (1H, dt, J = 2,8 Hz), 8.456 (1H, dd, J = 2,5 Hz), 8.619 (1H, dd, J = 1,2 Hz); melting point (DSC) was 101°C.

[0225] Example 2B. Preparation of abiraterone butanoate Butanoic acid abiraterone was prepared as follows.

[0226] 7.0 g (20.0 mmol) of abiraterone was added to a 500 ml round-bottom flask, followed by 210 ml of chloroform and 5.58 ml (40.0 mmol, 2.0 equivalents) of triethylamine. The flask was purged with nitrogen, and the mixture was cooled to 0°C in an ice bath. After stirring the mixture for 15 minutes, 2.28 ml (22.0 mmol, 1.1 equivalents) of butanoyl chloride was added dropwise, followed by a further 3.07 ml (22.0 mmol, 1.1 equivalents) of triethylamine. The ice bath was removed, and the solution was stirred for a further 2 hours. The reaction mixture was cooled again to 0°C, and a further 2.28 ml of butanoyl chloride and 3.07 ml of triethylamine were slowly added. The ice bath was removed again, and the reaction mixture was stirred for a further 16 hours. During the reaction, the color rapidly changed from a white mixture to a yellow solution, and then slowly to a red solution. After confirming the completion of the reaction by TLC and LC-MS, the solution was washed twice with 150 ml of water and once with 150 ml of brine. The organic phase was dried over sodium sulfate, concentrated under vacuum, and packed onto silica. The crude compound was purified by flash chromatography using an ethyl acetate / hexane solvent system. The desired compound was eluted with approximately 25% ethyl acetate. The pure fractions were mixed and concentrated under vacuum to obtain 5.5 g of abiraterone butanoate as a yellow solid. The chemical properties were LC-MS m / z 420.4 (M+H); 1 H NMR (CDCl3, 200MHz): δH 0.948 (3H, t, J= 7 Hz), 1.043 (3H, s), 1.090 (3H, s), 1.633 (15H, m), 1.842 (3H, m), 2.065 (3H,m), 2.297 (5H, m), 4.608 (1H, m) , 5.413 (1H, d, J = 5 Hz), 5.990 (1H, q, J = 5Hz), 7.215 (1H, ddd, J = 1,5,8 Hz), 7.643 (1H, dt, J = 2,8 Hz), 8.455 (1H, dd, J= 2,5 Hz), 8.615 (1H, The melting point (DSC) was 147°C (dd, J = 1,2 Hz).

[0227] Example 2C. Preparation of avirateron decanoate [ka] Abiraterone decanoate was prepared as follows.

[0228] 10.0 g (28.6 mmol) of abiraterone was added to a 500 ml round-bottom flask, followed by 300 ml of chloroform and 7.97 ml (57.2 mmol, 2.0 equivalents) of triethylamine. The flask was purged with nitrogen, and the mixture was cooled to 0°C in an ice bath. After stirring the mixture for 15 minutes, 6.53 ml (31.5 mmol, 1.1 equivalents) of decanoyl chloride was added dropwise, followed by a further 4.39 ml (31.5 mmol, 1.1 equivalents) of triethylamine. The ice bath was removed, and the solution was stirred for a further 2 hours. The reaction mixture was cooled again to 0°C, and a further 6.53 ml of decanoyl chloride and 4.39 ml of triethylamine were slowly added. The ice bath was removed again, and the reaction mixture was stirred for a further 16 hours. During the reaction, the color rapidly changed from a white mixture to a yellow solution, and then slowly to a red solution. After confirming the completion of the reaction by TLC and LC-MS, the solution was washed twice with 200 ml of water and once with 200 ml of brine. The organic phase was dried over sodium sulfate, concentrated under vacuum, and packed onto silica. The crude compound was purified by flash chromatography using an ethyl acetate / hexane solvent system. The desired compound was eluted with approximately 20% ethyl acetate. The pure fractions were mixed and concentrated under vacuum to obtain 8.0 g of abiraterone decanoate as a yellow solid. The chemical properties were LC-MS m / z 504.4 (M+H); 1H NMR (CDCl3, 200MHz): δH 0.877 (3H, t, J= 7 Hz), 1.043 (3H, s), 1.082 (3H, s), 1.268 (16H, m), 1.643 (15H, m), 1.842 (3H,m), 2.065 (3H, m), 2.290 (5H, m), 4.602 (1H, m) , 5.404 (1H, d, J = 5 Hz), 5.998(1H, q, J = 5 Hz), 7.215 (1H, ddd, J = 1,5,8 Hz), 7.643 (1H, dt, J = 2,8 Hz), 8.455(1H, dd, J = 2,5 Its temperature was 8.617 (1H, dd, J = 1,2 Hz); its melting point (DSC) was 38°C.

[0229] Example 2D. Preparation of abirateron pentanoate [ka] Abiraterone pentanoate was prepared using a procedure similar to that used to prepare abiraterone decanoate (Example 2C), but valeroyl chloride was used instead of decanoyl chloride. LCMSm / z 434.3 (M+H); 1 1H NMR (CDCl3, 200MHz): δ H 0.9-2.2(32H, m), 4.61 (1H, m), 5.41 (1H, d, J = 5 Hz), 5.99 (1H, q, J = 5 Hz), 7.22 (1H,ddd, J = 1,5,8 Hz), 7.63 (1H, dt, J = 2,8 Hz), 8.45 (1H, dd, J = 2,5 Hz), 8.62 (1H, dd, J = 1,2 Hz).

[0230] Example 2E. Preparation of aviraterone hexanoate [ka] Abiraterone hexanoate was prepared using a procedure similar to that used to prepare abiraterone decanoate (Example 2C), but hexanoyl chloride was used instead of decanoyl chloride. LCMSm / z 448.4 (M+H); 1 1H NMR (CDCl3, 200MHz): δ H 0.9-2.2(34H, m), 4.60 (1H, m), 5.40 (1H, d, J = 5 Hz), 5.98 (1H, q, J = 5 Hz), 7.21 (1H,ddd, J = 1,5,8 Hz), 7.62 (1H, dt, J = 2,8 Hz), 8.43 (1H, dd, J = 2,5 Hz), 8.60 (1H, dd, J = 1,2 Hz).

[0231] Example 2F. Preparation of abiraterone heptanoate [ka] Heptanoate abiraterone was prepared using a procedure similar to that used to prepare decanoate abiraterone (Example 2C), but heptanoyl chloride was used instead of decanoyl chloride. LCMSm / z 462.4 (M+H); 1 1H NMR (CDCl3, 200MHz): δ H 0.9-2.2(36H, m), 4.61 (1H, m), 5.40 (1H, d, J = 5 Hz), 6.00 (1H, q, J = 5 Hz), 7.21 (1H,ddd, J = 1,5,8 Hz), 7.64 (1H, dt, J = 2,8 Hz), 8.45 (1H, dd, J = 2,5 Hz), 8.61 (1H, dd, J = 1,2 Hz).

[0232] Example 2G. Preparation of abiraterone isocaproate [ka] Isocaproate abiraterone was prepared using a procedure similar to that used to prepare decanoate abiraterone (Example 2C), but 4-methylvaleryl chloride was used instead of decanoyl chloride. LCMSm / z 448.4 (M+H); 1 1H NMR (CDCl3, 200MHz): δ H 0.9-2.2(34H, m), 4.61 (1H, m), 5.40 (1H, d, J = 5 Hz), 6.00 (1H, q, J = 5 Hz), 7.22 (1H,ddd, J = 1,5,8 Hz), 7.64 (1H, dt, J = 2,8 Hz), 8.45 (1H, dd, J = 2,5 Hz), 8.62 (1H, dd, J = 1,2 Hz).

[0233] Example 2: Preparation of aviraterone H-cypionic acid [ka] Abiraterone cypionic acid was prepared using a procedure similar to that used to prepare abiraterone decanoate (Example 2C), but 3-cyclopentylpropanoyl chloride was used instead of decanoyl chloride. LCMSm / z 474.4 (M+H); 1 1H NMR (CDCl3, 200MHz): δ H 1 1H NMR (CDCl3, 200 MHz): δ H 0.9-2.3 (36H, m), 4.62 (1H, m), 5.41(1H, d, J = 5 Hz), 6.00 (1H, q, J = 5 Hz), 7.22 (1H, ddd, J = 1,5,8 Hz), 7.63 (1H,dt, J = 2,8 Hz), 8.45 (1H, dd, J = 2,5 Hz), 8.62 (1H, dd, J = 1,2 Hz).

[0234] Example 3. Preparation of abiraterone prodrug formulations Example 3A. Preparation of abiraterone acetate in castor oil solution The castor oil solution for abiraterone acetate injection (IM Depot) was prepared as follows.

[0235] 490 mg of abiraterone acetate was weighed and placed in a 10 mL serum vial with a crimp stopper. 8 mL of castor oil was placed in another 10 mL serum vial with a crimp stopper. The two vials were then wrapped in aluminum foil and sterilized in an autoclave using a 30-minute liquid cycle. After sterilization, the vials were transferred to a laminar flow hood. Next, 7 mL of sterile castor oil was removed and added to the sterile abiraterone acetate, the vials were re-stopped and crimp-sealed. The abiraterone acetate was then dissolved by sonication, vortexing, and by rotating the vials. The final concentration of the sterile abiraterone acetate solution was 70 mg / ml.

[0236] Example 3B. Preparation of a solution of abiraterone acetate, 90% castor oil, and 10% benzyl alcohol. A solution of abiraterone acetate for injection (IM Depot) containing 90% v / v castor oil and 10% v / v benzyl alcohol was prepared as follows.

[0237] 700 mg of abiraterone acetate was weighed and placed in a 10 mL serum vial with a crimp stopper. 8 mL of a 90% castor oil / 10% benzyl alcohol mixture was placed in another 10 mL serum vial with a crimp stopper. The two vials were then wrapped in aluminum foil and sterilized in an autoclave using a 30-minute liquid cycle. After sterilization, the vials were transferred to a laminar flow hood. Next, 7 mL of the sterile 90% castor oil / 10% benzyl alcohol solution was taken and added to the sterile abiraterone acetate, the vials were re-stopped and crimp-sealed. The abiraterone acetate was then dissolved by sonication, vortexing, and by rotating the vials. The final concentration of the sterile abiraterone acetate solution was 91 mg / ml.

[0238] Example 3C. Preparation of a solution of abiraterone acetate, 50% castor oil, and 50% benzyl benzoate. A solution of abiraterone acetate for injection (IM Depot) 50% v / v castor oil and 50% v / v benzyl benzoate was prepared as follows.

[0239] 980 mg of abiraterone acetate was weighed and placed in a 10 mL serum vial with a crimp stopper. 8 mL of a 50% castor oil / 50% benzyl benzoate mixture was placed in another 10 mL serum vial with a crimp stopper. The two vials were then wrapped in aluminum foil and sterilized in an autoclave using a 30-minute liquid cycle. After sterilization, the vials were transferred to a laminar flow hood. Next, 7 mL of the sterile 50% castor oil / 50% benzyl benzoate mixture solution was taken out and added to the sterile abiraterone acetate, the vials were re-stopped and crimp-sealed. The abiraterone acetate was then dissolved by sonication, vortexing, and by rotating the vials. The final concentration of the sterile abiraterone acetate solution was 124 mg / ml.

[0240] Example 3D. Preparation of a solution of abiraterone propionate, 90% castor oil, and 10% benzyl alcohol. A solution of abiraterone propionate for injection (IM Depot) 90% v / v castor oil and 10% v / v benzyl alcohol was prepared as follows.

[0241] 1,050 mg of abiraterone propionate was weighed and placed in a 10 mL serum vial with a crimp stopper. 8 mL of a 90% castor oil / 10% benzyl alcohol mixture was placed in another 10 mL serum vial with a crimp stopper. The solvent vials were then wrapped in aluminum foil and sterilized in an autoclave using a 30-minute liquid cycle. After sterilization, the vials were transferred to a laminar flow hood. Next, 8 mL of the sterile 90% castor oil / 10% benzyl alcohol solution was taken out and added to the abiraterone propionate, the vials were re-stopped and crimp-sealed. The abiraterone propionate was then dissolved by sonication, vortexing, and by rotating the vials. The final concentration of the sterile abiraterone propionate solution was 197 mg / ml.

[0242] Example 3E. Preparation of a solution of abiraterone propionate, 90% corn oil, and 10% benzyl alcohol. A solution of abiraterone propionate for injection (IM Depot) containing 90% v / v corn oil and 10% v / v benzyl alcohol was prepared as follows.

[0243] 1,050 mg of abiraterone propionate was weighed and placed in a 10 mL serum vial with a crimp stopper. 8 mL of a 90% corn oil / 10% benzyl alcohol mixture was placed in another 10 mL serum vial with a crimp stopper. The solvent vials were then wrapped in aluminum foil and sterilized in an autoclave using a 30-minute liquid cycle. After sterilization, the vials were transferred to a laminar flow hood. Next, 8 mL of the sterile 90% corn oil / 10% benzyl alcohol solution was taken out and added to the abiraterone propionate, the vials were re-stopped and crimp-sealed. The abiraterone propionate was then dissolved by sonication, vortexing, and by rotating the vials. The final concentration of the sterile abiraterone propionate solution was 168 mg / ml.

[0244] Example 3F. Preparation of a solution of abiraterone decanoate, 90% castor oil, and 10% benzyl alcohol. A solution of abiraterone decanoate for injection (IM Depot) containing 90% v / v castor oil and 10% v / v benzyl alcohol was prepared as follows.

[0245] 1,260 mg of abiraterone decanoate was weighed and placed in a 10 mL serum vial with a crimp stopper. 8 mL of a 90% castor oil / 10% benzyl alcohol mixture was placed in another 10 mL serum vial with a crimp stopper. The solvent vials were then wrapped in aluminum foil and sterilized in an autoclave using a 30-minute liquid cycle. After sterilization, the vials were transferred to a laminar flow hood. Next, 8 mL of the sterile 90% castor oil / 10% benzyl alcohol solution was taken out and added to the abiraterone decanoate, the vials were re-stopped and crimp-sealed. The abiraterone decanoate was then dissolved by sonication, vortexing, and by rotating the vials. The final concentration of the sterile abiraterone decanoate solution was 160 mg / ml.

[0246] Example 3G. Preparation of a solution of abiraterone decanoate, 90% corn oil, and 10% benzyl alcohol. A solution of abiraterone decanoate for injection (IM Depot) containing 90% v / v corn oil and 10% v / v benzyl alcohol was prepared as follows.

[0247] 1,260 mg of abiraterone decanoate was weighed and placed in a 10 mL serum vial with a crimp stopper. 8 mL of a 90% corn oil / 10% benzyl alcohol mixture was placed in another 10 mL serum vial with a crimp stopper. The solvent vials were then wrapped in aluminum foil and sterilized in an autoclave using a 30-minute liquid cycle. After sterilization, the vials were transferred to a laminar flow hood. Next, 8 mL of the sterile 90% corn oil / 10% benzyl alcohol solution was taken out and added to the abiraterone decanoate, the vials were re-stopped and crimp-sealed. The abiraterone decanoate was then dissolved by sonication, vortexing, and by rotating the vials. The final concentration of the sterile abiraterone decanoate solution was 170 mg / ml.

[0248] Example 3: Preparation of a solution containing H-decanoate abiraterone (approximately 200 mg / ml), 70% corn oil, 10% benzyl alcohol, and 20% benzyl benzoate. A solution of abiraterone decanoate for injection (IM Depot, approximately 200 mg / ml), 70% v / v corn oil, 10% v / v benzyl alcohol, and 20% v / v benzyl benzoate was prepared as follows.

[0249] 2,500 mg of abiraterone decanoate was weighed and placed in a 20 mL serum vial with a crimp stopper. 60 mL of a 70% corn oil / 10% benzyl alcohol / 20% benzyl benzoate mixture was placed in another 100 mL serum vial with a crimp stopper. The solvent vials were then wrapped in aluminum foil and sterilized in an autoclave using a 30-minute liquid cycle. After sterilization, the vials were transferred to a laminar flow hood. Next, 10 mL of the sterile 70% corn oil / 10% benzyl alcohol / 20% benzyl benzoate solution was taken and added to the abiraterone decanoate, the vials were re-stopped and crimp-sealed. The abiraterone decanoate was then dissolved by sonication, vortexing, and by rotating the vials. The final concentration of the sterile abiraterone decanoate solution was 209 mg / ml.

[0250] Example 3I. Preparation of a solution of abiraterone decanoate (approximately 240 mg / ml), 70% corn oil, 10% benzyl alcohol, and 20% benzyl benzoate. A solution of abiraterone decanoate for injection (IM Depot, approximately 240 mg / ml), 70% v / v corn oil, 10% v / v benzyl alcohol, and 20% v / v benzyl benzoate was prepared as follows.

[0251] 3,125 mg of abiraterone decanoate was weighed and placed in a 20 mL serum vial with a crimp stopper. 60 mL of a 70% corn oil / 10% benzyl alcohol / 20% benzyl benzoate mixture was placed in another 100 mL serum vial with a crimp stopper. The solvent vials were then wrapped in aluminum foil and sterilized in an autoclave using a 30-minute liquid cycle. After sterilization, the vials were transferred to a laminar flow hood. Next, 10 mL of the sterile 70% corn oil / 10% benzyl alcohol / 20% benzyl benzoate solution was taken and added to the abiraterone decanoate, the vials were re-stopped and crimp-sealed. The abiraterone decanoate was then dissolved by sonication, vortexing, and by rotating the vials. The final concentration of the sterile abiraterone decanoate solution was 242 mg / ml.

[0252] Example 3J. Preparation of a solution of abiraterone isocaproate, 90% corn oil, and 10% benzyl alcohol. A solution of abiraterone isocaproate for injection (IM Depot) containing 90% v / v corn oil and 10% v / v benzyl alcohol was prepared as follows.

[0253] 1190 mg of abiraterone isocaproate was weighed and placed in a 10 mL serum vial with a crimp stopper. 8 mL of a 90% corn oil / 10% benzyl alcohol mixture was placed in another 10 mL serum vial with a crimp stopper. The solvent vials were then wrapped in aluminum foil and sterilized in an autoclave using a 30-minute liquid cycle. After sterilization, the vials were transferred to a laminar flow hood. Next, 6.4 mL of the sterile 90% corn oil / 10% benzyl alcohol solution was taken out and added to the abiraterone isocaproate. The vials were then re-stopped and crimp-sealed. The abiraterone isocaproate was then dissolved by sonication, vortexing, and rotating the vials. The final concentration of the sterile abiraterone isocaproate solution was 158 mg / ml.

[0254] Example 4A. Solubility test of abiraterone prodrug The solubility of various abiraterone prodrugs was tested as follows. The results are shown in Table 2.

[0255] For each solvent studied, a sufficient amount of prodrug was weighed into separate glass vials, and 1–2 ml of solvent was added. The resulting suspensions were sonicated and vortexed. If the prodrug was completely dissolved, more prodrug was added until an excess was observed. If there was a large excess of undissolved prodrug, additional diluent may be added. The total mass and volume used were recorded. Each vial was tightly capped and wrapped in foil to protect from light as needed. The vials were placed in an experimental rotator in an incubator at 25°C (or any other temperature required). The samples were allowed to equilibrate for at least one day before evaluating solubility. Then, typically after about one week, the solubility of each prodrug was checked again.

[0256] At the appropriate time, the vials were removed from the incubator. A small amount of supernatant from each vial was transferred to a microcentrifuge tube equipped with a 0.22 or 0.45 μm filter. The tube was centrifuged at 10,000 rpm until all the liquid had passed through the filter and reached the bottom of the tube. Alternatively, the sample was filtered using a 0.22 or 0.45 μm syringe filter. The filtered liquid was evaluated using HPLC. The sample was diluted as needed and classified as homogeneous against the sample concentration standard.

[0257] [Table 5]

[0258] [Table 6]

[0259] Parenteral formulations must be sterilized before administration. This can be achieved by various techniques, including thermal sterilization (e.g., dry heat or moist heat), radiation sterilization (e.g., gamma ray sterilization), filtration sterilization (e.g., 0.22 micrometer membrane filter), or gas sterilization (e.g., formaldehyde or ethylene oxide gas).

[0260] Example 4B. Solubility, viscosity, and glide force tests of abiraterone decanoate formulations or oily solvents. In this example, the properties of various abiraterone decanoate formulations and oily solvents are tested.

[0261] First, we will demonstrate the solubility advantages of the abiraterone decanoate formulation—70% v / v corn oil, 10% v / v benzyl alcohol, and 20% v / v benzyl benzoate—based on further solubility studies. Please refer to Table 2A below. The abiraterone decanoate used in the study in Table 2A was obtained from Example 6A. The percentages of benzyl alcohol and benzyl benzoate are based on volume percentages (i.e., %v / v). [Table 7]

[0262] As this study demonstrates, the combination of benzyl alcohol and benzyl benzoate can significantly increase the solubility of abiraterone decanoate in corn oil. See also Figures 13A and 13B.

[0263] Additional experiments also showed that the viscosity and glide force of the oily solvent decreased when benzyl benzoate was included. Such oily solvents can be advantageously used as needed when formulating the abiraterone prodrugs described herein, and are expected to provide abiraterone prodrug formulations with low viscosity and low glide force.

[0264] Glide force tests were performed using a tensile and compression testing machine (e.g., Lloyd press or equivalent), NEXYGEN Plus material testing software, or an equivalent load cell 250N, 5 mL Luer lock syringe (e.g., Becton, Dickinson and Company / BD, P / N 309646), or an equivalent 23 gauge, 1.5 inch length, thin-walled, precision glide needle (e.g., Becton, Dickinson and Company / BD, P / N 305194), or an equivalent 27 gauge, 1.5 inch length, standard-walled, precision glide needle (e.g., Becton, Dickinson and Company / BD, P / N 301629), or an equivalent.

[0265] Table 2B shows the viscosity of oily solvents without additives, oily solvents containing 10% v / v benzyl alcohol, oily solvents containing 20% ​​v / v benzyl benzoate, or oily solvents containing a combination of 10% v / v benzyl alcohol and 20% v / v benzyl benzoate. See also Figure 13C. [Table 8]

[0266] Tables 2C and 2D show the glide force (N) of additive-free oily solvents, oily solvents containing 10% v / v benzyl alcohol, oily solvents containing 20% ​​v / v benzyl benzoate, or oily solvents containing a combination of 10% v / v benzyl alcohol and 20% v / v benzyl benzoate, respectively, when using a 23-gauge needle or a 27-gauge needle. See also Figures 13D and 13E. [Table 9] [Table 10]

[0267] Example 5. Aviraterone plasma pharmacokinetics in rats and dogs after administration of abiraterone prodrug formulations. Example 5A. PK study of abiraterone and abiraterone acetate in rats and dogs. In the initial rat studies, several formulations were investigated. These formulations consisted of abiraterone acetate as a solution in castor oil or as a suspension in sodium phosphate buffer, 0.1% Tween, as well as a castor oil suspension of abiraterone or an aqueous mixture in sodium phosphate buffer, 0.1% Tween. The preparation of these long-acting IM formulations follows a general procedure of placing the drug in one vial, the solubilizing solution in another vial, and sterilizing each vial. Immediately after sterilizing the components, they are mixed together under sterile conditions to produce the final product. Sterilization is performed individually because, if the drug is a solution, the drug may decompose during the sterilization process. In addition, this sterilization process was chosen over filter sterilization due to the viscosity of the oil or the suspension properties of the two formulations.

[0268] Another study was conducted using dogs instead of rats as an animal model. Four formulations were incorporated into this study: a solution of abiraterone acetate in an aqueous system (specifically IV), a solution of abiraterone acetate in castor oil, a solution of abiraterone acetate in 90% castor oil and 10% benzyl alcohol, or a solution of abiraterone acetate in 50% castor oil and 50% benzyl benzoate.

[0269] The above formulations were administered as IV or IM injections to the hind limbs (multiple limbs) of rats or dogs. Plasma samples were collected throughout the study period, and both the prodrug and abiraterone were analyzed. The results of the rat study are presented in Table 3 and Figure 1.

[0270] [Table 11]

[0271] Data from rat studies showed that formulations containing abiraterone acetate performed significantly better than formulations containing abiraterone alone. Furthermore, Group 1 formulations containing abiraterone acetate as a solution performed better than Group 2 formulations containing abiraterone acetate as a suspension rather than a solution.

[0272] Figure 1 shows the time course of mean plasma abiraterone concentration in rats after IM injection of abiraterone acetate at a dose of 35 mg / kg into the thigh muscle of five male rats. To evaluate systemic exposure after abiraterone acetate IM depot administration, blood samples were collected at 1, 2, 4, 8, 24, 48, 72, and 168 hours after administration, and abiraterone and abiraterone acetate were analyzed. In this study, the abiraterone acetate castor oil solution was compared with the abiraterone acetate aqueous suspension, as well as the abiraterone aqueous solution and castor oil suspension.

[0273] First, we attempted to administer abiraterone intramuscularly to rats as a suspension containing vegetable oil and aqueous solutions. Surprisingly, abiraterone alone resulted in very low plasma levels (see Figure 1). Also surprisingly, the use of abiraterone acetate in aqueous suspension resulted in low plasma levels (see Figure 1). Conversely, the vegetable oil solution of abiraterone acetate not only resulted in the highest plasma levels in rats after intramuscular injection, but also yielded the longest-lasting plasma concentration of abiraterone (see Figure 1).

[0274] The abiraterone acetate castor oil IM depot solution formulation showed superior plasma concentrations of abiraterone over 168 hours compared to abiraterone, abiraterone acetate aqueous solution, and castor oil suspension.

[0275] The results of the dog study are presented in Table 4 and Figure 2. [Table 12]

[0276] Data from dog studies showed that administering abiraterone acetate as a solution in castor oil (with or without benzyl alcohol) resulted in measurable blood levels up to 504 hours later. Furthermore, formulations containing benzyl benzoate produced measurable levels of abiraterone acetate, but these formulations were found to irritate the dogs at the injection site, with one or two dogs licking or biting the injection site, causing wounds. This significantly reduced the percentage of prodrug absorbed by these animals, resulting in a substantial decrease in the average percentage of absorbed prodrug in this administration group (61.7%). The absolute bioavailability results for these formulations ranged from 61.7% to 86.2%.

[0277] Figure 2 shows the time course of mean plasma abiraterone concentration in dogs after IM injection into the thigh muscle of male dogs (each formulation administered to three dogs) at doses of 19, 27, and 38 mg / kg. Blood samples were collected at 0.5, 1, 2, 3, 4, 5, 8, 24, 48, 60, 120, 168, 336, and 504 hours after administration to evaluate systemic exposure after abiraterone acetate IM depot administration, and analyzed for abiraterone and abiraterone acetate.

[0278] Castor oil, castor oil / benzyl alcohol, and castor oil / benzyl benzoate IM depot solution formulations of abiraterone acetate showed plasma concentrations of abiraterone over a long period of 504 hours.

[0279] To measure the bioavailability of the IM depot formulation, IV administration of abiraterone acetate (10 mg / kg dose) was included in this study. Bioavailability was found to be 86.2%, 85.7%, and 61.7%.

[0280] Using computer modeling, we predicted the human pharmacokinetic profile of abiraterone prodrugs administered via IM to humans, based on data obtained from IM rat and dog studies. In the modeling, administration of 600 mg to 2,000 mg of abiraterone acetate to human subjects every 2 to 4 weeks predicted the desired plasma pharmacokinetic profile in human subjects (i.e., bioavailability of more than 80% over at least 2 weeks, with abiraterone C100% between 1.0 ng / ml and more than 8.4 ng / ml, e.g., more than 1 ng / ml, more than 2 ng / ml, more than 4 ng / ml, or more than 8.4 ng / ml over 8.4 ng / ml). min The values, and the C of abiraterone, approximately 10 ng / ml to 400 ng / ml. max The predicted value was obtained. The predicted IM dose of 600 mg of abiraterone acetate administered every two weeks needs to be compared to the current oral dose of 1,000 mg / day of Zytiga® (14,000 mg over a two-week administration period). The higher bioavailability of IM delivery, with the elimination of the effect of food, should reduce patient variability, thereby resulting in better efficacy, along with higher and lower frequency plasma trough levels (see C for improvement of prostate-specific antigen response and progression-free survival in patients with castration-resistant prostate cancer). min (This is greater than 8.4 ng / ml) (Carton et al., Eur.J.Can.72:54,2017).

[0281] Example 5B. PK study of abiraterone propionate and abiraterone decanoate in dogs. This is a bioavailability study of single doses of several abiraterone prodrugs (propionate and decanoate) administered intramuscularly (IM) and intravenously to beagle dogs.

[0282] The formulations and dosages used in this study are shown below. 1) Intramuscular (IM): Administer abiraterone propionate in a 10% benzyl alcohol / 90% castor oil solution (197 mg / mL) at a dose of 41 mg / kg. 2) Intramuscular (IM): Administer abiraterone propionate in a 10% benzyl alcohol / 90% corn oil solution (168 mg / mL) at a dose of 41 mg / kg. 3) Intramuscular (IM): Administer aviraterone decanoate in a 10% benzyl alcohol / 90% castor oil solution (160 mg / mL) at a dose of 50 mg / kg. 4) Intramuscular (IM): Administer abiraterone decanoate in a 10% benzyl alcohol / 90% corn oil solution (170 mg / mL) at a dose of 50 mg / kg. 5) Intravenous (IV): Administer 40% HP-b-CD / 25 mM sodium phosphate (pH 7.4) solution of abiraterone propionate (0.57 mg / mL) at a dose of 1 mg / kg. 6) Intravenous (IV): Administer 40% HP-b-CD / 25 mM sodium phosphate (pH 7.4) solution of abiraterone decanoate (0.37 mg / mL) at a dose of 1.2 mg / kg.

[0283] A summary of the research design is shown in Table 5 below. [Table 13]

[0284] All animals were administered via IV. After a 72-hour washout period, all dogs were administered via IM. The dosage was based on an assumed body weight of 10 kg. After IV administration, blood was collected at 0.083, 0.1667, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, and 24 hours after administration. After IM administration, blood was collected at 0.5, 1, 2, 3, 4, 5, 8, and 12 hours after administration, and also at 1, 2, 3, 5, 7, 14, 21, 28, 35, 42, 49, 56 (decanoate only) and 63 (decanoate only) days (collected close to the time of administration). Blood was processed into plasma, and the resulting plasma samples were analyzed for the prodrug and abiraterone.

[0285] After IV administration of abiraterone propionate, only one or two quantifiable plasma concentrations were available in the animals, making it impossible to evaluate reliable pharmacokinetic parameters.

[0286] Pharmacokinetic analysis was performed based on plasma concentration-time data using the Phoenix WinNonlin (v8.1) non-compartmental analysis function (linear trapezoidal method for AUC calculation). Nominal dose values ​​and sampling times were used in the calculations. For the purpose of PK calculation, all concentrations reported as "BLQ" were set to zero.

[0287] C max and the corresponding T max The values ​​were determined by direct evaluation of concentration-time data. All AUC calculations were performed using the linear trapezoidal method.

[0288] To the extent that the data allowed, the terminal vanishing rate constant (lambda z, λz) was calculated. The value of λz was determined by the slope of the natural logarithmic transformation concentration-time regression line, subject to the following constraints. • Data points must be randomly distributed around a single straight line; In regression, C max You must use at least three data points after that; • Correlation coefficient of regression (R 2 ) must be greater than 0.80;

[0289] To optimize the reliability of the confirmed terminal phase (λz), the data points used to define λz were manually selected where possible. Lambda z profiles that do not meet the above guidelines are marked with an asterisk in the AUC of the profile for that animal. INF , t 1 / 2 The CL / F and Vz / F parameters were excluded, and the results were removed from the summary descriptive statistics.

[0290] AUC INF The value was calculated as follows: AUC last +(C last / λz). CL / F was calculated as follows: dose per dosing interval / (AUC INF ). Vz / F was calculated as follows: dose per dosing interval / (AUC INF * λz). Termination t 1 / 2 The lambda z interval was calculated as follows: ln(2) / λz. If the lambda z interval did not exceed twice the calculated half-life, the half-life value was flagged as unreliable with an asterisk and excluded from the descriptive statistics.

[0291] Mean plasma concentration-time data are presented with standard deviation (SD) and coefficient of variation (CV%), recorded to three significant figures. PK parameter values ​​are presented as mean, SD, and CV%. Individual T max Values ​​were recorded with two significant figures, while all other values ​​and descriptive statistics were recorded with three significant figures.

[0292] Tables 6 and 7 show the mean PK parameters for individual animals and groups of prodrugs and abiraterone after IV administration. Tables 8 and 9 show the mean PK parameters for individual animals and groups of prodrugs and abiraterone after IM administration. Figures 5 to 10 plot the time course of mean plasma concentrations by group after administration to dogs.

[0293] Results of IV administration: After IV administration of abiraterone decanoate (prodrug), the mean CL value of the prodrug was calculated to be 8.88 mL / min / kg, which was considered to be low clearance. When using a dose value of 0.84 mg / kg (assuming a 100% conversion rate of the prodrug to abiraterone), the mean CL / F value of abiraterone was 97.8 mL / min / kg. The mean Vz value of the prodrug was 0.659 L / kg, and the mean Vz / F value of abiraterone was 13.0 L / kg. 1 / 2 The response times were 0.86 hours for prodrugs and 1.5 hours for abiraterone, respectively.

[0294] Because exposure to abiraterone propionate was observed only at the first two time points after administration, reliable PK parameters could not be calculated. After IV administration of abiraterone propionate (prodrug), the mean CL / F value of abiraterone was 114 mL / min / kg, and the mean Vz / F value was 20.8 L / kg. 1 / 2 The value was 2.1 hours.

[0295] After IV administration of abiraterone propionate, the Cmax value of abiraterone was almost four times higher, but the AUC values ​​were equivalent (difference of less than twofold), indicating that the difference between prodrugs was very slight.

[0296] Results of IM administration: After administration of two decanoate ester preparations using IM, the average T15 of abiraterone was reduced. max The value for both formulations was 5.0 days, and the average T of decanoate ester was 5.0 days. max The values ​​ranged from 0.11 to 0.26 days between formulations. Average exposure to prodrugs and abiraterone (C max The difference between the two formulations (as indicated by the AUC value) was within twofold. The terminal elimination phase of the prodrug did not achieve a stable negative gradient after day 7, so additional kinetic parameters could not be evaluated. The mean t of abiraterone 1 / 2 Value (end t) 1 / 2 The period after administration was 23 and 24 days in two solvents. The estimated absolute bioavailability of abiraterone was given by mean AUC. INF Use the value to administer IV (145h * ng / mL) and IM administration (adjusted according to dosage and time unit = Group 5 is 104h) * ng / mL, and group 6 is 134h * The bioavailability was calculated after the ng / mL test. The bioavailability was 72% for group 5 and 92% for group 6, respectively.

[0297] After administration of two propionate ester preparations, the average abiraterone T between preparations maxThe values ​​range from 0.56 to 0.61 days, and the average T of propionate esters. max The values ​​ranged from 0.11 to 0.26 days (2.3 to 6.2 hours). Average exposure to prodrugs and abiraterone (C max The difference between the two formulations (as indicated by the AUC value) was within twofold. Except for the point at day 7 (there are no values ​​after day 7), the mean t1 / 2 values ​​of the prodrug were 0.98 to 1.7 days after administration in two different solvents. The mean t1 / 2 of abiraterone 1 / 2 The values ​​were 1.8 and 4.5 days after administration in the two solvents. The estimated absolute bioavailability of abiraterone was expressed as the mean AUC. INF Use the value for IV administration (127h * ng / mL) and IM administration (adjusted according to dosage and time unit = Group 3 is 105h) * ng / mL, and Group 4 was 94.1h * The bioavailability was calculated after the ng / mL test. The bioavailability was 83% for group 3 and 74% for group 4, respectively.

[0298] Tables 6-9 and Figures 5-10 present a summary of the PK research conducted in this embodiment.

[0299] Using computer modeling, we predicted the human pharmacokinetic profile of abiraterone decanoate administered intravenously (IM) to humans, based on data obtained from rat and canine studies. Pharmacokinetic (PK) modeling and simulation were performed using the fully-validated version (8.1) of WinNonlin Phoenix. A linear PK (exponential) model was fitted to the time course of plasma concentrations of abiraterone (acetate or decanoate formulations) after IV administration to rats and dogs. Derived PK parameters for clearance (CL) and volume of distribution (Vss) were predicted in humans using relative growth scaling. The rate of bioavailability (K01) and utilization rate (F) of abiraterone after IM administration to dogs were estimated by deconvolution, and it was assumed that the values ​​of K01 and F were equivalent in humans. Using predicted PK parameters (CL, Vss, K01, and F), we simulated the time course of plasma concentrations in humans after IM administration at various prescribed dosages and administrations (assuming a linear response rate of abiraterone). The modeling showed that small doses of approximately 120 mg of abiraterone decanoate IM every two weeks resulted in a steady state C2 concentration of over 8 ng / ml of abiraterone. min The value is approximately 14 ng / ml of abiraterone at steady state C max We predicted that therapeutically effective abiraterone plasma concentrations in humans could be achieved with the specified values. Furthermore, through modeling, we predicted that IM administration of abiraterone decanoate would be suitable for a dosage and administration in humans once a month or once every few months, thereby achieving therapeutically effective abiraterone plasma concentrations. For example, administering approximately 350 mg of abiraterone decanoate once every four weeks using IM would result in a steady-state abiraterone concentration of over approximately 8 ng / ml. min This is sufficient to provide the value. C in the steady state of aviraterone maxThe value is proportional to the dose. See also Figures 11A, 11B, 11C, and 11D. In light of this disclosure, the dosage and administration may, in some cases, include an initial administration period with a higher dose frequency or different abiraterone drugs to achieve a certain level of exposure to abiraterone in the patient being treated, followed by a monthly (or every few months) dosage and administration as described herein. For example, the dosage and administration may, in some cases, include an initial IM dose of abiraterone decanoate once every two weeks, e.g., about two to three doses, followed by a monthly dose of abiraterone decanoate. Computer modeling has shown that such a dosage and administration would result in a steady state of abiraterone exceeding approximately 8 ng / ml during the treatment period. min We predicted that the value could be achieved. [Table 14] [Table 15] [Table 16] [Table 17]

[0300] Example 6A. Large-scale preparation of aviraterone decanoate from decanoic acid [ka] To a suspension of abiraterone (381.9 g, 1.09 mol) in dichloromethane (3500 mL), triethylamine (165 g, 1.64 mol) and a catalytic amount of DMAP (13.35 g, 0.109 mol) were added. Decanoic acid (225 g, 1.31 mol) as a solution in dichloromethane (500 mL) was added to the suspension, followed by EDCI (293 g, 1.53 mol), and the reaction mixture was stirred at 20-25°C for 19 hours.

[0301] Next, 4000 mL of a 10% by weight NaH2PO4 aqueous solution was added, and the reaction mixture was stirred for 20 minutes. The organic layer was separated and extracted with 2000 mL of a 10% by weight NaH2PO4 aqueous solution and 2000 mL of brine. The organic layer was solvent-exchanged with acetoni...

Claims

1. A pharmaceutical composition for use in a method of treating or preventing a disease or disorder in a patient in need thereof, The method includes the step of administering the pharmaceutical composition to the patient, The pharmaceutical composition comprises a therapeutically effective amount of abiraterone decanoate or a pharmaceutically acceptable salt thereof, dispersed or dissolved in a pharmaceutically acceptable carrier. The aforementioned abiraterone decanoate has the following formula: 【Chemistry 1】 The abiraterone decanoate has a purity of at least 95% by weight, and the disease or disorder is selected from sex hormone-dependent benign or malignant diseases, syndromes caused by androgen excess, and syndromes caused by glucocorticoid excess. (i) The pharmaceutical composition has less than 100 EU / ml of bacterial endotoxin as measured according to USP<85>, and / or (ii) The pharmaceutical composition is characterized in that, when measured according to USP<788> and / or<789>, it contains 1,000 or fewer particles with a size of 10 μm or larger, and 300 or fewer particles with a size of 25 μm or larger.

2. (A) The abiraterone decanoate is characterized by having a purity of at least 98% by weight, and / or (B) Formula in which the abiraterone decanoate is less than 1% by weight: 【Chemistry 2】 It is characterized by having an ethyl plasterone decanoate ester having and / or (C) The pharmaceutical composition according to claim 1, characterized in that the avirateron decanoate does not contain a detectable amount of ethyl plasterone decanoate.

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil.

4. The pharmaceutical composition according to claim 3, wherein the pharmaceutically acceptable carrier further comprises a pharmaceutically acceptable solvent.

5. (A) The pharmaceutically acceptable oil comprises triglycerides, and the pharmaceutically acceptable solvent comprises alcohols, esters and / or acidic solvents, and / or (B) The pharmaceutical composition according to claim 4, wherein the pharmaceutically acceptable oil is selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil, and the pharmaceutically acceptable solvent comprises benzyl alcohol, benzyl benzoate, or a combination thereof.

6. The pharmaceutical composition according to claim 3, wherein the pharmaceutically acceptable carrier comprises corn oil, benzyl alcohol, and benzyl benzoate.

7. The pharmaceutical composition according to claim 1, wherein each milliliter contains (a) 100 mg to 300 mg of abiraterone decanoate in its basic form; (b) 50 mg to 150 mg of benzyl alcohol; (c) 100 mg to 300 mg of benzyl benzoate; and (d) an appropriate amount of corn oil per milliliter.

8. (A) The pharmaceutical composition has a viscosity of less than 0.1 Pa·s, and / or (B) The pharmaceutical composition has a glide force of 5 to 15 N when measured using a 23 G, 1.5 inch needle, and / or a glide force of 30 to 150 N when measured using a 27 G, 1.5 inch needle, and / or (C) The pharmaceutical composition according to any one of claims 1 to 7, characterized in that the pharmaceutical composition has less than 25 EU / ml of bacterial endotoxin when measured according to USP<85>.

9. The pharmaceutical composition according to any one of claims 1 to 8, comprising abiraterone decanoate at a concentration of 100 mg / ml to 300 mg / ml.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the disease or disorder is selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, lung cancer, endometriosis, polycystic ovary syndrome, Cushing's syndrome, Cushing's disease, classical or non-classical congenital adrenal hyperplasia, precocious puberty, hirsutism, and combinations thereof.

11. A pharmaceutical composition according to any one of claims 1 to 9 for treating prostate cancer.

12. (i) The patient suffering from prostate cancer has an increased amount of prostate-specific antigen, or (ii) The prostate cancer is localized prostate cancer, or (iii) The prostate cancer is metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer, non-metastatic castration-resistant prostate cancer, or metastatic castration-resistant prostate cancer, or (iv) The prostate cancer is a newly diagnosed high-risk metastatic hormone-sensitive prostate cancer, or (v) The prostate cancer is metastatic castration-resistant prostate cancer (mCRPC), and the patient is asymptomatic or mildly symptomatic after failure of androgen deprivation therapy, for which there is no clinical need for chemotherapy, or (vi) The prostate cancer is metastatic castration-resistant prostate cancer (mCRPC), and the patient's disease has progressed during or after a docetaxel-based chemotherapy regimen, or (vii) The pharmaceutical composition according to claim 11, wherein the prostate cancer is refractory prostate cancer.

13. The pharmaceutical composition according to any one of claims 1 to 12, further comprising treating the patient by radiotherapy or surgery.

14. (A) The method further comprises (i) administering to the patient one or more other agents selected from anticancer agents, hormone depletion agents, antiandrogens, differentiation agents, antitumor agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotics, immunotherapies, interferon-type agents, inserts, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloproteinase inhibitors, gene therapy drugs, or combinations thereof; or (ii) administering to the patient one or more other agents selected from chemotherapeutic agents, hormone replacement agents, or hormone depletion agents; or (iii) treating the patient with androgen depletion therapy; and / or (B) The patient is administered one or more drugs selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone, and / or (C) The patient has been administered a poly-ADP-ribose polymerase (PARP) inhibitor and / or (D) The patient has been administered a gonadotropin-releasing hormone (GnRH) agonist and / or a GnRH antagonist, and / or (E) The patient has been administered a first-generation androgen receptor antagonist and / or (F) The patient has been administered a second-generation androgen receptor antagonist and / or (G) The patient is administered a third-generation androgen receptor antagonist or an androgen receptor degradation-inducing molecule alone or in combination with one or more first-generation or second-generation androgen receptor antagonists, and / or (H) The patient is administered a chemotherapy agent and / or (I) The patient is treated with radiotherapy and / or (J) The patient was administered radium-223 and / or, (K) The patient has been administered an immunotherapy agent and / or (L) The patient is administered a kinase inhibitor and / or (M) The patient has been administered a bone protective agent, and the patient has prostate cancer with bone metastases, and / or (N) The patient is administered a therapeutic agent selected from 1) anti-IL23 targeted monoclonal antibody; 2) selenium; 3) EZH2 inhibitor; 4) CDK4 / 6 inhibitor; 6) bromodomain and extraterminal domain (BET) inhibitor; 7) anti-CD105 antibody; 8) niclosamide; 9) A2A receptor antagonist; 10) PI3K inhibitor; 11) further nonsteroidal CYP17A1 inhibitor; 12) antiprogestogen; 13) navitoclax; 14) HSP90 inhibitor; 15) HSP27 inhibitor; 16) 5α-reductase inhibitor; 17) metformin; 18) AMG-386; 19) dextromethorphan; 20) theophylline; 21) hydroxychloroquine; and 22) lenalidomide, and / or (O) The pharmaceutical composition according to any one of claims 1 to 13, wherein the patient is administered one or more kinase modulators selected from FLT-3 (FMS-like tyrosine kinase) inhibitors, AXL (anexelekto) inhibitors, CDK (cyclin-dependent kinase) inhibitors, retinoblastoma (Rb) inhibitors, protein kinase B (AKT) inhibitors, SRC inhibitors, Ikappa B kinase 1 (IKK1) inhibitors, PIM-1 modulators, Lemur tyrosine kinase 2 (LMTK2) modulators, Lyn inhibitors, Aurora A inhibitors, ANPK (nuclear protein kinase A) inhibitors, extracellular signal-regulated kinase (ERK) modulators, c-jun N-terminal kinase (JNK) modulators, Big MAP kinase (BMK) modulators, p38 mitogen-activated protein kinase (MAPK) modulators, and combinations thereof.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the patient is chemotherapy-naive or hormone therapy-naive before being administered the pharmaceutical composition.

16. (A) The disease or disorder is breast cancer, (B) The pharmaceutical composition according to any one of claims 1 to 9, wherein the disease or disorder is related to 21-hydroxylase deficiency.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the pharmaceutical composition is administered to the patient via intramuscular injection, intradermal injection, or subcutaneous injection.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the pharmaceutical composition is administered to the patient once a week or once every few weeks.

19. The pharmaceutical composition according to any one of claims 1 to 17, wherein the pharmaceutical composition is administered to the patient once a month or once every few months.

20. The pharmaceutical composition according to any one of claims 1 to 17, wherein the pharmaceutical composition is administered to the patient once every two months or once every three months.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein the pharmaceutical composition is administered to the patient regardless of meals.

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