A pharmaceutical composition containing abiraterone acetate and a preparation method and application thereof

Abstract

The application discloses a pharmaceutical composition containing abiraterone acetate and a preparation method and application thereof. An excipient of the pharmaceutical composition contains at least one oil phase, at least one emulsifier and at least one co-emulsifier. The pharmaceutical composition can significantly improve bioavailability and stability of a preparation. The pharmaceutical composition can be further prepared into a capsule.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a pharmaceutical composition containing abiraterone acetate, its preparation method, and its application. Background Technology

[0002] Abiraterone acetate is a white to off-white, non-hygroscopic crystalline powder; its chemical name is (3β)-17-(3-pyridyl)androst-5,16-dien-3-yl acetate, and its molecular formula is C2. 26 H 33 NO2. Abiraterone acetate is converted in vivo to the androgen biosynthesis inhibitor abiraterone, which inhibits 17α-hydroxylase / C17,20-lyase (CYP17). It can be used in combination with prednisone for the treatment of patients with metastatic castration-refractory prostate cancer (CRPC) who have previously received docetaxel-containing chemotherapy. However, abiraterone acetate is a lipophilic compound with an octanol-water partition coefficient of 5.12 (LogP) and an aromatic nitrogen pKa of 5.19. It is almost insoluble in water (less than 0.01 mg / ml) and has poor permeability, classifying it as a Class IV BCS drug with extremely low bioavailability upon oral absorption.

[0003]

[0004] Zytiga, the original brand-name abiraterone acetate, is a tablet. Each Zytiga tablet contains 250 mg of abiraterone acetate. Inactive ingredients include colloidal silica, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. Zytiga has very low oral bioavailability (less than 10%), with single doses up to 1000 mg, but only less than 10% of the drug is effective.

[0005] Furthermore, food significantly affects the absorption of abiraterone acetate, and commercially available formulations require administration only at specific times before meals. The Zytiga package insert emphasizes that systemic exposure to abiraterone acetate increases when administered with food. When abiraterone acetate is administered with a low-fat diet (7% fat, 300 calories), Cmax and AUC0-∞ increase by approximately 7-fold and 5-fold, respectively; when administered with a high-fat diet (57% fat, 825 calories), Cmax and AUC0-∞ increase by approximately 17-fold and 10-fold, respectively. Considering the normal variation in dietary content and composition, administration with food may result in increased and highly variable exposure. To control abiraterone plasma concentrations, it must be taken on an empty stomach, and no food should be consumed for at least two hours before and at least one hour after the stated dose. Although oral abiraterone acetate is effective in treating advanced prostate cancer, its low solubility and poor permeability present challenges in formulation design.

[0006] Yonsa, manufactured by India's Sun Pharmaceutical Industries Ltd using SoluMatrix microparticle technology, offers a modified abiraterone acetate tablet that promotes abiraterone acetate dissolution, resulting in double the oral bioavailability compared to the original drug Zytiga. Although the dosage of Yonsa has been reduced to 500mg, this only alters the drug's crystal form and size, improving the dissolution rate, and does not increase the permeability of abiraterone acetate to gastrointestinal epithelial cells; therefore, Yonsa's oral bioavailability remains low.

[0007] Patent document CN107278152A relates to an abiraterone acetate complex, its preparation method, and a pharmaceutical composition comprising the same, comprising 5-40 wt% abiraterone acetate, 5-80 wt% polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and 0.1-50 wt% sodium deoxycholate. This complex can reduce the need for food to be taken on an empty stomach, and can increase oral bioavailability by up to 5 times; however, the preparation process of its complex formulation is complex. Summary of the Invention

[0008] The purpose of this invention is to provide a pharmaceutical composition that can significantly improve the oral absorption of abiraterone acetate.

[0009] Those skilled in the art will understand that, due to the low solubility and poor permeability of abiraterone acetate, while preparing it into a self-emulsifying solution could potentially eliminate the pre- and post-meal differences in abiraterone acetate and improve its oral bioavailability, abiraterone acetate exhibits low solubility in various solvents and emulsifiers. Although the drug dissolves rapidly at high temperatures, it is prone to crystallization and loss of self-emulsifying properties when stored at room temperature. Furthermore, the large dosage of abiraterone acetate necessitates the design of a self-emulsifying solution with a high drug content that remains stable at room temperature. These technical challenges constitute a major bottleneck in the formulation design. In addition, whether the self-emulsifying solution can spontaneously form a homogeneous and stable nanoemulsion with water is another challenge in the formulation design.

[0010] Through in-depth research, the inventors discovered that by preparing abiraterone acetate into a composition with specific excipients, its oral bioavailability can be increased by up to ten times compared to the original drug Zytiga.

[0011] The present invention adopts the following technical solution:

[0012] A pharmaceutical composition containing abiraterone acetate, comprising (consisting of the following components):

[0013] Active ingredient: Abiraterone acetate;

[0014] Excipients: at least one oil phase;

[0015] At least one emulsifier;

[0016] And at least one co-emulsifier.

[0017] The pharmaceutical composition containing abiraterone acetate according to the present invention has a concentration of abiraterone acetate between 20 and 100 mg / mL based on the total volume of the excipients.

[0018] The pharmaceutical composition of the present invention is a solution that readily forms a nanoemulsion with water, which can increase drug solubility, promote absorption, and improve bioavailability.

[0019] The excipients (a homogeneous, transparent solution composed of an oil phase, emulsifier, and co-emulsifier) ​​provided by this invention can serve as carriers for hydrophobic, poorly absorbed, or easily hydrolyzed drugs. Upon oral administration, they spontaneously disperse in the gastrointestinal tract under peristalsis to form O / W nanoemulsions (oil-in-water nanoemulsions). The resulting nanoemulsions have small particle sizes, increasing permeability to intestinal epithelial cells and significantly improving drug bioavailability. Compared to microemulsions, the self-emulsifying solution exhibits higher stability, meeting the requirements for long-term storage, and can also be directly packaged into soft capsules or hard capsules.

[0020] The abiraterone acetate comprises 2-20% of the total mass of the pharmaceutical composition, preferably 5-15%, more preferably 5-10%.

[0021] The pharmaceutical composition containing abiraterone acetate according to the present invention has at least one of the following properties:

[0022] a) When mixed with water, it can spontaneously form nanoemulsions with high clarity, uniform particle size, and stable properties with a particle size of less than 250 nm.

[0023] b) The contents can remain in a stable solution form when stored at room temperature;

[0024] c) Compared with the original drug Zytiga, the difference between pre- and post-meal intake was significantly reduced;

[0025] d) Compared with the original drug Zytiga, oral bioavailability is increased by several times to ten times.

[0026] The pharmaceutical composition containing abiraterone acetate according to the present invention, preferably,

[0027] The oil phase is selected from one or at least two of hydrogenated castor oil, glyceryl monooleate, propylene glycol monocaprylate, corn oil, soybean oil, medium-chain triglycerides or ethyl oleate, and glyceryl monolinoleate.

[0028] The oil phase accounts for 20-50% of the total mass of the pharmaceutical composition containing abiraterone acetate, preferably 20-45%, more preferably 25-45%.

[0029] Preferably, the oil phase is selected from one or at least two of hydrogenated castor oil, glyceryl monooleate, propylene glycol monocaprylate, soybean oil, medium-chain triglycerides or ethyl oleate, and glyceryl monolinoleate; more preferably, the oil phase is selected from one or at least two of glyceryl monolinoleate, medium-chain triglycerides, hydrogenated castor oil, and glyceryl monooleate.

[0030] The pharmaceutical composition containing abiraterone acetate according to the present invention, preferably,

[0031] The emulsifier is selected from one or at least two of the following: polyoxyethylene castor oil EL35, polyoxyethylene 40 hydrogenated castor oil, Span 80, Tween 80, polyethylene glycol-15 hydroxystearate (Solutol), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus).

[0032] The emulsifier accounts for 20-70% of the total mass of the pharmaceutical composition, preferably 20-50%, more preferably 20-35%;

[0033] Preferably, the emulsifier is selected from one or at least two of polyoxyethylene castor oil EL35, polyoxyethylene 40 hydrogenated castor oil, Span 80, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus); more preferably, the emulsifier is polyoxyethylene castor oil EL35 or polyoxyethylene 40 hydrogenated castor oil.

[0034] The pharmaceutical composition containing abiraterone acetate according to the present invention, preferably,

[0035] The co-emulsifier is selected from one or at least two of ethanol, propylene glycol, polyethylene glycol 400, and diethylene glycol monoethyl ether.

[0036] The co-emulsifier accounts for 20-80% of the total mass of the pharmaceutical composition containing abiraterone acetate, preferably 20-60%, more preferably 20-50%, and even more preferably 20-45%.

[0037] More preferably, the co-emulsifier is selected from a combination of propylene glycol and ethanol, the content of which is more preferably 20-30%, or diethylene glycol monoethyl ether, the content of which is more preferably 25-45%.

[0038] In the compositions of the present invention, the sum of the contents of all expressly listed components is less than or equal to 100% by mass.

[0039] Beyond theoretical limitations, the inventors of this invention unexpectedly discovered that the specific co-emulsifier of this invention, together with the oil phase and the emulsifier, forms a homogeneous and transparent solution, thus serving as a carrier for hydrophobic, poorly absorbed, or easily hydrolyzed drugs. Pharmaceutical compositions containing the co-emulsifier of this invention, upon oral administration, spontaneously disperse in the gastrointestinal tract under peristalsis to form O / W nanoemulsions (oil-in-water nanoemulsions). The resulting nanoemulsions have small particle sizes, increasing permeability to intestinal epithelial cells and significantly promoting absorption and improving bioavailability. The pharmaceutical compositions of this invention can also significantly reduce the influence of food on the absorption of abiraterone acetate, minimizing pre- and post-meal differences, thereby allowing the drug to be taken on both empty and full stomachs, reducing restrictions on medication timing.

[0040] As a preferred embodiment of the present invention, the pharmaceutical composition containing abiraterone acetate preferably comprises, by weight percentage, the following components (composed of the following components):

[0041] 2-20% abiraterone acetate;

[0042] 20-50% oil phase, wherein the oil phase is one or both of hydrogenated castor oil and glyceryl monooleate;

[0043] 20-60% emulsifier, wherein the emulsifier is polyoxyethylene castor oil EL35 or polyoxyethylene 40 hydrogenated castor oil;

[0044] 20-30% co-emulsifier, wherein the co-emulsifier is a mixture of ethanol and propylene glycol;

[0045] or,

[0046] 2-20% abiraterone acetate;

[0047] 20-50% oil phase, wherein the oil phase is one or both of hydrogenated castor oil and glyceryl monooleate;

[0048] 20-60% emulsifier, wherein the emulsifier is one or both of polyoxyethylene castor oil EL35 and Span 80;

[0049] 20-30% co-emulsifier, wherein the co-emulsifier is a mixture of ethanol and propylene glycol;

[0050] or,

[0051] 2-20% abiraterone acetate;

[0052] 20-50% oil phase, wherein the oil phase is one or both of monolinoleic acid glycerides and medium-chain triglycerides;

[0053] 20-70% emulsifier, wherein the emulsifier is polyoxyethylene castor oil EL35 or polyoxyethylene 40 hydrogenated castor oil;

[0054] 20-80% co-emulsifier, wherein the co-emulsifier is diethylene glycol monoethyl ether.

[0055] The pharmaceutical composition containing abiraterone acetate according to the present invention, preferably,

[0056] The excipients may further include one or two of antioxidants and preservatives, wherein the antioxidants or preservatives account for 0.005%-0.3% (preferably 0.005%-0.1%) of the total mass of the pharmaceutical composition; preferably, the antioxidants are selected from one or a mixture of two of tert-butyl-p-hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).

[0057] As a preferred embodiment of the present invention, the pharmaceutical composition containing abiraterone acetate preferably comprises, by weight percentage, the following components (composed of the following components):

[0058] 5-20% abiraterone acetate;

[0059] 20-50% oil phase, wherein the oil phase is hydrogenated castor oil and glyceryl monooleate;

[0060] 20-60% emulsifier, wherein the emulsifier is one or both of polyoxyethylene castor oil EL35 or polyoxyethylene 40 hydrogenated castor oil;

[0061] 20-30% co-emulsifier, wherein the co-emulsifier is ethanol and propylene glycol;

[0062] 0.005-0.1% BHA and / or BHT;

[0063] or,

[0064] 5-20% abiraterone acetate;

[0065] 25-40% oil phase, wherein the oil phase is one or both of monolinoleic acid glycerides and medium-chain triglycerides;

[0066] 25-70% emulsifier, wherein the emulsifier is polyoxyethylene castor oil EL35 or polyoxyethylene 40 hydrogenated castor oil;

[0067] 20-80% co-emulsifier, wherein the co-emulsifier is diethylene glycol monoethyl ether;

[0068] 0.005-0.1% BHA and / or BHT;

[0069] or,

[0070] 2-20% abiraterone acetate;

[0071] Abiraterone acetate,

[0072] 20-50% oil phase, wherein the oil phase is one or both of hydrogenated castor oil and glyceryl monooleate;

[0073] 20-60% emulsifier, wherein the emulsifier is one or both of polyoxyethylene castor oil EL35 and Span 80;

[0074] 20-30% co-emulsifier, wherein the co-emulsifier is a mixture of ethanol and propylene glycol;

[0075] 0.005-0.1% BHA and / or BHT.

[0076] As a preferred embodiment of the present invention, the pharmaceutical composition containing abiraterone acetate preferably comprises (composed of the following components) according to parts by mass and parts by volume:

[0077] Abiraterone acetate 1-2 parts by weight Hydrogenated castor oil 3-5 parts by volume Glyceryl monooleate 3-5 parts by volume Polyoxyethylene castor oil EL35 6-10 parts by volume Propylene glycol 1-3 parts by volume ethanol 2-5 parts by volume;

[0078] or,

[0079] Abiraterone acetate 3-5 parts by weight Sipan 80 5-10 parts by volume Polyoxyethylene castor oil EL35 5-10 parts by volume Glyceryl monooleate 5-8 parts by volume Hydrogenated castor oil 8-12 parts by volume Propylene glycol 3-5 parts by volume ethanol 5-10 parts by volume BHA 0.005-0.01 parts by weight BHT 0.01-0.02 parts by weight;

[0080] or,

[0081] Abiraterone acetate 1-2 parts by weight monolinoleic glycerides 3.5-5 parts by volume medium-chain triglycerides 2-3.5 parts by volume Polyoxyethylene 40 hydrogenated castor oil 2-5 parts by volume Diethylene glycol monoethyl ether 3-5.5 parts by volume BHA 0.002-0.005 parts by weight BHT 0.01-0.018 parts by weight;

[0082] or,

[0083]

[0084]

[0085] As an explanation and illustration, in the above technical solution, 1 part by weight : 1 part by volume = 1g : 1mL.

[0086] The pharmaceutical composition containing abiraterone acetate according to the present invention, preferably,

[0087] The active ingredients also include prednisone.

[0088] The pharmaceutical composition of the present invention exhibits excellent therapeutic efficacy, particularly demonstrating outstanding inhibitory activity against 17α-hydroxylase / C17,20-lyase (CYP17). Because the pharmaceutical composition of the present invention can significantly reduce pre- and post-meal differences and improve oral bioavailability, it can be used in combination with prednisone for the treatment of patients with metastatic castration-refractory prostate cancer (CRPC) who have previously received docetaxel-containing chemotherapy, with remarkable efficacy.

[0089] The pharmaceutical composition containing abiraterone acetate provided by this invention can be used alone to treat diseases, such as those including but not limited to prostate cancer. In practice, the pharmaceutical composition provided by this invention can be administered in (e.g., but not limited to) the following manner:

[0090] For administration to adults at daily intervals (e.g., once a day). Preferably, the effective amount of abiraterone acetate per dose is 25 mg to 200 mg; more preferably 50 mg to 150 mg, and even more preferably 75 mg to 100 mg.

[0091] The present invention also provides the use of the pharmaceutical composition in the preparation of pharmaceutical formulations; preferably, in the preparation of pharmaceutical formulations for treating prostate cancer; more preferably, the prostate cancer is selected from one or both of metastatic castration-resistant prostate cancer and metastatic high-risk castration-sensitive prostate cancer.

[0092] The present invention also provides a pharmaceutical preparation containing any one of the pharmaceutical compositions described above, preferably, the pharmaceutical preparation being a capsule.

[0093] The capsule formulation of the present invention includes the pharmaceutical composition containing abiraterone acetate as described in any one of the above-mentioned claims and the capsule shell; the capsule shell is a hard capsule and / or soft capsule material well known in the art, such as gelatin hard capsules or gelatin soft capsules, which can be purchased or prepared commercially and are not specifically limited herein.

[0094] Preferably, each capsule of the present invention contains less than 100 mg of abiraterone acetate.

[0095] This invention specifies that the abiraterone acetate capsules, based on abiraterone acetate, have a single oral dose of 50-200 mg.

[0096] The present invention also provides a drug combination (method), comprising:

[0097] One of the pharmaceutical compositions described in any of the above technical solutions, and one of the abiraterone acetate capsules described in any of the above technical solutions.

[0098] And prednisone.

[0099] The pharmaceutical combinations (methods) described herein include, but are not limited to, the application of prednisone as one of the active ingredients, and the administration of the pharmaceutical composition or capsules before or after prednisone. These can be performed in accordance with conventional practices in the art.

[0100] The present invention further provides the use of abiraterone acetate capsules as described in any of the above-mentioned technical solutions, and / or the drug combination as described in any of the above-mentioned technical solutions, in the preparation of a drug for treating prostate cancer.

[0101] Preferably, the prostate cancer is selected from one or both of metastatic castration-resistant prostate cancer and metastatic high-risk castration-sensitive prostate cancer.

[0102] The present invention also provides a method for preparing a pharmaceutical composition containing abiraterone acetate as described in any of the above technical solutions, wherein the oil phase, the emulsifier and the active ingredient are mixed, and then the co-emulsifier (which may also include antioxidants and / or preservatives) is added to obtain the composition.

[0103] Those skilled in the art will understand that the preparation method may include steps of mechanical stirring, emulsification, and ultrasonication, and the preferred technical solution is as follows:

[0104] The oil phase and the emulsifier are stirred (at room temperature or with heating) until homogeneous. Abiraterone acetate is then added and stirred in the dark. Finally, the co-emulsifier (which may also include antioxidants and / or preservatives) is added and mixed thoroughly to obtain the final product.

[0105] More specifically, it includes the following steps:

[0106] The oil phase and the emulsifier are stirred (at room temperature or under heating) until homogeneous. Abiraterone acetate is then added, and the mixture is sonicated for 10-20 minutes under light-protected conditions. The mixture is then mechanically stirred at 100-400 rpm for 10-30 minutes. Finally, the co-emulsifier is added and mixed thoroughly to obtain the final product.

[0107] The method for preparing the pharmaceutical formulation described in this invention can also be performed by those skilled in the art using conventional methods. Preferred technical solutions for preparing capsules are provided below:

[0108] A pharmaceutical composition containing abiraterone acetate is prepared according to the aforementioned method; the pharmaceutical composition is sealed in a soft capsule or a hard capsule; preferably, each capsule contains 0.5-1 ml of the pharmaceutical composition.

[0109] The pharmaceutical composition containing abiraterone acetate provided by this invention has a concentration of abiraterone acetate that can be controlled at 50-100 mg / mL, with a single oral dose of 75-100 mg. When mixed with water, biologically relevant media (e.g., SGF, FessiF, and FassiF media), or gastrointestinal fluid, it spontaneously forms a clear, uniform, and stable O / W nanoemulsion with a particle size less than 250 nm. The contents remain in a stable solution form when stored at room temperature. Even under influencing conditions (40℃±2℃, or 90% relative humidity), the content of the pharmaceutical composition of this invention remains stable.

[0110] Compared to the original drug Zytiga, the difference between pre- and post-meal bioavailability is significantly reduced; oral bioavailability is increased several times to ten times. The pharmaceutical composition can also be further formulated into capsules, which are stable and have homogeneous contents.

[0111] This invention also relates to a treatment method for prostate cancer, comprising administering the aforementioned pharmaceutical composition containing abiraterone acetate or abiraterone acetate capsules, preferably, a single dose of 25 mg-200 mg based on abiraterone acetate; more preferably 50 mg-200 mg; even more preferably 50 mg-150 mg; and even more preferably 75 mg-100 mg. Preferably, the pharmaceutical composition or capsules can be administered before or after meals. Preferably, the prostate cancer is selected from one or both of metastatic castration-resistant prostate cancer and metastatic high-risk castration-sensitive prostate cancer. Attached Figure Description

[0112] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0113] Figure 1 This is a particle size distribution diagram of the contents of abiraterone acetate capsules in Example 1 after microemulsion in water.

[0114] Figure 2This is a particle size distribution diagram of the contents of abiraterone acetate capsules in Example 2 after microemulsion in water.

[0115] Figure 3 This is a particle size distribution diagram of the contents of abiraterone acetate capsules in Example 8 after microemulsion in water.

[0116] Figure 4 This is the drug-time curve for the tablet and capsule fasting tests in Experiment Example 4.

[0117] Figure 5 This is the drug-time curve for the capsule fasting and postprandial tests in Experiment Example 4. Detailed Implementation

[0118] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0119] Example 1

[0120] This embodiment provides a pharmaceutical composition containing abiraterone acetate, comprising the following components:

[0121]

[0122]

[0123] This embodiment further provides an abiraterone acetate capsule, using the above-mentioned pharmaceutical composition as the contents, which are filled in the capsule shell.

[0124] The preparation method is provided as follows:

[0125] Take hydrogenated castor oil, glyceryl monooleate, and polyoxyethylene castor oil EL35, then add abiraterone acetate. Sonicate for 10 minutes under light-protected conditions, then stir mechanically (300 rpm) for 20 minutes to fully dissolve the mixture. Add propylene glycol and ethanol until a transparent and homogeneous self-emulsifying solution is formed. Fill the solution into soft capsules or seal it in hard capsules under nitrogen protection for storage.

[0126] Example 2

[0127] This embodiment provides a pharmaceutical composition containing abiraterone acetate, comprising the following components:

[0128] Abiraterone acetate 4.00g， Sipan 80 9.0mL, Polyoxyethylene castor oil EL35 7.0mL, Glyceryl monooleate 7.0mL, Hydrogenated castor oil 9.0mL, Propylene glycol 4.0mL, ethanol 8.0mL, BHA 0.009g， BHT 0.014g。

[0129] This embodiment further provides an abiraterone acetate capsule, using the above-mentioned pharmaceutical composition as the contents, which are filled in the capsule shell.

[0130] The preparation method is provided as follows:

[0131] Take Span 80, hydrogenated castor oil, glyceryl monooleate, and polyoxyethylene castor oil EL35, then add abiraterone acetate. Stir mechanically (300 rpm) for 25 minutes to fully dissolve the ingredients. Then add BHA, BHT, propylene glycol, and ethanol until a clear and homogeneous self-emulsifying solution is formed. Fill the solution into soft capsules or seal it in hard capsules under nitrogen protection for storage.

[0132] Example 3

[0133] This embodiment provides a pharmaceutical composition containing abiraterone acetate, comprising the following components:

[0134]

[0135]

[0136] This embodiment further provides an abiraterone acetate capsule, using the above-mentioned pharmaceutical composition as the contents, which are filled in the capsule shell.

[0137] The preparation method is provided as follows:

[0138] Take medium-chain triglycerides, monolinoleic acid glycerides, and polyoxyethylene 40 hydrogenated castor oil, then add abiraterone acetate. Stir mechanically (300 rpm) for 30 minutes to fully dissolve the ingredients. Then add diethylene glycol monoethyl ether, BHT, and BHA until a transparent and homogeneous self-emulsifying solution is formed. Fill the solution into soft capsules or seal it in hard capsules under nitrogen protection for storage.

[0139] Example 4

[0140] This embodiment provides a pharmaceutical composition containing abiraterone acetate, comprising the following components:

[0141] Abiraterone acetate 1.47g， monolinoleic glycerides 4.4 mL, Polyoxyethylene 40 hydrogenated castor oil 3.6mL, Diethylene glycol monoethyl ether 7.6mL, BHA 0.004g， BHT 0.012g。

[0142] This embodiment further provides an abiraterone acetate capsule, using the above-mentioned pharmaceutical composition as the contents, which are filled in the capsule shell.

[0143] The preparation method is provided as follows:

[0144] Take glyceryl monolinoleate and polyoxyethylene 40 hydrogenated castor oil, then add abiraterone acetate. Stir mechanically (300 rpm) for 30 minutes to fully dissolve the mixture. Then add diethylene glycol monoethyl ether, BHT, and BHA until a transparent and homogeneous self-emulsifying solution is formed. Fill the solution into soft capsules or seal it in hard capsules under nitrogen protection for storage.

[0145] Example 5

[0146] This embodiment provides a pharmaceutical composition containing abiraterone acetate, comprising the following components:

[0147] Abiraterone acetate 1.32g， monolinoleic glycerides 5.6mL, medium-chain triglycerides 2.8mL, Polyoxyethylene 40 hydrogenated castor oil 4.8mL Propylene glycol 2.8mL, ethanol 1.6 mL; BHA 0.004g， BHT 0.009g。

[0148] This embodiment further provides an abiraterone acetate capsule, using the above-mentioned pharmaceutical composition as the contents, which are filled in the capsule shell.

[0149] The preparation method is provided as follows:

[0150] Take medium-chain triglycerides, monolinoleic acid glycerides, and polyoxyethylene 40 hydrogenated castor oil, then add abiraterone acetate. Stir mechanically (300 rpm) for 30 minutes to fully dissolve the ingredients. Then add ethanol, propylene glycol, BHT, and BHA until a transparent and homogeneous self-emulsifying solution is formed. Fill the solution into soft capsules or seal it in hard capsules under nitrogen protection for storage.

[0151] Example 6

[0152] This embodiment provides a pharmaceutical composition containing abiraterone acetate, comprising the following components:

[0153] Abiraterone acetate 2.2g， Twain 80 5.0mL, Polyoxyethylene 40 hydrogenated castor oil 8.0mL, Glyceryl monooleate 9.0mL, corn oil 10.0 mL, Propylene glycol 4.0mL, ethanol 8.0 mL.

[0154] This embodiment further provides an abiraterone acetate capsule, using the above-mentioned pharmaceutical composition as the contents, which are filled in the capsule shell.

[0155] The preparation method is also provided: measure Tween 80, corn oil, glyceryl monooleate, and polyoxyethylene 40 hydrogenated castor oil, then weigh abiraterone acetate and add it. After fully mixing, add propylene glycol and ethanol. Under water bath heating conditions, a transparent and homogeneous solution is formed. After cooling to room temperature, the homogeneous phase is destroyed, and the drug crystallizes out.

[0156] Example 7

[0157] This embodiment provides a pharmaceutical composition containing abiraterone acetate, comprising the following components:

[0158] Abiraterone acetate 4.40g， Twain 80 3.0mL, Polyoxyethylene castor oil EL35 5.0mL, Polyoxyethylene 40 hydrogenated castor oil 8.0mL, Glyceryl monooleate 8.0mL, Hydrogenated castor oil 8.0mL, Propylene glycol 2.0mL, ethanol 10.0 mL.

[0159] This embodiment further provides an abiraterone acetate capsule, using the above-mentioned pharmaceutical composition as the contents, which are filled in the capsule shell.

[0160] The preparation method is also provided as follows: measure Tween 80, polyoxyethylene 40 hydrogenated castor oil, hydrogenated castor oil, glyceryl monooleate, and polyoxyethylene castor oil EL35, then add abiraterone acetate and dissolve them completely. Then add propylene glycol and ethanol until a transparent and homogeneous self-emulsifying solution is formed. Fill the solution into soft capsules or seal it in hard capsules under nitrogen protection for storage.

[0161] Example 8

[0162] This embodiment provides a pharmaceutical composition containing abiraterone acetate, comprising the following components:

[0163] Abiraterone acetate 4.40g， Sipan 80 8.4 mL, Solutol 2.6mL, Polyoxyethylene castor oil EL35 5.0mL, Glyceryl monooleate 8.0mL, Hydrogenated castor oil 8.0mL, Propylene glycol 2.0mL, ethanol 10.0 mL.

[0164] This embodiment further provides an abiraterone acetate capsule, using the above-mentioned pharmaceutical composition as the contents, which are filled in the capsule shell.

[0165] The preparation method is also provided as follows: measure Span 80, Solutol, hydrogenated castor oil, glyceryl monooleate, and polyoxyethylene castor oil EL35, then add abiraterone acetate and dissolve them completely. Then add propylene glycol and ethanol until a transparent and homogeneous self-emulsifying solution is formed. Fill the solution into soft capsules or seal it in hard capsules under nitrogen protection for storage.

[0166] Example 9

[0167] This embodiment provides a pharmaceutical composition containing abiraterone acetate, comprising the following components:

[0168] Abiraterone acetate 4.40g， Sipan 80 8.8mL, Polyoxyethylene castor oil EL35 4.4 mL, Glyceryl monooleate 8.0mL, Hydrogenated castor oil 9.6mL, Propylene glycol 4.4 mL, ethanol 8.8 mL.

[0169] This embodiment further provides an abiraterone acetate capsule, using the above-mentioned pharmaceutical composition as the contents, which are filled in the capsule shell.

[0170] The preparation method is also provided as follows: measure Span 80, hydrogenated castor oil, glyceryl monooleate, and polyoxyethylene castor oil EL35, then add abiraterone acetate and dissolve them completely. Then add propylene glycol and ethanol until a transparent and homogeneous self-emulsifying solution is formed. Fill the solution into soft capsules or seal it in hard capsules under nitrogen protection for storage.

[0171] Example 10

[0172] Except that the propylene glycol was replaced with 1.0 mL instead of 2.0 mL and the ethanol was replaced with 2.0 mL instead of 4.0 mL, the other conditions were the same as in Example 1.

[0173] Example 11

[0174] Except for replacing 4.8 mL of diethylene glycol monoethyl ether with 1.6 mL, the other conditions are the same as in Example 3.

[0175] Example 12

[0176] Except for replacing 4.8 mL of diethylene glycol monoethyl ether with 17.6 mL, the other conditions were the same as in Example 3.

[0177] Example 13

[0178] Except for replacing 4.8 mL of diethylene glycol monoethyl ether with 36.8 mL, the other conditions are the same as in Example 3.

[0179] Experimental Example 1

[0180] This test provides dissolution tests for abiraterone acetate capsules and the original drug Zytiga tablets provided in Examples 1-4.

[0181] Test method: The dissolution of abiraterone acetate was determined according to the United States Pharmacopeia (USP) method, at 37°C, 900 mL of release medium, and 50 rpm, for abiraterone acetate capsules (prepared in Examples 1, 2, and 3) and the original drug Zytiga tablets.

[0182] The phosphate buffer solution with a pH of 4.5 is prepared by adding 56.5 mM sodium dihydrogen phosphate to water and adjusting the pH to 4.5 with sodium hydroxide or phosphoric acid.

[0183] The specific method is as follows:

[0184]

[0185] Table 1. Dissolution rates (%) of abiraterone acetate capsules and Zytiga tablets in medium 1.

[0186] Sampling points / min Zytiga Example 1 Example 2 Example 3 Example 4 5 22 73 80 74 75 10 42 93 97 91 90 15 64 96 99 97 96 20 71 98 99 99 97 30 89 99 97 99 99 45 91 98 99 99 99

[0187] Table 2. Dissolution rates (%) of abiraterone acetate capsules and Zytiga tablets in medium 2.

[0188]

[0189]

[0190] The comparison results in Tables 1 and 2 show that: the abiraterone acetate capsules of the present invention (Examples 1, 2, 3, 4) were basically completely dissolved in medium 1 within 15 minutes, while the commercially available abiraterone acetate tablets Zytiga still could not be completely dissolved after 45 minutes; the abiraterone acetate capsules of the present invention (Examples 1, 2, 3, 4) were basically completely dissolved in medium 2, while the commercially available abiraterone acetate tablets Zytiga showed extremely low dissolution.

[0191] The experimental results above show that the abiraterone acetate capsules of the present invention can effectively improve the dissolution rate of abiraterone acetate under both USP and non-UPS conditions, which will help improve the oral bioavailability of abiraterone acetate and reduce individual differences.

[0192] Experimental Example 2

[0193] This test provides stability tests for the abiraterone acetate capsules provided in Examples 1-9.

[0194] (1) Long-term test: After filling abiraterone acetate capsules into polyethylene plastic bottles, the samples were placed at a temperature of 25℃±2℃ and a relative humidity of 60%±10% to observe the physical stability of the drug composition inside the capsules. The test results are shown in Table 3.

[0195] Table 3 Physical stability of the drug compositions

[0196]

[0197]

[0198] - Clear solution, no drug precipitation.

[0199] +: Clear solution, trace amounts of drug precipitate.

[0200] ++: Clear solution, with a small amount of drug precipitated.

[0201] +++: Clear solution, with noticeable drug precipitation.

[0202] As shown in Table 3, the pharmaceutical compositions formed by the specific emulsifier, oil phase, and co-emulsifier of the present invention with abiraterone acetate exhibit good physical stability. In particular, the combination of 20%-80% (by mass percentage relative to the total mass of the composition) of a specific co-emulsifier with specific emulsifiers (polyoxyethylene castor oil EL35, polyoxyethylene 40 hydrogenated castor oil, Span 80, and polyethylene glycol-15 hydroxystearate) achieves significantly better physical stability. Furthermore, considering factors such as drug safety, chemical stability, and formulation production, the mass percentage of the co-emulsifier is preferably below 60%, particularly between 20% and 60%.

[0203] (2) Accelerated test: After filling abiraterone acetate capsules into polyethylene plastic bottles, samples were released at a temperature of 40℃±2℃ and a relative humidity of 60%±10% to test the content of the drug composition and related substances. The results are shown in Table 4. The abiraterone acetate capsules prepared in Examples 1, 2, 3, and 4 showed stable content.

[0204] Table 4 Accelerated stability of drug compositions

[0205]

[0206]

[0207] Experimental Example 3

[0208] This test provides self-emulsifying ability and particle size tests of the pharmaceutical compositions provided in Examples 1-9.

[0209] The pharmaceutical compositions prepared in Examples 1-9 were added to purified water, and their appearance was observed after gentle shaking. The particle size of the emulsion was measured using a nanoparticle size analyzer, as shown in Table 5-1.

[0210] Table 5-1 Properties and particle size of pharmaceutical compositions after emulsification

[0211] Properties Nanoemulsion particle size Example 1 Clear and transparent nanoemulsion ~100nm Example 2 Clear, transparent nanoemulsion with a slightly bluish luster ~110nm Example 3 Clear, transparent nanoemulsion with a slightly bluish luster ~70nm Example 4 Clear, transparent nanoemulsion with a slightly bluish luster ~90nm Example 5 Clear, transparent nanoemulsion with a slightly bluish luster ~90nm Example 6 Unable to form a homogeneous system, oil droplets are always present. Untested Example 7 milky Untested Example 8 Clear, transparent, pale blue opalescent nanoemulsion ~270nm Example 9 Clear, transparent, pale blue opalescent nanoemulsion ~140nm

[0212] This experimental example also provides the determination of the stability of the nanoemulsions obtained after emulsifying the pharmaceutical compositions of Examples 1-9, and the determination method is as follows:

[0213] Long-term test: Samples were placed at a temperature of 25℃±2℃ and a relative humidity of 60%±10% to observe the stability of the nanoemulsion after emulsification of the drug composition. The results are shown in Table 5-2.

[0214] Table 5-2 Properties of Nanoemulsions after Emulsification of Pharmaceutical Compositions

[0215] 0 o'clock 2 weeks 4 weeks Example 1 Clear and transparent nanoemulsion - - Example 2 Clear, transparent nanoemulsion with a slightly bluish luster - - Example 3 Clear, transparent nanoemulsion with a slightly bluish luster - - Example 4 Clear, transparent nanoemulsion with a slightly bluish luster - - Example 8 Clear, transparent, pale blue opalescent nanoemulsion - - Example 9 Clear, transparent, pale blue opalescent nanoemulsion - -

[0216] -: Represents no difference

[0217] See attached image. Figure 1 This is a particle size distribution diagram of the contents of abiraterone acetate capsules in Example 1 after microemulsion in water. Figure 2 This is a particle size distribution diagram of the contents of abiraterone acetate capsules in water after microemulsion formation in Example 2. Figure 3 This is a particle size distribution diagram of the contents of abiraterone acetate capsules in Example 8 after microemulsion in water.

[0218] Test Example 4

[0219] This experimental example provides pharmacokinetic testing of Example 1 and the original abiraterone acetate drug Zytiga.

[0220] Test methods and targets:

[0221] Six healthy beagle dogs were randomly divided into three groups of two dogs each, and three cycles of the experiment were conducted, with a three-day washout period between cycles.

[0222] The experimental design is divided into fasting test and postprandial test.

[0223] Fasting test: Fast for 10 hours before the test, administer the drug on an empty stomach, and feed the patient 4 hours after administration.

[0224] Postprandial test: Fasting for 10 hours before the test, followed by administration of the drug after a high-fat meal (feeding and administration to be completed within 30 minutes).

[0225] The test tablets were the original abiraterone acetate drug Zytiga, with each tablet containing 250 mg of abiraterone acetate.

[0226] The test capsule was the abiraterone acetate capsule provided in Example 1, with each capsule containing 50 mg of abiraterone acetate.

[0227] Sampling design: Blood samples of 2 mL were collected at 15 min, 30 min, 1 h, 1.5 h, 2.0 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h after drug administration, and plasma was separated by centrifugation.

[0228] Table 6 Experimental Groups

[0229] Experimental grouping First cycle Second cycle Third cycle 1 Two tablets on an empty stomach (T1) One capsule after meals (T3) Take 1 capsule on an empty stomach (T2). 2 Take 1 capsule on an empty stomach (T2). Two tablets on an empty stomach (T1) One capsule after meals (T3) 3 One capsule after meals (T3) Take 1 capsule on an empty stomach (T2). Two tablets on an empty stomach (T1)

[0230] Among them, T1 is the fasting test - the original drug Zytiga group (in the appendix) Figure 4 The middle group was designated as the fasting tablet group, and the second group was designated as the fasting test-abiraterone acetate capsule group (in the appendix). Figure 4 Appendix Figure 5 The middle group was marked as the fasting capsule group, and T3 was the postprandial test - abiraterone acetate capsule group (in the appendix). Figure 5 (The middle part is marked as the postprandial capsule group).

[0231] Table 7 Fasting Test: Pharmacokinetic parameters of the original drug Zytiga 500mg compared with abiraterone acetate capsules 50mg

[0232]

[0233] Where T1 / 2 is the drug half-life, Tmax is the time to peak concentration, Cmax is the maximum plasma concentration (peak concentration), and AUClast is the AUC (area of ​​influence of the drug-time curve) of the duration from the start of administration to the last point.

[0234] The results are attached. Figure 4As shown, the drug-time curves of abiraterone acetate capsules 50mg (T2) and abiraterone acetate capsules administered after a high-fat meal (T3) in beagle dogs under fasting conditions are presented in the fasting test.

[0235] As shown in Table 7, the oral bioavailability of one abiraterone acetate capsule (containing 50 mg of abiraterone acetate) administered orally to a beagle on an empty stomach reached 98% compared to two tablets of the original drug Zytiga (250 mg / tablet). This indicates that the abiraterone acetate pharmaceutical composition of the present invention has a 10-fold higher oral bioavailability than the original drug Zytiga (250 mg / tablet), and the inter-individual variability in time to peak concentration, peak concentration, and absorption level is significantly lower than that of the original drug Zytiga.

[0236] Table 8. Postprandial Trial: Pharmacokinetic Parameters of Abiraterone Acetate Capsules 50mg Before and After Meals

[0237]

[0238]

[0239] Where T1 / 2 is the drug half-life, Tmax is the time to peak concentration, Cmax is the maximum plasma concentration (peak concentration), and AUClast is the AUC (area of ​​influence of the drug-time curve) of the duration from the start of administration to the last point.

[0240] The results are attached. Figure 5 As shown, this is the drug-time curve of abiraterone acetate capsule 50mg in Example 1 in a postprandial test in beagle dogs before (T2) and after (T3) meals.

[0241] As shown in Table 8, there was no significant difference in the time to peak drug concentration in beagle dogs when abiraterone acetate capsules (containing 50 mg of abiraterone acetate) were administered on an empty stomach and after a high-fat meal. The oral bioavailability after a meal was only 1.2 times that before a meal.

[0242] Compared to the original drug Zytiga, whose peak concentration and absorption value after a high-fat meal are 17 times and 10 times higher than those under fasting conditions as stated in the product information, the abiraterone acetate capsules provided by this invention can reduce the pre- and post-meal differences.

[0243] Although the present invention has been described in detail above with general descriptions, specific embodiments, and experiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A pharmaceutical composition containing abiraterone acetate, characterized in that, include: Active ingredient: Abiraterone acetate; Excipients: The oil phase is hydrogenated castor oil and glyceryl monooleate, the emulsifier is polyoxyethylene castor oil EL35, and the co-emulsifier is a mixture of ethanol and propylene glycol; or, the oil phase is glyceryl monooleate and medium-chain triglycerides, the emulsifier is polyoxyethylene 40 hydrogenated castor oil, and the co-emulsifier is diethylene glycol monoethyl ether; or, the oil phase is glyceryl monooleate and medium-chain triglycerides, the emulsifier is polyoxyethylene 40 hydrogenated castor oil, and the co-emulsifier is a mixture of ethanol and propylene glycol. The abiraterone acetate comprises 2-20% of the total mass of the pharmaceutical composition, the oil phase comprises 20-50% of the total mass of the pharmaceutical composition containing abiraterone acetate, the co-emulsifier comprises 20-50% of the total mass of the pharmaceutical composition, and the emulsifier comprises 20-50% of the total mass of the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, characterized in that, Based on the total volume of the excipients, the concentration of abiraterone acetate is between 50 and 100 mg / mL.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The excipients also include one or two of antioxidants and preservatives; the antioxidants or preservatives account for 0.005%-0.1% of the total mass of the pharmaceutical composition.

4. The pharmaceutical composition according to claim 3, characterized in that, The antioxidant is selected from one or both of tert-butylhydroanisole (BHA) and butylated hydroxytoluene (BHT).

5. A method for preparing the pharmaceutical composition according to any one of claims 1-4, characterized in that, The process includes the following steps: mixing the oil phase, the emulsifier, and the active ingredient, and then adding the co-emulsifier.

6. The preparation method according to claim 5, characterized in that, The process includes the following steps: after stirring the oil phase and the emulsifier until uniform, add abiraterone acetate, sonicate for 10-20 minutes under light-protected conditions, mechanically stir at 100-400 rpm for 10-30 minutes, and finally add the co-emulsifier and mix well to obtain the final product.

7. Use of the pharmaceutical composition according to any one of claims 1-4 in the preparation of a pharmaceutical formulation for treating prostate cancer.

8. An abiraterone acetate capsule, comprising contents and a capsule shell, characterized in that, The pharmaceutical composition according to any one of claims 1-4 is used as the contents.

9. The abiraterone acetate capsules according to claim 8, characterized in that, The capsule shell is made of hard capsule or soft capsule material.

10. The abiraterone acetate capsules according to claim 8 or 9, characterized in that, Based on abiraterone acetate, the single oral dose is 25-200 mg.

11. The use of abiraterone acetate capsules according to any one of claims 8-10 in the preparation of a medicament for treating prostate cancer.

12. A drug combination, characterized in that, include: The pharmaceutical composition according to any one of claims 1-4, the abiraterone acetate capsules according to any one of claims 8-10, and prednisone.

13. Use of the pharmaceutical combination of claim 12 in the preparation of a medicament for treating prostate cancer.

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