Pharmaceutical composition containing abiraterone acetate and preparation method thereof

Abstract

The invention discloses a pharmaceutical composition containing abiraterone acetate and a preparation method thereof. The raw materials of the pharmaceutical composition include abiraterone acetate and a carrier, wherein the carrier is hydroxypropyl methylcellulose acetate succinate and methacrylic acid copolymer type C; or the carrier is hydroxypropyl methylcellulose acetate succinate. The pharmaceutical composition containing abiraterone acetate of the invention is an amorphous drug, which has high thermal stability, does not undergo crystal transformation for at least 45 days under accelerated conditions, and exists in a stable amorphous state; in the saliva and small intestine pH environment, it has higher instantaneous solubility and dissolution rate than abiraterone acetate, can be prepared into various forms of pharmaceutical preparations for administration, and has broad clinical application prospects.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and more specifically, the present invention relates to a pharmaceutical composition containing abiraterone acetate and a preparation method thereof. Background Art

[0002] Prostate cancer is the second most common cancer in men worldwide after lung cancer. Abiraterone is a pregnenolone analog that can effectively and irreversibly inhibit the CYP17 enzyme in the human body. Therefore, it can inhibit the synthesis of androgens from the source and inhibit the growth of androgen-dependent prostate cancer.

[0003] According to the instructions of the original developer Johnson & Johnson, when abiraterone acetate is taken with food, the maximum absorption concentration and systemic exposure of abiraterone drugs increase by 17 times and 10 times respectively, showing a significant food effect. Given the diversity and variability of food, taking it with food may lead to increased exposure and an increase in the individual coefficient of variation. Abiraterone acetate requires that you should not eat for at least 2 hours before and 1 hour after taking the drug. The residue of the drug in the body is the main cause of the food effect.

[0004] Abiraterone acetate has poor water solubility. It is soluble in organic solvents but almost insoluble in aqueous media. After administration into the body, it is difficult to dissolve and absorb at the absorption site. Therefore, increasing solubility, improving dissolution rate, and then improving bioavailability are the key to the research of abiraterone acetate drugs.

[0005] There are two main ways to improve the oral bioavailability of drugs. One is to change the physical and chemical properties of the drug to improve its ability to penetrate the membrane or improve its solubility characteristics, such as micronization (including nanocrystals), solid dispersion technology, inclusion technology, etc. The other way is to improve the membrane properties to increase the membrane permeability of the drug, or inhibit the efflux pump to prevent the body from excreting the absorbed drug, that is, the use of oral absorption enhancers.

[0006] CN103070828B discloses the preparation of a solid dispersion using polyvidone as a carrier material. According to CN105267224A, the discovery of this patent is repeated, because the viscosity of polyvidone is too strong, it is difficult for the solvent to evaporate. CN105267224A discloses a pharmaceutical composition of abiraterone acetate, which uses a grinding method to prepare an amorphous mixture of abiraterone acetate and lactose to improve the dispersibility and solubility of a solid oral preparation, and further improve human bioavailability. However, lactose generally has a high hygroscopicity and is easy to absorb moisture, resulting in crystal transformation of the composition. CN107278152A uses polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) and sodium deoxycholate to form a composite through a microfluidic flow meter, and then forms a solid by spray drying or freeze drying. The composite can reduce the effect of food and abandon the requirement of taking the medicine on an empty stomach; in an in vivo experiment, the bioavailability of an embodiment in beagle dogs is 11 times higher than that of the original research, and 4 times higher in adult males; but the technology has the problems of complex preparation process and high energy consumption, and the technology will use a large amount of organic solvent tetrahydrofuran, which has environmental protection and production safety problems. Patent document CN110538150A relates to a pharmaceutical composition containing abiraterone acetate and its preparation method and application, the auxiliary materials include: at least one oil phase, at least one emulsifier and at least one auxiliary emulsifier, and the composition formula contains ethanol, because ethanol has an important role in increasing the solubility of API and reducing the droplet size in the formula, and ethanol is very volatile, which will affect the stability and efficacy of the product.

[0007] Abiraterone acetate is a poorly soluble drug with pH-dependent solubility in water. It has high solubility in acidic environments, but its solubility decreases significantly as pH increases. Since the main absorption site of oral drugs is the small intestine, its pH is about 6.8. According to the BCS classification, abiraterone acetate belongs to BCS IV drugs. In order to improve the bioavailability of abiraterone acetate, an amorphous composition of abiraterone acetate can be prepared. The amorphous form of the drug has a higher dissolution rate in body fluids compared to its crystalline state due to the disordered arrangement of its molecules. However, the amorphous form is in a high-energy state and is prone to crystal transformation, which becomes an obstacle to the preparation of amorphous drugs. In particular, the melting point of abiraterone acetate is relatively low at only 146°C, and its amorphous form will be less stable than other high-melting point compounds.

[0008] Therefore, it is very meaningful to provide an amorphous abiraterone acetate composition with stable drug amorphous form, high solubility in the small intestine environment, and high dissolution rate. Summary of the invention

[0009] Based on this, the object of the present invention is to provide a pharmaceutical composition containing abiraterone acetate and a preparation method thereof. The pharmaceutical composition of the present invention can greatly improve the solubility of abiraterone acetate in the small intestine environment, and the drug is amorphous and stable.

[0010] The technical solutions for achieving the above-mentioned invention objectives include the following.

[0011] The first aspect of the present invention provides a pharmaceutical composition, the raw materials of which include abiraterone acetate and a carrier, wherein the carrier is hydroxypropyl methylcellulose acetate succinate (HPMCAS) and methacrylic acid copolymer type C (Eudragit L100-55), or the carrier is hydroxypropyl methylcellulose acetate succinate.

[0012] The second aspect of the present invention provides a method for preparing the above-mentioned pharmaceutical composition, comprising the following steps: completely dissolving abiraterone acetate and a carrier in a solvent, spray drying, drying under reduced pressure, and removing the solvent to obtain the pharmaceutical composition.

[0013] The third aspect of the present invention provides a drug for treating prostate cancer, which is prepared from the above-mentioned pharmaceutical composition and a pharmaceutically acceptable carrier or excipient.

[0014] The present invention has the following beneficial effects:

[0015] In the present invention, the inventors found after a large number of experiments that: HPMCAS or a mixture of HPMCAS and Eudragit is selected as a carrier of abiraterone acetate, and the mass ratio of the carrier to abiraterone acetate is controlled within a certain range (when HPMCAS is used as a carrier, the drug loading is controlled at 5-10%, and when a mixture of HPMCAS and Eudragit is used as a carrier, the drug loading is controlled at 5-30%), and the prepared pharmaceutical composition containing abiraterone acetate is an amorphous drug, which has high thermal stability and can withstand high process temperatures in the preparation process according to its glass transition temperature; under accelerated conditions (40°C, 75% RH), no crystal transformation occurs for at least 45 days, and it exists in a stable amorphous state; in the saliva and small intestine pH environment, it has higher instantaneous solubility and dissolution rate relative to abiraterone acetate, and the apparent solubility is increased by about 8 times. In addition, the pharmaceutical composition of the present invention avoids the toxicity of surfactants, can be prepared into various forms of pharmaceutical preparations for administration, and has broad clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This is the X-ray powder diffraction pattern of the pharmaceutical composition ① prepared in Example 1 of the present invention.

[0017] Figure 2This is the X-ray powder diffraction pattern of the pharmaceutical composition ② prepared in Example 2 of the present invention.

[0018] Figure 3 It is the X-ray powder diffraction pattern of the pharmaceutical composition ③ prepared in Comparative Example 1 of the present invention.

[0019] Figure 4 This is the X-ray powder diffraction pattern of the pharmaceutical composition ④ prepared in Comparative Example 2 of the present invention.

[0020] Figure 5 This is the X-ray powder diffraction pattern of the pharmaceutical composition ⑤ prepared in Comparative Example 3 of the present invention.

[0021] Figure 6 This is the X-ray powder diffraction pattern of the pharmaceutical composition ⑥ prepared in Comparative Example 4 of the present invention.

[0022] Figure 7 This is the DSC chart of the pharmaceutical composition ① prepared in Example 1 of the present invention.

[0023] Figure 8 This is the DSC chart of the pharmaceutical composition ② prepared in Example 2 of the present invention.

[0024] Fig. 9 It is the DSC graph of the pharmaceutical composition ③ prepared in Comparative Example 1 of the present invention.

[0025] Fig.10 It is the DSC chart of the pharmaceutical composition ④ prepared in Comparative Example 2 of the present invention.

[0026] Fig.11 It is the DSC chart of the pharmaceutical composition ⑤ prepared in Comparative Example 3 of the present invention.

[0027] Fig.12 It is the DSC chart of the pharmaceutical composition ⑥ prepared in Comparative Example 4 of the present invention.

[0028] Fig.13 This is a comparison of the X-ray powder diffraction patterns of the pharmaceutical composition ① of Example 1 of the present invention at 40° C. and 75% RH for 45 days and 0 day.

[0029] Fig.14 This is a comparison of the X-ray powder diffraction patterns of the pharmaceutical composition ② of Example 2 of the present invention at 40° C. and 75% RH for 45 days and 0 day.

[0030] Fig.15 This is a comparison chart of the X-ray powder diffraction patterns of the pharmaceutical composition ③ of comparative example 1 of the present invention at 40° C. and 75% RH for 45 days and 0 day.

[0031] Fig.16This is a comparison chart of the X-ray powder diffraction patterns of the pharmaceutical composition ④ of comparative example 2 of the present invention at 40° C. and 75% RH for 7 days and 0 days.

[0032] Fig.17 This is a comparison chart of dissolution measurement data of the pharmaceutical composition ① of Example 1 of the present invention and abiraterone acetate from a medium of pH=1 to pH=6.8.

[0033] Fig.18 It is a comparison chart of dissolution measurement data of pharmaceutical composition ① of Example 1 of the present invention, pharmaceutical composition ⑤ of Comparative Example 3, pharmaceutical composition ⑥ of Comparative Example 4, and abiraterone acetate in a pH=6.8 medium. DETAILED DESCRIPTION

[0034] In order to facilitate the understanding of the present invention, the present invention will be described more fully below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0035] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used in the present invention includes any and all combinations of one or more of the related listed items.

[0036] The experimental methods in the following examples where specific conditions are not specified are generally carried out under conventional conditions, such as those described in Green and Sambrook et al., Molecular Cloning: A Laboratory Manual, 2013, or under conditions recommended by the manufacturer. The various commonly used chemical reagents used in the examples are all commercially available products.

[0037] In some embodiments of the present invention, a pharmaceutical composition containing abiraterone acetate is disclosed, wherein the raw materials include abiraterone acetate and a carrier, wherein the carrier is hydroxypropyl methylcellulose acetate succinate (HPMCAS) and methacrylic acid copolymer type C (Eudragit L100-55); or the carrier is hydroxypropyl methylcellulose acetate succinate.

[0038] In some of the embodiments, the carrier is hydroxypropyl methylcellulose acetate succinate and methacrylic acid copolymer type C, and the drug loading amount of the pharmaceutical composition is 5wt% to 30wt%.

[0039] In some embodiments, the hydroxypropyl methylcellulose acetate succinate (HPMCAS) accounts for 5% to 60% of the carrier; and the methacrylic acid copolymer type C accounts for 40% to 90% of the carrier.

[0040] In some of the embodiments, the mass ratio of hydroxypropyl methylcellulose acetate succinate (HPMCAS) to methacrylic acid copolymer type C in the carrier is 0.8-1.2:2.

[0041] In some of the embodiments, the mass ratio of abiraterone acetate, hydroxypropyl methylcellulose acetate succinate and methacrylic acid copolymer type C is 0.8-1.2:0.8-1.2:2. Preferably, the mass ratio of abiraterone acetate, hydroxypropyl methylcellulose acetate succinate and methacrylic acid copolymer type C is 1:1:2.

[0042] In some embodiments, the carrier is hydroxypropyl methylcellulose acetate succinate, and the drug loading amount of the pharmaceutical composition is 5wt% to 10wt%.

[0043] In other embodiments of the present invention, a method for preparing a pharmaceutical composition containing abiraterone acetate is disclosed, comprising the following steps: completely dissolving abiraterone acetate and a carrier in a solvent, spray drying, drying under reduced pressure, and removing the solvent to obtain.

[0044] In some of the embodiments, the solvent is one or more of ethanol, dichloromethane, methanol, isopropanol, acetone, ethyl acetate, and acetonitrile; preferably, the solvent is methanol and dichloromethane in a volume ratio of 1:2.

[0045] In other embodiments of the present invention, a drug for treating prostate cancer is disclosed, which is prepared by combining the above-mentioned pharmaceutical composition with a pharmaceutically acceptable carrier or excipient according to the disclosed conventional technology.

[0046] In some embodiments, the pharmaceutically acceptable carrier or excipient is a lubricant, a permeation aid, a filler, a disintegrant, a plasticizer, a diluent, a flavoring agent, a binder, an antioxidant, a light stabilizer, a free radical scavenger, a surfactant, a pH adjuster, a drug complexing agent or a stabilizer against microbial attack, or a combination thereof.

[0047] In the following examples, abiraterone acetate was purchased from Jiangsu Aikang Biopharmaceutical Research and Development Co., Ltd., hydroxypropyl methylcellulose acetate succinate was purchased from Shin-Etsu Chemical Co., Ltd.; Eudragit L100-55 was purchased from Evonik Degussa Specialty Chemicals (Shanghai) Co., Ltd.; PVPVA64 was purchased from BASF SE; and HPMC E5 was purchased from Shin-Etsu Chemical Co., Ltd.

[0048] In the following examples, the test parameters used for characterization are as follows:

[0049] Powder X-ray diffraction (PXRD): The crystallization of the samples was checked using a PANalytical Empyrean X-ray powder diffractometer (PW3040 / 60, PANalytical Analytical Instruments Ltd., the Netherlands), using Cu-Kα radiation at a wavelength of Equipped with Bragg-Brentano High Definition. Light path: divergence slit 1 / 8°, Soller slit 0.04rad, light shielding frame Mask10mm, anti-scatter slit 1 / 2°; diffraction light path: anti-scatter slit P7.5; X-ray sample stage: rotation mode; scanning detector: PIXcel1D-Medipix3; X-ray tube voltage 45kV, X-ray tube current 40mA, scanning range 2-40°(2θ), step length 0.026°, step time: 36.465s.

[0050] Modulated DSC: Differential scanning calorimeter Q2000 (TA Instruments, USA) was used to analyze the thermal properties of the samples. The samples were tested in the modulation mode, with a nitrogen purge flow of 50 mL / min in the sample chamber, balanced at 40°C (25°C in Comparative Example 1), a modulation cycle of 60 s, an amplitude of 0.8°C, and a heating rate of 5°C / min to 200°C. The data analysis software TA Universal Analysis (TA Instruments, USA) was used.

[0051] The present invention is described in detail below with reference to the accompanying drawings and specific embodiments.

[0052] Example 1 Pharmaceutical composition containing abiraterone acetate

[0053] The pharmaceutical composition containing abiraterone acetate provided in this embodiment is prepared by the following steps:

[0054] 1. Add 0.15 g of abiraterone acetate, 0.15 g of HPMCAS, and 0.3 g of Eudragit L100-55 into 15 mL of a mixed solvent of methanol / dichloromethane (1:2 volume ratio), and completely dissolve them by magnetic stirring;

[0055] 2. The obtained solution was spray dried by a B290 micro spray dryer of Buchi, Switzerland, to obtain powder; the parameter settings of the spray drying process are shown in Table 1.

[0056] Table 1

[0057] parameter Setting Value Suction power 40kg / h Inlet temperature 80℃ Outlet temperature 50～60℃ Injection rate 5mL / min Atomizing air flow 0.5kg / h Inert loop cooling temperature 20℃

[0058] 3. Place in a vacuum drying oven at 35°C and dry under reduced pressure for 16 hours to remove excess solvent to obtain a pharmaceutical composition of abiraterone acetate: HPMCAS: Eudragit L100-55 (1:1:2) (hereinafter referred to as pharmaceutical composition ①).

[0059] The X-ray powder diffractometer was used to test the pharmaceutical composition of this example. The results are as follows Figure 1 As shown, its physical state is determined to be amorphous.

[0060] Example 2 Pharmaceutical composition containing abiraterone acetate

[0061] The pharmaceutical composition containing abiraterone acetate provided in this embodiment is prepared by the following steps:

[0062] 1. Add 0.2 g of abiraterone acetate and 1.8 g of HPMCAS into 40 mL of a mixed solvent of methanol / dichloromethane (1:2 volume ratio) and completely dissolve them by magnetic stirring;

[0063] 2. The obtained solution was spray dried by a B290 micro spray dryer of Buchi, Switzerland, to obtain powder; the parameter settings of the spray drying process are shown in Table 1.

[0064] 3. Place in a vacuum drying oven at 35°C and dry under reduced pressure for 16 hours to remove excess solvent, thereby obtaining a pharmaceutical composition of abiraterone acetate: HPMCAS (1:9) (hereinafter referred to as pharmaceutical composition ②).

[0065] The X-ray powder diffractometer was used to test the pharmaceutical composition of this example. The results are as follows Figure 2 As shown, its physical state is determined to be amorphous.

[0066] Example 3 Tablets containing abiraterone acetate

[0067] Tablets containing abiraterone acetate were prepared according to the formulation in Table 2.

[0068] Table 2

[0069] substance Unit dose (mg) Proportion Pharmaceutical composition① 600 62.50％ Microcrystalline Cellulose 192 20.00％ Sodium 8-(2-hydroxybenzamido)octanoate 120 12.50％ Cross-linked carboxymethyl cellulose sodium 30 3.12％ Colloidal Silica 9 0.94％ Magnesium Stearate 9 0.94％ Total weight 960 100％

[0070] The preparation method is as follows:

[0071] (1) Weighing: Weigh each component according to the prescription ratio in Table 2.

[0072] (2) Preliminary mixing: The pharmaceutical composition ① prepared in Example 1 was mixed with microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and sodium 8-(2-hydroxybenzamido)octanoate and passed through a 40-mesh sieve. The sieved powder was placed in a multi-directional motion mixer and mixed for 15 minutes.

[0073] (3) Dry granulation: The mixed materials are added into a dry granulator for granulation.

[0074] (4) Total mixing: The granules after dry granulation were mixed with colloidal silicon dioxide and passed through a 20-mesh sieve, and magnesium stearate was added and mixed for 10 minutes.

[0075] (5) Compress the tablets and package them (150 mg).

[0076] Comparative Example 1: Pharmaceutical composition containing abiraterone acetate

[0077] The pharmaceutical composition containing abiraterone acetate provided in this embodiment is prepared by the following steps:

[0078] 1. Add 0.2 g of abiraterone acetate and 0.6 g of HPMCAS into 20 mL of a mixed solvent of methanol / dichloromethane (1:2 volume ratio) and completely dissolve them by magnetic stirring;

[0079] 2. The obtained solution was spray dried by a B290 micro spray dryer of Buchi, Switzerland, to obtain powder; the parameter settings of the spray drying process are shown in Table 1.

[0080] 3. Place the mixture in a vacuum drying oven at 35°C and dry under reduced pressure for 24 hours to remove excess solvent, thereby obtaining a pharmaceutical composition of abiraterone acetate: HPMCAS (1:3) (hereinafter referred to as pharmaceutical composition ③).

[0081] The X-ray powder diffractometer was used to test the pharmaceutical composition of this example. The results are as follows Figure 3 As shown, its physical state is determined to be amorphous.

[0082] Comparative Example 2

[0083] The pharmaceutical composition containing abiraterone acetate provided in this comparative example is prepared by the following steps:

[0084] 1. Add 0.2 g of abiraterone acetate and 0.6 g of PVP VA64 into 15 mL of a mixed solvent of methanol / dichloromethane (1:2 volume ratio) and completely dissolve them by magnetic stirring;

[0085] 2. The obtained solution was spray dried by a B290 micro spray dryer of Buchi, Switzerland, to obtain powder; the parameter settings of the spray drying process are shown in Table 1.

[0086] 3. Place in a vacuum drying oven at 35°C and dry under reduced pressure for 24 hours to remove excess solvent to obtain a pharmaceutical composition of abiraterone acetate: PVPVA64 (1:3) (hereinafter referred to as pharmaceutical composition ④).

[0087] The X-ray powder diffractometer was used to test the pharmaceutical composition of this comparative example. The results are as follows Figure 4 As shown, its physical state is determined to be amorphous.

[0088] Comparative Example 3

[0089] The pharmaceutical composition containing abiraterone acetate provided in this comparative example is prepared by the following steps:

[0090] 1. Add 0.2 g of abiraterone acetate and 0.6 g of Eudragit L100-55 into 15 mL of a mixed solvent of methanol / dichloromethane (1:2 volume ratio) and completely dissolve them by magnetic stirring;

[0091] 2. The obtained solution was spray dried by a B290 micro spray dryer of Buchi, Switzerland, to obtain powder; the parameter settings of the spray drying process are shown in Table 1.

[0092] 3. Place in a vacuum drying oven at 35°C and dry under reduced pressure for 24 hours to remove excess solvent to obtain a pharmaceutical composition of abiraterone acetate:Eudragit L100-55 (1:3) (hereinafter referred to as pharmaceutical composition ⑤).

[0093] The X-ray powder diffractometer was used to test the pharmaceutical composition of this comparative example. The results are as follows Figure 5 As shown, its physical state is determined to be amorphous.

[0094] Comparative Example 4

[0095] The pharmaceutical composition containing abiraterone acetate provided in this comparative example is prepared by the following steps:

[0096] 1. Add 0.2 g of abiraterone acetate, 0.2 g of HPMCAS, and 0.4 g of HPMC E5 into 15 mL of a mixed solvent of methanol / dichloromethane (1:2 volume ratio), and completely dissolve them by magnetic stirring;

[0097] 2. The obtained solution was spray dried by a B290 micro spray dryer of Buchi, Switzerland, to obtain powder; the parameter settings of the spray drying process are shown in Table 1.

[0098] 3. Place in a vacuum drying oven at 35°C and dry under reduced pressure for 24 hours to remove excess solvent to obtain a pharmaceutical composition of abiraterone acetate: HPMCAS: HPMC E5 (1:1:2) (hereinafter referred to as pharmaceutical composition ⑥).

[0099] The X-ray powder diffractometer was used to test the pharmaceutical composition of this comparative example. The results are as follows Figure 6 As shown, its physical state is determined to be amorphous.

[0100] Experimental Example 1 Modulated Differential Scanning Calorimetry (mDSC)

[0101] The thermal properties of the samples were analyzed using a differential scanning calorimeter Q2000 (TA Instruments, USA). Figures 7 to 12 Its glass transition temperature is shown in Table 3.

[0102] Table 3 Glass transition temperature of the pharmaceutical composition

[0103] Pharmaceutical composition Drug loading Excipients Glass transition temperature(℃) Pharmaceutical composition① 25％ HPMCAS:Eudragit(1:2) 104.0 Pharmaceutical composition ② 10％ HPMCAS 102.8 Pharmaceutical composition ③ 25％ HPMCAS 82.7 Pharmaceutical composition ④ 25％ PVPVA64 53.2 Pharmaceutical composition⑤ 25％ Eudragit 112.3 Pharmaceutical composition ⑥ 25％ HPMCAS:HPMCE5(1:2) 91.6

[0104] As can be seen from Table 3, the glass transition temperatures of drug composition ① (abiraterone acetate: HPMCAS:Eudragit (1:1:2)), drug composition ② (abiraterone acetate: HPMCAS (1:9)), and drug composition ⑤ are 104.0°C, 102.8°C, and 112.3°C, respectively, which meet the temperature requirements of general preparation processes, indicating that the drug compositions prepared with HPMCAS, Eudragit, and HPMCAS+Eudragit as carriers and with specific drug loading amounts have good thermal stability.

[0105] At the same drug loading, the glass transition temperature of drug composition ① is increased by 21.3°C relative to drug composition ③, an increase of about 26%, indicating that drug composition ① has higher stability.

[0106] Under the same carrier HPMCAS conditions, the glass transition temperature of the drug composition ② with a low drug loading is higher than that of the drug composition ③ with a high drug loading, indicating that when HPMCAS is selected as a carrier, a lower drug loading is required to achieve higher stability.

[0107] The drug composition ④ uses PVPVA64 as a carrier, and its glass transition temperature is only 53.2°C. Its thermal stability is poor and it is not suitable as a carrier for abiraterone acetate.

[0108] The glass transition temperature of drug composition ⑥ using HPMCAS and HPMC E5 is only increased by 8.9°C (only increased by 11%) compared with drug composition ③, which is much lower than that of drug composition ①, indicating that the thermal stability of the drug composition using HPMCAS and HPMC E5 as carriers is worse than that of the drug composition using HPMCAS and Eudragit as carriers.

[0109] Test Example 2 Study on the Amorphous Stability of a Pharmaceutical Composition Containing Abiraterone Acetate

[0110] According to the guidelines for stability testing of raw materials and preparations in the Chinese Pharmacopoeia 9001, the obtained pharmaceutical compositions ①, ②, ③, and ④ were placed in an artificial climate chamber under accelerated conditions (40°C, 75% RH), and PXRD samples were taken regularly for testing. The results are as follows: Figures 13-16shown.

[0111] As can be seen from the figure, the pharmaceutical composition ① and the pharmaceutical composition ② prepared in Examples 1 to 2 did not undergo crystal transformation after being placed under accelerated conditions (40°C, 75% RH) for 45 days ( Figures 13-14 ), has obvious amorphous stability advantage. However, the pharmaceutical composition ③ prepared in comparative example 1, when placed under accelerated conditions for 24 days, showed a weak sharp characteristic peak. In the PXRD spectrum after 45 days, a sharp characteristic peak that was basically consistent with the characteristic peak of the PXRD of the crystalline abiraterone acetate of the starting material appeared, that is, the amorphous state of the pharmaceutical composition ③ was unstable, and it turned into a crystalline state after 24 days of acceleration ( Fig.15 ); After 7 days of storage, the pharmaceutical composition ④ (abiraterone acetate: PVPVA64 (1:3)) prepared in Comparative Example 2 showed obvious sharp characteristic diffraction peaks, which were basically consistent with the characteristic peaks of PXRD of crystalline abiraterone acetate of the starting material, that is, obvious crystal transformation ( Fig.16 ).

[0112] Test Example 3 Dissolution test of the pharmaceutical composition containing abiraterone acetate of the present invention

[0113] The dissolution test of the abiraterone acetate: HPMCAS: Eudragit L100-55 (1:1:2) pharmaceutical composition prepared in Example 1 was performed using a dissolution apparatus. 180 mg of the pharmaceutical composition ① prepared in Example 1 was taken, and 45 mg of abiraterone acetate was taken as a control group. The material was added to a medium of 500 mL 0.1 N hydrochloric acid solution (pH = 1), the temperature was maintained at 37 ° C ± 0.5 ° C, the basket method, and the rotation speed was 100 rpm. The timing was started after the feeding was completed, and 2.5 mL of samples were taken at 5, 10, 15, 30, 45, and 60 minutes (while adding an equal amount of isothermal dissolution medium), and filtered with a 0.22 micron microporous membrane as the test solution.

[0114] After 1 hour of dissolution, add 500 mL of pH = 6.8 phosphate buffer solution (add appropriate amount of 10N sodium hydroxide to pH 6.8), and the rehydration process is completed within 10 minutes. Then, 2.5 mL of samples are taken at 75, 80, 85, 100, 115, and 130 minutes (add an equal amount of isothermal dissolution medium at the same time), and filtered with a 0.22 micron microporous membrane as the test solution.

[0115] Use an ultraviolet spectrophotometer to detect the absorbance of the test solution at a wavelength of 251nm, and calculate the release amount of each test solution at different times using the ultraviolet absorbance according to the external standard method. Each group is tested in parallel 3 times, and the results are averaged. Fig.17 shown.

[0116] The results showed that in a medium with a pH value of 6.8, at 75 minutes of dissolution, the cumulative dissolution of the pharmaceutical composition ① of Example 1 reached about 57%, while the abiraterone acetate showed a decreasing concentration trend, dissolving only about 26%. When the dissolution test was carried out for 100 minutes, the cumulative dissolution of the pharmaceutical composition ① was about 97%, while the solubility of abiraterone acetate dropped to 2%.

[0117] Therefore, compared with abiraterone acetate, the pharmaceutical composition ① of Example 1 of the present invention can significantly improve the solubility of abiraterone acetate in a small intestinal pH environment such as pH=6.8.

[0118] Test Example 4 Dissolution test of the pharmaceutical composition containing abiraterone acetate of the present invention at pH=6.8

[0119] The dissolution test was performed on the pharmaceutical composition ① prepared in Example 1, the pharmaceutical composition ⑤ prepared in Comparative Example 3, and the pharmaceutical composition ⑥ prepared in Comparative Example 4 using a dissolution apparatus.

[0120] Take 180 mg of the pharmaceutical composition ① prepared in Example 1, the pharmaceutical composition ⑤ prepared in Comparative Example 3, and the pharmaceutical composition ⑥ prepared in Comparative Example 4, respectively, and take 45 mg of abiraterone acetate (equivalent to the active ingredient in the pharmaceutical composition) as a control group. Add the material to 500 mL of phosphate buffer solution (pH = 6.8) medium, keep the temperature at 37 ° C ± 0.5 ° C, paddle method, and the speed is 100 rpm. Start timing after the feeding is completed, and sample 2.5 mL at 5, 10, 15, 30, 45, and 60 minutes (add an equal amount of isothermal dissolution medium at the same time), filter with a 0.22 micron microporous membrane, and use it as the test solution.

[0121] Use an ultraviolet spectrophotometer to detect the absorbance of the test solution at a wavelength of 251nm, and calculate the release amount of each test solution at different times using the ultraviolet absorbance according to the external standard method. Each group is tested in parallel 3 times, and the results are averaged. Fig.18 shown.

[0122] The results showed that in a medium with a pH value of 6.8, after 60 minutes of dissolution, the cumulative dissolution of the drug composition ① of Example 1 reached about 73%, the drug composition ⑤ only dissolved about 38%, and the drug composition ⑥ and abiraterone acetate were basically not dissolved.

[0123] Therefore, relative to abiraterone acetate, the pharmaceutical composition ① of Example 1 of the present invention can significantly improve the solubility of abiraterone acetate in a small intestinal pH environment such as pH = 6.8, and its dissolution improvement is far greater than that of the pharmaceutical composition ⑤, while the dissolution improvement of abiraterone acetate by the pharmaceutical composition ⑥ is not obvious.

[0124] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0125] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A pharmaceutical composition, characterized in that The raw materials include abiraterone acetate and a carrier, wherein the carrier is hydroxypropyl methylcellulose acetate succinate and methacrylic acid copolymer type C; the drug loading amount of the pharmaceutical composition is 5wt%-30wt%; the hydroxypropyl methylcellulose acetate succinate accounts for 5%-60% of the carrier; the methacrylic acid copolymer type C accounts for 40%-90% of the carrier; and the mass ratio of the abiraterone acetate, hydroxypropyl methylcellulose acetate succinate and methacrylic acid copolymer type C is 0.8-1.2:0.8-1.2:

2.

2. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of the abiraterone acetate, hydroxypropyl methylcellulose acetate succinate and methacrylic acid copolymer type C is 1:1:

2.

3. The method for preparing the pharmaceutical composition according to claim 1 or 2, characterized in that: The following steps are involved: The abiraterone acetate and the carrier are completely dissolved in the solvent, spray-dried, and then dried under reduced pressure to obtain the product.

4. The method for preparing the pharmaceutical composition according to claim 3, characterized in that: The solvent is one or more of ethanol, dichloromethane, methanol, isopropanol, acetone, ethyl acetate and acetonitrile.

5. The method for preparing the pharmaceutical composition according to claim 4, characterized in that: The solvent is methanol and dichloromethane in a volume ratio of 1:

2.

6. A drug for treating prostate cancer, characterized in that: The pharmaceutical composition is prepared from the pharmaceutical composition according to claim 1 or 2 and a pharmaceutically acceptable carrier or auxiliary material.

7. The drug according to claim 6, characterized in that The pharmaceutically acceptable carrier or excipient is a lubricant, a permeation aid, a filler, a disintegrant, a plasticizer, a flavoring agent, a binder, an antioxidant, a light stabilizer, a free radical scavenger, a surfactant, a pH adjuster or a combination thereof.

8. The drug according to claim 6, characterized in that The medicine is in the form of tablets, capsules or granules.

Images