WO2023000873A1 - 一种醋酸阿比特龙软胶囊及其制备方法和应用 - Google Patents

一种醋酸阿比特龙软胶囊及其制备方法和应用 Download PDF

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WO2023000873A1
WO2023000873A1 PCT/CN2022/099013 CN2022099013W WO2023000873A1 WO 2023000873 A1 WO2023000873 A1 WO 2023000873A1 CN 2022099013 W CN2022099013 W CN 2022099013W WO 2023000873 A1 WO2023000873 A1 WO 2023000873A1
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abiraterone acetate
content
mass
accounts
soft capsule
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PCT/CN2022/099013
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English (en)
French (fr)
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倪晟
王振环
夏金强
廖志雄
赵航
徐兵勇
周亮
陈鸿翔
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浙江和泽医药科技股份有限公司
浙江和泽坤元药业有限公司
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Priority to CN202280003906.1A priority Critical patent/CN116033925B/zh
Publication of WO2023000873A1 publication Critical patent/WO2023000873A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and in particular relates to an abiraterone acetate soft capsule and a preparation method and application thereof.
  • Abiraterone Acetate is a white to off-white, non-hygroscopic crystalline powder.
  • Abiraterone acetate is a prodrug of abiraterone, a selective irreversible inhibitor of 17 ⁇ -hydroxylase/C17,20-lyase (CYP17).
  • the enzyme is expressed in testis and adrenal gland tissues and catalyzes the conversion of pregnene and nandrolone and progesterone to testosterone precursors, DHEA and androstenedione, respectively, through 17 ⁇ hydroxylation and cleavage of C17,20 bonds.
  • Abiraterone can inhibit the activity of CYP17 to prevent testosterone synthesis in testes, adrenal glands and tumors.
  • Prostate cancer is an androgen-dependent disease, and testosterone suppression is a key pharmacological tool in controlling prostate cancer development.
  • the chemical structure of abiraterone acetate is shown in formula 1 below:
  • abiraterone acetate As a lipophilic compound, abiraterone acetate has an octanol-water partition coefficient of 5.12 (LogP), an aromatic nitrogen pKa of 5.19, is almost insoluble in water (0.01mg/ml), and has an osmotic pressure difference of BCS
  • LogP octanol-water partition coefficient
  • aromatic nitrogen pKa 5.19
  • BCS osmotic pressure difference
  • the original drug Zytiga Abiraterone Acetate Tablets (specification 250mg) was developed by Janssen-Cilag International N.V. in Belgium.
  • the inactive ingredients include: colloidal titanium dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline Cellulose, povidone and sodium lauryl sulfate. Approved in the United States in combination with prednisone for the treatment of metastatic castration-resistant prostate cancer (mCRPC).
  • mCRPC metastatic castration-resistant prostate cancer
  • the oral bioavailability of the original drug Zytiga is very low (less than 10%), and the daily dosage is as high as 1000mg, but only less than 10% of the drug can exert its efficacy.
  • the prescription information of the original research drug Zytiga states that it must be taken on an empty stomach, and food should not be ingested within at least 2 hours before taking the medicine and at least 1 hour after taking the medicine, indicating that food has a great influence on the absorption of abiraterone acetate.
  • the preparations are required to be taken only at a specific time period before meals.
  • the Zytiga labeling emphasizes the increased systemic exposure of abiraterone acetate when administered with food.
  • abiraterone acetate when abiraterone acetate was given together with a low-fat meal (7% fat, 300 calories), the Cmax and AUC 0- ⁇ of abiraterone increased by about 7-fold and 5-fold, respectively; Abiraterone Cmax and AUC 0- ⁇ increased approximately 17-fold and 10-fold, respectively, when administered with a meal (57% fat, 825 calories).
  • abiraterone acetate has a good effect in the oral treatment of advanced prostate cancer, its low solubility and poor osmotic pressure have brought serious problems to the development of preparations.
  • Patent CN106687112A provides an improved abiraterone acetate preparation, by controlling the particle size of the raw material abiraterone acetate, a unit dosage form of abiraterone is made, wherein the unit dosage form of 500mg dose and 1000mg dose of Zytiga in the fasting state Bioequivalence and bioavailability doubled in healthy male subjects.
  • the dose of the preparation was reduced by 500mg, only abiraterone acetate was pulverized, and the particle size was controlled in a small range to facilitate dissolution and absorption, and it failed to increase the permeability of abiraterone acetate to gastrointestinal epithelial cells.
  • the bioavailability is still very low, and after crushing, the specific surface area of abiraterone acetate is too large, which increases the risk of oxidation of abiraterone acetate.
  • Patent CN102961358B relates to a liquid capsule of abiraterone acetate, including a capsule shell and contents, characterized in that: the contents are composed of abiraterone acetate, solvent, monoglyceride and antioxidant: the solvent is selected from : Fatty acid diesters, fatty acid triglycerides, 1,2-propanediol and their mixtures.
  • the content of the liquid capsule contains propylene glycol, which can volatilize from the content during storage, resulting in a serious reduction in the content of propylene glycol in the content, resulting in the precipitation of abiraterone, which may cause major quality problems.
  • Patent document CN107278152A relates to a kind of abiraterone acetate compound, its preparation method and the pharmaceutical composition containing them, which comprises 5-40% by weight of abiraterone acetate, 5-80% by weight of polyethylene caprolactam-polyvinyl acetate Ester-polyethylene glycol graft copolymer, 0.1-50% by weight of sodium deoxycholate.
  • the compound can reduce the effect of food and give up the requirement of taking medicine on an empty stomach, and can increase the oral bioavailability by up to 5 times, but the preparation process of the compound preparation is complicated.
  • Patent document CN110538150A The invention relates to the technical field of pharmaceutical preparations, in particular to a pharmaceutical composition containing abiraterone acetate and its preparation method and application.
  • the pharmaceutical composition includes: active ingredient: abiraterone acetate; auxiliary materials: at least one oil phase, at least one emulsifier, and at least one emulsifier.
  • the pharmaceutical composition provided by the present invention spontaneously disperses in the gastrointestinal tract to form an O/W nanoemulsion under gastrointestinal peristalsis.
  • the formed nanoemulsion has a small particle size, increases the penetration of intestinal epithelial cells, and can significantly improve the bioavailability of drugs.
  • the content of the pharmaceutical composition of the invention is stable. Compared with the original drug Zytiga, the difference before and after meals is significantly reduced; the pharmaceutical composition can also be further prepared into capsules, and the capsules have stable properties.
  • the co-emulsifier ethanol and propylene glycol used in this patent can be released from the content during storage, resulting in a serious reduction in the content of ethanol or propylene glycol in the content, which may cause abiraterone to precipitate during long-term storage.
  • abiraterone acetate has the characteristics of low solubility and poor osmotic pressure.
  • the problem of poor oral bioavailability cannot be significantly solved.
  • the preparation of abiraterone acetate into liquid capsules can obviously improve the oral bioavailability of abiraterone acetate and eliminate the influence of food in theory, but the content of the liquid capsules consists of propylene glycol or ethanol, which is volatile and may cause Abiraterone can precipitate during long-term storage.
  • the object of the present invention is to provide a soft capsule preparation that can significantly improve the oral absorption bioavailability of abiraterone acetate, reduce inter-individual variability, and eliminate the influence of food.
  • An abiraterone acetate soft capsule comprises content and a capsule shell.
  • the content contains active ingredients abiraterone acetate, caprylic capric acid mono-diglyceride, Tween 80, Span 80 and an antioxidant.
  • the antioxidant is butyl hydroxyanisole.
  • the preferred total volume of the content, the concentration of the abiraterone acetate is between 60-100mg/ml;
  • the mass of the abiraterone acetate accounts for 6-10% of the total mass of the content.
  • the mass of the caprylic acid mono-diglyceride accounts for 60-77% of the total mass of the content.
  • the content includes: the mass of the abiraterone acetate accounts for 6-10% of the total mass of the content, and the mass of the caprylic mono-diglyceride accounts for the total mass of the content. 60-77% of the mass.
  • the mass of the Tween 80 accounts for 6-15% of the total mass of the content.
  • the mass of the spanner 80 accounts for 7-19% of the total mass of the content.
  • the mass of the abiraterone acetate accounts for 6-10% of the total mass of the content
  • the mass of the caprylic mono-diglyceride accounts for 60-77% of the total mass of the content
  • the mass of the Tween 80 accounts for 6-15% of the total mass of the contents
  • the mass of the Span 80 accounts for 7-19% of the total mass of the contents.
  • the mass of butylated hydroxyanisole accounts for 0.01%-0.1% of the total mass of the content.
  • the capsule shell is made of soft capsule material, and its composition includes: gelatin, water, glycerin, sorbitol and sorbitan solution MDF85, and the ratio of each component is 1:0.74:0.35:0.35.
  • the content includes: the mass of the abiraterone acetate accounts for 6-10% of the total mass of the content, and the mass of the caprylic mono-diglyceride accounts for the total mass of the content. 60-77% of the mass, the mass of the Tween 80 accounts for 6-15% of the total mass of the contents, and the mass of the Span 80 accounts for 7-19% of the total mass of the contents, so The mass of butyl hydroxyanisole accounts for 0.01%-0.1% of the total mass of the content.
  • a kind of abiraterone acetate soft capsule comprises content and capsule shell, and in described content: the mass of described abiraterone acetate accounts for 6-10% of the total mass of described content, and described
  • the mass of caprylic capric acid mono-diglyceride accounts for 60-77% of the total mass of the content
  • the mass of the Tween 80 accounts for 6-15% of the total mass of the content
  • the mass of the Span 80 The mass accounts for 7-19% of the total mass of the content
  • the mass of the butylated hydroxyanisole accounts for 0.01%-0.1% of the total mass of the content
  • the capsule shell is made of soft capsule material, which
  • the composition includes: gelatin, water, glycerin, and sorbitol sorbitan solution (MDF85), and the ratio of each component is 1:0.74:0.35:0.35.
  • the present invention also discloses a preparation method for the above-mentioned abiraterone acetate soft capsule, the method comprising: 1) gelatinization: adding glycerin, sorbitol and water in the prescription amount into the rubberization barrel, and opening Stir until the temperature in the barrel rises to 75-80°C. After the materials are mixed evenly, add the prescribed amount of gelatin, and vacuumize to -0.05 ⁇ -0.06MPa at the same time.
  • Pill making adopt soft capsule machine to make pills; 4) dry.
  • the abiraterone soft capsule calculated as abiraterone acetate, has a single oral dose of 36-60 mg.
  • the invention also discloses the application of abiraterone acetate soft capsules in the preparation of pharmaceutical preparations
  • the application in the preparation of pharmaceutical preparations for the treatment of prostate cancer is preferably, the application in the preparation of pharmaceutical preparations for the treatment of prostate cancer
  • the prostate cancer is one or both of metastatic castration-resistant prostate cancer and metastatic high-risk castration-sensitive prostate cancer.
  • the adjuvant of the content provided by the present invention can be used as a carrier of hydrophobic, poorly soluble or easily hydrolyzed drugs. After oral administration, it will spontaneously disperse and form O/W milk droplets under the peristalsis of the gastrointestinal tract, which increases the penetration of intestinal epithelial cells, can increase the dissolution of drugs, promote absorption, and can significantly improve the bioavailability of drugs. It is directly loaded into soft capsules, which can meet the requirements of long-term stable storage.
  • the soft capsule containing abiraterone acetate of the present invention has at least one of the following properties:
  • Abiraterone acetate is made into soft capsules to increase the dissolution of the drug, and when mixed with water, milk droplets with high clarity and stable properties can be formed spontaneously;
  • patent CN110538150A contains propylene glycol and ethanol. As the storage time prolongs, propylene glycol and ethanol may penetrate the capsule shell and volatilize, reducing the solubility of the drug and causing abiraterone acetate to precipitate. This patent will successfully avoids this problem and is easier to store;
  • Each component in the prescription is a conventional excipient, which is easy to obtain, and the preparation process is simple, the product quality is stable, and it is easy for commercial production.
  • Abiraterone soft capsule preparation is composed of the content and soft capsule shell of Abiraterone soft capsule. It is necessary to study the content prescription at the same time.
  • abiraterone acetate has higher solubility in ethanol, castor oil, caprylic acid mono-diglyceride, but when ethanol is used as solvent, a large amount of crystals are separated out after standing at room temperature for 24 hours; Only 3% (25°C) is dissolved in the ester, and it is almost insoluble in hydrogenated castor oil and purified water. 2 Generally speaking, the self-microemulsification drug delivery system is finally made into soft capsules or hard capsules.
  • ethanol and other volatile components may penetrate the capsule shell, reduce the solubility of the drug, and lead to the precipitation of lipophilic drugs, that is, If ethanol is used as the solvent for the self-developed preparation, because ethanol is easy to ooze out and volatilize from the capsule shell, the proportion of ethanol in the contents will be seriously reduced during the preparation and storage process, which may cause the crystallization of the drug;
  • the dissolution of castor oil and caprylic mono-diglyceride is known. It is found that abiraterone acetate is more soluble in caprylic capric mono-diglyceride, and caprylic capric mono-diglyceride itself has a certain emulsifying effect, which is beneficial to self-developed preparations. Spontaneously disperse and form O/W emulsion droplets under gastrointestinal peristalsis. Therefore, this preparation selects caprylic capric acid mono-diglyceride as the solvent of this self-developed preparation.
  • the surfactants are mostly hydrophilic-lipophilic balance (HLB) values (generally 9-20)
  • HLB hydrophilic-lipophilic balance
  • the choice of surfactant should consider the matching with the oil phase.
  • composition of these two surfactants is now used to prepare soft capsules, and its influence on product quality is investigated.
  • the surfactant composition of the self-developed preparation is Span 80 and Tween 80, and on this basis, the dosage of each surfactant is further optimized, see Examples 1-4 for details.
  • Fig. 1 is the drug-time curve of abiraterone in blood plasma after dog oral self-development soft capsule (T) on an empty stomach in embodiment 1;
  • Fig. 2 is the drug-time curve of abiraterone in the blood plasma after the oral original drug Zytiga tablet soft capsule (R1st) of the dog on an empty stomach in embodiment 1;
  • Fig. 3 is the drug-time curve of abiraterone in blood plasma after oral administration of original research drug Zytiga tablet soft capsule (R2nd) in dog in embodiment 1;
  • Fig. 4 is the average drug-time curve (Mean+SD) of abiraterone in blood plasma after 6 dogs were taken orally with different preparations on an empty stomach in embodiment 1;
  • Fig. 5 is the average drug-time curve (Mean+SD) of abiraterone in blood plasma of 8 dogs in Example 1 after oral administration of the self-developed formulation on an empty stomach or after meals.
  • the present embodiment provides a kind of abiraterone acetate soft capsule (batch: 1000), and its content comprises following component:
  • the above pharmaceutical composition is filled in the soft capsule shell as the content, and the components of the soft capsule shell include: gelatin, water, glycerin, sorbitol and sorbitan solution MDF85, and the ratio of each component is 1:0.74:0.35:0.35.
  • the preparation method is provided as follows:
  • Chemical glue Add the prescribed amount of glycerin, sorbitol and water into the chemical glue barrel, start stirring, seal and heat to 75°C, after the materials are evenly mixed, add the prescribed amount of gelatin, and simultaneously vacuumize to -0.05 ⁇ -0.06MPa, keep stirring under negative pressure for 25-35min, open the capping respirator until the vacuum disappears, keep warm and degas at 55-60°C, and wait for use; 2) Preparation of contents: Dissolve abiraterone acetate in In the mixed solution of caprylic capric acid mono-diglyceride, Tween 80, Span 80 and antioxidant, stir evenly, and set aside; 3) pill making: adopt soft capsule machine to make pill; 4) dry.
  • the present embodiment provides a kind of abiraterone acetate soft capsule (batch: 1000), and its content comprises following component:
  • the above pharmaceutical composition is filled in the soft capsule shell as the content, and the components of the soft capsule shell include: gelatin, water, glycerin, sorbitol and sorbitan solution MDF85, and the ratio of each component is 1:0.74:0.35:0.35.
  • the preparation method is provided as follows:
  • Chemical glue Add the prescribed amount of glycerin, sorbitol and water into the chemical glue barrel, start stirring, seal and heat to 75°C, after the materials are evenly mixed, add the prescribed amount of gelatin, and simultaneously vacuumize to -0.05 ⁇ -0.06MPa, keep stirring under negative pressure for 25-35min, open the capping respirator until the vacuum disappears, keep warm and degas at 55-60°C, and wait for use; 2) Preparation of contents: Dissolve abiraterone acetate in In the mixed solution of caprylic capric acid mono-diglyceride, Tween 80, Span 80 and antioxidant, stir evenly, and set aside; 3) pill making: adopt soft capsule machine to make pill; 4) dry.
  • the present embodiment provides a kind of abiraterone acetate soft capsule (batch: 1000), and its content comprises following component:
  • the above pharmaceutical composition is filled in the soft capsule shell as the content, and the components of the soft capsule shell include: gelatin, water, glycerin, sorbitol and sorbitan solution MDF85, and the ratio of each component is 1:0.74:0.35:0.35.
  • the preparation method is provided as follows:
  • Chemical glue Add the prescribed amount of glycerin, sorbitol and water into the chemical glue barrel, start stirring, seal and heat to 75°C, after the materials are evenly mixed, add the prescribed amount of gelatin, and simultaneously vacuumize to -0.05 ⁇ -0.06MPa, keep stirring under negative pressure for 25-35min, open the capping respirator until the vacuum disappears, keep warm and degas at 55-60°C, and wait for use; 2) Preparation of contents: Dissolve abiraterone acetate in In the mixed solution of caprylic capric acid mono-diglyceride, Tween 80, Span 80 and antioxidant, stir evenly, and set aside; 3) pill making: adopt soft capsule machine to make pill; 4) dry.
  • the present embodiment provides a kind of abiraterone acetate soft capsule (batch: 1000), and its content comprises following component:
  • the above pharmaceutical composition is filled in the soft capsule shell as the content, and the components of the soft capsule shell include: gelatin, water, glycerin, sorbitol and sorbitan solution MDF85, and the ratio of each component is 1:0.74:0.35:0.35.
  • the preparation method is provided as follows:
  • Chemical glue Add the prescribed amount of glycerin, sorbitol and water into the chemical glue barrel, start stirring, seal and heat to 75°C, after the materials are evenly mixed, add the prescribed amount of gelatin, and simultaneously vacuumize to -0.05 ⁇ -0.06MPa, keep stirring under negative pressure for 25-35min, open the capping respirator until the vacuum disappears, keep warm and degas at 55-60°C, and wait for use; 2) Preparation of contents: Dissolve abiraterone acetate in In the mixed solution of caprylic capric acid mono-diglyceride, Tween 80, Span 80 and antioxidant, stir evenly, and set aside; 3) pill making: adopt soft capsule machine to make pill; 4) dry.
  • This Comparative Example 1 further provides an abiraterone acetate capsule, which uses the above-mentioned pharmaceutical composition as the content, and the content is filled in the capsule shell.
  • the preparation method is provided as follows:
  • This test example provides the dissolution test of the abiraterone acetate soft capsules and the original drug Zytiga tablets provided in Examples 1-4 and Comparative Example 1.
  • Test method According to (the second method of "Chinese Pharmacopoeia” 2015 edition Sibu general rule 0931), the dissolution rate of abiraterone acetate soft capsules was detected. Under the conditions of 37 ° C, 900 ml pH4. Abiraterone acetate soft capsules (prepared in Examples 1 and 2) and original drug Zytiga tablets were tested for dissolution.
  • pH4.5-0.25% SDS medium weigh 6.78g of anhydrous sodium dihydrogen phosphate, add 1000ml of water to dissolve, adjust the pH value to 4.5 with 5mol/L sodium hydroxide solution, and obtain the buffer solution, weigh 2.5g Dialkyl sodium sulfate is added to the buffer, dissolved, and obtained.
  • Abiraterone acetate soft capsule (embodiment 1, 2, 3, 4) of the present invention dissolves completely completely in 15 minutes in the medium (note: original research drug Zytiga dissolution standard: 45min Must not be less than 85.0% of marked quantity), and listing abiraterone acetate tablet Zytiga dissolution rate still can not reach 85.0% when 30min; 2. abiraterone acetate soft capsule of the present invention (embodiment 1,2,3,4)
  • the dissolution rate and comparative example 1 have no significant difference. Therefore, the abiraterone acetate capsule of the present invention can effectively improve the dissolution rate of abiraterone, and significantly improve the oral bioavailability of abiraterone acetate.
  • This test example provides the stability (long-term test and accelerated test) tests of the abiraterone acetate soft capsules provided in Examples 1-4, and the test results are shown in Table 2-1 and Table 2-2.
  • ND means not detected
  • NA means not detected
  • abiraterone acetate soft capsule (embodiment 1,2,3,4) of the present invention in long-term 9 months, the content character does not have significant change, and comparative example 1 is in long-term 6 There is no significant difference within one month, but a small amount of medicine is separated out during the long-term September.
  • This test example provides the self-emulsifying ability and stability test of the abiraterone acetate soft capsules provided in Examples 1-4.
  • This test example provides the pharmacokinetic test of Example 1 and the original drug Zytiga of abiraterone acetate.
  • Test objects 6 healthy Beagle dogs were randomly divided into 3 groups, 2 dogs in each group, and a 3-cycle crossover test was carried out. Drink water freely during the test period, fast for more than 12 hours before the administration of each cycle, and the preparations are all taken with 20ml of water during administration, and fed after 6 hours of administration.
  • the cycle cleaning period is 7 days.
  • T Abiraterone Acetate Soft Capsules, 1 capsule/dog, that is, 40mg/dog;
  • R Abiraterone acetate tablets, 2 capsules/dog, that is, 500mg/dog.
  • Tmax is the peak time
  • Cmax is the maximum blood drug concentration (peak concentration)
  • AUClast is the AUC (drug-time curve area) of the duration from the beginning of administration to the last point
  • This test example provides a test of the influence of food on the absorption of Example 1.
  • Test objects 8 healthy Beagle dogs were randomly divided into 2 groups, 4 dogs in each group, and a 3-cycle crossover test was carried out. Water was freely available during the experiment. For fasting administration, fast for more than 12 hours before administration. During administration, the preparations are all taken with 20ml of water, and fed 6 hours after administration; for postprandial administration, quantitative feeding is given by gastric tube 30 minutes before administration. The cycle cleaning period is 7 days.
  • T Abiraterone Acetate Soft Capsules, 1 capsule/dog, that is, 40mg/dog.
  • Table 5-2 The pharmacokinetic parameters of abiraterone in plasma after oral administration of abiraterone acetate soft capsules in dogs on an empty stomach

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Abstract

一种醋酸阿比特龙软胶囊及其制备方法，胶囊是由内容物和胶囊壳组成，内容物包含醋酸阿比特龙、辛酸癸酸单双甘油酯、吐温80、司盘80和丁基羟基茴香醚；胶囊壳由软胶囊材质组成，其组成包括：明胶、水、甘油、山梨醇山梨坦溶液，各组分比例为1:0.74:0.35:0.35。醋酸阿比特龙软胶囊空腹口服后，与原研药Zytiga相比，口服生物利用度提高至12.5倍，个体间变异性低，且消除了原研药Zytiga餐后给药出现的阿比特龙暴露量明显升高的现象。

Description

一种醋酸阿比特龙软胶囊及其制备方法和应用 技术领域
本发明属于药物制剂领域，具体涉及一种醋酸阿比特龙软胶囊及其制备方法和应用。
背景技术
醋酸阿比特龙(Abiraterone Acetate)为一种白色至灰白色、不吸湿的结晶性粉末。醋酸阿比特龙是阿比特龙前体药物，一种17α-羟化酶/C17,20-裂解酶(CYP17)的选择性不可逆抑制剂。该酶可在睾丸和肾上腺组织中表达并通过17α羟化作用和C17,20键的裂解分别催化孕烯诺龙和孕酮向睾酮前体、DHEA和雄烯二酮的转化。阿比特龙可以抑制CYP17的活性从而阻止睾丸、肾上腺和肿瘤中的睾酮合成。前列腺癌是一种雄激素依赖疾病，在控制前列腺癌的发展中睾酮的抑制是一个关键的药理工具。醋酸阿比特龙的化学结构如下式1所示：
Figure PCTCN2022099013-appb-000001
醋酸阿比特龙作为一种亲脂性化合物，其辛醇-水分配系数为5.12(LogP)，芳族氮的pKa为5.19，几乎不溶于水(0.01mg/ml)，且渗透压差，为BCS四类药物，口服吸收时的生物利用率极低。
原研药Zytiga醋酸阿比特龙片剂(规格250mg)由比利时Janssen-Cilag International N.V.开发，非活性成分包括：胶体二氧化钛、交联羧甲基纤维素钠、一水合乳糖、硬脂酸镁、微晶纤维素、聚维酮和十二烷基硫酸钠。在美国被批准与与泼尼松合用，治疗转移性去势抵抗性前列腺癌(mCRPC)。原研药Zytiga口服生物利用度非常低(小于10％)，每天给药剂量高达1000mg，但仅有小于10％的药物能够发挥药效。
原研药Zytiga的处方信息说明，必须在空腹时服用，并且在服药之前至少2小时内和服药后至少1小时内不应摄入食物，说明食物对醋酸阿比特龙吸收有很大影响，市售制剂要求仅能在餐前特定时间段服用。Zytiga说明书强调醋酸阿比特龙与食物一起给予时，阿比特龙的全身性暴露量增加。具体地，在醋酸阿比特龙与低脂肪膳食(7％脂肪、300卡路里)一起给予时，阿比特龙Cmax和AUC 0-∞分别增加约7倍和5倍；在醋酸阿比特龙与高脂肪膳食(57％脂肪、825卡路里)一起给予时，阿比特龙Cmax和AUC 0-∞分别增加约17倍和10倍。虽然 醋酸阿比特龙口服治疗晚期前列腺癌效果良好，但其溶解性低、渗透压差的特性给制剂开发带来了严重困扰。
专利CN106687112A提供了一种改良型醋酸阿比特龙制剂，通过控制原料药醋酸阿比特龙的粒径，使得一种阿比特龙的单位剂型，其中500mg剂量的单位剂型与1000mg剂量Zytiga在空腹状态的健康男性受试者中生物等效、生物利用度提高1倍。虽然该制剂剂量缩减500mg，但仅将醋酸阿比特龙进行粉碎，控制粒径在较小范围，以利于溶出和吸收，并未能增加醋酸阿比特龙对胃肠道上皮细胞的渗透性，口服生物利用度仍然很低，且粉碎后导致醋酸阿比特龙比表面积过大，增大了醋酸阿比特龙氧化的风险。
专利CN102961358B涉及一种醋酸阿比特龙液体胶囊，包括胶囊壳和内容物，其特征在于：所述内容物由醋酸阿比特龙、溶剂、单脂肪酸甘油酯和抗氧剂组成：所述溶剂选自：甘油脂肪酸双酯、甘油脂肪酸三酯、1，2-丙二醇和它们的混合物。但该液体胶囊内容物中含有丙二醇在储存过程中可以从内容物中挥发，致使内容物中丙二醇含量会严重降低，导致阿比特龙析出，可能产生重大的质量问题。
专利文献CN107278152A涉及一种醋酸阿比特龙复合物、其制备方法及包含它们的药物组合物，其包括5-40重量％的醋酸阿比特龙、5-80重量％的聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物、0.1-50重量％的脱氧胆酸钠。该复合物可降低食物作用放弃空腹服药要求，最高可使口服生物利用度提高5倍，但其复合物制剂制备工艺复杂。
专利文献CN110538150A本发明涉及药物制剂技术领域，尤其涉及一种含有醋酸阿比特龙的药物组合物及其制备方法和应用。所述药物组合物包括：活性成分：醋酸阿比特龙；辅料：至少一种油相，至少一种乳化剂，和至少一种乳化剂。本发明所提供的药物组合物口服后遇胃肠道在胃肠蠕动下自发分散形成O/W型纳米乳。所形成的纳米乳粒径小，增加了肠道上皮细胞的穿透性，可显著提高药物生物利用度。与微乳相比，自乳化溶液稳定性更高，可以满足长期保存的要求。本发明的药物组合物含量稳定。与原研药Zytiga相比，餐前餐后差异显著降低；还可以进一步将所述药物组合物制备成胶囊剂，所述胶囊剂性质稳定。但该专利中所用到助乳化剂乙醇、丙二醇等在储存过程中可以从内容物中发挥，致使内容物中乙醇或丙二醇含量会严重降低，可能会造成在长期储存过程中阿比特龙会析出。
综上所述可见，醋酸阿比特龙存在溶解性低、渗透压差的特性，通过将醋酸阿比特龙进行粉碎，控制粒径在较小范围，未能显著地解决其口服生物利用度差的问题，而将醋酸阿比特龙制备成液体胶囊，从理论上可以明显提高醋酸阿比特龙的口服生物利用度，消除食物影响，但其液体胶囊中内容物组成丙二醇或乙醇易挥发，可能会造成在长期储存过程中阿比特 龙会析出。
发明内容
针对现有技术存在上述问题，本发明的目的是提供一种可显著提高醋酸阿比特龙口服吸收生物利用度、降低个体间变异性、消除了食物影响的软胶囊制剂。
本发明提供的技术方案：
一种醋酸阿比特龙软胶囊，包括内容物和胶囊壳，所述内容物包含活性成分醋酸阿比特龙、辛酸癸酸单双甘油酯、吐温80、司盘80和抗氧剂。
所述抗氧剂为丁基羟基茴香醚。
优选的所述内容物的总体积，所述醋酸阿比特龙的浓度在60-100mg/ml之间；
和/或
所述醋酸阿比特龙的质量占所述内容物的总质量的6-10％。
优选的，所述辛酸癸酸单双甘油酯的质量占所述内容物的总质量的60-77％。
更优的，所述内容物包括：所述醋酸阿比特龙的质量占所述内容物的总质量的6-10％，所述辛酸癸酸单双甘油酯的质量占所述内容物的总质量的60-77％。
优选的，所述吐温80的质量占所述内容物的总质量的6-15％。
优选的，所述司盘80的质量占所述内容物的总质量的7-19％。
更优的，所述醋酸阿比特龙的质量占所述内容物的总质量的6-10％，所述辛酸癸酸单双甘油酯的质量占所述内容物的总质量的60-77％，所述吐温80的质量占所述内容物的总质量的6-15％，所述司盘80的质量占所述内容物的总质量的7-19％。
优选的，所述丁基羟基茴香醚的质量占所述内容物的总质量的0.01％-0.1％。
优选的，所述胶囊壳由软胶囊材质组成，其组成包括：明胶、水、甘油、山梨醇山梨坦溶液MDF85，各组分比例为1:0.74:0.35:0.35。
更优的，所述内容物包括：所述醋酸阿比特龙的质量占所述内容物的总质量的6-10％，所述辛酸癸酸单双甘油酯的质量占所述内容物的总质量的60-77％，所述吐温80的质量占所述内容物的总质量的6-15％，所述司盘80的质量占所述内容物的总质量的7-19％，所述丁基羟基茴香醚的质量占所述内容物的总质量的0.01％-0.1％。
更优的，一种醋酸阿比特龙软胶囊，包括内容物和胶囊壳，所述内容物中：所述醋酸阿比特龙的质量占所述内容物的总质量的6-10％，所述辛酸癸酸单双甘油酯的质量占所述内容物的总质量的60-77％，所述吐温80的质量占所述内容物的总质量的6-15％，所述司盘80的质量占所述内容物的总质量的7-19％，所述丁基羟基茴香醚的质量占所述内容物的总质量的 0.01％-0.1％；所述胶囊壳由软胶囊材质组成，其组成包括：明胶、水、甘油、山梨醇山梨坦溶液(MDF85)，各组分比例为1:0.74:0.35:0.35。
本发明还公开了一种制备上述所述的醋酸阿比特龙软胶囊的制备方法，该方法包括：1)化胶：将处方量的甘油、山梨醇山梨坦和水加入化胶桶中，开启搅拌，待桶内温度升至75-80℃，物料混合均匀后，加入处方量明胶后，同时抽真空至-0.05～-0.06MPa，保持负压搅拌25-35min后，打开灌顶呼吸器至真空消失，在55-60℃保温脱气，待用；2)内容物制备：醋酸阿比特龙溶解于加热至50℃的辛酸癸酸单双甘油酯、吐温80、司盘80和抗氧剂的混合溶液中，搅拌均匀，待用；3)制丸：采用软胶囊机进行制丸；4)干燥。
其中，如上述所述阿比特龙软胶囊，以醋酸阿比特龙计，单次口服剂量为36-60mg。
本发明还公开了一种醋酸阿比特龙软胶囊在制备药物制剂中应用；
优选地，在制备治疗前列腺癌的药物制剂中的应用；
更优选，所述前列腺癌自转移去势抵抗性前列腺癌和转移性高风险去势敏感型前列腺癌中的一种或两种。
本发明所提供的内容物的辅料可作为疏水性、难溶解或易水解药物的载体。口服后遇胃肠道蠕动下自发分散形成O/W型乳滴，其增加了肠道上皮细胞的穿透性，可增加药物溶解，促进吸收，可显著提高药物生物利用度，并将内容物直接装入软胶囊中，可以满足长期稳定保存的要求。
本发明所述的含醋酸阿比特龙的软胶囊，至少具有如下性质中的一种：
1)将醋酸阿比特龙制成软胶囊，增加药物溶解，与水混合可迅速地自发形成澄明度高、性质稳定的乳滴；
2)在室温储存，质量稳定可控，且在加速6月内，质量优于专利CN110538150A实施例1；
3)专利CN110538150A的内容物处方中含有丙二醇和乙醇，随着储存时间的延长，丙二醇和乙醇中可能会穿透囊壳而挥发掉，降低药物的溶解度，导致醋酸阿比特龙沉淀，本专利将成功避免此问题，更易于储存；
4)与原研药Zytiga相比，餐前餐后差异显著降低，降低了个体间变异性；
5)与原研药Zytiga相比，醋酸阿比特龙软胶囊空腹口服后，在消化道上无需经过原研药Zytiga的溶出步骤，口服生物利用度提高至12.5倍；
6)处方中各成分均为常规辅料，易获得，且制备工艺简单，产品质量稳定，易于商业化生产。
溶剂的确定
阿比特龙软胶囊制剂是由阿比特龙软胶囊的内容物和软胶囊壳组成，需要同时研究内容处方，首先确定自研制剂的溶剂。本次试验研究阿比特龙软胶囊的内容物中原料药在在各种溶剂中溶解情况。本次试验分别取纯化水、乙醇、castor oil(蓖麻油)、capmul MCM(辛酸癸酸单双甘油酯)、氢化蓖麻油、中链甘油三酯各10g，研究醋酸阿比特龙(API)在这些溶剂中溶解情况，详见表1。
表1.醋酸阿比特龙的溶解情况
Figure PCTCN2022099013-appb-000002
由表1可知，①醋酸阿比特龙在乙醇、蓖麻油、辛酸癸酸单双甘油酯中溶解度较高，但乙醇作为溶剂时，在室温放置24小时后有大量晶体析出；在中链甘油三酯中仅溶解3％(25℃)，在氢化蓖麻油和纯化水中几乎不溶。②一般来说，自微乳化释药系统最终制成软胶囊或硬胶囊，如果含有乙醇及其它挥发性成分，这些物质可能会穿透囊壳，降低药物的溶解度，导致亲脂性药物沉淀，即如自研制剂选用乙醇作为溶剂，因乙醇易从胶囊壳渗出并挥发，在制备及储存过程中，内容物中乙醇的比例会严重降低，可能造成药物结晶析出；③对比醋酸阿比特龙在蓖麻油和辛酸癸酸单双甘油酯溶解情况可知，发现醋酸阿比特龙在辛酸癸酸单双甘油酯中更易溶解，且辛酸癸酸单双甘油酯本身具有一定乳化作用，有利于自研制剂在胃肠蠕动下自发分散形成O/W型乳滴。因此，该制剂选用辛酸癸酸单双甘油酯作为本自研制剂的溶剂。
表面活性剂的确定
为了使自研制剂口服后遇胃肠液在胃肠蠕动下自发分散形成O/W型乳滴，其表面活性剂多为亲水亲油平衡(HLB)值较高(一般为9～20)的非离子型表面活性剂，毒性低，在溶液中比较稳定，不受强电介质、无机盐类和酸、碱的影响，与其它类型表面活性剂的相容性 好，溶血作用小，能与大多数药物配伍，能引起胃肠道壁渗透性的可逆性转变。同时，表面活性剂的选择要考虑与油相的匹配。本次试验选择聚氧乙烯蓖麻油(EL-40)、司盘80、吐温80和聚乙二醇-15羟基硬脂酸酯(Solutol)等表面活性剂，并将这些表面活性剂中两种或三种进行有机组合，意外发现，当聚氧乙烯蓖麻油：吐温80：司盘80＝1:1:0.25和吐温80：司盘80＝1:1.25时，乳化效果最好，轻微震荡形成带蓝色乳光的乳滴，并且能稳定存在。详见表2。
表2.表面活性剂的选择
Figure PCTCN2022099013-appb-000003
现采用这2种表面活性剂的组成，来制备软胶囊，考察其对产品质量的影响。
表3.表面活性剂对产品质量的影响(40℃±2℃/75％RH±5％RH)
Figure PCTCN2022099013-appb-000004
Figure PCTCN2022099013-appb-000005
由表3可知，不同表面活性剂组成，对产品质量不同，当吐温80：司盘80＝1:1.25，其产品质量符合要求，且在加速3月时，其总杂明显低于处方2。
综上所述，自研制剂的表面活性剂组成为司盘80和吐温80，并在此基础上进一步优化各表面活性剂的用量，具体详见实施例1-4。
附图说明
图1是实施例1中犬空腹口服自研制剂软胶囊(T)后血浆中阿比特龙的药时曲线；
图2是实施例1中犬空腹口服原研药Zytiga片剂软胶囊(R1st)后血浆中阿比特龙的药时曲线；
图3是实施例1中犬空腹口服原研药Zytiga片剂软胶囊(R2nd)后血浆中阿比特龙的药时曲线；
图4是实施例1中6只犬空腹口服不同制剂后血浆中阿比特龙的平均药时曲线(Mean+SD)；
图5是实施例1中8只犬空腹或餐后口服自研制剂后血浆中阿比特龙的平均药时曲线(Mean+SD)。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显示所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
本实施例提供一种醋酸阿比特龙软胶囊(批量：1000颗)，其内容物包括如下组分：
Figure PCTCN2022099013-appb-000006
Figure PCTCN2022099013-appb-000007
以上药物组合物作为内容物填充于软胶囊壳中，软胶囊壳的组分包括：明胶、水、甘油、山梨醇山梨坦溶液MDF85，各组分比例为1:0.74:0.35:0.35。
提供制备方法如下：
1)化胶：将处方量的甘油、山梨醇山梨坦和水加入化胶桶中，开启搅拌，密封加热至75℃，物料混合均匀后，加入处方量明胶后，同时抽真空至-0.05～-0.06MPa，保持负压搅拌25-35min后，打开灌顶呼吸器至真空消失，在55-60℃保温脱气，待用；2)内容物制备：醋酸阿比特龙溶解于加热至50℃的辛酸癸酸单双甘油酯、吐温80、司盘80和抗氧剂的混合溶液中，搅拌均匀，待用；3)制丸：采用软胶囊机进行制丸；4)干燥。
实施例2
本实施例提供一种醋酸阿比特龙软胶囊(批量：1000颗)，其内容物包括如下组分：
Figure PCTCN2022099013-appb-000008
以上药物组合物作为内容物填充于软胶囊壳中，软胶囊壳的组分包括：明胶、水、甘油、山梨醇山梨坦溶液MDF85，各组分比例为1:0.74:0.35:0.35。
提供制备方法如下：
1)化胶：将处方量的甘油、山梨醇山梨坦和水加入化胶桶中，开启搅拌，密封加热至75℃，物料混合均匀后，加入处方量明胶后，同时抽真空至-0.05～-0.06MPa，保持负压搅拌25-35min后，打开灌顶呼吸器至真空消失，在55-60℃保温脱气，待用；2)内容物制备：醋酸阿比特龙溶解于加热至50℃的辛酸癸酸单双甘油酯、吐温80、司盘80和抗氧剂的混合溶液中，搅拌均匀，待用；3)制丸：采用软胶囊机进行制丸；4)干燥。
实施例3
本实施例提供一种醋酸阿比特龙软胶囊(批量：1000颗)，其内容物包括如下组分：
Figure PCTCN2022099013-appb-000009
Figure PCTCN2022099013-appb-000010
以上药物组合物作为内容物填充于软胶囊壳中，软胶囊壳的组分包括：明胶、水、甘油、山梨醇山梨坦溶液MDF85，各组分比例为1:0.74:0.35:0.35。
提供制备方法如下：
1)化胶：将处方量的甘油、山梨醇山梨坦和水加入化胶桶中，开启搅拌，密封加热至75℃，物料混合均匀后，加入处方量明胶后，同时抽真空至-0.05～-0.06MPa，保持负压搅拌25-35min后，打开灌顶呼吸器至真空消失，在55-60℃保温脱气，待用；2)内容物制备：醋酸阿比特龙溶解于加热至50℃的辛酸癸酸单双甘油酯、吐温80、司盘80和抗氧剂的混合溶液中，搅拌均匀，待用；3)制丸：采用软胶囊机进行制丸；4)干燥。
实施例4
本实施例提供一种醋酸阿比特龙软胶囊(批量：1000颗)，其内容物包括如下组分：
Figure PCTCN2022099013-appb-000011
以上药物组合物作为内容物填充于软胶囊壳中，软胶囊壳的组分包括：明胶、水、甘油、山梨醇山梨坦溶液MDF85，各组分比例为1:0.74:0.35:0.35。
提供制备方法如下：
1)化胶：将处方量的甘油、山梨醇山梨坦和水加入化胶桶中，开启搅拌，密封加热至75℃，物料混合均匀后，加入处方量明胶后，同时抽真空至-0.05～-0.06MPa，保持负压搅拌25-35min后，打开灌顶呼吸器至真空消失，在55-60℃保温脱气，待用；2)内容物制备：醋酸阿比特龙溶解于加热至50℃的辛酸癸酸单双甘油酯、吐温80、司盘80和抗氧剂的混合溶液中，搅拌均匀，待用；3)制丸：采用软胶囊机进行制丸；4)干燥。
对比实施例1
参照专利CN110538150A实施例1，提供对比实施例1的处方工艺，其内容物包括如下 组分：
Figure PCTCN2022099013-appb-000012
本对比实施例1进一步提供一种醋酸阿比特龙胶囊剂，以上述药物组合物作为内容物，所述内容物填充于胶囊壳中。
提供制备方法如下：
取氢化蓖麻油/蓖麻油、单油酸甘油酯、聚氧乙烯蓖麻油EL35，再加入醋酸阿比特龙，再避光条件下超声10min，采用机械搅拌(300rpm)，搅拌20min，使其充分溶解后加入丙二醇和乙醇待其形成透明均一的自乳化溶液，填充于软胶囊或氮气保护条件下密封于硬胶囊中保存。
实施例5
本试验例提供实施例1-4和对比实施例1所提供的醋酸阿比特龙软胶囊和原研药Zytiga片剂的溶出度测试。
测试方法：按照(《中国药典》2015年版四部通则0931第二法)，检测醋酸阿比特龙软胶囊溶出度，在37℃、900ml pH4.5-0.25％SDS介质50转/min条件下，分别对醋酸阿比特龙软胶囊(实施例1、2制备)和原研药Zytiga片剂进行溶出度检测。
其中，pH4.5-0.25％SDS介质：称取无水磷酸二氢钠6.78g，加水1000ml溶解，用5mol/L氢氧化钠溶液调节pH值至4.5，即得缓冲液，称取2.5g十二烷基硫酸钠加入缓冲液中，溶解，即得。
具体方法如下所示：
Figure PCTCN2022099013-appb-000013
Figure PCTCN2022099013-appb-000014
表1-1.醋酸阿比特龙软胶囊和Zytiga片剂的溶出度(％)
取样点/min Zytiga 实施例1 实施例2 实施例3 实施例4 对比实施例1
5 13.77 69.01 68.61 71.51 72.01 73
10 28.03 93.51 92.01 93.15 94.51 93
15 41.78 95.83 94.91 96.41 96.83 96
20 57.99 97.62 96.72 97.52 98.05 98
30 79.15 98.70 99.10 99.60 98.20 99
45 92.88 98.52 99.52 98.41 99.12 98
由表1-1的对比结果表明：①本发明的醋酸阿比特龙软胶囊(实施例1、2、3、4)在介质中，15min基本溶出完全(注：原研药Zytiga溶出度标准：45min不得小于标示量的85.0％)，而上市醋酸阿比特龙片剂Zytiga在30min时溶出度仍不能达到85.0％；②本发明的醋酸阿比特龙软胶囊(实施例1、2、3、4)的溶出度与对比实施例1无显著区别。因此，本发明的醋酸阿比特龙胶囊能有效提高阿比特龙的溶出度，显著提高醋酸阿比特龙的口服生物利用度。
实施例6
本试验例提供实施例1-4所提供醋酸阿比特龙软胶囊的稳定性(长期试验和加速试验)测试，检测结果详见表2-1和表2-2。
表2-1.样品在长期试验(25℃±2℃/60％RH±5％RH)下的稳定性
Figure PCTCN2022099013-appb-000015
注：“-”代表：澄明溶液，药物无析出；
“+”代表：澄明溶液，药物有少量析出。
表2-2.样品在加速试验(40℃±2℃/75％RH±5％RH)下的稳定性
Figure PCTCN2022099013-appb-000016
Figure PCTCN2022099013-appb-000017
注：“ND”代表未检出；“NA”代表未检测。
由表2-1的对比结果表明：本发明的醋酸阿比特龙软胶囊(实施例1、2、3、4)在长期9月内，内容物性状无显著变化，对比实施例1在长期6月内无显著区别，但在长期9月时有少量药物析出，其原因：对比实施例1的内容物处方中含有丙二醇和乙醇，随着储存时间的延长，丙二醇和乙醇中可能会穿透囊壳而挥发掉，降低药物的溶解度，导致醋酸阿比特龙沉淀。
由表2-2的对比结果表明：①本发明的醋酸阿比特龙软胶囊(实施例1、2、3、4)在加速6月内总杂有增长趋势，且符合产品质量要求(注：原研药Zytiga质量标准中总杂不得过2.0％)；②本发明的醋酸阿比特龙软胶囊(实施例1、2、3、4)在加速6月内，其总杂的增长幅度明显小于对比实施例1
实施例7
本试验例提供实施例1-4所提供的醋酸阿比特龙软胶囊的自乳化能力及稳定性试验。
将实施例1-4制备的醋酸阿比特龙软胶囊加入纯化水中，轻微振摇后观察外观性状，及在室温下溶液稳定性。详见表3-1
表3-1.样品自乳化能力及稳定性结果
Figure PCTCN2022099013-appb-000018
实施例8
本试验例提供实施例1和醋酸阿比特龙原研药Zytiga的药代动力学测试。
试验设计：因原研药Zytiga(醋酸阿比特龙片)在体内变异性大，本次药代动力学研究采用6只犬三周期交叉试验，空腹口服1次醋酸阿比特龙软胶囊(规格：40mg)和2次原研药Zytiga(规格：250mg，每次2片)，采集血样，测定血浆中阿比特龙的浓度，计算主要药动学参数。详见表4-1。
测试对象：健康比格犬6只，随机分成3组，每组2只，进行3周期交叉试验。试验期间自由饮水，每周期给药前禁食12小时以上，给药时制剂均以20ml水送服，给药6小时后喂食。周期间清洗期7天。
表4-1比较性药动学研究组别设计
Figure PCTCN2022099013-appb-000019
注：T：醋酸阿比特龙软胶囊，给药1粒/犬，即40mg/犬；
R：醋酸阿比特龙片，给药2粒/犬，即500mg/犬。
表4-2原研药Zytiga 500mg对比醋酸阿比特龙软胶囊40mg药动学参数(空腹试验)
Figure PCTCN2022099013-appb-000020
Figure PCTCN2022099013-appb-000021
注：Tmax为达峰时间，Cmax为最大血药浓度(达峰浓度)，AUClast为从给药开始至最后一个点的持续时间的AUC(药时曲线面积)；
由表4-2可知，比格犬空腹口服1粒醋酸阿比特龙软胶囊(规格40mg)对比原研药Zytiga(R1st)和原研药Zytiga(R2nd)口服生物利用度(AUClast)分别达到101.9％和95.3％。表明本发明的醋酸阿比特龙软胶囊与原研药Zytiga(规格250mg)相比，口服生物利用度提高至12.5倍，且AUClast的变异性更小。
由图1、图2和图3可知，醋酸阿比特龙软胶囊不同个体阿比特龙的药时曲线相互接近，而原研药Zytiga不同个体间药时曲线则较为离散。其原因可能是软胶囊剂型在消化道上无需经过原研药Zytiga的溶出步骤，而该步骤直接影响药物的吸收，从而提高了生物利用度缩小了个体差异。
综上所述，①犬空腹口服醋酸阿比特龙软胶囊后，在消化道上跳过了原研药Zytiga的溶出步骤，醋酸阿比特龙软胶囊口服生物利用度(AUClast)为原研药Zytiga的12.5倍，且醋酸阿比特龙软胶囊可在个体间获得更一致的T max、C max和AUC，从而有利于临床治疗的实施和安全风险的控制。
实施例9
本试验例提供食物对实施例1的吸收影响试验。
试验设计：8只犬双周期交叉试验，分别空腹和餐后口服醋酸阿比特龙软胶囊，采集血样，测定血浆中阿比特龙的浓度，计算主要药动学参数。详见表5-1。
测试对象：健康比格犬8只，随机分成2组，每组4只，进行3周期交叉试验。试验期间自由饮水。空腹给药于给药前禁食12小时以上，给药时制剂均以20ml水送服，给药6小时后喂食；餐后给药于给药前30分钟胃管定量喂食。周期间清洗期7天。
表5-1食物影响研究组别设计
Figure PCTCN2022099013-appb-000022
注：T：醋酸阿比特龙软胶囊，给药1粒/犬，即40mg/犬。
表5-2犬空腹口服醋酸阿比特龙软胶囊后血浆中阿比特龙的药动学参数
Figure PCTCN2022099013-appb-000023
表5-3犬餐后口服醋酸阿比特龙软胶囊后血浆中阿比特龙的药动学参数
Figure PCTCN2022099013-appb-000024
*每个个体的相对生物利用度F＝(醋酸阿比特龙软胶囊餐后AUC 0-t/空腹AUC 0-t)*100％
由表5-2和表5-3可知，与空腹口服醋酸阿比特龙软胶囊相比，犬餐后30min口服醋酸阿比特龙软胶囊后，相对生物利用度为79.19％(44.45％～106.80％)。主要药动学参数自然对数转换后的配对t检验结果见表5-4。
表5-4犬空腹或餐后口服醋酸阿比特龙软胶囊后血浆中阿比特龙的主要药动学参数配对t检验结果
Figure PCTCN2022099013-appb-000025
由表5-4可知，与空腹口服醋酸阿比特龙软胶囊相比，犬餐后口服软胶囊后，Cmax的差异有显著性意义(P<0.01)，而AUC0-t和AUCinf的差异无统计学意义。
文献报道，原研药Zytiga高脂餐后阿比特龙的暴露量可达空腹暴露量的10倍。本试验中，犬空腹或餐后口服醋酸阿比特龙软胶囊后，阿比特龙暴露量未增加，其原因可能是醋酸阿比特龙软胶囊在消化道上无需经过原研药Zytiga的溶出步骤，不必再借助食物中的脂肪来实现药物的溶解即已达到较高的暴露量，食物的存在不能再提高其吸收程度。餐后给药的阿比特龙相对生物利用度略低于空腹，其原因可能是食物促进消化道蠕动排空，使药物在主要吸收部位停留时间缩短。
综上所述，与空腹相比，犬餐后口服自研制剂后，阿比特龙的暴露量略有降低，无原研药Zytiga餐后给药出现的阿比特龙暴露量明显升高的现象。因此，醋酸阿比特龙软胶囊可降低饮食造成的阿比特龙暴露量相关的安全性风险。
虽然，上文中已经用一般性说明、具体实施方式及试验，对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改后改进，均属于本发明要求保护的范围。

Claims (16)

  1. 一种醋酸阿比特龙软胶囊，包括内容物和胶囊壳，其特征在于，所述内容物包含活性成分醋酸阿比特龙、辛酸癸酸单双甘油酯、吐温80、司盘80和丁基羟基茴香醚。
  2. 如权利要求1所述的一种醋酸阿比特龙软胶囊，其特征在于：基于所述内容物的总体积，所述醋酸阿比特龙的浓度在60-100mg/ml之间；
    和/或
    所述醋酸阿比特龙的质量占所述内容物的总质量的6-10％。
  3. 如权利要求1所述的一种醋酸阿比特龙软胶囊，其特征在于，所述辛酸癸酸单双甘油酯的质量占所述内容物的总质量的60-77％。
  4. 如权利要求1所述的一种醋酸阿比特龙软胶囊，其特征在于，所述醋酸阿比特龙的质量占所述内容物的总质量的6-10％，所述辛酸癸酸单双甘油酯的质量占所述内容物的总质量的60-77％。
  5. 如权利要求1所述的一种醋酸阿比特龙软胶囊，其特征在于，所述吐温80的质量占所述内容物的总质量的6-15％。
  6. 如权利要求1所述的一种醋酸阿比特龙软胶囊，其特征在于，所述司盘80的质量占所述内容物的总质量的7-19％。
  7. 如权利要求1所述的一种醋酸阿比特龙软胶囊，其特征在于，所述醋酸阿比特龙的质量占所述内容物的总质量的6-10％，所述辛酸癸酸单双甘油酯的质量占所述内容物的总质量的60-77％，所述吐温80的质量占所述内容物的总质量的6-15％，所述司盘80的质量占所述内容物的总质量的7-19％。
  8. 如权利要求1所述的一种醋酸阿比特龙软胶囊，其特征在于，所述丁基羟基茴香醚的质量占所述内容物的总质量的0.01％-0.1％。
  9. 如权利要求1所述的一种醋酸阿比特龙软胶囊，其特征在于，所述醋酸阿比特龙的质量占所述内容物的总质量的6-10％，所述辛酸癸酸单双甘油酯的质量占所述内容物的总质量的60-77％，所述吐温80的质量占所述内容物的总质量的6-15％，所述司盘80的质量占所述内容物的总质量的7-19％，所述丁基羟基茴香醚的质量占所述内容物的总质量的0.01％-0.1％。
  10. 如权利要求1所述的一种醋酸阿比特龙软胶囊，其特征在于，所述胶囊壳由软胶囊材质组成，其组成包括：明胶、水、甘油、山梨醇山梨坦溶液MDF85，各组分比例为1:0.74:0.35:0.35。
  11. 如权利要求1所述的一种醋酸阿比特龙软胶囊，其特征在于，所述内容物中：所述醋酸阿比特龙的质量占所述内容物的总质量的6-10％，所述辛酸癸酸单双甘油酯的质量占所 述内容物的总质量的60-77％，所述吐温80的质量占所述内容物的总质量的6-15％，所述司盘80的质量占所述内容物的总质量的7-19％，所述丁基羟基茴香醚的质量占所述内容物的总质量的0.01％-0.1％；所述胶囊壳由软胶囊材质组成，其组成包括：明胶、水、甘油、山梨醇山梨坦溶液(MDF85)，各组分比例为1:0.74:0.35:0.35。
  12. 一种制备如权利要求1-11任一项所述的醋酸阿比特龙软胶囊的制备方法，该方法包括：1)化胶：将处方量的甘油、山梨醇山梨坦和水加入化胶桶中，开启搅拌，待桶内温度升至75-80℃，物料混合均匀后，加入处方量明胶后，同时抽真空至-0.05～-0.06MPa，保持负压搅拌25-35min后，打开灌顶呼吸器至真空消失，在55-60℃保温脱气，待用；2)内容物制备：醋酸阿比特龙溶解于加热至50℃的辛酸癸酸单双甘油酯、吐温80、司盘80和抗氧剂的混合溶液中，搅拌均匀，待用；3)制丸：采用软胶囊机进行制丸；4)干燥。
  13. 一种如权利要求1-11任一项所述的醋酸阿比特龙软胶囊在制备药物制剂中应用，其特征在于，所述的药物制剂用于治疗前列腺癌。
  14. 如权利要求13所述的醋酸阿比特龙软胶囊在制备药物制剂中应用，其特征在于，所述前列腺癌为自转移去势抵抗性前列腺癌和转移性高风险去势敏感型前列腺癌中的一种或两种。
  15. 如权利要求13或14所述的醋酸阿比特龙软胶囊在制备药物制剂中应用，其特征在于，以醋酸阿比特龙计，单次口服剂量为36-60mg。
  16. 如权利要求15所述的醋酸阿比特龙软胶囊在制备药物制剂中应用，其特征在于，以醋酸阿比特龙计，单次口服剂量为40mg。
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