CN114762693A

CN114762693A - Abiraterone pharmaceutical composition with high drug loading rate as well as preparation method and application thereof

Info

Publication number: CN114762693A
Application number: CN202011641086.8A
Authority: CN
Inventors: 唐珊; 石凯荣; 黄依娟; 赵小芳; 张丽月; 陈礼莉; 李英富
Original assignee: Chengdu Haibowei Pharmaceutical Co ltd
Current assignee: Chengdu Haibowei Pharmaceutical Co ltd
Priority date: 2020-12-31
Filing date: 2020-12-31
Publication date: 2022-07-19

Abstract

The invention discloses an abiraterone medicine composition with high medicine-loading rate, a preparation method and application thereof, wherein the abiraterone medicine composition comprises the following components in parts by weight: 1-80 parts of active ingredients, 1-50 parts of fatty acids, 5-75 parts of grease, 10-70 parts of surfactants and 1-50 parts of cosurfactants; the active ingredient is abiraterone acetate and/or abiraterone, and preferably the abiraterone acetate. The preparation of the invention increases the drug-loading rate of the abiraterone acetate, improves the bioavailability of the abiraterone acetate medicinal preparation, can reduce the difference of blood concentration before meals and after meals by compounding the abiraterone acetate with fatty acid, and is convenient to take. Meanwhile, the abiraterone acetate medicinal preparation has the advantages of few components, good stability, simple preparation process, realization of large-scale industrial production and convenience in production and transportation.

Description

Abiraterone pharmaceutical composition with high drug loading rate as well as preparation method and application thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an abiraterone pharmaceutical composition and a preparation method and application thereof.

Background

The abiraterone acetate is a derivative of steroid progesterone developed by Qiangsheng company, is a prodrug of abiraterone, and can be rapidly hydrolyzed and deacetylated in vivo to be abiraterone. Abiraterone inhibits 17 α -hydroxylase/C17, 20-lyase (CYP17), which is expressed in testicular, adrenal and prostate tumor tissue and is essential for androgen biosynthesis. The drug molecule has been approved in many countries for metastatic Castration Resistant Prostate Cancer (CRPC), and abiraterone acetate was also incorporated into the world health organization "basic drug list".

The chemical name of the abiraterone acetate is (3 beta) -17- (3-pyridyl) androstane-5, 16-diene-3-yl acetate, the molecular formula is C₂₆H₃₃NO₂And has a molecular weight of 391.55 and the formula:

it is a white to off-white, non-hygroscopic crystalline powder, a lipophilic compound having an octanol-water partition coefficient (logP) of 5.12 and an aromatic nitrogen pKa of 5.19, and being hardly soluble in water. BCS is classified as a class IV compound, hypo-lytic and hypotonic.

Zytiga is a primary drug of abiraterone acetate, which is a tablet, with the specification of 250mg, the daily dose of 1000mg, four tablets per day, wherein the inactive ingredients are lactose monohydrate, croscarmellose sodium, microcrystalline cellulose, povidone, colloidal silicon dioxide, magnesium stearate and sodium lauryl sulfate.

According to the information disclosed by Zytiga original medicine, the medicine is orally taken in a human body mass balance research¹⁴After C-abiraterone acetate, about 88% of the radioactive dose was found in feces (55% of abiraterone acetate, 22% of abiraterone acetate) and about 5% in urine. Thus, Zytiga has very low bioavailability, and a single administration of 1000mg results in only less than 10% of the drug being absorbed. The extremely low bioavailability results in waste of the raw material drug and increased cost of administration for patients.

Furthermore, according to the original prescription information, Zytiga must be taken on an empty stomach and food should not be consumed at least two hours before and one hour after the administration. This is because the original study discloses the C of mCRPC patients at a dose of 1000mg per day_maxThe steady state mean was 226 + -178 ng/mL, the AUC steady state mean was 1173 + -690 ng.hr/mL, and the Zytiga protocol emphasizes that systemic exposure to abiraterone acetate increased when given with food. Specifically, there was an approximately 7-fold and 5-fold increase in abiraterone Cmax and AUC 0- ∞ respectively when abiraterone acetate was administered with a low fat diet (7% fat, 300 calories); abiraterone Cmax and AUC 0- ∞ increased about 17-fold and 10-fold, respectively, when given with a high fat diet (57% fat, 825 calories). The medicine taking mode caused by the pharmacokinetic characteristics of Zytiga brings great inconvenience to the life of patients, and meanwhile, the medicine can be taken by mistake of high-fat foodThe latter higher exposure carries a certain safety risk.

In addition, Zytiga, a size of 250mg, has low bioavailability, requires a daily dose of up to 1000mg, is taken four times a day, and has a tablet weight of up to 736mg, which causes difficulty in oral administration for patients. Particularly, the main disease group of the prostatic cancer is old men, and the old group often has the characteristic of dysphagia, so that Zytiga also has the clinical problem of poor oral compliance.

In 2018, in order to solve the above problems of Zytiga in the original research, Sun Pharmaceutical company in India developed and marketed YONZA as an improved preparation of abiraterone acetate. YONZA adopts micronization technology, improves the dissolution rate of the medicine, doubles the bioavailability of the original preparation Zytiga, takes 500mg orally, which is equivalent to 1000mg in the original preparation, and has low bioavailability according to the bioavailability of the original preparation. Although the difference in absorption by the food is reduced, there is still a large deviation. Meanwhile, the specification is 125mg, 4 tablets are taken once a day, and the problem of certain oral compliance still exists for patients with dysphagia. Thus, the advent of YONZA did not reliably solve the problems of Zytiga in the prior art.

Patent document CN107278152A adopts polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and sodium deoxycholate to form a composite by a microfluid flow meter, and then the composite is spray-dried or freeze-dried to form a solid. The complex can reduce food effect and give up on an empty stomach for medication. In vivo, one example bioavailability in beagle dogs was 11 fold higher than in the original study and 4 fold higher in adult males. However, the technology has the problems of complex preparation process and high energy consumption, and a large amount of organic solvent tetrahydrofuran is used in the technology, so that the problems of environmental protection and production safety exist.

Patent document CN110538150A relates to a pharmaceutical composition containing abiraterone acetate, and a preparation method and an application thereof, wherein the auxiliary materials include: at least one oil phase, at least one emulsifier and at least one co-emulsifier. In vivo testing in beagle dogs, example 1 showed a 10-fold increase in bioavailability over the original study, while overcoming the food effect. However, this technique also has two problems: (1) the formula of the patent contains ethanol, and the ethanol plays an important role in increasing the solubility of API and reducing the particle size of milk particles in the formula, is very easy to volatilize, and can bring influence on the stability and curative effect of the product. (2) The drug loading in the technology is still limited, the drug loading is 20-100mg/mL, if the drug is improved by 11 times in CN10728152A beagle dogs and 4 times in human bodies, the bioavailability of the drug in human bodies is improved by 3.5 times, the drug dosage per time is 286mg, the oil content in soft capsules per time is 14.3-2.86 mL according to the drug loading calculation, and 0# capsule can only fill 0.5mL per capsule, which means that 25-6 large-size capsules need to be taken orally by patients each time, and the practical application in clinic is poor.

Patent document CN111012745A discloses an abiraterone oral emulsion and a preparation method thereof. In vivo tests show that the bioavailability of one embodiment in beagle dogs is improved by 3.4 times, so that the technology does not remarkably improve the bioavailability, and the emulsion form is not easy to store and transport and is poor in oral feeling of patients.

Patent document PCT/EP2016/056689 discloses a lipid composition comprising abiraterone acetate. The technique eliminates the food effect and in the beagle in vivo test, the bioavailability is improved by 5 times compared with the original research. However, the drug loading of the technology is low, wherein the drug loading of the embodiment with the highest bioavailability is 6%, and the patient needs to take 9 capsules with large size orally each time according to the conversion of the bioavailability of beagle dogs in human and the calculation of the drug loading.

Therefore, the existing abiraterone preparation has the problems of low bioavailability, low drug loading, inconvenient administration, poor stability, inconvenient transportation, complex production process, large environmental pollution and the like, and greatly influences the commercial development of the existing abiraterone preparation, so that the development of the abiraterone preparation which can improve the bioavailability and the drug loading, reduce the difference of blood concentration before meals, has simple and stable prescription process and convenient transportation has important significance for the clinical application of abiraterone or abiraterone acetate is realized.

Disclosure of Invention

The invention mainly solves the technical problem of providing the abiraterone medicine composition with high medicine-loading rate, and the abiraterone medicine composition is added with fatty acid as an oil solvent, so that the bioavailability is high and the medicine-loading rate is high.

Many studies have been made to improve the bioavailability of abiraterone-related drugs and the drug-taking experience of patients, but the improvement effect of oral preparations is still not ideal.

Some researchers consider adjusting the type of preparation, and prepare the medicine into properties such as inhalant or oral spray, etc., so as to change the absorption mode of the medicine and improve the bioavailability of the medicine, but the inhalant or oral spray is generally used for local administration, such as treatment of halitosis, sore throat, respiratory diseases, etc.

Although theoretically, inhalants or oral sprays can also enter the body through abundant capillaries of mucous membranes, the inhalants often cause burden to the lungs, and if not necessary for pulmonary administration, long-term use of the inhalants can cause influence on the health of the lungs; the secretion and swallowing of saliva in the oral cavity can easily cause that the medicine is not absorbed in time and is brought into the stomach by the saliva; therefore, the two preparations are difficult to be absorbed by the whole body, and have very large individual difference in practical application and administration, and can be influenced by the pressure of a patient on the sprayer, the batch number of the sprayer (which can influence the size and the scattering position of fogdrops), the salivary secretion speed of the patient and the swallowing frequency, so that the bioavailability of the medicament is greatly influenced, uncertain factors are more, and the safety risk is higher. In addition, the cost of an inhalant or oral spray is often many times higher than that of an oral drug, which imposes an economic burden on the patient.

Therefore, the abiraterone capable of being orally taken and acting on the whole body is improved as much as possible, the universality and the safety are higher, and the drug-loading rate and the bioavailability of the abiraterone oral preparation can be obviously improved by adopting a new oil solvent.

In the present invention, the "oral preparation" refers to a preparation absorbed through the gastrointestinal tract after administration, and does not include a mouth spray absorbed in a sublingual manner.

In order to solve the problems, the invention provides an abiraterone medicinal composition which comprises the following components in parts by weight: 1-80 parts of active ingredients, 1-50 parts of fatty acid, 5-75 parts of grease, 10-70 parts of surfactant and 1-50 parts of cosurfactant; the active ingredient is abiraterone acetate and/or abiraterone, and preferably the abiraterone acetate.

Further, the abiraterone pharmaceutical composition comprises the following components in parts by weight: 5-30 parts of active ingredients, 1-40 parts of fatty acid, 10-50 parts of grease, 20-55 parts of surfactant and 5-35 parts of cosurfactant.

Further, the abiraterone pharmaceutical composition comprises the following components in parts by weight: 5-15 parts of active ingredients, 1-10 parts of fatty acid, 20-40 parts of grease, 25-45 parts of surfactant and 5-30 parts of cosurfactant.

Further, the abiraterone pharmaceutical composition comprises the following components in parts by weight: 5-10 parts of active ingredients, 4-10 parts of fatty acid, 25-40 parts of grease, 30-45 parts of surfactant and 5-30 parts of cosurfactant.

Furthermore, the abiraterone pharmaceutical composition comprises the following components in parts by weight: 8.99 parts of active ingredients, 4.22 parts of fatty acid, 37.7 parts of grease, 42.89 parts of surfactant and 6.11 parts of cosurfactant;

or comprises the following components in parts by weight: 6.95 parts of active ingredients, 6.02 parts of fatty acid, 27.35 parts of grease, 33.64 parts of surfactant and 26.04 parts of cosurfactant;

or comprises the following components in parts by weight: 6.74 parts of active ingredients, 1.08 parts of fatty acid, 37.63 parts of grease, 39.61 parts of surfactant and 14.93 parts of cosurfactant;

or comprises the following components in parts by weight: 8.99 parts of active ingredients, 6.54 parts of fatty acid, 35.94 parts of grease, 38.74 parts of surfactant and 9.77 parts of cosurfactant.

Further, the fatty acid is selected from one or more of linolenic acid, oleic acid, linoleic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, eicosapentaenoic acid, docosahexaenoic acid and acetic acid, preferably one or more of linolenic acid, oleic acid and acetic acid, more preferably oleic acid and/or acetic acid, and more preferably oleic acid.

Further, the oil is selected from one or more of glycerol monolinoleate, polyethylene glycol oleate, glycerol monooleate, medium chain triglyceride, polyethylene glycol oleate, soybean oil, sesame oil, glyceryl triacetate, ethyl oleate, propylene glycol dicaprylate, refined castor oil, fish oil, algae oil, olive oil, peanut oil, propylene glycol monolaurate, propylene glycol monocaprylate, caprylic/capric monoglyceride, glyceryl monocaprylate and glyceryl monocaprate, preferably one or more of glycerol monolinoleate, propylene glycol monolaurate and propylene glycol monocaprylate, more preferably propylene glycol monolaurate and/or propylene glycol monocaprylate, and more preferably propylene glycol monocaprylate.

Further, the surfactant is selected from nonionic surfactants with HLB value more than 8, and is further selected from one or more of polysorbate surfactants, polyoxyethylene fatty acid ester surfactants, polyoxyethylene fatty alcohol ether surfactants, polyoxyethylene-polyoxypropylene copolymer surfactants and soluplus.

Further, the surfactant is selected from one or more of caprylic/capric acid polydiethylene glycol glyceride, tween 80, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 castor oil and polyethylene glycol 15 hydroxystearate, preferably one or more of tween 80, polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 35 castor oil, more preferably polyoxyethylene 40 hydrogenated castor oil and/or polyoxyethylene 35 castor oil, and more preferably polyoxyethylene 35 castor oil.

Further, the cosurfactant is selected from one or more of propylene glycol, ethanol, PEG400, glycerol, diethylene glycol monoethyl ether, caprylic capric acid polyethylene glycol glyceride, polyglycerol oleate, propylene glycol monocaprylate and oleic acid polyethylene glycol glyceride, is further selected from one or more of propylene glycol, ethanol, PEG400, glycerol and diethylene glycol monoethyl ether, is preferably propylene glycol and/or diethylene glycol monoethyl ether, and is more preferably propylene glycol.

Further, an antioxidant is also included; further, the composition also comprises 0.005-0.5 part of antioxidant, preferably 0.01-0.2 part.

Further, the antioxidant is selected from tert-butyl p-hydroxyanisole and/or dibutyl hydroxy toluene.

Furthermore, the abiraterone pharmaceutical composition comprises the following components in parts by weight: 8.99 parts of active ingredient, 6.54 parts of fatty acid, 35.94 parts of grease, 38.74 parts of surfactant, 9.77 parts of cosurfactant and 0.02 part of antioxidant.

Further, cholate is also included; further, the detergent also comprises 20-70 parts of cholate.

Further, the cholate is sodium glycocholate and/or sodium taurocholate.

The invention also provides a preparation method of the abiraterone medicinal composition, which is characterized by comprising the following steps of: mixing the active ingredient and the rest components, and dissolving.

Further, mixing and dissolving the active ingredients and the fatty acid, and then adding other components; or mixing the components except for the active ingredient, and mixing with the active ingredient for dissolving.

Further, the mixing and dissolving method is selected from one or more of stirring, ultrasound and heating.

The invention also provides an abiraterone composition, which comprises the abiraterone medicine composition and an adsorbent.

The adsorbent is a solid preparation auxiliary material commonly used in the field, has strong adsorbability on oil or water, does not cause chemical property change, and is suitable for the invention as long as the adsorbent meets the condition.

For example, cellulose and its derivatives, sugars, silicates, silicas, calcium phosphate, magnesium phosphate, calcium hydrogen phosphate, croscarmellose sodium, sodium acetate, sodium bicarbonate, sodium carbonate, ammonium acetate, and the like are commonly used as adsorbent materials in the art.

Further, the adsorbent is selected from one or more of microcrystalline cellulose, lactose, starch, sorbitol, dextran, silicon dioxide, magnesium aluminum silicate, kaolin, ordered mesoporous silicate, calcium phosphate, magnesium phosphate, calcium hydrogen phosphate, croscarmellose sodium, sodium acetate, sodium bicarbonate, sodium carbonate and ammonium acetate.

In a specific embodiment of the invention, the adsorbent is selected from one or more of calcium hydrogen phosphate, sodium hydrogen acetate, sodium carbonate and ammonium acetate.

Further, the mass amount of the adsorbent is 0.5-10 times, preferably 1.5-5 times, and more preferably 1.8-3 times of the mass amount of the abiraterone medicine composition.

The invention also provides a preparation method of the abiraterone composition, which comprises the following steps: adsorbing the abiraterone medicinal composition on an adsorbent.

In the preparation process, the abiraterone medicinal composition is adsorbed on the adsorbent, so that subsequent processing production can be carried out, and more different preparations can be prepared.

The invention also provides the use of the abiraterone medicinal composition or the abiraterone composition in preparing medicinal preparations; further, the formulation is an oral formulation.

Further, the preparation is selected from tablets, capsules, pills, powders, granules, solutions, emulsions or suspensions, preferably tablets or capsules, and the capsules are selected from soft capsules or hard capsules.

When the abiraterone pharmaceutical composition is used for preparing a preparation, the obtained liquid composition can be directly filled into a soft capsule or a hard capsule, or the liquid composition can be solidified by adopting a solid carrier adsorption (adsorbents include but are not limited to silicon dioxide, dextran, microcrystalline cellulose, croscarmellose sodium and the like) and then filled into the hard capsule or pressed into a tablet after being solidified by a process commonly used in the field of spray drying, pellet coating, melt granulation and the like. The cured pharmaceutical composition is more stable for a long time.

After the medicinal composition is contacted with water, under the action of the surfactant and the cosurfactant, emulsion particles with small oil-in-water O/W (less than 500 nm) particle size can be formed by slight stirring, and a uniform dispersion system is formed. The medicinal composition of the invention is not easy to separate out in solvent, the formed emulsion particles can keep stable in simulated gastrointestinal fluid, and can also protect the abiraterone acetate from being hydrolyzed by lipase, and volatile auxiliary materials are not involved in the composition, so that the composition can keep the stability of each component for a long time, and the emulsion effect can not be changed due to the change of the content of the components during administration.

The invention has the beneficial effects that:

(1) the abiraterone medicinal preparation disclosed by the invention can be used for well improving the bioavailability and the drug-loading rate by adding the fatty acid and the grease, reducing the dosage, and having good medicine taking feeling and high patient compliance.

(2) The abiraterone medicinal preparation has good medicinal stability, and can meet the requirement of declaration and the requirement of medication.

(3) The abiraterone pharmaceutical preparation disclosed by the invention can reduce or eliminate the difference of blood concentration before/after meals, and has high medication safety.

(4) The abiraterone medicinal preparation disclosed by the invention is few in components, good in stability, simple in preparation process, capable of realizing large-scale industrial production and convenient to produce and transport.

Drawings

FIG. 1 is a graph of pre-prandial plasma concentrations versus time for example 1, example 2, example 3 and example 4 on adult SD rats;

FIG. 2 is a graph of plasma concentration after a meal versus time for example 4 and example 15 on adult SD rats;

FIG. 3 is a graph of plasma concentration versus time for the original formulation and example 14 before a meal on a cynomolgus monkey.

Detailed Description

The technical solutions of the present invention are clearly and completely described below, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Abbreviations in the detailed description of the invention have the following meanings:

RH 40: polyoxyethylene 40 hydrogenated castor oil

RH 35: polyoxyethylene 35 Castor oil

BHA: tert-butyl p-hydroxyanisole

BHT: dibutylhydroxytoluene

Screening a prescription:

the preparation method comprises the following steps: mixing oleic acid, surfactant and cosurfactant, adding abiraterone acetate, and stirring or ultrasonic treating.

TABLE 1 screening of cosurfactants

As can be seen from Table 1, the content of abiraterone acetate, the type of co-surfactant, etc. all affect the state of the emulsion. Generally, the smaller the content of the abiraterone acetate is, the better the emulsifying effect is, but the too small content of the abiraterone acetate can cause the increase of the clinical medication volume and reduce the compliance of patients. Under the condition of the same content of abiraterone acetate, the selection of propylene glycol as the co-emulsifier is obviously superior to PEG400, polyglycerol oleate and diethylene glycol monoethyl ether.

TABLE 2

As can be seen from table 2, the emulsifying effect of surfactant tween 80 is close to that of caprylic capric acid macrogol glyceride.

TABLE 3

The preparation method of the formula 15-22 comprises the following steps: mixing oleic acid or acetic acid with other adjuvants, adding abiraterone acetate, and stirring or ultrasonic treating.

As can be seen from Table 3, the above formulations all formed clear and transparent nanoemulsion solutions in water.

TABLE 4

The preparation method of the formula 23-29 comprises the following steps: mixing oleic acid, RH35 and propylene glycol uniformly, adding abiraterone acetate, stirring or ultrasonic treating to dissolve completely to form a uniform clear solution; the solution is then mixed with an adsorbent material to be completely adsorbed by the adsorbent.

The results in table 4 show that the pharmaceutical composition of the present invention can form clear and transparent nanoemulsion solution in water after being treated by different adsorbents.

Example 1

The embodiment provides a pharmaceutical composition containing abiraterone acetate, wherein the composition comprises the following components in parts by mass:

name ratio (mass ratio)

Abiraterone acetate 28.6%

Oleic acid 71.4%

The preparation method comprises the following steps: adding abiraterone acetate into oleic acid, stirring or performing ultrasonic treatment to completely dissolve the abiraterone acetate, and forming a uniform and clear solution.

In the stomach and intestine of a human body, a large amount of bile salts are secreted, and phospholipids in the human body can self-emulsify oil-soluble substances, so the embodiment is the simplest combination of the embodiments of the invention.

Example 2

the preparation method comprises the following steps: mixing oleic acid, polyoxyethylene 40 hydrogenated castor oil and propylene glycol uniformly, adding abiraterone acetate, stirring or performing ultrasonic treatment to completely dissolve the abiraterone acetate to form a uniform and clear solution.

Example 3

the preparation method comprises the following steps: mixing oleic acid, polyoxyethylene 35 castor oil and propylene glycol uniformly, adding abiraterone acetate, stirring or ultrasonic treating to dissolve completely to form uniform clear solution.

Example 4

Example 5

the preparation method comprises the following steps: mixing abiraterone acetate and oleic acid, sequentially adding polyoxyethylene 35 castor oil and propylene glycol, mixing, stirring or ultrasonic treating to dissolve completely to obtain a uniform and clear solution.

Example 6

The embodiment provides a pharmaceutical composition containing abiraterone acetate, which comprises the following components in parts by mass:

the preparation method comprises the following steps: mixing oleic acid, polyoxyethylene 40 hydrogenated castor oil and diethylene glycol monoethyl ether uniformly, adding abiraterone acetate, stirring or ultrasonic treating to dissolve completely to form a uniform and clear solution.

Example 7

the preparation method comprises the following steps: mixing oleic acid, caprylic/capric polyethylene glycol glyceride and propylene glycol uniformly, adding abiraterone acetate, stirring or performing ultrasonic treatment to completely dissolve the abiraterone acetate to form a uniform and clear solution.

Example 8

the preparation method comprises the following steps: mixing oleic acid, polyethylene glycol 15 hydroxystearate and diethylene glycol monoethyl ether uniformly, adding abiraterone acetate, stirring or performing ultrasonic treatment to completely dissolve the abiraterone acetate to form a uniform and clear solution.

Example 9

the preparation method comprises the following steps: mixing oleic acid, Tween 80 and diethylene glycol monoethyl ether, adding abiraterone acetate, stirring or ultrasonic treating to dissolve completely to obtain a uniform and clear solution, and filling into soft capsule or canning into hard capsule under nitrogen protection.

Example 10

the preparation method comprises the following steps: mixing oleic acid, Tween 80 and propylene glycol, adding abiraterone acetate, stirring or ultrasonic treating to dissolve completely to obtain a uniform clear solution, and filling into soft capsule or filling into hard capsule under nitrogen protection.

Example 11

the preparation method comprises the following steps: mixing oleic acid, polyethylene glycol 15 hydroxy stearate, and propylene glycol, adding abiraterone acetate, stirring or ultrasonic treating to dissolve completely to obtain uniform clear solution, and filling into soft capsule or canning into hard capsule under nitrogen protection.

Example 12

the preparation method comprises the following steps: dissolving abiraterone acetate in oleic acid, adding glycerol monolinoleate, hydrogenated castor oil and propylene glycol, stirring at 400rpm, mixing completely to obtain a uniform and clear solution, and filling into soft capsule or canning into hard capsule under nitrogen protection.

Example 13

the preparation method comprises the following steps: dissolving abiraterone acetate in acetic acid, adding propylene glycol monocaprylate, hydrogenated castor oil and propylene glycol, stirring at 400rpm, mixing completely to obtain a uniform and clear solution, and filling into soft capsules or canning into hard capsules under the protection of nitrogen.

Example 14

the preparation method comprises the following steps: dissolving abiraterone acetate in oleic acid, adding propylene glycol monocaprylate, hydrogenated castor oil and propylene glycol, stirring at 400rpm, mixing completely to obtain a uniform and clear solution, and filling into soft capsules or canning into hard capsules under the protection of nitrogen.

Example 15

the preparation method comprises the following steps:

dissolving abiraterone acetate in oleic acid, dissolving BHA and BHT in propylene glycol, mixing the above two mixed solutions, adding propylene glycol monolaurate and hydrogenated castor oil, stirring at 400rpm, mixing completely to obtain a clear solution, and filling into soft capsule or filling into hard capsule under nitrogen protection.

The related performance and quality of the pharmaceutical composition of the invention are examined, and in the following test examples, all tests related to hard capsules are obtained by filling the pharmaceutical composition of the invention into No. 1 hard capsules, the filling amount is between 0.5g and 1.0g, and the actual filling amount of the hard capsules used in the test examples is 0.7 g.

The related performance and quality of the pharmaceutical composition of the invention are examined and tested, in the following test examples, all tests related to hard capsules are that the pharmaceutical composition of the invention is filled into No. 1 hard capsules, the filling amount is between 0.5g and 1.0g, and the actual filling amount of the hard capsules used in the test examples is 0.7 g.

Test example 1

The pharmaceutical compositions of the examples were tested for their emulsified state in water and their average particle size after emulsification: taking 0.5ml of the pharmaceutical composition of the invention, taking 8ml of water in addition, heating to 37 ℃ in a water bath, slowly dripping 0.5ml of the pharmaceutical composition into 8ml of water while stirring, observing the phenomenon after emulsification, and detecting the particle size of emulsion particles. The order of merits of the emulsified state is: the transparency > translucency > grey-white milky > blue milky > milky-white milky, and the detection results are shown in Table 6.

TABLE 5

Sample (I)	Emulsified state	Particle size of milk particles
			Example 2	Transparent to translucent emulsions	39nm
Example 3	Transparent to translucent emulsions	28nm
			Example 4	Translucent to off-white emulsion	124nm
Example 5	Translucent to off-white emulsion	87nm

From the data in Table 5, it can be seen that examples 2 to 3 have the best emulsifying properties in water, ranging from transparent to translucent emulsions, and examples 4 to 5 follow.

Test example 2

The pharmaceutical compositions of examples 2 to 4 were subjected to dissolution measurement using a hydrochloric acid medium having a pH of 1.0 and a phosphate medium having a pH of 6.8, respectively.

Dissolution conditions: medium 1 is a hydrochloric acid solution medium at ph1.0 and medium 2 is a phosphate buffer solution medium at ph 6.8. The dissolving-out method is a slurry method, the rotating speed is 75r/min, the medium temperature is 37 ℃, the medium volume is 900ml, and a 0.45um filter membrane is adopted for filtration after sampling.

Dissolution test investigation samples:

the original preparation: trade name Zytiga, size 250mg, tablet;

self-made preparation: the pharmaceutical compositions of examples 1-7 were filled into hard capsules.

The dissolution measurement results are shown in tables 6 and 7

TABLE 6 dissolution in hydrochloric acid medium at pH1.0

TABLE 7 phosphate buffer medium pH6.8

As can be seen from the results of tables 6 and 7, the capsules of the pharmaceutical composition of the present invention showed higher dissolution rates in media of pH1.0 and pH6.8, while the original formulation Zytiga showed little dissolution rate and was not substantially dissolved. The medicinal composition has higher dissolution rate, which indicates that the medicinal composition can be quickly dissolved in gastrointestinal tracts, and the dissolution rate of the abiraterone acetate is higher than that of the original research, so that the medicinal composition is favorable for improving the bioavailability of the medicament.

Test example 3

Evaluation of simulated gastric digestion of pharmaceutical compositions: the auxiliary materials of the medicinal composition are mostly oily ester auxiliary materials, and the medicinal composition can be digested in vivo, and the digestion of the oily ester auxiliary materials can cause the particle size of emulsion particles to be enlarged or cause precipitation of abiraterone acetate to influence the absorption of the medicament. Abiraterone acetate is easily hydrolyzed into abiraterone in the gastrointestinal tract, and the abiraterone is poor in dissolution and permeation, so that if the abiraterone acetate is hydrolyzed more, the absorption of the medicine in the body is influenced to a certain extent.

The present invention was digested with FaSSIF (from Biorelevant) simulating gastric juice in the stomach and the original formulation was used to evaluate the stability in the stomach. The adopted method is to prepare solution according to the preparation method of FaSSIF provided by Biorelevant company, 50ml of the prepared FaSSIF is taken and heated under the condition of 37 ℃ water bath, 1ml of the composition is taken and added into the FaSSIF solution while stirring, the stirring is continued for 4 hours, the state of the emulsion is observed, and the contents of abiraterone acetate and abiraterone are sampled and detected at 0 hour, 2 hours and 4 hours.

TABLE 8 results of the data for the evaluation of the gastric digestion of the pharmaceutical composition of the present invention

As can be seen from the data in Table 8, the amount of abiraterone acetate hydrolyzed into abiraterone in the pharmaceutical composition is obviously smaller than that of the original preparation, which indicates that the pharmaceutical composition has a certain protective effect on the stability of the abiraterone acetate in the stomach and can further increase the bioavailability of the prescription.

Test example 4 storage stability examination

The hard capsules prepared according to the formulas of examples 5 and 12 are placed under different conditions for stability examination, and the results are shown in tables 9-10.

TABLE 9 example 5 stability test at 60 ℃ at elevated temperature

Table 10 example 12 stability under various conditions

The experimental result shows that the stability of the prescription of the preparation in example 12 of the invention is obviously superior to that in example 5, and the stability of the preparation can be improved after the grease component is added. Compared with the prescription using oleic acid reported in patent CN105055314A, the prescription of the invention in example 12 has 1.1% of total impurities at 15-20 ℃ on the preparation day, the stability is also obviously better, impurities can be controlled at a lower level, the generated impurities account for the largest proportion of abiraterone, the abiraterone is an active substance which actually takes effect after the abiraterone acetate enters the body, and according to the current stability conjecture, the generation of the abiraterone in the prescription of the invention within two years can not exceed 2%, and the clinical and quality requirements can be met.

Test example 5 Experimental data for rat Synthesis

The experimental scheme is as follows:

adult male SD rats, randomly grouped, 3 per group;

experiment design: fasting single gastric lavage is carried out, fasting is carried out for more than 10 hours before the experiment, and feeding is carried out 4 hours after the administration; administration dose: 90 mg/kg; blood sampling time points: 15min, 30min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h and 12 h.

Control group: the original formulation Zytiga, 250mg in size, was ground into powder and dispersed in water for administration.

The pharmacokinetic parameters of the original formulation Zytiga and the formulations of examples 1-4 tested in rats are shown in table 11 and fig. 1:

TABLE 11

Where Tmax is the time to peak, Cmax is the maximum plasma concentration, and AUC (last) is the AUC, i.e. the area of the curve at drug time, of the duration from the beginning of the administration to the last blood sampling point, the graph of the time curve of the original formulation Zytiga in rats under fasting condition with drugs of examples 1, 2, 3, and 4 is shown in fig. 1.

As can be seen from Table 3, the exposure of examples 1, 2, 3 and 4 in rats was higher than that of the original preparation, and the bioavailability was improved to 7.1 times.

Test example 6 examination of bioavailability of examples 4 and 15 after a meal in SD rats

The experimental scheme is as follows:

adult SD male rats, randomly grouped, 4 per group;

experiment design:

fasting group: single gastric lavage administration, fasting for more than 10 hours before experiment, and feeding for 4 hours after administration;

postprandial group: administration within half an hour after meal

Administration dose: 90 mg/kg;

blood sampling time points: 15min, 30min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h and 10 h.

The pharmacokinetic parameters of the drug solutions of example 4 and example 15 before and after meals in SD rats are shown in Table 12 and FIG. 2:

table 12 partial pharmacokinetic parameters of example 4 and example 15 on male SD rats

The pharmacokinetic data for example 4 show that the bioavailability of the formula after meal was 51.69%, 37.27% respectively, with a postprandial exposure of 0.72 times the preprandial exposure. The pharmacokinetic data for example 15 show that the bioavailability of the formula after a meal was 41.26%, 31.99% respectively, with a postprandial exposure of 0.78 times the preprandial exposure. It was reported that the abiraterone Cmax and AUC 0- ∞ increase about 7-fold and 5-fold, respectively, when Zytiga is given with a low fat diet (7% fat, 300 calories); abiraterone Cmax and AUC 0- ∞ increased about 17-fold and 10-fold, respectively, when given with a high fat diet (57% fat, 825 calories).

Test example 7 examination of pharmacokinetics in beagle dogs of example 4 and example 14

The experimental scheme is as follows:

male beagle dogs, randomly grouped, 2 per group;

experiment design: animals were fasted the day before dosing (fasting time 10-18 hours) and given regular diet 4h after dosing.

Administration dose: from preparation, 50 mg/preparation, the original preparation, 500 mg/preparation (2 tablets)

Blood sampling time points: 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24 h.

The pharmacokinetics of example 4 and example 14 before the meal of male beagle dogs are shown in table 13.

TABLE 13 comparison of pharmacokinetic parameters of example 4, example 14 and original study before meal on male beagle dogs

	Original research	Example 4	Example 14
				Cmax(ug/L)	126.44	530.24	470.31
AUC0-t(ug/L*h)	278.36	986.38	610.87
				Tmax(h)	0.63	1.00	0.50

The Cmax, AUC (0-t) and Tmax for 50mg of the test formulation (example 4) were 530.24ug/L, 986.38ug/L × h and 1.00h, respectively, and 4.19, 3.54 and 1.59 times greater than for 500mg of the original formulation, respectively, administered fasted.

The Cmax, AUC (0-t) and Tmax for 50mg of the test formulation (example 14) administered fasted were 470.31ug/L, 610.87ug/L h and 0.50h, respectively, which were 3.72, 2.19 and 0.79 times those of the 500mg original formulation.

Test example 8 examination of pharmacokinetics in cynomolgus monkeys in example 14

The experimental scheme is as follows:

male cynomolgus monkeys, randomly grouped, 2 per group;

experiment design: animals were fasted the day before dosing (fasting time 10-18 hours), and conventional feed was given 4 hours after dosing;

administration dose: 1000mg of the original preparation per unit, and 200mg of the original preparation per unit;

blood sampling time points: 0.25h, 0.5h, 1h, 1.5h, 2h, 4h, 6h, 8h, 12h and 24 h;

example 14 pharmacokinetics before meals on male cynomolgus monkeys are shown in table 14 and figure 3.

TABLE 14

	Original research	Example 14
			Cmax(ug/L)	1025.31	2247.80
AUC0-t(ug/L*h)	6550.30	11055.50
			Tmax(h)	7.00	3.00

The Cmax, AUC (0-t) and Tmax for 200mg of the test formulation (example 14) administered fasted were 2247.80ug/L, 11055.50 ug/Lxh and 3.00h, respectively, which were 2.19, 1.69 and 0.43 times those of the 1000mg of the original formulation.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims

1. An abiraterone pharmaceutical composition is characterized by comprising the following components in parts by weight: 1-80 parts of active ingredients, 1-50 parts of fatty acid, 5-75 parts of grease, 10-70 parts of surfactant and 1-50 parts of cosurfactant; the active ingredient is abiraterone acetate and/or abiraterone, and preferably the abiraterone acetate.

2. An abiraterone pharmaceutical composition of claim 1, which comprises the following components in parts by weight: 5-30 parts of active ingredients, 1-40 parts of fatty acid, 10-50 parts of grease, 20-55 parts of surfactant and 5-35 parts of cosurfactant;

further, the composition comprises the following components in parts by weight: 5-15 parts of active ingredients, 1-20 parts of fatty acid, 20-40 parts of grease, 25-50 parts of surfactant and 5-30 parts of cosurfactant;

further, the composition comprises the following components in parts by weight: 5-10 parts of active ingredients, 1-10 parts of fatty acid, 25-40 parts of grease, 30-45 parts of surfactant and 5-30 parts of cosurfactant;

further, the composition comprises the following components in parts by weight: 9 parts of active ingredients, 6.5 parts of fatty acid, 33.8 parts of grease, 43.7 parts of surfactant and 7.1 parts of cosurfactant;

or 6.95 parts of active ingredients, 6.02 parts of fatty acid, 27.35 parts of grease, 33.64 parts of surfactant and 26.04 parts of cosurfactant;

or 6.74 parts of active ingredients, 1.08 parts of fatty acid, 37.63 parts of grease, 39.61 parts of surfactant and 14.93 parts of cosurfactant;

or 8.99 parts of active ingredients, 6.54 parts of fatty acid, 35.94 parts of grease, 38.74 parts of surfactant and 9.77 parts of cosurfactant.

3. An abiraterone pharmaceutical composition according to claim 1, wherein the fatty acid is selected from one or more of linolenic acid, oleic acid, linoleic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, eicosapentaenoic acid, docosahexaenoic acid and acetic acid, preferably one or more of linolenic acid, oleic acid and acetic acid, more preferably oleic acid and/or acetic acid, and even more preferably oleic acid.

4. An abiraterone pharmaceutical composition according to claim 1, wherein the oil is selected from glycerol monolinoleate, polyethylene glycol glycerol oleate, glycerol monooleate, medium chain triglycerides, polyethylene glycol glycerol oleate, soybean oil, sesame oil, glycerol triacetate, ethyl oleate, propylene glycol dicaprylate, refined castor oil, fish oil, algae oil, olive oil, peanut oil, propylene glycol monolaurate, propylene glycol monocaprylate, caprylic capric acid monoglyceride, glyceryl monocaprylate, one or more of propylene glycol monocaprylate, preferably propylene glycol monolaurate, propylene glycol monocaprylate, more preferably propylene glycol monolaurate and/or propylene glycol monocaprylate, more preferably propylene glycol monocaprylate.

5. An abiraterone composition of claim 1, wherein the surfactant is selected from nonionic surfactants having HLB value greater than 8, and further selected from one or more of polysorbate surfactants, polyoxyethylene fatty acid ester surfactants, polyoxyethylene fatty alcohol ether surfactants, polyoxyethylene-polyoxypropylene copolymer surfactants, and soluplus;

further, the surfactant is selected from one or more of caprylic capric acid polyethylene glycol glyceride, tween 80, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 castor oil and polyethylene glycol 15 hydroxystearate, preferably one or more of tween 80, polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 35 castor oil, more preferably polyoxyethylene 40 hydrogenated castor oil and/or polyoxyethylene 35 castor oil, and more preferably polyoxyethylene 35 castor oil.

6. An abiraterone pharmaceutical composition according to claim 1, wherein the co-surfactant is selected from one or more of propylene glycol, ethanol, PEG400, glycerol, diethylene glycol monoethyl ether, caprylic capric acid polyethylene glycol glyceride, polyglycerol oleate, propylene glycol monocaprylate, oleic acid polyethylene glycol glyceride, further selected from one or more of propylene glycol, ethanol, PEG400, glycerol, diethylene glycol monoethyl ether, preferably propylene glycol and/or diethylene glycol monoethyl ether, more preferably propylene glycol.

7. An abiraterone pharmaceutical composition of any of claims 1 to 6, further comprising an antioxidant; further, 0.005-0.5 part of antioxidant, preferably 0.01-0.2 part;

further, the antioxidant is selected from tert-butyl p-hydroxyanisole and/or dibutyl hydroxy toluene;

furthermore, the abiraterone pharmaceutical composition comprises the following components in parts by weight: 8.99 parts of active ingredients, 6.54 parts of fatty acid, 35.94 parts of grease, 38.74 parts of surfactant, 9.77 parts of cosurfactant and 0.02 part of antioxidant.

8. An abiraterone pharmaceutical composition of any of claims 1 to 7, further comprising a cholate; further, 20-70 parts of cholate;

further, the cholate is sodium glycocholate and/or sodium taurocholate.

9. A process for the preparation of an abiraterone pharmaceutical composition of any of claims 1 to 8, comprising: mixing the active ingredient and the rest components, and dissolving;

further, mixing and dissolving the active ingredients and the fatty acid, and then adding other components; or mixing the components except the active ingredient, and mixing with the active ingredient for dissolving;

10. An abiraterone composition, comprising the abiraterone pharmaceutical composition of any of claims 1-7 and an adsorbent; further, the adsorbent is selected from one or more of cellulose and derivatives thereof, saccharides, silicates, silicon dioxide, calcium phosphate, magnesium phosphate, calcium hydrogen phosphate, croscarmellose sodium, sodium acetate, sodium bicarbonate, sodium carbonate and ammonium acetate;

further, the adsorbent is selected from one or more of microcrystalline cellulose, lactose, starch, sorbitol, dextran, silicon dioxide, magnesium aluminum silicate, kaolin, ordered mesoporous silicate, calcium phosphate, magnesium phosphate, calcium hydrophosphate, croscarmellose sodium, sodium acetate, sodium bicarbonate, sodium carbonate and ammonium acetate;

further, the adsorbent is selected from one or more of calcium hydrogen phosphate, sodium hydrogen acetate, sodium carbonate and ammonium acetate;

further, the mass amount of the adsorbent is 0.5-10 times, preferably 1.5-5 times, and more preferably 1.8-3 times of that of the abiraterone medicine composition of any one of claims 1-8.

11. A process for the preparation of an abiraterone composition of claim 9, which comprises the following: adsorbing the abiraterone pharmaceutical composition of any of claims 1-8 onto an adsorbent.

12. Use of an abiraterone pharmaceutical composition of any of claims 1 to 8 or an abiraterone composition of claim 10 for the preparation of a pharmaceutical formulation; further, the formulation is an oral formulation;

further, the preparation is selected from tablets, capsules, pills, powder, granules, solutions, emulsions or suspensions, preferably tablets or capsules, and the capsules are selected from soft capsules or hard capsules.