CN113616614A - Abiraterone acetate soft capsule and preparation method thereof - Google Patents
Abiraterone acetate soft capsule and preparation method thereof Download PDFInfo
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- 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
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- 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
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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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention discloses an abiraterone acetate soft capsule and a preparation method thereof. The soft capsule consists of a content and a capsule shell, wherein the content comprises abiraterone acetate, caprylic/capric acid monoglyceride and diglyceride, tween 80, span 80 and butyl hydroxy anisol; the capsule shell is made of soft capsule materials, and comprises the following components: gelatin, water, glycerol and sorbitol sorbitan solution, wherein the ratio of the components is 1:0.74:0.35: 0.35. Compared with the original medicine Zytiga (specification of 250mg), the abiraterone acetate soft capsule provided by the invention is orally taken on an empty stomach, the dissolution step of the original medicine Zytiga is not needed on the digestive tract, the oral bioavailability is improved to 12.5 times, the inter-individual variability is low, and the phenomenon that the abiraterone exposure is obviously increased when the original medicine Zytiga is taken after a meal is eliminated.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to an abiraterone acetate soft capsule and a preparation method thereof.
Background
Abiraterone Acetate (Abiraterone Acetate) is a white to off-white, non-hygroscopic crystalline powder. Abiraterone acetate is an abiraterone prodrug, a selective irreversible inhibitor of 17 α -hydroxylase/C17, 20-lyase (CYP 17). The enzyme is expressed in testicular and adrenal tissues and catalyzes the conversion of pregnenolone and progesterone to testosterone precursors, DHEA and androstenedione, respectively, by 17 alpha hydroxylation and cleavage of the C17,20 bond. Abiraterone inhibits the activity of CYP17 and thus prevents testosterone synthesis in the testes, adrenal glands and tumors. Prostate cancer is an androgen-dependent disease and inhibition of testosterone in controlling the progression of prostate cancer is a key pharmacological tool. The chemical structure of abiraterone acetate is shown as the following formula 1:
abiraterone acetate, a lipophilic compound, has an octanol-water partition coefficient of 5.12(LogP), a pKa of aromatic nitrogen of 5.19, is almost insoluble in water (0.01mg/ml), and has a difference in osmotic pressure, which is a BCS class four drug, and is extremely low in bioavailability upon oral absorption.
The original drug Zytiga abiraterone acetate tablet (specification 250mg) was developed by Janssen-Cilag International n.v. belgium, and inactive ingredients included: colloidal titanium dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. Approved in the united states for treatment of metastatic castration resistant prostate cancer (mCRPC) in combination with prednisone. The original drug Zytiga has very low oral bioavailability (less than 10%), and the dosage is up to 1000mg per day, but only less than 10% of the drugs can exert the drug effect.
The prescription information of the original drug Zytiga indicates that it must be taken on an empty stomach and that food should not be taken at least 2 hours before taking it and at least 1 hour after taking it, indicating that food has a great influence on the absorption of abiraterone acetate and that the commercially available formulations are required to be taken only a certain period of time before a meal. The Zytiga specification emphasizes that systemic exposure to abiraterone acetate increases when administered with food. Specifically, abiraterone acetate Cmax and AUC when given with a low fat diet (7% fat, 300 calories) were0-∞An increase of about 7-fold and 5-fold, respectively; abiraterone acetate Cmax and AUC when given with a high fat diet (57% fat, 825 calories)0-∞An increase of about 17-fold and 10-fold, respectively. Although the abiraterone acetate has good effect on treating advanced prostate cancer by oral administration, the characteristics of low solubility and osmotic pressure difference bring serious troubles to the development of the preparation.
Patent CN106687112A provides an improved abiraterone acetate preparation, which is a unit dosage form of abiraterone by controlling the particle size of raw material drug abiraterone acetate, wherein the unit dosage form of 500mg dose is bioequivalent to the unit dosage form of 1000mg dose of Zytiga in healthy male subjects in fasting state, and the bioavailability is improved by 1 time. Although the dosage of the preparation is reduced by 500mg, only the abiraterone acetate is crushed, the particle size is controlled to be in a small range so as to be beneficial to dissolution and absorption, the permeability of the abiraterone acetate to gastrointestinal epithelial cells is not increased, the oral bioavailability is still very low, the specific surface area of the abiraterone acetate is too large after crushing, and the risk of oxidation of the abiraterone acetate is increased.
Patent CN102961358B relates to an abiraterone acetate liquid capsule, including capsule shell and content, its characterized in that: the content consists of abiraterone acetate, a solvent, fatty acid monoglyceride and an antioxidant: the solvent is selected from: glycerin fatty acid diester, glycerin fatty acid triester, 1, 2-propanediol, and mixtures thereof. However, the propylene glycol contained in the content of the liquid capsule can volatilize from the content in the storage process, so that the content of the propylene glycol in the content can be seriously reduced, the abiraterone is separated out, and a great quality problem can be caused.
Patent document CN107278152A relates to an abiraterone acetate complex, a preparation method thereof and a pharmaceutical composition containing the same, which comprises 5-40 wt% of abiraterone acetate, 5-80 wt% of a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and 0.1-50 wt% of sodium deoxycholate. The compound can reduce food effect and give up the requirement of taking medicine on an empty stomach, and can improve the oral bioavailability by 5 times at most, but the preparation process of the compound preparation is complex.
The invention discloses patent document CN110538150A, relates to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing abiraterone acetate, and a preparation method and application thereof. The pharmaceutical composition comprises: active ingredients: abiraterone acetate; auxiliary materials: at least one oil phase, at least one emulsifier, and at least one emulsifier. The pharmaceutical composition provided by the invention spontaneously disperses under gastrointestinal peristalsis to form O/W type nanoemulsion when meeting gastrointestinal tract after oral administration. The formed nanoemulsion has small particle size, increases the penetrability of epithelial cells of the intestinal tract, and can obviously improve the bioavailability of the medicament. Compared with microemulsion, the self-emulsifying solution has higher stability and can meet the requirement of long-term storage. The pharmaceutical composition has stable content. Compared with the original medicine Zytiga, the difference after meal before meal is obviously reduced; the pharmaceutical composition can be further prepared into capsules, and the capsules have stable properties. However, the co-emulsifiers ethanol and propylene glycol used in the patent can be released from the contents during storage, so that the content of ethanol or propylene glycol in the contents is seriously reduced, and abiraterone may be precipitated during long-term storage.
In conclusion, the abiraterone acetate has the characteristics of low solubility and osmotic pressure difference, the particle size is controlled to be in a small range by crushing the abiraterone acetate, the problem of poor oral bioavailability cannot be solved remarkably, the abiraterone acetate is prepared into the liquid capsule, the oral bioavailability of the abiraterone acetate can be improved obviously in theory, food influence is eliminated, and the phenomenon that the abiraterone is separated out in the long-term storage process due to the fact that propylene glycol or ethanol which is formed by contents in the liquid capsule is volatile is likely to happen.
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide a soft capsule preparation which can significantly improve the oral absorption bioavailability of abiraterone acetate, reduce inter-individual variability and eliminate food influence.
The technical scheme provided by the invention is as follows:
an abiraterone acetate soft capsule comprises a content and a capsule shell, and is characterized in that the content comprises active ingredients of abiraterone acetate, caprylic/capric acid monoglyceride and diglyceride, tween 80, span 80 and butylated hydroxyanisole.
Preferably, the concentration of the abiraterone acetate is between 60 and 100 mg/ml;
and/or
The mass of the abiraterone acetate accounts for 6-10% of the total mass of the medicine contents.
Preferably, the mass of the caprylic/capric acid monoglyceride is 60-77% of the total mass of the drug content.
More preferably, the contents include: the mass of the abiraterone acetate accounts for 6-10% of the total mass of the medicine contents, and the mass of the caprylic/capric acid monoglyceride accounts for 60-77% of the total mass of the medicine contents.
Preferably, the mass of the tween 80 accounts for 6 to 15 percent of the total mass of the medicine content.
Preferably, the weight of the span 80 accounts for 7-19% of the total weight of the drug content.
More preferably, the mass of the abiraterone acetate accounts for 6-10% of the total mass of the medicine contents, the mass of the caprylic/capric acid mono-diglyceride accounts for 60-77% of the total mass of the medicine contents, the mass of the Tween 80 accounts for 6-15% of the total mass of the medicine contents, and the mass of the span 80 accounts for 7-19% of the total mass of the medicine contents.
Preferably, the mass of the butyl hydroxy anisole accounts for 0.01-0.1% of the total mass of the medicine content.
Preferably, the capsule shell is made of soft capsule materials, and the soft capsule shell comprises the following components: gelatin, water, glycerol and sorbitol sorbitan solution MDF85, wherein the ratio of the components is 1:0.74:0.35: 0.35.
More preferably, the contents include: the mass of the abiraterone acetate accounts for 6-10% of the total mass of the medicine contents, the mass of the caprylic/capric acid monoglyceride accounts for 60-77% of the total mass of the medicine contents, the mass of the Tween 80 accounts for 6-15% of the total mass of the medicine contents, the mass of the span 80 accounts for 7-19% of the total mass of the medicine contents, and the mass of the butyl hydroxy anisole accounts for 0.01-0.1% of the total mass of the medicine contents.
Preferably, the abiraterone acetate soft capsule comprises contents and a capsule shell, wherein the contents comprise: the mass of the abiraterone acetate accounts for 6-10% of the total mass of the medicine contents, the mass of the caprylic/capric acid monoglyceride accounts for 60-77% of the total mass of the medicine contents, the mass of the Tween 80 accounts for 6-15% of the total mass of the medicine contents, the mass of the span 80 accounts for 7-19% of the total mass of the medicine contents, and the mass of the butyl hydroxy anisole accounts for 0.01-0.1% of the total mass of the medicine contents; the capsule shell is made of soft capsule materials, and comprises the following components: gelatin, water, glycerol and sorbitol sorbitan solution (MDF85), wherein the ratio of the components is 1:0.74:0.35: 0.35.
The invention also discloses a preparation method for preparing the abiraterone acetate soft capsule, which comprises the following steps: 1) glue melting: adding glycerol, sorbitan sorbate and water in a formula amount into a gelatin melting barrel, starting stirring, after the temperature in the barrel rises to 75-80 ℃, uniformly mixing the materials, adding gelatin in a formula amount, simultaneously vacuumizing to-0.05-0.06 MPa, keeping negative pressure and stirring for 25-35min, opening a top filling respirator until the vacuum disappears, and keeping the temperature at 55-60 ℃ and degassing for later use; 2) preparation of contents: dissolving abiraterone acetate in a mixed solution of caprylic acid capric acid mono-diglyceride, tween 80, span 80 and an antioxidant which is heated to 50 ℃, and uniformly stirring for later use; 3) pelleting: making into pill with soft capsule machine; 4) and (5) drying.
Wherein, the single oral dosage of the abiraterone soft capsule is 36-60mg calculated by abiraterone acetate.
The invention also discloses an application of the abiraterone acetate soft capsule in preparing a pharmaceutical preparation;
preferably, the use thereof for the preparation of a pharmaceutical preparation for the treatment of prostate cancer;
more preferably, the prostate cancer is selected from one or both of metastatic castration-resistant prostate cancer and metastatic high risk castration-sensitive prostate cancer.
The auxiliary material of the content provided by the invention can be used as a carrier of hydrophobic, insoluble or easily hydrolyzed drugs. The O/W type emulsion drops are spontaneously dispersed under the action of gastrointestinal peristalsis after being taken orally, the penetrability of intestinal epithelial cells is improved, the dissolution of the medicine can be improved, the absorption is promoted, the bioavailability of the medicine can be obviously improved, and the content is directly filled into a soft capsule, so that the requirement of long-term stable storage can be met.
The soft capsule containing abiraterone acetate of the invention at least has one of the following properties:
1) preparing abiraterone acetate into soft capsule, increasing drug dissolution, and mixing with water to rapidly and spontaneously form emulsion droplets with high clarity and stable properties;
2) the quality is stable and controllable when the product is stored at room temperature, and the quality is better than that of the product in patent CN110538150A example 1 within 6 months;
3) the content prescription of patent CN110538150A contains propylene glycol and ethanol, and as the storage time is prolonged, the propylene glycol and the ethanol can penetrate through the capsule shell and volatilize, so that the solubility of the drug is reduced, and the abiraterone acetate precipitates;
4) compared with the original medicine Zytiga, the difference between meals is obviously reduced, and the inter-individual variability is reduced;
5) compared with the original grinding medicine Zytiga, after the abiraterone acetate soft capsule is orally taken on an empty stomach, the dissolution step of the original grinding medicine Zytiga is not needed on the digestive tract, and the oral bioavailability is improved to 12.5 times;
6) the components in the prescription are conventional auxiliary materials, so the preparation method is easy to obtain, simple in preparation process, stable in product quality and easy for commercial production.
Determination of solvent
The abiraterone soft capsule preparation consists of an abiraterone soft capsule content and a soft capsule shell, and a content prescription needs to be researched simultaneously, so that a solvent of a self-developed preparation is firstly determined. This experiment investigated the dissolution of the crude drug in the contents of the abiraterone soft capsule in various solvents. In this experiment, 10g of each of purified water, ethanol, castor oil, capmul MCM (caprylic/capric acid mono-diglyceride), hydrogenated castor oil and medium-chain triglyceride is taken, and the dissolution of abiraterone Acetate (API) in these solvents is studied, which is detailed in Table 1.
TABLE 1 dissolution of abiraterone acetate
As can be seen from Table 1, abiraterone acetate has high solubility in ethanol, castor oil and caprylic/capric acid mono-diglyceride, but when ethanol is used as a solvent, a large amount of crystals are separated out after the abiraterone acetate is placed at room temperature for 24 hours; only 3% (25 ℃) in medium chain triglycerides, and almost insoluble in hydrogenated castor oil and purified water. Secondly, generally speaking, the self-microemulsifying drug delivery system is finally prepared into soft capsules or hard capsules, if ethanol and other volatile components are contained, the substances may penetrate through capsule shells to reduce the solubility of the drugs, so that lipophilic drugs are precipitated, namely, if the self-developing agent selects ethanol as a solvent, the ethanol is easy to seep out of the capsule shells and volatilize, and the proportion of the ethanol in the contents is seriously reduced in the preparation and storage processes, so that the drugs are likely to be crystallized and separated out; comparing the dissolution conditions of the abiraterone acetate in the castor oil and the caprylic/capric acid monoglyceride and diglyceride, the abiraterone acetate is found to be more easily dissolved in the caprylic/capric acid monoglyceride and the caprylic/capric acid monoglyceride has a certain emulsification effect, so that the abiraterone acetate is beneficial to the self-research reagent to form O/W type emulsion droplets by spontaneous dispersion under gastrointestinal peristalsis. Therefore, the preparation selects caprylic capric acid mono-diglyceride as the solvent of the self-developing agent.
Determination of surfactants
In order to enable the self-developing agent to spontaneously disperse under gastrointestinal peristalsis when meeting gastrointestinal fluids after oral administration to form O/W type emulsion droplets, most of the surfactants are nonionic surfactants with higher hydrophilic-lipophilic balance (HLB) values (generally 9-20), the surfactant is low in toxicity, relatively stable in solution, free from the influence of strong dielectrics, inorganic salts, acids and bases, good in compatibility with other types of surfactants, small in hemolytic effect, compatible with most of medicines and capable of causing reversible transformation of gastrointestinal tract wall permeability. Also, the surfactant is selected to allow for matching with the oil phase. In this experiment, surfactants such as polyoxyethylene castor oil (EL-40), span 80, tween 80 and polyethylene glycol-15 hydroxystearate (Solutol) were selected, and two or three of these surfactants were organically combined, and it was unexpectedly found that when the polyoxyethylene castor oil: tween 80: span 80 ═ 1:1:0.25 and tween 80: when span 80 is 1:1.25, the emulsifying effect is best, emulsion drops with blue opalescence are formed by slight shaking, and the emulsion drops can exist stably. See table 2 for details.
TABLE 2 selection of surfactants
The soft capsules are prepared by adopting the compositions of the 2 surfactants, and the influence of the soft capsules on the product quality is examined.
TABLE 3 Effect of surfactants on product quality (40 ℃. + -. 2 ℃/75% RH. + -. 5% RH)
As can be seen from table 3, different surfactant compositions, different product qualities, when tween 80: span 80 is 1:1.25, the product quality meets the requirement, and the total impurities are obviously lower than the prescription 2 in 3 months acceleration.
In conclusion, the surfactant composition of the self-developing agent is span 80 and tween 80, and the dosage of each surfactant is further optimized on the basis, and the details are shown in examples 1-4.
Drawings
FIG. 1 is a graph of abiraterone plasma timing following fasting oral administration of the self-triturating agent softgel (T) to dogs in example 1;
FIG. 2 is a graph of abiraterone profile in plasma of a dog of example 1 after fasting oral administration of the primary drug Zytiga tablet softgel (R1 st);
FIG. 3 is a graph of abiraterone plasma of the dog of example 1 after fasting oral administration of the primary drug Zytiga tablet soft capsule (R2 nd);
FIG. 4 is the Mean time curve (Mean + SD) of abiraterone in plasma of 6 dogs of example 1 after fasting oral administration of the different formulations;
figure 5 is the Mean time curve (Mean + SD) of abiraterone in plasma after fasting or postprandial oral administration of self-development agent for 8 dogs in example 1.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is shown that the described embodiments are only a part of the embodiments of the present invention, but not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Example 1
The embodiment provides an abiraterone acetate soft capsule (batch: 1000 granules), the content of which comprises the following components:
the medicinal composition is filled in a soft capsule shell as a content, and the soft capsule shell comprises the following components: gelatin, water, glycerol and sorbitol sorbitan solution MDF85, wherein the ratio of the components is 1:0.74:0.35: 0.35.
The preparation method is as follows:
1) glue melting: adding glycerol, sorbitan sorbate and water in a formula amount into a gelatin melting barrel, starting stirring, sealing and heating to 75 ℃, uniformly mixing the materials, adding gelatin in a formula amount, simultaneously vacuumizing to-0.05 to-0.06 MPa, keeping negative pressure and stirring for 25-35min, opening a top filling respirator until the vacuum disappears, and keeping the temperature and degassing at 55-60 ℃ for later use; 2) preparation of contents: dissolving abiraterone acetate in a mixed solution of caprylic acid capric acid mono-diglyceride, tween 80, span 80 and an antioxidant which is heated to 50 ℃, and uniformly stirring for later use; 3) pelleting: making into pill with soft capsule machine; 4) and (5) drying.
Example 2
The embodiment provides an abiraterone acetate soft capsule (batch: 1000 granules), the content of which comprises the following components:
the medicinal composition is filled in a soft capsule shell as a content, and the soft capsule shell comprises the following components: gelatin, water, glycerol and sorbitol sorbitan solution MDF85, wherein the ratio of the components is 1:0.74:0.35: 0.35.
The preparation method is as follows:
1) glue melting: adding glycerol, sorbitan sorbate and water in a formula amount into a gelatin melting barrel, starting stirring, sealing and heating to 75 ℃, uniformly mixing the materials, adding gelatin in a formula amount, simultaneously vacuumizing to-0.05 to-0.06 MPa, keeping negative pressure and stirring for 25-35min, opening a top filling respirator until the vacuum disappears, and keeping the temperature and degassing at 55-60 ℃ for later use; 2) preparation of contents: dissolving abiraterone acetate in a mixed solution of caprylic acid capric acid mono-diglyceride, tween 80, span 80 and an antioxidant which is heated to 50 ℃, and uniformly stirring for later use; 3) pelleting: making into pill with soft capsule machine; 4) and (5) drying.
Example 3
The embodiment provides an abiraterone acetate soft capsule (batch: 1000 granules), the content of which comprises the following components:
the medicinal composition is filled in a soft capsule shell as a content, and the soft capsule shell comprises the following components: gelatin, water, glycerol and sorbitol sorbitan solution MDF85, wherein the ratio of the components is 1:0.74:0.35: 0.35.
The preparation method is as follows:
1) glue melting: adding glycerol, sorbitan sorbate and water in a formula amount into a gelatin melting barrel, starting stirring, sealing and heating to 75 ℃, uniformly mixing the materials, adding gelatin in a formula amount, simultaneously vacuumizing to-0.05 to-0.06 MPa, keeping negative pressure and stirring for 25-35min, opening a top filling respirator until the vacuum disappears, and keeping the temperature and degassing at 55-60 ℃ for later use; 2) preparation of contents: dissolving abiraterone acetate in a mixed solution of caprylic acid capric acid mono-diglyceride, tween 80, span 80 and an antioxidant which is heated to 50 ℃, and uniformly stirring for later use; 3) pelleting: making into pill with soft capsule machine; 4) and (5) drying.
Example 4
The embodiment provides an abiraterone acetate soft capsule (batch: 1000 granules), the content of which comprises the following components:
the medicinal composition is filled in a soft capsule shell as a content, and the soft capsule shell comprises the following components: gelatin, water, glycerol and sorbitol sorbitan solution MDF85, wherein the ratio of the components is 1:0.74:0.35: 0.35.
The preparation method is as follows:
1) glue melting: adding glycerol, sorbitan sorbate and water in a formula amount into a gelatin melting barrel, starting stirring, sealing and heating to 75 ℃, uniformly mixing the materials, adding gelatin in a formula amount, simultaneously vacuumizing to-0.05 to-0.06 MPa, keeping negative pressure and stirring for 25-35min, opening a top filling respirator until the vacuum disappears, and keeping the temperature and degassing at 55-60 ℃ for later use; 2) preparation of contents: dissolving abiraterone acetate in a mixed solution of caprylic acid capric acid mono-diglyceride, tween 80, span 80 and an antioxidant which is heated to 50 ℃, and uniformly stirring for later use; 3) pelleting: making into pill with soft capsule machine; 4) and (5) drying.
Comparative example 1
With reference to patent CN110538150A, example 1, a process for formulation of comparative example 1 is provided, the contents of which comprise the following components:
this comparative example 1 further provides an abiraterone acetate capsule having the above-mentioned pharmaceutical composition as a content, and the content is filled in a capsule shell.
The preparation method is as follows:
taking hydrogenated castor oil/castor oil, glyceryl monooleate and polyoxyethylene castor oil EL35, adding abiraterone acetate, performing ultrasonic treatment for 10min in the dark, stirring for 20min by adopting mechanical stirring (300rpm) to fully dissolve the materials, adding propylene glycol and ethanol to form a transparent and uniform self-emulsifying solution, filling the self-emulsifying solution into a soft capsule or sealing the self-emulsifying solution in a hard capsule under the nitrogen protection condition, and storing the self-emulsifying solution.
Example 5
The present experimental example provides dissolution tests of the abiraterone acetate soft capsules and the original ground drug Zytiga tablets provided in examples 1-4 and comparative example 1.
The test method comprises the following steps: according to the second method of 0931 of the four ministry of communications in the edition of "Chinese pharmacopoeia" 2015, the dissolution rate of the abiraterone acetate soft capsule is detected, and the dissolution rate detection is respectively carried out on the abiraterone acetate soft capsule (prepared in examples 1 and 2) and the Zytiga tablet of the original medicine under the conditions of 37 ℃ and 900ml of SDS medium with the pH value of 4.5-0.25% and 50 r/min.
Wherein, pH4.5-0.25% SDS medium: weighing 6.78g of anhydrous sodium dihydrogen phosphate, adding 1000ml of water for dissolving, adjusting the pH value to 4.5 by using 5mol/L sodium hydroxide solution to obtain a buffer solution, weighing 2.5g of sodium dodecyl sulfate, adding into the buffer solution, and dissolving to obtain the sodium dodecyl sulfate buffer solution.
The specific method is as follows:
TABLE 1-1 dissolution (%). of Abiraterone acetate soft capsules and Zytiga tablets
| Sampling point/min | Zytiga | Example 1 | Example 2 | Example 3 | Example 4 | Comparative example 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 |
As shown by the comparison results in Table 1-1: firstly, the abiraterone acetate soft capsule (examples 1, 2, 3 and 4) is basically completely dissolved out in a medium for 15min (note: the dissolution rate standard of the original grinding medicament Zytiga: 45min is not less than 85.0 percent of the marked amount), while the dissolution rate of the abiraterone acetate tablet on the market still can not reach 85.0 percent in 30 min; ② the dissolution rate of the abiraterone acetate soft capsule (examples 1, 2, 3 and 4) of the invention has no significant difference with the comparative example 1. Therefore, the abiraterone acetate capsule provided by the invention can effectively improve the dissolution rate of abiraterone and obviously improve the oral bioavailability of the abiraterone acetate.
Example 6
This test example provides stability (long-term test and accelerated test) tests of the abiraterone acetate soft capsules provided in examples 1 to 4, and the test results are detailed in tables 2 to 1 and 2 to 2.
TABLE 2-1 stability of samples under long term test (25 ℃. + -. 2 ℃/60% RH. + -. 5% RH)
Note: "-" represents: the solution is clear, and the medicine is not precipitated;
"+" represents: the solution was clear and a small amount of drug precipitated.
TABLE 2-2 stability of samples in accelerated tests (40 ℃. + -. 2 ℃/75% RH. + -. 5% RH)
Note: "ND" means not detected; "NA" represents no detection.
As shown by the comparison results in Table 2-1: the abiraterone acetate soft capsules (examples 1, 2, 3 and 4) of the invention have no significant change in the content properties within a long period of 9 months, and the comparative example 1 has no significant difference within a long period of 6 months, but a small amount of medicine is separated out within a long period of 9 months, which is caused by the following reasons: the contents of comparative example 1 were formulated to contain propylene glycol and ethanol, which may penetrate the capsule shell and volatilize with prolonged storage time, reducing the solubility of the drug, resulting in precipitation of abiraterone acetate.
As shown by the comparison results in Table 2-2: the abiraterone acetate soft capsule (examples 1, 2, 3 and 4) has a growing trend of total impurities within 6 months, and meets the product quality requirement (note: the total impurities in the quality standard of the original grinding medicament Zytiga can not exceed 2.0%); ② the abiraterone acetate soft capsule (examples 1, 2, 3, 4) of the invention has a total impurity increase range obviously smaller than that of the comparative example 1 in 6 months
Example 7
This test example provides the self-emulsifying ability and stability tests of the abiraterone acetate soft capsules provided in examples 1 to 4.
The abiraterone acetate soft capsules prepared in examples 1 to 4 were added to purified water, and appearance properties and solution stability at room temperature were observed after slight shaking. See Table 3-1 for details
TABLE 3-1 sample self-emulsifying Capacity and stability results
Example 8
This experimental example provides pharmacokinetic testing of example 1 and abiraterone acetate proto-research drug Zytiga.
And (3) experimental design: because the original research medicine Zytiga (abiraterone acetate tablets) has large in-vivo variability, the pharmacokinetic research adopts 6 dogs in a three-cycle cross test, 1 time of abiraterone acetate soft capsule (specification: 40mg) and 2 times of original research medicine Zytiga (specification: 250mg, 2 tablets each) are orally taken on an empty stomach, blood samples are collected, the concentration of abiraterone in plasma is measured, and main pharmacokinetic parameters are calculated. See Table 4-1 for details.
Test objects: healthy beagle dogs, 6, were randomized into 3 groups of 2 dogs each and subjected to 3-cycle crossover trials. During the test period, water is freely drunk, the food is fasted for more than 12 hours before the drug administration in each period, the preparation is taken with 20ml of water when the drug is administered, and the preparation is fed after 6 hours of the drug administration. The washing period is 7 days in the week period.
TABLE 4-1 comparative pharmacokinetic study group design
Note: t: abiraterone acetate soft capsule is administered to 1 dog, namely 40 mg/dog;
r: abiraterone acetate tablets were administered at 2/dog, i.e. 500 mg/dog.
TABLE 4-2 original drug Zytiga 500mg vs. abiraterone acetate soft capsule 40mg pharmacokinetic parameters (open web test)
Note: tmax is the time to peak, Cmax is the maximum plasma concentration (peak concentration), AUClast is the AUC (area of curve at time of drug) of the duration from the start of administration to the last point;
as can be seen from Table 4-2, the oral bioavailability (AUClast) of 1 granule of abiraterone acetate soft capsule (specification 40mg) orally administered to beagle dogs on an empty stomach compared with Zytiga (R1st) and Zytiga (R2nd) in the former research respectively reaches 101.9% and 95.3%. The result shows that compared with the original medicine Zytiga (specification of 250mg), the abiraterone acetate soft capsule of the invention has the advantages that the oral bioavailability is improved to 12.5 times, and the variability of AUClast is smaller.
As can be seen from FIG. 1, FIG. 2 and FIG. 3, the abiraterone acetate soft capsule has similar time curve for abiraterone administration of different individuals, while the original grinding medicine Zytiga has more discrete time curve for different individuals. The reason for this may be that the soft capsule formulation does not need to go through the dissolution step of the original ground drug Zytiga in the digestive tract, which directly affects the absorption of the drug, thereby improving bioavailability and reducing individual differences.
In summary, after the abiraterone acetate soft capsule is orally taken by dogs on an empty stomach, the dissolution step of the original research medicine Zytiga is skipped on the digestive tract, the oral bioavailability (AUClast) of the abiraterone acetate soft capsule is 12.5 times of the original research medicine Zytiga, and the abiraterone acetate soft capsule can obtain more consistent T among individualsmax、CmaxAnd AUC, thereby facilitating the implementation of clinical treatments and the control of safety risks.
Example 9
This test example provides the absorption impact test of food on example 1.
And (3) experimental design: 8 dogs are subjected to a double-cycle cross test, and the abiraterone acetate soft capsules are orally taken respectively after a fasting state and a meal, blood samples are collected, the concentration of the abiraterone in blood plasma is measured, and main pharmacokinetic parameters are calculated. See Table 5-1 for details.
Test objects: healthy beagle dogs, 8, were randomized into 2 groups of 4 dogs each, and 3 cycle crossover trials were performed. Water was freely drunk during the test. Fasting administration is carried out for more than 12 hours before administration, the preparation is taken with 20ml of water during administration, and the preparation is fed after 6 hours of administration; postprandial dosing was given 30 minutes prior to dosing by gastric tube dosing. The washing period is 7 days in the week period.
TABLE 5-1 food impact study group design
Note: t: abiraterone acetate soft capsule is administered at a dose of 1 capsule per dog, i.e. 40mg per dog.
TABLE 5-2 pharmacokinetic parameters of Abiraterone in plasma after oral Abiraterone acetate Soft capsules on an empty stomach of dogs
TABLE 5-3 pharmacokinetic parameters of Abiraterone in plasma after oral administration of Abiraterone acetate Soft capsules after Canine meal
Relative bioavailability per individual F ═ AUC after meal of abiraterone acetate softgel0-tFasting AUC0-t)*100％
As shown in tables 5-2 and 5-3, the oral administration of abiraterone acetate soft capsule 30min after the dog meal resulted in 79.19% (44.45% -106.80%) of the relative bioavailability compared to the oral administration of abiraterone acetate soft capsule on empty stomach. The results of the paired t-test after natural log transformation of the major pharmacokinetic parameters are shown in tables 5-4.
TABLE 5-4 results of t-test for major pharmacokinetic parameter pairings of Abiraterone in plasma after oral administration of Abiraterone acetate Soft capsules on dogs with fasting plasma or postprandial plasma
As shown in tables 5-4, compared with the soft capsule of Abiraterone acetate taken on an empty stomach, the difference of Cmax after the soft capsule is taken by dogs after meals has significant significance (P <0.01), and the difference of AUC0-t and AUCinf has no statistical significance.
The literature reports that the exposure of the original research drug Zytiga high-fat postprandial abiraterone can reach 10 times of the fasting exposure. In the test, after the abiraterone acetate soft capsule is orally taken by dogs on an empty stomach or after meals, the exposure of the abiraterone is not increased, and the reason probably is that the abiraterone acetate soft capsule does not need to be subjected to the dissolution step of the original grinding medicine Zytiga on the digestive tract, the medicine is dissolved without fat in food, namely, the higher exposure is achieved, and the absorption degree of the abiraterone acetate soft capsule cannot be improved any more due to the existence of the food. The relative bioavailability of abiraterone administered after a meal is slightly lower than that of fasting, probably because food promotes peristaltic emptying of the digestive tract, resulting in a shorter residence time of the drug at the site of primary absorption.
In conclusion, compared with the fasting state, after the dog takes the self-research preparation orally after meal, the exposure of the abiraterone is slightly reduced, and the phenomenon that the exposure of the abiraterone is obviously increased when the original medicine Zytiga is taken after meal is avoided. Thus, the abiraterone acetate soft capsules can reduce the safety risks associated with abiraterone exposure caused by diet.
While the invention has been described in detail in the foregoing by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that certain modifications may be made in the invention without departing from the spirit thereof. Accordingly, such modifications and variations that do not depart from the gist of the invention are intended to be within the scope of the invention as claimed.
Claims (14)
1. An abiraterone acetate soft capsule comprises a content and a capsule shell, and is characterized in that the content comprises active ingredients of abiraterone acetate, caprylic/capric acid monoglyceride and diglyceride, tween 80, span 80 and butylated hydroxyanisole.
2. The abiraterone acetate soft capsule of claim 1, wherein: the concentration of the abiraterone acetate is between 60 and 100mg/ml based on the total volume of the contents;
and/or
The mass of the abiraterone acetate accounts for 6-10% of the total mass of the medicine contents.
3. The abiraterone acetate soft capsule of claim 1, wherein the mass of the caprylic/capric acid monoglyceride is 60-77% of the total mass of the drug content.
4. The abiraterone acetate soft capsule of claim 1, wherein the mass of the abiraterone acetate accounts for 6-10% of the total mass of the drug contents, and the mass of the caprylic capric acid monoglyceride accounts for 60-77% of the total mass of the drug contents.
5. The abiraterone acetate soft capsule of claim 1, wherein the mass of the tween 80 is 6-15% of the total mass of the drug content.
6. The abiraterone acetate soft capsule of claim 1, wherein the weight of the span 80 accounts for 7-19% of the total weight of the drug content.
7. The abiraterone acetate soft capsule of claim 1, wherein the mass of the abiraterone acetate accounts for 6-10% of the total mass of the drug contents, the mass of the caprylic/capric acid monoglyceride accounts for 60-77% of the total mass of the drug contents, the mass of the tween 80 accounts for 6-15% of the total mass of the drug contents, and the mass of the span 80 accounts for 7-19% of the total mass of the drug contents.
8. The abiraterone acetate soft capsule of claim 1, wherein the mass of the butylated hydroxyanisole accounts for 0.01% -0.1% of the total mass of the drug contents.
9. The abiraterone acetate soft capsule of claim 1, wherein the mass of the abiraterone acetate accounts for 6-10% of the total mass of the medicine contents, the mass of the caprylic capric acid monoglyceride accounts for 60-77% of the total mass of the medicine contents, the mass of the tween 80 accounts for 6-15% of the total mass of the medicine contents, the mass of the span 80 accounts for 7-19% of the total mass of the medicine contents, and the mass of the butyl hydroxyanisole accounts for 0.01-0.1% of the total mass of the medicine contents.
10. The abiraterone acetate soft capsule of claim 1, wherein the capsule shell is made of soft capsule material, and comprises: gelatin, water, glycerol and sorbitol sorbitan solution MDF85, wherein the ratio of the components is 1:0.74:0.35: 0.35.
11. The abiraterone acetate soft capsule of claim 1, wherein the contents comprise: the mass of the abiraterone acetate accounts for 6-10% of the total mass of the medicine contents, the mass of the caprylic/capric acid monoglyceride accounts for 60-77% of the total mass of the medicine contents, the mass of the Tween 80 accounts for 6-15% of the total mass of the medicine contents, the mass of the span 80 accounts for 7-19% of the total mass of the medicine contents, and the mass of the butyl hydroxy anisole accounts for 0.01-0.1% of the total mass of the medicine contents; the capsule shell is made of soft capsule materials, and comprises the following components: gelatin, water, glycerol and sorbitol sorbitan solution (MDF85), wherein the ratio of the components is 1:0.74:0.35: 0.35.
12. A process for preparing the abiraterone acetate soft capsule of claims 1-11, comprising: 1) glue melting: adding glycerol, sorbitan sorbate and water in a formula amount into a gelatin melting barrel, starting stirring, after the temperature in the barrel rises to 75-80 ℃, uniformly mixing the materials, adding gelatin in a formula amount, simultaneously vacuumizing to-0.05-0.06 MPa, keeping negative pressure and stirring for 25-35min, opening a top filling respirator until the vacuum disappears, and keeping the temperature at 55-60 ℃ and degassing for later use; 2) preparation of contents: dissolving abiraterone acetate in a mixed solution of caprylic acid capric acid mono-diglyceride, tween 80, span 80 and an antioxidant which is heated to 50 ℃, and uniformly stirring for later use; 3) pelleting: making into pill with soft capsule machine; 4) and (5) drying.
13. The abiraterone acetate soft capsule of claims 1-11, wherein the single oral dose is 36-60mg, preferably 40mg, calculated as abiraterone acetate.
14. Use of the abiraterone acetate soft capsule of claims 1-11 in the preparation of a pharmaceutical formulation;
preferably, the use thereof for the preparation of a pharmaceutical preparation for the treatment of prostate cancer;
more preferably, the prostate cancer is selected from one or both of metastatic castration-resistant prostate cancer and metastatic high risk castration-sensitive prostate cancer.
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| CN114306236A (en) * | 2021-12-15 | 2022-04-12 | 湖南慧泽生物医药科技有限公司 | Self-microemulsion system for loading abiraterone acetate, composition and application |
| WO2023000873A1 (en) * | 2021-07-22 | 2023-01-26 | 浙江和泽医药科技股份有限公司 | Abiraterone acetate soft capsule and preparation method therefor and application thereof |
| WO2023109758A1 (en) * | 2021-12-15 | 2023-06-22 | Hunan Huize Biopharma S&T Co., Ltd | Abiraterone acetate-containing composition and application thereof |
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