CN111012745A - Abiraterone oral emulsion and preparation method thereof - Google Patents
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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Abstract
The invention discloses an abiraterone oral emulsion and a preparation method thereof. The preparation comprises: the active component is abiraterone acetate or abiraterone, and comprises 2-10% of abiraterone acetate or abiraterone, 20-70% of solubilizer, 20-40% of emulsifier and 0.01-1% of solubilizer in percentage by weight. The abiraterone oral emulsion disclosed by the invention is high in drug loading, good in stability and capable of spontaneously emulsifying to form emulsion when meeting water. The formed emulsion is stable and has little influence on digestion, and can improve the dissolution of the medicine in the gastrointestinal tract, promote the medicine absorption and improve the bioavailability.
Description
Technical Field
The invention relates to an abiraterone oral emulsion and a preparation method thereof.
Background
The structure of abiraterone (17- (3-pyridyl) -androstane-5, 16-diene-3-ol, CAS number: 154229-19-3, molecular formula: C24H31NO, molecular weight: 349.5g/mol) is shown in the specification.
Abiraterone acetate (17- (3-pyridyl) -androstane-5, 16-diene-3 β -acetate, CAS number: 154229-18-2, molecular formula: C26H33NO2, molecular weight: 391.55g/mol) has the following structure.
Abiraterone acetate is a prodrug of abiraterone, which is converted in vivo to abiraterone. The current clinical application is the abiraterone acetate tablet, the trade name is:
registration number of imported drugs: h20150264, originally developed by qiangsheng corporation and approved by the U.S. drug administration in 2011 for the treatment of metastatic castration resistant prostate cancer in combination with prednisone or prednisolone, and subsequently approved for the treatment of newly diagnosed high-risk metastatic endocrine treatment sensitive prostate cancer.
The abiraterone acetate has poor water solubility, so that the bioavailability of the abiraterone acetate tablet is low. According to the published data of the FDA, the abiraterone acetate tablet has extremely low bioavailability. Animal drug experiments revealed that the relative bioavailability in rats was 37% and in monkeys and minipigs was only 1.6-1.7%. Clinical pharmacology data do not provide exact bioavailability data, only from14Mass balance of C-labeled drugs. The data disclosed in the mass balance experiments indicate that 88% (of 55% abiraterone acetate and 22% of abiraterone acetate) of the drug was excreted in feces and 5% of the drug was excreted in urine after oral administration, which is calculated to be less than 10% bioavailable in humans.
Abiraterone acetate tablets also had a significant food effect. According to the published data of the FDA, the absorption of abiraterone acetate tablets is very much affected by food and does not eat within 2 hours before and 1 hour after the administration. Feeding can be controlled by C, respectively, as compared to the fasted statemaxAnd AUC0-24hIncrease by 7 times and 5 times, if eating high fat meal, can make C respectivelymaxAnd AUC0-24hThe improvement is 17 times and 10 times.
Therefore, there is a need for an improved abiraterone acetate tablet, which improves its oral bioavailability and reduces the effect of food on its absorption.
The emulsion is a liquid preparation, and the active component is dissolved in the lipid adjuvant, thereby bypassing the dissolution process and having high dissolution rate. The components of the emulsion can be digested to directly solubilize the drug, or indirectly solubilize the drug by forming micelles with phospholipids and bile acids in the digestive system. The emulsion can inhibit P-gp and other drug pumps, increase drug permeability, and can be absorbed by intestinal lymphatic system to avoid first pass effect. Therefore, the emulsion is a technology which can improve the drug absorption from the dissolution angle, and also from the aspects of penetration and metabolism.
Emulsions can be divided into four categories according to their composition:
(1) class I, which is mainly composed of fatty glyceride, the glyceride is insoluble in water, so the emulsion can form emulsion after being digested, and then is absorbed;
(2) class II, adding a low HLB surfactant as an emulsifier on the basis of class I, wherein the emulsion can spontaneously form colostrum after meeting water, and the particle size of the emulsion is micron-sized, so that compared with class I, the emulsion has a larger surface area and is easier to digest so as to promote absorption;
(3) class III, adding a high HLB surfactant as an emulsifier on the basis of the former two classes, spontaneously emulsifying in water to form an emulsion, wherein the particle size is usually nano-scale, and the emulsion can provide solubilization for active components without digestion to promote absorption;
(4) and IV, the oil-in-water type surfactant does not contain fatty glyceride, mainly comprises a high HLB surfactant and a cosolvent, is dispersed and dissolved in water, and directly solubilizes active components to promote absorption.
According to the report of the literature, 26 emulsion medicines are clinically used in the search, wherein 16 emulsion medicines exist in the I class, 3 emulsion medicines exist in the II class, 5 emulsion medicines exist in the III class, and 2 emulsion medicines exist in the IV class. Class I
Approved earlier than 1941, class II
Approved at the earliest in 1983, class III
Approved earliest in 1995, class IV
Was first approved in 1999 reflecting the course of emulsion development.
Although it is widely known that an emulsion solubilizes poorly soluble drugs and improves bioavailability, the proportion of the emulsion in drugs is estimated to be about 2 to 3%, and considering that the poorly soluble drugs account for about 40% of the drugs already on the market and account for more than 70% of the drugs in development lines, the proportion of the emulsion is very low. This presents difficulties in the development of emulsions, mainly including:
(1) first, APIs are relatively unstable in emulsions and are easily degraded, whereas good stability is a prerequisite for pharmaceutical products.
(2) Secondly, sufficient drug loading is also a key factor in drug potency. The drug loading is the amount of API in the emulsion in which the API needs to be completely dissolved, and is therefore limited by the solubility of the API in the solubilizer, emulsifier, etc. in the emulsion. If the drug loading is too low, it means that too much adjuvant is used in a single administration, and the dosage is more than the conventional daily administration dosage, which may cause a safety problem.
(3) Finally, the emulsion is mainly composed of grease and surfactant, and after entering the gastrointestinal tract, the grease and the surfactant can take the effect of digesting the environment in the body, influence the stability of the formed emulsion, cause the precipitation of the medicine and limit the absorption of the medicine.
Currently, attempts have been made to develop abiraterone acetate emulsions.
Chinese patent CN102961358B discloses an abiraterone acetate liquid capsule, which is mainly characterized in that abiraterone acetate is dissolved in fatty acid glyceride type auxiliary materials, and a surfactant is not used as an emulsifier, so that the abiraterone acetate liquid capsule is a type I emulsion.
US9511078B2 discloses an abiraterone acetate emulsion, which is prepared by screening out lipid auxiliary materials which are good for dissolving abiraterone acetate as a solubilizer and adding a surfactant with high HLB value as an emulsifier according to calculation of theoretical dissolving parameters. According to the results of example 3, the addition of crystallization inhibitors is essential to improve the stability of the emulsion droplets and to reduce the particle size of the emulsion droplets.
Chinese patent CN107073127A discloses an abiraterone acetate solid emulsion, which is mainly characterized in that: (1) long-chain fatty glyceride is used for promoting abiraterone acetate to be absorbed by lymph, so that the first pass effect caused by metabolism is avoided; (2) the liquid emulsion is absorbed into solid carrier, and then made into oral tablet by tabletting.
They all have more or less drawbacks, such as the emulsion described in chinese patent CN102961358B, although it can bypass the dissolution process and has a fast dissolution rate, but the release of the drug is difficult because the oil is insoluble in water. Emulsions such as those described in US9511078B2 rely on crystallization inhibitors to maintain emulsion stability. For example, the preparation described in Chinese patent CN107073127A needs to use a large amount of solid carriers to solidify the emulsion, thereby greatly reducing the drug loading.
Disclosure of Invention
The invention aims to provide an abiraterone emulsion and a preparation method thereof, and solves the technical problem of low bioavailability of abiraterone or abiraterone acetate.
The abiraterone emulsion disclosed by the invention contains active components, a solubilizer, an emulsifier and an antioxidant, is liquid at room temperature, and can be formed into an emulsion by adding the emulsion into water of which the volume is 5-100 times that of the emulsion and stirring, wherein the active components dissolved in a water phase account for 50-100%; the emulsion is stable in simulated gastric or intestinal digestive fluid, and contains active components dissolved in water phase 50-100%.
The active component of the invention is abiraterone acetate or abiraterone, preferably abiraterone acetate.
The solubilizer is fatty acid ester, specifically refers to mixed glyceride, propylene glycol fatty acid ester or a mixture of the two, wherein the mixed glyceride is caprylic capric acid monoglyceride and linolic acid glyceride, the propylene glycol fatty acid ester is propylene glycol monocaprylate, and more preferably, the solubilizer is caprylic capric acid monoglyceride, propylene glycol monocaprylate, linolic acid glyceride, or a mixture of caprylic capric acid monoglyceride and propylene glycol monocaprylate.
The emulsifier in the invention is a nonionic surfactant with HLB value more than 10, such as polyoxyethylene castor oil, polyethylene glycol glyceride, tween, etc., preferably polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil or a mixture of the two, further the emulsifier is preferably polyoxyethylene hydrogenated castor oil, more preferably polyoxyethylene 40 hydrogenated castor oil.
The antioxidant is tert-butyl p-hydroxyanisole, dibutyl hydroxy toluene or a mixture of the tert-butyl p-hydroxyanisole and the dibutyl hydroxy toluene, and the dibutyl hydroxy toluene is preferred.
The abiraterone emulsion comprises 2-10 wt% of abiraterone acetate or abiraterone, 20-70 wt% of solubilizer, 20-40 wt% of emulsifier and 0.01-1 wt% of solubilizer; preferably 5 to 10 percent of active component, 50 to 70 percent of solubilizer, 30 to 40 percent of emulsifier and 0.01 to 1 percent of antioxidant. Further, the abiraterone emulsion contains 2-10% of abiraterone acetate, 0-30% of caprylic/capric acid monoglyceride, 20-60% of propylene glycol monocaprylate, 20-40% of polyoxyethylene 40 hydrogenated castor oil and 0.01-1% of dibutyl hydroxy toluene; preferably 5-10% of abiraterone acetate, 10-30% of caprylic/capric acid monoglyceride, 30-60% of propylene glycol monocaprylate, 30-40% of polyoxyethylene 40 hydrogenated castor oil and 0.01% -1% of dibutyl hydroxy toluene. Or, contains 2-10% of abiraterone acetate, 0-60% of glycerol monolinoleate, 20-60% of propylene glycol monocaprylate, 20-40% of polyoxyethylene 40 hydrogenated castor oil and 0.01% -1% of dibutyl hydroxy toluene; preferably 10% abiraterone acetate, 10-60% glycerol monolinoleate, 30-60% propylene glycol monocaprylate, 30-40% polyoxyethylene 40 hydrogenated castor oil, 0.01% -1% dibutyl hydroxy toluene.
The abiraterone self-emulsifying drug delivery system has the advantages of high drug loading, good stability and formation of emulsion by spontaneous emulsification when meeting water. The formed emulsion is stable and is slightly influenced by digestion, the adverse influence of abiraterone acetate hydrolysis on drug dissolution can be reduced, the dissolution of the drug in gastrointestinal tracts can be improved, the drug absorption is promoted, and the bioavailability is improved.
Detailed Description
The present invention will be further described with reference to specific examples for better illustrating the present invention, but the present invention is not limited to the examples.
All reagents are commercial reagents, the analysis is pure, and all auxiliary materials are commercial auxiliary materials and meet the standards for medicine and injection or the pharmacopoeia standards.
The term 1: mixed glycerides refer to: a mixture of fatty acid monoglyceride, fatty acid diglyceride, and fatty acid glyceride triglyceride is prepared by partial hydrolysis of fatty acid glyceride triglyceride and glycerol. The commercially available pharmaceutical adjuvant caprylic/capric acid mono-di-glyceride is mixed caprylic/capric acid glyceride (such as Capmul MCM of abitec), the mono-linoleic acid glyceride (such as Maisine CC of Jiafa lion) is mixed linoleic acid glyceride, and the mono-oleic acid glyceride (such as Peceol of Jiafa lion) is mixed oleic acid glyceride.
The term 2: propylene glycol monoesters are products formed by esterification of propylene glycol with fatty acids, typically containing over 90% propylene glycol monoester, and-10% propylene glycol diester. For example, propylene glycol monocaprylate is a product formed by esterifying propylene glycol with caprylic acid, more than 90% of the propylene glycol monocaprylate can be obtained by process control, and no more than 10% of the propylene glycol dicaprylate can be contained. The commercially available pharmaceutical adjuvant propylene glycol monocaprylate is a mixture of propylene glycol monocaprylate (> 90%) and propylene glycol dicaprylate (< 10%) (e.g., Capmul PG-8 from Abitec and Capryol 90 from Jiafao).
The term 3: the polyoxyethylene castor oil and the polyoxyethylene hydrogenated castor oil are products generated by respectively reacting epoxy ethylene with castor oil and hydrogenated castor oil, and the chain length of polyoxyethylene can be controlled according to different feeding amounts. For example, polyoxyethylene 40 hydrogenated castor oil is a product of the reaction of 40mol of ethylene oxide with 1mol of hydrogenated castor oil, and the pharmaceutical excipient Kolliphor RH40 sold by Basff is polyoxyethylene 40 hydrogenated castor oil.
Example 1: investigation of auxiliary materials
Table 1: examination of solubility of auxiliary materials
Table 2: examination of emulsification Properties of auxiliary materials
Table 3: investigation of stability of auxiliary Material
The results show that: (1) after the abiraterone acetate is dissolved into the ester auxiliary materials, the abiraterone acetate is very easy to degrade; (2) the stability of the abiraterone acetate in the emulsion can be effectively improved by adding the antioxidant.
Example 2: preparation of abiraterone oral emulsion
The preparation method of the abiraterone emulsion comprises the following steps:
(1) heating the solubilizer and the emulsifier to 60 ℃, and uniformly stirring to obtain a solution 1;
(2) adding an antioxidant into the solution 1, and stirring and dissolving to obtain a solution 2;
(3) adding the active ingredients into the solution 2, stirring and dissolving to obtain the emulsion.
Example 3: emulsion evaluation
The emulsion was prepared according to the ratio of the components as described in example 2. 1g of the emulsion was weighed, added to 9ml of purified water, dissolved with stirring, and the emulsion properties were observed.
(1) Simulated gastric digestion evaluation:
according to The Koziolek, M., et al (2019), "The mechanism of pharmacological food-drug interactions-A curative from The UNGAP group," European journal of Pharmaceutical Sciences 134:31-59, it is reported that The amount of liquid in The stomach is greatly affected by eating conditions, that The amount of liquid in The stomach is about 35ml in fasting conditions, and that The pH is about 1. First 5g of the emulsion was diluted to 50ml of emulsion, then mixed with 35ml of artificial gastric juice (chinese pharmacopoeia, containing pepsin) and gastric digestion was simulated for 1 hour at 37 ℃. And (4) centrifugally separating an oil phase from a digested sample, and separating out solids, and then determining the concentration of the active component in the water phase.
(2) Simulated intestinal digestion evaluation:
according to The document Koziolek, M., et al (2019), "The mechanisms of pharmacological food-drug interactions-A periodic from The UNGAP group," European journal of Pharmaceutical Sciences 134:31-59, it is reported that The amount of intestinal fluid is not substantially affected by eating conditions, and in The fasting and satiety conditions is about 80 ml. First 5g of the emulsion was diluted to 50ml of emulsion, then mixed with 80ml of simulated intestinal fluid and gastric digestion was simulated for 1 hour at 37 ℃. Preparation of intestinal fluids reference Porter, c.j.h.and w.n.charman (2001), "In vitro assessment of organic lipid based formulations," Advanced drug delivery Reviews 50: S127-S147. after digestion, samples were centrifuged to separate the oil phase and precipitate solids, and the concentration of active ingredient In the aqueous phase was determined.
The compositions of the components and the evaluation and investigation results are detailed in the following table:
the results of the experiment are shown in the following table:
the results show that the absorption of abiraterone acetate of component 1 and component 9 can be respectively improved by 3.4 times and 2.4 times compared with the original tablet.
In conclusion, the dosage form, the formula and the preparation method provided by the invention successfully improve the absorption of the abiraterone acetate, and are expected to reduce the clinical dosage, thereby reducing the medicine cost and relieving the burden of patients.
Claims (12)
1. An abiraterone oral emulsion is characterized by comprising active ingredients, a solubilizer, an emulsifier and an antioxidant;
the active ingredient is abiraterone (I) or abiraterone acetate (II), and the active ingredient has the following structural formula:
2. an abiraterone oral emulsion of claim 1 wherein, by weight, the active ingredients are 2% -10%, the solubilizer is 20% -70%, the emulsifier is 20% -40%, and the antioxidant is 0.01% -1%; the emulsifier is a nonionic surfactant with HLB value more than 10.
3. An abiraterone oral emulsion of claim 2 wherein the active components are, by weight, 5% -10%, the solubilizer is 50% -70%, the emulsifier is 30% -40%, and the antioxidant is 0.01% -1%.
4. An abiraterone oral emulsion of any of claims 1 to 3 wherein the solubilizing agent is a mixed glyceride, a propylene glycol fatty acid ester or a mixture of both, the emulsifying agent is a polyoxyethylene castor oil, a polyoxyethylene hydrogenated castor oil or a mixture of both, and the antioxidant is t-butyl p-hydroxyanisole, dibutyl hydroxy toluene or a mixture of both.
5. An abiraterone oral emulsion of claim 4 wherein the solubilizer blend glycerides are preferably caprylic capric acid mono-di-glyceride, mono-linoleic acid glyceride; the propylene glycol fatty acid ester is preferably propylene glycol monocaprylate; the emulsifier is preferably polyoxyethylene hydrogenated castor oil.
6. An abiraterone oral emulsion of claim 5 wherein the polyoxyethylene hydrogenated castor oil is preferably polyoxyethylene 40 hydrogenated castor oil.
7. An oral emulsion of abiraterone as claimed in claim 1 or claim 2 wherein the active ingredient is abiraterone acetate, the solubilising agent is caprylic capric acid monoglyceride, propylene glycol monocaprylate or a mixture of caprylic capric acid monoglyceride and propylene glycol monocaprylate and the emulsifier is polyoxyethylene 40 hydrogenated castor oil.
8. An abiraterone oral emulsion of claim 7 which comprises, by weight, 2-10% abiraterone acetate, 0-30% caprylic/capric acid monoglyceride, 20-60% propylene glycol monocaprylate, 20-40% polyoxyethylene 40 hydrogenated castor oil, 0.01% -1% dibutylhydroxytoluene.
9. An abiraterone oral emulsion of claim 8 which comprises, by weight, 5-10% abiraterone acetate, 10-30% caprylic/capric acid monoglyceride, 30-60% propylene glycol monocaprylate, 30-40% polyoxyethylene 40 hydrogenated castor oil, 0.01% -1% dibutylhydroxytoluene.
10. An abiraterone oral emulsion of claim 1 or claim 2 wherein the active ingredient is abiraterone acetate, the solubilising agent is glyceryl monolinoleate, propylene glycol monocaprylate, or a mixture of glyceryl monocaprylate and propylene glycol monocaprylate, and the emulsifier is polyoxyethylene 40 hydrogenated castor oil.
11. An abiraterone oral emulsion of claim 10 which comprises, by weight, 2-10% abiraterone acetate, 0-60% glyceryl monolinoleate, 20-60% propylene glycol monocaprylate, 20-40% polyoxyethylene 40 hydrogenated castor oil, 0.01% -1% dibutylhydroxytoluene.
12. An abiraterone oral emulsion of claim 11 which comprises, by weight, 5-10% abiraterone acetate, 10-60% glyceryl monolinoleate, 30-60% propylene glycol monocaprylate, 30-40% polyoxyethylene 40 hydrogenated castor oil, 0.01% -1% dibutylhydroxytoluene.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113616614A (en) * | 2021-07-22 | 2021-11-09 | 浙江和泽医药科技股份有限公司 | Abiraterone acetate soft capsule and preparation method thereof |
| CN113750032A (en) * | 2020-06-01 | 2021-12-07 | 成都海博为药业有限公司 | Oral abiraterone medicinal composition and preparation method and application thereof |
| 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 |
| US11806313B2 (en) | 2021-12-15 | 2023-11-07 | Hunan Huize Biopharma S&T Co., Ltd. | Abiraterone acetate containing composition and application thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113750032A (en) * | 2020-06-01 | 2021-12-07 | 成都海博为药业有限公司 | Oral abiraterone medicinal composition and preparation method and application thereof |
| CN113616614A (en) * | 2021-07-22 | 2021-11-09 | 浙江和泽医药科技股份有限公司 | Abiraterone acetate soft capsule and preparation method thereof |
| CN116033925A (en) * | 2021-07-22 | 2023-04-28 | 浙江和泽医药科技股份有限公司 | Abiraterone acetate soft capsule and preparation method and application thereof |
| CN116033925B (en) * | 2021-07-22 | 2024-02-27 | 浙江和泽医药科技股份有限公司 | Abiraterone acetate soft capsule and preparation method and application thereof |
| 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 |
| US11806313B2 (en) | 2021-12-15 | 2023-11-07 | Hunan Huize Biopharma S&T Co., Ltd. | Abiraterone acetate containing composition and application thereof |
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