CN110742870A - Abiraterone acetate preparation and preparation method thereof - Google Patents
Abiraterone acetate preparation and preparation method thereof Download PDFInfo
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- CN110742870A CN110742870A CN201911225983.8A CN201911225983A CN110742870A CN 110742870 A CN110742870 A CN 110742870A CN 201911225983 A CN201911225983 A CN 201911225983A CN 110742870 A CN110742870 A CN 110742870A
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- abiraterone acetate
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- glutathione
- malic acid
- abiraterone
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2063—Proteins, e.g. gelatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention belongs to the technical field of medicines, and particularly relates to an abiraterone acetate preparation and a preparation method thereof. The abiraterone acetate preparation disclosed by the invention contains not only abiraterone acetate, but also glutathione and L-malic acid, wherein in every 1000 preparation units, the dosage of the abiraterone acetate is 250g, the dosage of the glutathione is 100g, and the dosage of the L-malic acid is 15 g. The abiraterone acetate preparation disclosed by the invention is small in auxiliary material dosage, simple in preparation process, good in solubility and stable in quality.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an abiraterone acetate preparation and a preparation method thereof.
Background
Abiraterone acetate, chemical name (3 β) -17- (3-pyridine) androst-5, 16-diene-3-yl acetate, is an orally effective CYP17 enzyme irreversible inhibitor developed by Centocor Ortho company in America, is approved by the FDA in America at 4 months in 2011 and is clinically used with prednisone to treat castration-resistant prostate cancer.
In order to solve this problem, many methods have been tried in the prior art, such as preparation techniques of solid dispersion, inclusion compound, particle size control, etc., or addition of a large amount of different preparation adjuvants, etc. For example: chinese applications 201110329128.9, 201510596145.7, 201710466293.6 employ dispersion formulations; the Chinese application 201910551447.0 adopts an inclusion preparation process; the particle size needs to be controlled in the preparation process of Chinese applications 201210169791.1 and 201210262101.7; chinese application 201410611711.2 requires control of porosity. However, these technical means have great defects, for example, these systems all need to add a large amount of auxiliary materials, and the addition of a large amount of auxiliary materials causes a significant increase in the risk of medication safety, and increases the cost of the preparation, which puts a burden on patients. In addition, the preparation process of the dispersion system preparation and the clathrate compound preparation is complex and tedious, and the process uniformity is poor.
Disclosure of Invention
The invention aims to solve the problems in the prior art, provides an abiraterone acetate preparation which is simple in preparation technology, small in auxiliary material dosage, good in solubility and stable in quality, and can simplify the preparation process and improve the safety of medication. Therefore, the inventor conducts a large number of experiments, and unexpectedly finds that the dissolution rate of the abiraterone acetate preparation can be improved by adding glutathione and L-malic acid into the abiraterone acetate preparation, the abiraterone acetate preparation has excellent stability, and meanwhile, the preparation process is extremely simple and easy to operate.
The technical scheme provided by the invention is as follows:
the abiraterone acetate preparation contains not only abiraterone acetate, but also glutathione and L-malic acid.
Preferably, every 1000 preparation units, the dosage of the abiraterone acetate is 250g, the dosage of the glutathione is 100g, and the dosage of the L-malic acid is 15 g.
Preferably, the abiraterone acetate formulation is 0.25g in size.
Preferably, the abiraterone acetate formulation is a tablet.
Preferably, the abiraterone acetate tablet is prepared by the following method:
(1) sequentially sieving abiraterone acetate, glutathione and L-malic acid which are dried at 60 ℃ in advance through a 80-mesh sieve;
(2) mixing all the raw materials, measuring content, determining tablet weight according to specification, tabletting, inspecting, and packaging.
The invention also provides a preparation method of the abiraterone acetate tablet, which comprises the following steps:
(1) drying the abiraterone acetate, the glutathione and the L-malic acid according to the prescription amount at 60 ℃ in advance, and then sequentially sieving the dried substances through a 80-mesh sieve;
(2) mixing all the raw materials, measuring content, determining tablet weight according to specification, tabletting, inspecting, and packaging.
Preferably, the prescribed amounts are:
every 1000 abiraterone acetate tablets contain:
abiraterone acetate: 250g of,
Glutathione: 100g of,
L-malic acid: 15 g.
The invention adopts glutathione and L-malic acid as the auxiliary materials of the abiraterone acetate tablet, the use of the 2 auxiliary materials is beneficial to increasing the solubility and the stability of the abiraterone acetate, and the effect of the specific proportion of adding 100g of glutathione and 15g of L-malic acid to every 250g of abiraterone acetate is optimal.
Detailed Description
In order that the invention may be more readily understood, specific embodiments thereof will be described further below.
Example 1
Prescription:
abiraterone acetate: 25g of,
Glutathione: 10g of,
L-malic acid: 1.5g of a mixture of (A) and (B),
made into 100 pieces
The process comprises the following steps:
(1) drying the abiraterone acetate, the glutathione and the L-malic acid according to the prescription amount at 60 ℃ in advance, and then sequentially sieving the dried substances through a 80-mesh sieve;
(2) mixing all the raw materials, measuring content, determining tablet weight according to specification, tabletting, inspecting, and packaging.
Example 2
Prescription:
abiraterone acetate: 250g of,
Glutathione: 100g of,
L-malic acid: 15g of the total weight of the mixture is 15g,
making into 1000 pieces
The process comprises the following steps:
(1) drying the abiraterone acetate, the glutathione and the L-malic acid according to the prescription amount at 60 ℃ in advance, and then sequentially sieving the dried substances through a 80-mesh sieve;
(2) mixing all the raw materials, measuring content, determining tablet weight according to specification, tabletting, inspecting, and packaging.
Example 3
Prescription:
abiraterone acetate: 500g
Glutathione: 200g
L-malic acid: 30g of
Making into 2000 pieces
The process comprises the following steps:
(1) drying the abiraterone acetate, the glutathione and the L-malic acid according to the prescription amount at 60 ℃ in advance, and then sequentially sieving the dried substances through a 80-mesh sieve;
(2) mixing all the raw materials, measuring content, determining tablet weight according to specification, tabletting, inspecting, and packaging.
Comparative example 1
Prescription:
abiraterone acetate: 25g of
Glutathione: 0g
L-malic acid: 1.5g
Made into 100 pieces
The process comprises the following steps:
(1) drying the abiraterone acetate, the glutathione and the L-malic acid according to the prescription amount at 60 ℃ in advance, and then sequentially sieving the dried substances through a 80-mesh sieve;
(2) mixing all the raw materials, measuring content, determining tablet weight according to specification, tabletting, inspecting, and packaging.
Comparative example 2
Prescription:
abiraterone acetate: 25g of
Glutathione: 10g
L-malic acid: 0g
Made into 100 pieces
The process comprises the following steps:
(1) drying the abiraterone acetate, the glutathione and the L-malic acid according to the prescription amount at 60 ℃ in advance, and then sequentially sieving the dried substances through a 80-mesh sieve;
(2) mixing all the raw materials, measuring content, determining tablet weight according to specification, tabletting, inspecting, and packaging.
Comparative example 3
Prescription:
abiraterone acetate: 25g of
Glutathione: 9g of
L-malic acid: 1g
Made into 100 pieces
The process comprises the following steps:
(1) drying the abiraterone acetate, the glutathione and the L-malic acid according to the prescription amount at 60 ℃ in advance, and then sequentially sieving the dried substances through a 80-mesh sieve;
(2) mixing all the raw materials, measuring content, determining tablet weight according to specification, tabletting, inspecting, and packaging.
Comparative example 4
Prescription:
abiraterone acetate: 25g of
Glutathione: 11g
L-malic acid: 2g
Made into 100 pieces
The process comprises the following steps:
(1) drying the abiraterone acetate, the glutathione and the L-malic acid according to the prescription amount at 60 ℃ in advance, and then sequentially sieving the dried substances through a 80-mesh sieve;
(2) mixing all the raw materials, measuring content, determining tablet weight according to specification, tabletting, inspecting, and packaging.
In order to make the technical effect of the combined use of glutathione and L malic acid easier to understand, the following experiment explains the effect of the combined use of glutathione and L malic acid on the dissolution rate of abiraterone acetate:
sample 1: the abiraterone acetate tablet prepared in the embodiment 1 of the invention.
Sample 2: the abiraterone acetate tablet prepared in the embodiment 2 of the invention.
3-6 of samples: the abiraterone acetate tablets prepared in comparative examples 1-4 are provided by the invention.
Sample 7: commercially available abiraterone acetate tablets.
The dissolution test method is as follows: referring to the dissolution method of the abiraterone acetate tablet in the FDA dissolution database, the determination method comprises the following steps: paddle method, 50 rpm, 900ml dissolution medium. Thus, the elution profiles in a pH1.0 hydrochloric acid solution, a pH4.5 acetate buffer solution + 0.25% SDS, purified water + 2.0% SDS and a pH6.8 phosphate buffer solution + 2.0% SDS were measured, respectively, and 5ml of the solution was taken at different elution times and filtered through a 10 μm filter, and the subsequent filtrate was taken as a sample solution; and precisely weighing 30mg of abiraterone acetate reference substance, placing the abiraterone acetate reference substance into a 100ml measuring flask, adding 4ml of acetonitrile to dissolve, adding a dissolution medium to dilute, diluting to a scale with the dissolution medium, and shaking up to obtain a reference substance solution. According to high performance liquid chromatography (0512 high performance liquid chromatography of the four-part general regulation of the Chinese pharmacopoeia 2015 edition), octadecyl silica gel bonded silica gel is used as a filler chromatographic column, acetonitrile-water-formic acid (550:500:0.5) is used as a mobile phase, the detection wavelength is 252nm, the column temperature is 40 ℃, 10ul of the solution is precisely measured, the solution is injected into a liquid chromatograph, the chromatogram is recorded, and the dissolution is calculated according to the peak area by an external standard method, which is shown in tables 1 to 5.
TABLE 1 results of comparative test of glutathione and L-malic acid at different prescribed amounts for 60min dissolution time
As can be seen from the results of table 1: the combined use of the glutathione and the L malic acid has obvious effect on the improvement of the dissolution rate of the abiraterone acetate, and particularly, the effect of adding 10g of the glutathione and 1.5g of the L-malic acid into 25g of the abiraterone acetate in a specific proportion is the best.
Table 2 dissolution comparison of samples 1 and 7 (%)
TABLE 3 dissolution comparison of samples 1 and 7 (%)
TABLE 4 dissolution comparison (%)
TABLE 5 dissolution comparison of samples 1 and 7 (%)
As can be seen from the results in tables 2-5, the abiraterone acetate tablets prepared by the invention have good dissolution effect and obvious advantages compared with the products on the market, and similar results are obtained by carrying out the same tests in other examples of the invention.
Test for influencing factor
The influencing factor test method is as follows: the samples 1 and 7 were subjected to the influence factor test for 10 days under high temperature (60 ℃), high humidity (25 ℃, RH 75% ± 5%), illumination (4500lx), respectively, and the content and related substances were examined on the 10 th day, and the results were compared with the results on the 0 th day, as shown in table 6.
TABLE 6 test results of influencing factors of samples 1 and 7
As can be seen from the results in table 6, the abiraterone acetate tablet prepared by the present invention has good stability under high temperature, high humidity and illumination conditions, and has obvious advantages compared with the products on the market, and similar results are obtained by performing the same tests in other embodiments of the present invention.
Accelerated test
The accelerated test method is as follows: samples 1 and 7 were subjected to accelerated stability studies (40 ℃. + -. 2 ℃ C., RH 75%. + -. 5%) and sampled at 1, 2, 3, and 6 months, respectively, for content and related substances, and the results are shown in Table 7.
TABLE 7 results of accelerated testing of samples 1 and 7
As can be seen from the results in table 7, the abiraterone acetate tablets prepared by the present invention have good stability under accelerated conditions and have obvious advantages compared with the products on the market, and similar results are obtained by performing the same tests on other examples of the present invention.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (7)
1. The abiraterone acetate preparation is characterized in that: the preparation contains abiraterone acetate, glutathione and L-malic acid.
2. The abiraterone acetate formulation of claim 1, wherein: every 1000 preparation units contain 250g of abiraterone acetate, 100g of glutathione and 15g of L-malic acid.
3. The abiraterone acetate formulation of claim 1 or 2, wherein: the abiraterone acetate preparation is a tablet.
4. The abiraterone acetate tablet of claim 3, wherein: the specification of the abiraterone acetate tabletting agent is 0.25 g.
5. The abiraterone acetate formulation of any of claims 1 to 4, which is prepared by the following method:
(1) sequentially sieving abiraterone acetate, glutathione and L-malic acid which are dried at 60 ℃ in advance through a 80-mesh sieve;
(2) mixing all the raw materials, measuring content, determining tablet weight according to specification, tabletting, inspecting, and packaging.
6. A preparation method of abiraterone acetate tablets is characterized by comprising the following steps:
(1) drying the abiraterone acetate, the glutathione and the L-malic acid according to the prescription amount at 60 ℃ in advance, and then sequentially sieving the dried substances through a 80-mesh sieve;
(2) mixing all the raw materials, measuring content, determining tablet weight according to specification, tabletting, inspecting, and packaging.
7. The method of claim 6, wherein the prescribed amounts are:
every 1000 tablets of the abiraterone acetate tablets contain:
abiraterone acetate: 250g of,
Glutathione: 100g of,
L-malic acid: 15 g.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201911225983.8A CN110742870B (en) | 2019-12-04 | 2019-12-04 | Abiraterone acetate preparation and preparation method thereof |
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| CN201911225983.8A CN110742870B (en) | 2019-12-04 | 2019-12-04 | Abiraterone acetate preparation and preparation method thereof |
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| CN110742870B CN110742870B (en) | 2021-04-20 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116297910A (en) * | 2023-01-18 | 2023-06-23 | 河北省药品医疗器械检验研究院(河北省化妆品检验研究中心) | Method for detecting dissolution rate of abiraterone acetate tablet |
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| WO2014009437A1 (en) * | 2012-07-11 | 2014-01-16 | Sandoz Ag | Oxidation stability of abiraterone acetate |
| CN105596303A (en) * | 2014-11-03 | 2016-05-25 | 重庆安格龙翔医药科技有限公司 | Stable abiraterone acetate tablets and preparation method thereof |
| US20160303143A1 (en) * | 2013-12-12 | 2016-10-20 | Basf Se | Solid form of abiraterone acetate |
| CN106687112A (en) * | 2014-09-18 | 2017-05-17 | 冰由提卡公司 | Abiraterone acetate formulation and methods of use |
-
2019
- 2019-12-04 CN CN201911225983.8A patent/CN110742870B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014009437A1 (en) * | 2012-07-11 | 2014-01-16 | Sandoz Ag | Oxidation stability of abiraterone acetate |
| US20160303143A1 (en) * | 2013-12-12 | 2016-10-20 | Basf Se | Solid form of abiraterone acetate |
| CN106687112A (en) * | 2014-09-18 | 2017-05-17 | 冰由提卡公司 | Abiraterone acetate formulation and methods of use |
| CN105596303A (en) * | 2014-11-03 | 2016-05-25 | 重庆安格龙翔医药科技有限公司 | Stable abiraterone acetate tablets and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| JEF STAPPAERTS ET AL: "Rapid conversion of the ester prodrug abiraterone acetate results in intestinal supersaturation and enhanced absorption of abiraterone:In vitro, rat in situ and human in vivo studies", 《EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS》 * |
| 丁亚明等: "阿比特龙醋酸酯的研究进展", 《化学工程与装备》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116297910A (en) * | 2023-01-18 | 2023-06-23 | 河北省药品医疗器械检验研究院(河北省化妆品检验研究中心) | Method for detecting dissolution rate of abiraterone acetate tablet |
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