A tablet of a vitamin a derivative and a method for preparing the same

Abstract

The application discloses a kind of vitamin A derivative tablets, comprising: 11% to 12% of tretinoin, 83% to 87.8% of the compound of two microcrystalline celluloses, 1.0% to 2.0% of magnesium stearate by weight percentage;Microcrystalline cellulose is selected from TF series, TL series;Two microcrystalline celluloses are TF525 and TL565 respectively;The weight ratio of two microcrystalline celluloses is 32 to 39:39 to 45.The preparation method of tablet comprises:1) weighing: the raw and auxiliary materials are weighed according to the prescription amount, and passed through 40 mesh screen;2) total mixing: the material is added into wet granulator, the stirring speed is set to 220-280rpm, the shearing speed is set to 1000-1600rpm, and the mixing time is 5-10min;3) tabletting: the theoretical tablet weight is 180±13mg, and the hardness is controlled to 30-50N;4) coating: the coating weight gain is 3-5%;5) aluminum package: the heat sealing temperature is set to 110-140℃, and the main machine speed is 4-8rpm.The tretinoin tablet prepared in the application has good dissolution performance and stability.

Description

Technical Field

[0001] The present application belongs to the field of pharmaceutical chemistry, and specifically relates to a tretinoin tablet and a preparation method thereof. Background Art

[0002] A vitamin A derivative tablet, retinoic acid tablets, the main ingredient of which is all-trans retinoic acid, is a cell differentiation-inducing drug with a wide range of medical uses. Its chemical name is 3,7-dimethyl-9-(2,6,6-trimethylcyclohexene)-2,4,6,8-all-trans nonatetraenoic acid, and its molecular formula is C 20 H 28 O2, with a molecular weight of 300.44. This drug is a light yellow tablet with good oral absorption. It is mainly used to treat various skin diseases and acute promyelocytic leukemia (APL). The research and development background of retinoic acid tablets can be traced back to the in-depth study of vitamin A and its metabolites. As a metabolic intermediate of vitamin A, retinoic acid plays an important role in regulating cell growth, differentiation and metabolism. With the continuous deepening of the understanding of the pathogenesis of APL, scientists have found that retinoic acid can induce the differentiation and maturation of APL cells, thus becoming an important drug for the treatment of APL. In addition, retinoic acid has also shown good efficacy in the treatment of various skin diseases, further broadening its scope of clinical application.

[0003] For commercially available tretinoin tablets (sold by Shandong Liangfu Pharmaceutical Co., Ltd.), after accelerated exposure to light, high temperature, and high humidity, samples of both plain and coated tablets showed a gradual increase in Impurity G and total impurities, exceeding limits by March. While the growth of Impurity G and total impurities in packaged samples improved, significant levels of impurities remained at 10 and 90 days. Therefore, while ensuring basic performance, such as dissolution, improving the stability of tretinoin tablets remains a challenge. Summary of the Invention

[0004] The present application provides a tretinoin tablet having good dissolution performance and stability.

[0005] A tretinoin tablet comprises, by weight percentage, 11%-12% of tretinoin, 83%-87.8% of a compound of two types of microcrystalline cellulose, and 1.0%-2.0% of magnesium stearate.

[0006] In a specific embodiment of the present invention, the two microcrystalline celluloses are selected from TF series, TL series.

[0007] In a specific embodiment of the present invention, the two microcrystalline celluloses are TF525 and TL565.

[0008] In a specific embodiment of the present invention, the weight ratio of the two types of microcrystalline cellulose is 32-39:39-45.

[0009] In one embodiment of the present invention, the weight ratio of the two types of microcrystalline cellulose is 39:40.

[0010] In one embodiment of the present invention, the two microcrystalline celluloses are TF525 and The weight ratio of TL565 is 39:40.

[0011] In a specific embodiment of the present invention, a tretinoin tablet comprises: by weight percentage, 11.11% tretinoin, 87.78% of a combination of two microcrystalline celluloses, and 1.11% magnesium stearate.

[0012] The present invention also provides a method for preparing tretinoin tablets, comprising:

[0013] 1) Weighing: Weigh the raw materials and excipients according to the prescribed amount and pass through a 40-mesh sieve;

[0014] 2) Total mixing: Add the materials to the wet granulator, set the stirring speed to 220-280 rpm, the shear speed to 1000-1600 rpm, and the mixing time to 5-10 min;

[0015] 3) Tabletting: Theoretical tablet weight is 180±13 mg, and the hardness is controlled at 30-50N;

[0016] 4) Coating: coating weight gain 3-5%;

[0017] 5) Aluminum package: Heat sealing temperature is set to 110-140℃, and the main engine speed is 4-8rpm.

[0018] Beneficial effects:

[0019] 1) Excellent stability: After extensive experiments, the inventors discovered a new formula for tretinoin tablets. This formula uses only two types of microcrystalline cellulose in a certain proportion, and then adds a lubricant, magnesium stearate. The tretinoin tablets are prepared through a powder direct compression process. The formula is simple and the chemical properties are stable. After accelerated testing under high temperature, high humidity and light conditions, the tablets can still maintain good stability. Compared with existing commercially available tretinoin tablets, the content of impurity G and single and total impurities changes little.

[0020] 2) Dissolution close to commercially available preparations: The inventors adjusted the new formula to prepare tretinoin tablets, which have a dissolution curve close to that of commercially available preparations in the same medium. DETAILED DESCRIPTION

[0021] The technical solutions in the embodiments of the present application are clearly described below. Obviously, the embodiments described are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field are within the scope of protection of this application.

[0022] The terms "first," "second," and the like in the specification and claims of this application are used to distinguish similar objects, and are not used to describe a specific order or precedence. It should be understood that the terms used in this manner are interchangeable where appropriate, so that the embodiments of this application can be implemented in an order other than that described herein, and that the objects distinguished by "first," "second," and the like are generally of the same type, and do not limit the number of objects; for example, the first object can be one or more. In addition, the term "and / or" in the specification and claims refers to at least one of the connected objects, and the character " / " generally indicates that the objects connected are in an "or" relationship.

[0023] The present application is not limited to the above-mentioned specific implementation methods. The above-mentioned specific implementation methods are merely illustrative and not restrictive. Under the guidance of the present application, ordinary technicians in this field can also make many forms without departing from the purpose of the present application and the scope of protection of the claims, all of which are protected by the present application.

[0024] The present application provides a tretinoin tablet comprising, by weight, 11%-12% tretinoin, 83%-87.8% of a combination of two microcrystalline celluloses, and 1.0%-2.0% of magnesium stearate. The weight percentages of the two microcrystalline celluloses may be 83%, 85%, or 87.8%, preferably 87.8%.

[0025] Preferably, the microcrystalline cellulose is selected from TF series, TL series. TF series microcrystalline cellulose and TL series microcrystalline cellulose is produced by Zhuhai Dongchen Pharmaceutical Co., Ltd. TF series microcrystalline cellulose can be TF515, TF525, TF915, TF925; TL series crystalline cellulose can be TL565 or TL965.

[0026] Preferably, the two microcrystalline celluloses are TF525 and TL565.

[0027] Preferably, the weight ratio of the two microcrystalline celluloses is 32-39:39-45, and can be 32:40, 35:40, 39:40, 39:39, 39:45, and is preferably 39:40.

[0028] Preferably, two microcrystalline cellulose TF525 and The weight ratio of TL565 is 39:40.

[0029] Preferably, a tretinoin tablet comprises, by weight percentage, 11.11% tretinoin, 87.78% of a combination of two microcrystalline celluloses, and 1.11% magnesium stearate.

[0030] The present invention also provides a method for preparing tretinoin tablets, comprising:

[0031] 1) Weighing: Weigh the raw materials and excipients according to the prescribed amount and pass through a 40-mesh sieve;

[0032] 2) Total mixing: Add the materials to the wet granulator, set the stirring speed to 220-280 rpm, the shear speed to 1000-1600 rpm, and the mixing time to 5-10 min; the stirring speed can be 220 rpm, 240 rpm, and 280 rpm; the shear speed can be 1000 rpm, 1200 rpm, and 1600 rpm; the mixing time is 5 min, 8 min, and 10 min;

[0033] 3) Tabletting: Theoretical tablet weight is 180±13 mg, and the hardness is controlled at 30-50N;

[0034] 4) Coating: coating weight gain 3-5%;

[0035] 5) Aluminum package: The heat sealing temperature is set to 110-140℃, and the main engine speed is 4-8rpm. The heat sealing temperature can be 110, 120, or 140℃, and the main engine speed is 4rpm, 6rpm, or 8rpm.

[0036] The tretinoin tablets prepared by the invention have excellent dissolution performance and stability.

[0037] Example 1

[0038] 1) The prescription quantity of 2000 20mg / tablet tretinoin tablets is shown in Table 1

[0039] Table 1 Prescription amount of Example 1

[0040] Material Name Prescription quantity of 2000 large-size tretinoin tablets (g) retinoic acid 40 Microcrystalline cellulose TF525 156 Microcrystalline cellulose TL565 160 magnesium stearate 4 total 360

[0041] 2) Mixing process see Table 2

[0042] Table 2 Example 1 Mixing process

[0043]

[0044] 3) See Table 3 for process parameters of large-scale tableting

[0045] Table 3 Tableting process parameters of Example 1

[0046]

[0047] 4) Coating process parameters are shown in Table 4

[0048] Table 4 Coating process parameters of Example 1

[0049]

[0050]

[0051] The formula for calculating coating weight gain is as follows:

[0052]

[0053] Coating weight gain is approximately: 5%

[0054] 5) Aluminum cladding process parameters are shown in Table 5

[0055] Table 5 Aluminum cladding process parameters of Example 1

[0056] Heat sealing temperature 130℃ Host speed 6 rpm

[0057] The difference between Examples 2 to 3 and Comparative Examples 1 to 5 and Example 1 is that the two types of microcrystalline cellulose are different. The microcrystalline cellulose used in Examples 2 and 3 is selected from TF series, TL series, comparative examples 1 to 5 were respectively set up to use only one type of microcrystalline cellulose, not all TF series and TL series of microcrystalline cellulose, all do not use TF series and In the comparative experiment of TL series microcrystalline cellulose, other conditions including the total amount of microcrystalline cellulose used, the weight ratio of the two microcrystalline celluloses, the amount of other excipients used, and all process conditions were the same. Detailed data are shown in Table 6.

[0058] The difference between Examples 4 to 6 and Comparative Examples 6 to 9 and Example 1 is only that the weight ratio of the two microcrystalline celluloses is different. In Examples 4 to 6, the weight ratio of the two microcrystalline celluloses is set between 32 to 39:39 to 45, while Comparative Examples 6 to 9 respectively set experiments in which the weight ratio of the two microcrystalline celluloses is not within the above range. Other conditions, including the type of microcrystalline cellulose, the total amount of microcrystalline cellulose used, the amount of other excipients used, and all process conditions are the same. Detailed data are shown in Table 6.

[0059] Table 6 List of variables in Examples 1-7 and Comparative Examples 1-11

[0060]

[0061]

[0062] The stability test was performed on the tretinoin tablets prepared in Examples 1-6 and Comparative Examples 1-9. 20 mg / tablet tretinoin tablets (batch number 231001) sold by Shandong Liangfu Pharmaceutical Co., Ltd. were selected as the standard preparation. An accelerated test was conducted under high temperature of 60°C, high humidity of 95%, and light of 5000 Lx to examine the impurity content and active substance content in the tretinoin tablets at 30 days, 90 days, and 180 days under the above conditions. It is known that under high temperature, high humidity, and light, the content of impurity G and various impurities in tretinoin tablets changes significantly. The impurity information is shown in Table 7.

[0063] Table 7 Impurity information

[0064]

[0065]

[0066] Causes of impurities:

[0067] Impurities A to F mentioned in the table above are all included in the European Pharmacopoeia, Edition 10.0. Impurity A is also included in the Chinese Pharmacopoeia, 2020 Edition. Impurity A is isotretinoin, which is both a process impurity and a degradation impurity of tretinoin. Impurities B, D, and G are also both process impurities and degradation impurities. Impurities C and F are process impurities that may be generated during the synthesis of the API. They are easily degraded under hot and humid conditions to form impurities A, B, D, and G.

[0068] The measurement results of the impurity content and active ingredient content of the tretinoin tablets prepared in Examples 1-6 and Comparative Examples 1-9 and commercially available preparations under high temperature 60°C, high humidity 95%, and light 5000Lx are shown in Table 8 below.

[0069] Table 8 Measurement results of impurity contents and active ingredient contents of Examples 1-6 and Comparative Examples 1-9 under high temperature 60°C, high humidity 95%, and light 5000Lx

[0070]

[0071]

[0072]

[0073]

[0074] Note: ND means not detected

[0075] Comparing Examples 1, 2, 3 and Comparative Examples 1 to 4, it can be seen that after being placed under high temperature, high humidity and light conditions for 3 months and 6 months, the content of impurity G, total impurities and active substances in Examples 1, 2 and 3 has changed little; while under the same conditions, after being placed for 3 months and 6 months, the content of impurity G, total impurities and active substances in Comparative Examples 1 to 4 has changed greatly. Therefore, when other conditions are the same, the microcrystalline cellulose selected from TF series, TL series, the tretinoin tablets produced are more stable.

[0076] Comparing Examples 1, 4, 5, 6 and Comparative Examples 6, 7, 8, 9, it can be seen that after being placed under high temperature, high humidity and light conditions for 3 months and 6 months, the content of impurity G, total impurities and active substances in Examples 1, 4, 5, 6 has changed little; while after being placed under the same conditions for 3 months and 6 months, the content of impurity G, total impurities and active substances in Comparative Examples 6, 7, 8, 9 has changed greatly. Therefore, when other conditions are the same, the two microcrystalline cellulose TF525 and When the weight ratio of TL565 is 32-39:39-45, the prepared tretinoin tablets are more stable.

[0077] Comparing Examples 1-6 with commercially available preparations, it can be seen that after 3 and 6 months of storage under high temperature, high humidity, and light conditions, the changes in the contents of impurity G, total impurities, and active ingredients in Examples 1-6 were smaller than those in the commercial preparations under the same conditions. Therefore, it can be seen that the tretinoin tablets provided by the present invention are more stable than commercially available preparations.

[0078] The dissolution performance of the tretinoin tablets prepared in Examples 1-6 and Comparative Examples 1-9 was evaluated.

[0079] The dissolution rate and release rate determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0931, Second Method) was used for determination. Water, 0.1 mol / L HCl solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer were used as dissolution media, respectively. The speed was 100 rpm. The operation was carried out in accordance with the law. Samples were taken at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min, respectively. The dissolution data of the tretinoin tablets prepared in Examples 1-6 and Comparative Examples 1-9 were tested. The detailed data are shown in Table 9.

[0080] Table 9 Dissolution data of tretinoin tablets prepared in Examples 1-6 and Comparative Examples 1-9

[0081]

[0082]

[0083]

[0084]

[0085] The f2 factors of the dissolution curves of the tretinoin tablets prepared in Examples 1-6 and Comparative Examples 1-9 and the commercially available preparations were tested. The results are shown in Table 10.

[0086] Table 10 Dissolution curve f2 factors of tretinoin tablets and reference reagents prepared in Examples 1-6 and Comparative Examples 1-9

[0087]

[0088]

[0089] Comparing Examples 1 to 3 with Comparative Examples 1 to 4, it can be seen that the dissolution factors f2 of Examples 1 to 3 in water, 0.1 mol / L HCl solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer as dissolution media are relatively larger than the dissolution factors f2 of Comparative Examples 1 to 4 under the same conditions. Therefore, when other conditions are the same, the microcrystalline cellulose selected from TF series, When the TL series is used, the dissolution of the prepared tretinoin tablets is closer to that of the commercially available preparations.

[0090] Comparing Examples 1, 4, 5, 6 with Comparative Examples 6, 7, 8, 9, it can be seen that the dissolution factors f2 of Examples 1, 4, 5, 6 in water, 0.1 mol / L HCl solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer as dissolution media are relatively larger than the dissolution factors f2 of Comparative Examples 6, 7, 8, and 9 under the same conditions. Therefore, when other conditions are the same, the two microcrystalline cellulose TF525 and When the weight ratio of TL565 is 32-39:39-45, the dissolution of the prepared tretinoin tablets is closer to that of the commercially available preparation.

[0091] It is understood that the above embodiments are merely exemplary embodiments for illustrating the principles of the present application, and the present application is not limited thereto. Those skilled in the art may make various modifications and improvements without departing from the spirit and substance of the present application, and such modifications and improvements are also considered to be within the scope of protection of the present invention.

Claims

1. A vitamin A derivative tablet, characterized in that: include: In percentage by weight, 11%-12% of tretinoin, 83%-87.8% of a mixture of two microcrystalline celluloses, and 1.0%-2.0% of magnesium stearate, wherein the two microcrystalline celluloses are selected from TONCELLUS ® TF series, TONCELLUS ® TL series, the TONCELLUS ® TF series and TONCELLUS ® The weight ratio of the TL series is 32~39:39~45.

2. A vitamin A derivative tablet according to claim 1, characterized in that: The two microcrystalline celluloses are TONCELLUS ® TF525 and Toncellus ® TL565.

3. The vitamin A derivative tablet according to claim 1, characterized in that: The Toncellus ® TF series and TONCELLUS ® The weight ratio of the TL series is 39:

40.

4. The vitamin A derivative tablet according to claim 2, characterized in that: The microcrystalline cellulose is TONCELLUS ® TF525 and Toncellus ® The weight ratio of TL565 is 32~39:39~45.

5. The vitamin A derivative tablet according to claim 2, characterized in that: The microcrystalline cellulose is TONCELLUS ® TF525 and Toncellus ® The weight ratio of TL565 is 39:

40.

6. The vitamin A derivative tablet according to claim 1, characterized in that: include: In terms of weight percentage, the proportions of the components are: 11.11% tretinoin, 87.78% combination of two types of microcrystalline cellulose, and 1.11% magnesium stearate.

7. The method for preparing a vitamin A derivative tablet according to any one of claims 1 to 6, characterized in that: include: 1) Weighing: Weigh the raw and auxiliary materials according to the prescribed amount and pass through a 40-mesh sieve; 2) Total mixing: Add the materials to the wet granulator, set the stirring speed to 220-280 rpm, the shear speed to 1000-1600 rpm, and the mixing time to 5-10 minutes; 3) Tablet compression: Theoretical tablet weight is 180±13 mg, and the hardness is controlled at 30-50N; 4) Coating: coating weight gain 3-5%; 5) Aluminum package: Heat sealing temperature is set to 110-140℃, and the main engine speed is 4-8rpm.

8. The method for preparing a vitamin A derivative tablet according to claim 7, characterized in that: include: 1) Weighing: Weigh the raw and auxiliary materials according to the prescribed amount and pass through a 40-mesh sieve; 2) Total mixing: Add the materials to the wet granulator, set the stirring speed to 240 rpm, the shear speed to 1200 rpm, and the mixing time to 8 minutes; 3) Tabletting: Theoretical tablet weight is 180±13 mg, and the hardness is controlled at 40N; 4) Coating: coating weight gain 5%; 5) Aluminum package: Heat sealing temperature is set to 120℃, main engine speed is 6rpm.

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