Butanedisulfonic acid ademetionine enteric-coated tablet and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to butanedisulfonic acid ademetionine enteric-coated tablets and a preparation method thereof. The invention provides a butanedisulfonic acid ademetionine enteric-coated tablet. The butanedisulfonic acid ademetionine enteric-coated tablet comprises a tablet core and an enteric coating layer, wherein the tablet core comprises butanedisulfonic acid adenosyl methionine, glyceryl behenate, a filling agent, a disintegrating agent and a lubricating agent; the enteric coating layer comprises a coating premix; the coating premix comprises hydroxypropyl methylcellulose acetate succinate and an anhydrous solvent. The ademetionine butanedisulfonate enteric-coated tablet obtained by matching the glyceryl behenate and the hydroxypropyl methylcellulose acetate succinate is lower in water content, degradation of S-S ademetionine and increase of related substances are not obvious under an accelerated test condition, the product stability is better, and the medication safety of a patient can be better ensured.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to enteric-coated succinate ademethionine tablets and a preparation method thereof. Background Art

[0002] Adenosylmethionine butanedisulfonate is a physiologically active molecule commonly found in human tissues and body fluids. It participates in important biochemical reactions in the body as a methyl donor (transmethylation) and a precursor (transsulfuration) of physiological sulfhydryl compounds (such as cysteine, taurine, glutathione and coenzyme A).

[0003] Abbott Laboratories developed a drug called Adenosylmethionine Butadiene Disulfonate Enteric-Coated Tablets for the treatment of intrahepatic cholestasis in pre-cirrhotic and cirrhotic patients, as well as intrahepatic cholestasis of pregnancy. The raw material Adenosylmethionine Butadiene Disulfonate accounts for a very high proportion of the enteric-coated tablets. This material is highly hygroscopic and heat-sensitive. Upon moisture absorption, the Adenosylmethionine Butadiene Disulfonate content gradually decreases, while the levels of related substances gradually increase. This significantly impacts the product's quality and stability, and also poses significant challenges to the production of the formulation.

[0004] CN114306266A discloses an enteric-coated succinate ademethionine composition and its preparation method. The composition utilizes dry granulation combined with vacuum drying to remove moisture from the tablets. After granulation, multiple coatings, including a moisture barrier layer and an enteric layer, are applied to produce enteric-coated tablets. The resulting product maintains a total impurity level of 1.55% after three months of storage. However, this preparation method is complex, requiring the use of a large amount of organic solvents during the coating process. Furthermore, the drying temperature during the preparation process is 40°C, which can lead to degradation of SS ademethionine and elevated adenine levels in the product, posing a significant stability risk.

[0005] CN115998701A discloses a process for producing enteric-coated succinate ademethionine tablets. The process involves pre-drying the excipients in an oven and applying a coating agent as a barrier layer before applying the enteric coating. The tablets produced by this method have a low moisture content and exhibit an impurity content growth rate of 0.1-0.2% after three months at room temperature. However, this process involves drying the tablets at a temperature of 42-47°C, which can lead to degradation of SS ademethionine and elevated adenine levels in the product, posing a risk to product stability.

[0006] Although the drying process or coating process used in the existing technology can overcome the moisture absorption problem of succinate dimethionine to a certain extent, the prepared product still has the problem of high levels of SS succinate dimethionine and adenine, and the product quality stability is difficult to ensure; and the multiple coating process not only increases the process cost, but also inevitably uses organic solvents, resulting in an increased risk of residual organic solvents in the product, increasing safety and environmental protection pressures.

[0007] Therefore, it is very necessary to develop an enteric-coated tablet of succinate ademethionine that takes into account the hygroscopicity of the raw materials and has high product stability. Summary of the Invention

[0008] In order to overcome the problems existing in the prior art, the present invention provides an enteric-coated tablet of ademethionine butanedisulfonate with high product stability, while solving the problem that the raw materials of the enteric-coated tablets are extremely easy to absorb moisture, thereby reducing the medication risk for patients.

[0009] To achieve the above object, the present invention provides the following technical solutions:

[0010] Adenosylmethionine succinate enteric-coated tablet comprises a tablet core and an enteric coating layer; the tablet core comprises denosylmethionine succinate, glyceryl behenate, a filler, a disintegrant, and a lubricant; the enteric coating layer comprises a coating premix; the coating premix comprises hypromellose acetate succinate and an anhydrous solvent. The hydrophobic groups in the hypromellose acetate succinate form a molecular-level moisture barrier, effectively isolating the denosylmethionine succinate raw material from moisture in the environment and reducing the risk of moisture absorption by the raw material.

[0011] In a specific embodiment of the present invention, the core of the enteric-coated succinate ademethionine tablets contains 80-100 parts of succinate ademethionine, 8-15 parts of behenic acid glyceryl, 5-10 parts of filler, 1-5 parts of disintegrant and 0.5-2 parts of lubricant; the coating premix contains 5-8 parts of hydroxypropyl methylcellulose acetate succinate; preferably, the core contains 95 parts of succinate ademethionine, 12 parts of behenic acid glyceryl, 8 parts of filler, 3 parts of disintegrant and 1 part of lubricant; the coating premix contains 6 parts of hydroxypropyl methylcellulose acetate succinate.

[0012] In a preferred embodiment of the present invention, the coating premix further comprises a plasticizer, and the plasticizer is selected from one or more of trioctyl trimellitate, dioctyl adipate and dipropylene glycol dibenzoate; the plasticizer can reduce the brittleness of the coating and improve the integrity of the coating; preferably, the plasticizer is selected from dioctyl adipate.

[0013] In a preferred embodiment of the present invention, the weight ratio of hydroxypropyl methylcellulose acetate succinate and plasticizer in the coating premix is ​​3-10:1.

[0014] In a specific embodiment of the present invention, the anhydrous solvent of the coating premix is ​​selected from one or more of anhydrous ethanol, anhydrous acetone, or an anhydrous ethanol-acetone mixed solvent.

[0015] In a specific embodiment of the present invention, the filler is selected from one or more of sorbitol, calcium hydrogen phosphate, microcrystalline cellulose, lactose, mannitol, and pregelatinized starch; the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and cross-linked sodium carboxymethyl cellulose; and the lubricant is selected from one or more of magnesium stearate, stearic acid, calcium stearate, talc, and sodium stearyl fumarate.

[0016] The present invention also provides a method for preparing the above-mentioned enteric-coated tablets of ademethionine butanedisulfonate, comprising the following steps:

[0017] (1) Adenosylmethionine disulfate and glyceryl behenate are mixed evenly, pre-mixed with a filler, and then dry-granulated. Finally, the mixture is mixed with a disintegrant and a lubricant, and tabletted to obtain a tablet core for later use;

[0018] (2) Preparation of enteric coating solution: dissolve hydroxypropyl methylcellulose acetate succinate in an anhydrous solvent to obtain a coating solution for later use;

[0019] (3) coating the tablet core obtained in step (1) with the coating solution obtained in step (2), and drying under reduced pressure to obtain enteric-coated succinate methionine tablets; wherein the coating weight gain is 5-7%.

[0020] In the above-mentioned method for preparing enteric-coated succinate methionine tablets, the anhydrous solvent in step (2) is selected from anhydrous ethanol, anhydrous acetone, or an anhydrous ethanol-acetone mixed solvent; the anhydrous solvent can reduce the introduction of water and reduce the risk of moisture absorption by the raw materials. The solid content of the coating solution is controlled at 15-20%.

[0021] In a specific embodiment of the present invention, the preparation of the enteric coating solution in step (2) further comprises the process of dissolving a plasticizer in an anhydrous solvent; specifically, the plasticizer is selected from one or more of trioctyl trimellitate, dioctyl adipate and dipropylene glycol dibenzoate.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] (1) By adding glyceryl behenate to the core of the enteric-coated tablets of adenosylmethionine butanedisulfate, the hygroscopicity of the core drug can be effectively reduced. This may be attributed to the strong hydrophobicity of the C22 long-chain fatty acid molecular structure of glyceryl behenate itself. The non-polar group at the tail of the long-chain fatty acid can effectively block moisture penetration and reduce the contact between the raw material and moisture in the environment. At the same time, the present invention also provides an enteric coating premix with both moisture-proof and enteric functions, wherein the enteric coating material, hydroxypropyl methylcellulose acetate succinate, can effectively avoid the risk of raw material moisture absorption caused by contact between environmental moisture and the core drug. The combination of the enteric coating material and glyceryl behenate in the core can effectively solve the problem of the raw material being extremely hygroscopic. In addition, the applicant unexpectedly found that adding dioctyl adipate as a plasticizer to the coating premix of the present invention can further improve the stability of the product.

[0024] (2) Compared with other glycerides or other enteric coating materials, the enteric-coated tablets of succinate ademethionine succinate obtained by combining glyceryl behenate and hydroxypropyl methylcellulose acetate succinate in the present invention have lower water content, and the degradation of SS ademethionine and the increase of related substances under accelerated test conditions are not obvious. The product stability is better, and the safety of patient use can be better ensured.

[0025] (3) The preparation process of the enteric-coated tablets of the present invention is simple, and the degradation of SS adenosylmethionine or the increase of related substances in the enteric-coated tablets can be effectively controlled without an additional drying step, so that the enteric-coated tablets have better product stability; the combination of behenic acid glyceride and a specific enteric coating material in the present invention can make the preparation environment of the enteric-coated tablets of succinate adenosylmethionine do not need to be too harsh, and can avoid the cost increase problem caused by the multiple coating process used in the prior art. The preparation method is simple and more suitable for process production. DETAILED DESCRIPTION

[0026] In order to better understand the technical solution of the present invention, further description is given below in conjunction with specific implementation examples, but those skilled in the art should realize that the present invention is not limited to these embodiments.

[0027] Example 1

[0028]

[0029] Preparation method:

[0030] (1) Weighed adenosyl methionine disulfate and glyceryl behenate are mixed evenly, premixed with microcrystalline cellulose, and dry granulated. Finally, the mixture is mixed with sodium carboxymethyl starch and magnesium stearate, and tableted to obtain tablet cores for later use.

[0031] (2) Preparation of enteric coating solution: Dissolve weighed hydroxypropyl methylcellulose acetate succinate in anhydrous ethanol to obtain a coating solution for use, wherein the solid content is 16%;

[0032] (3) coating the tablet core obtained in step (1) with the coating solution obtained in step (2), and drying under reduced pressure to obtain enteric-coated succinate methionine tablets; wherein the coating weight gain is 5-7%.

[0033] Example 2

[0034]

[0035]

[0036] Preparation method:

[0037] (1) Weighed adenosyl methionine disulfate and glyceryl behenate are mixed evenly, premixed with microcrystalline cellulose, and dry granulated. Finally, the mixture is mixed with sodium carboxymethyl starch and magnesium stearate, and tableted to obtain tablet cores for later use.

[0038] (2) Preparation of enteric coating solution: Dissolve weighed hydroxypropyl methylcellulose acetate succinate and dioctyl adipate in anhydrous ethanol to obtain a coating solution for use, wherein the solid content is 20%;

[0039] (3) coating the tablet core obtained in step (1) with the coating solution obtained in step (2), and drying under reduced pressure to obtain enteric-coated succinate methionine tablets; wherein the coating weight gain is 5-7%.

[0040] Example 3

[0041]

[0042] Preparation method:

[0043] (1) Weighed adenosylmethionine disulfate and glyceryl behenate are mixed evenly, premixed with sorbitol, and then dry granulated. Finally, the mixture is mixed with sodium carboxymethyl starch and stearic acid, and tableted to obtain tablet cores for later use.

[0044] (2) Preparation of enteric coating solution: Dissolve weighed hydroxypropyl methylcellulose acetate succinate and trioctyl trimellitate in anhydrous ethanol to obtain a coating solution for use, wherein the solid content is about 18%;

[0045] (3) coating the tablet core obtained in step (1) with the coating solution obtained in step (2), and drying under reduced pressure to obtain enteric-coated succinate methionine tablets; wherein the coating weight gain is 5-7%.

[0046] Example 4

[0047]

[0048]

[0049] Preparation method:

[0050] (1) Weighed adenosylmethionine disulfate and glyceryl behenate are mixed evenly, premixed with calcium hydrogen phosphate, and then dry granulated. Finally, the mixture is mixed with cross-linked polyvinylpyrrolidone and calcium stearate, and tableted to obtain tablet cores for later use;

[0051] (2) Preparation of enteric coating solution: Dissolve weighed hydroxypropyl methylcellulose acetate succinate and dipropylene glycol dibenzoate in anhydrous acetone to obtain a coating solution for use, wherein the solid content is about 18%;

[0052] (3) coating the tablet core obtained in step (1) with the coating solution obtained in step (2), and drying under reduced pressure to obtain enteric-coated succinate methionine tablets; wherein the coating weight gain is 5-7%.

[0053] Example 5

[0054]

[0055] Preparation method:

[0056] (1) Weighed adenosylmethionine disulfate and glyceryl behenate are mixed evenly, premixed with mannitol, and then dry granulated. Finally, the mixture is mixed with low-substituted hydroxypropyl cellulose and talc, and tableted to obtain tablet cores for later use;

[0057] (2) Preparation of enteric coating solution: Dissolve weighed hydroxypropyl methylcellulose acetate succinate and dioctyl adipate in anhydrous acetone to obtain a coating solution for use, wherein the solid content is about 18%;

[0058] (3) coating the tablet core obtained in step (1) with the coating solution obtained in step (2), and drying under reduced pressure to obtain enteric-coated succinate methionine tablets; wherein the coating weight gain is 5-7%.

[0059] Example 6

[0060]

[0061]

[0062] Preparation method:

[0063] (1) Weighed adenosyl methionine disulfate and glyceryl behenate are mixed evenly, premixed with pregelatinized starch, and then dry-granulated. Finally, the mixture is mixed with cross-linked sodium carboxymethyl cellulose and sodium stearyl fumarate, and tableted to obtain tablet cores for later use.

[0064] (2) Preparation of enteric layer coating: Dissolve weighed hydroxypropyl methylcellulose acetate succinate and dioctyl adipate in anhydrous acetone to obtain a coating solution with a solid content of 15%.

[0065] (3) coating the tablet core obtained in step (1) with the coating solution obtained in step (2), and drying under reduced pressure to obtain enteric-coated succinate methionine tablets; wherein the coating weight gain is 5-7%.

[0066] Comparative Example 1-Comparative Example 7

[0067]

[0068] The preparation methods of Comparative Examples 1 to 6 are the same as those of Example 2.

[0069] Compared with Example 2, the core portion of the enteric-coated tablets of Comparative Example 1 does not contain glyceryl behenate; the core portions of the enteric-coated tablets of Comparative Example 2 and Comparative Example 3 do not contain glyceryl behenate, and are replaced by glyceryl monostearate and glyceryl tristearate, respectively; the enteric-coated tablet coating premixes of Comparative Examples 4 to Comparative Example 6 do not contain hypromellose acetate succinate, and are replaced by hypromellose phthalate, cellulose acetate phthalate, and methacrylic acid-ethyl acrylate copolymer, respectively.

[0070] The enteric-coated tablets of Comparative Example 7 contain a double-layer coating, and the composition of the tablet core and the enteric layer coating are the same as those in Example 2, except that an isolation layer coating is provided between the tablet core and the enteric layer coating. The isolation layer coating can be coated with a finished moisture-proof coating premix, and the finished moisture-proof coating premix here is a moisture-proof film coating powder.

[0071] Stability investigation

[0072] In order to investigate the product stability of the enteric-coated succinate ademethionine tablets of the present invention, the applicant conducted the following stability test. First, the moisture content of the enteric-coated succinate ademethionine tablets prepared in Examples 1 to 6 and Comparative Examples 1 to 7 was tested, and the results are shown in the table below. Furthermore, the changes in the content of SS-ademethionine and related substances in the enteric-coated succinate ademethionine tablets of Examples 1 to 6 and Comparative Examples 1 to 7 were investigated after accelerated testing for one month and three months, respectively. The test conditions were: temperature 40°C ± 2°C, relative humidity 75% ± 5%. The test results are shown in the table below:

[0073]

[0074]

[0075] From the stability test data, we can see that

[0076] (1) The initial moisture content of the enteric-coated tablets of succinate ademethionine prepared in Examples 1 to 6 of the present invention is 0.8-1.2%, indicating that the enteric-coated tablets of succinate ademethionine prepared by combining glyceryl behenate and the specific enteric coating material, hydroxypropyl methylcellulose acetate succinate, of the present invention have a relatively ideal low moisture content compared to Comparative Examples 1 to 7. This low moisture content can ensure the stability of the product when it is obtained.

[0077] (2) The enteric-coated tablets of succinate ademethionine prepared in Examples 1 to 6 of the present invention showed no significant changes in the content of S,S-ademethionine, related substances and total impurities in the accelerated test for 1 month and 3 months, indicating that the enteric-coated tablets of the present invention had better product stability under accelerated conditions and were not easy to absorb moisture. However, under the same conditions, the enteric-coated tablets of Comparative Examples 1 to 7 showed a significant decrease in the content of S,S-ademethionine, and a significant increase in the content of related substances and total impurities, indicating that the enteric-coated tablets of succinate ademethionine prepared by combining glyceryl behenate and the specific enteric coating material, hydroxypropyl methylcellulose acetate succinate, had a significant advantage in product stability compared with Comparative Examples 1 to 7.

[0078] (3) The water content of the products obtained in Examples 2, 5, and 6 of the present invention and the product stability under accelerated conditions are more advantageous than those in other examples, indicating that adding dioctyl adipate as a plasticizer to the coating premix of the enteric-coated tablets of the present invention can further improve the stability of the product.

[0079] It should be understood that the above-described specific embodiments of the present invention are merely illustrative or illustrative of the principles of the present invention and do not constitute limitations of the present invention. Therefore, any modifications, equivalent substitutions, improvements, etc. made without departing from the spirit and scope of the present invention should be included within the scope of protection of the present invention. In addition, the appended claims are intended to cover all variations and modifications that fall within the scope and metes and bounds of the appended claims, or equivalents thereof.

Claims

1. A succinyl methionine disulfate enteric-coated tablet, characterized in that: The enteric-coated tablet comprises a tablet core and an enteric coating layer, wherein the tablet core comprises adenosylmethionine disulfonate, glyceryl behenate, a filler, a disintegrant and a lubricant; the enteric coating layer comprises a coating premix, and the coating premix comprises hydroxypropyl methylcellulose acetate succinate and an anhydrous solvent.

2. The enteric-coated tablets of claim 1, wherein: The tablet core contains 80-100 parts of adenosylmethionine disulfate, 8-15 parts of glyceryl behenate, 5-10 parts of a filler, 1-5 parts of a disintegrant and 0.5-2 parts of a lubricant; and the coating premix contains 5-8 parts of hydroxypropyl methylcellulose acetate succinate.

3. The enteric-coated tablets of claim 2, wherein: The tablet core comprises 95 parts of adenosylmethionine disulfate, 12 parts of glyceryl behenate, 8 parts of a filler, 3 parts of a disintegrant and 1 part of a lubricant; and the coating premix comprises 6 parts of hydroxypropyl methylcellulose acetate succinate.

4. The enteric-coated tablets of claim 1, wherein: The coating premix further comprises a plasticizer; the plasticizer is selected from one or more of trioctyl trimellitate, dioctyl adipate and dipropylene glycol dibenzoate.

5. The enteric-coated tablets of claim 4, wherein: The plasticizer is selected from dioctyl adipate.

6. The enteric-coated tablets of claim 4, wherein: The weight ratio of the hydroxypropyl methylcellulose acetate succinate and the plasticizer in the coating premix is ​​3-10:

1.

7. The enteric-coated tablets of claim 1, wherein: The anhydrous solvent is selected from one or more of anhydrous ethanol, anhydrous acetone or an anhydrous ethanol-acetone mixed solvent.

8. The enteric-coated tablets according to any one of claims 1 to 7, characterized in that: The filler is selected from one or more of sorbitol, calcium hydrogen phosphate, microcrystalline cellulose, lactose, mannitol, and pregelatinized starch; the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and cross-linked sodium carboxymethyl cellulose; and the lubricant is selected from one or more of magnesium stearate, stearic acid, calcium stearate, talc, and sodium stearyl fumarate.

9. A method for preparing the enteric-coated tablets of claim 1, characterized in that: The specific steps include: (1) Adenosylmethionine disulfate and glyceryl behenate are mixed evenly, pre-mixed with a filler, and then dry-granulated. Finally, the mixture is mixed with a disintegrant and a lubricant, and tabletted to obtain a tablet core for later use; (2) Preparation of enteric coating solution: dissolve hydroxypropyl methylcellulose acetate succinate in an anhydrous solvent to obtain a coating solution for later use; (3) coating the tablet core obtained in step (1) with the coating solution obtained in step (2), and drying under reduced pressure to obtain enteric-coated succinate methionine tablets; wherein the coating weight gain is 5-7%.

10. The method for preparing enteric-coated tablets of claim 9, wherein: The solid content of the coating solution in step (2) is controlled at 15-20%.

11. The method for preparing enteric-coated tablets of claim 9, wherein: The step (2) further comprises a process of dissolving the plasticizer in an anhydrous solvent.

Images