Butanedisulfonic acid ademetionine enteric-coated tablet and preparation method thereof

Abstract

The invention discloses a butanedisulfonic acid ademetionine enteric-coated tablet and a preparation method thereof. The preparation method comprises the following steps: powder mixing and direct tabletting, vacuum drying of a plain tablet, coating of an enteric coating, vacuum drying of a coated tablet, blister packaging and the like. The vacuum drying temperature is controlled to be 25 DEG C or below, the vacuum degree is controlled to be 100 Pa or below, the water content of a final finished product is controlled not to exceed 2.0%, and a polyamide / aluminum / polyvinyl chloride cold stamping formed solid medicinal composite hard sheet and a medicinal aluminum foil blister package are adopted. According to the method, the content of S and S isomers in the product is effectively increased, the content of related substances in the product is reduced, and the stability of the product is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparation, and particularly relates to a succinate enteric-coated tablet and a preparation method thereof. Background Art

[0002] Adenosylmethionine 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 (transsulfhydrylation) of physiological sulfhydryl compounds (such as cysteine, taurine, glutathione and coenzyme A, etc.).

[0003] Adenosylmethionine butanedisulfonate was developed by Abbott Laboratories. Its marketed dosage forms include freeze-dried powder injection and enteric-coated tablets. Its domestic marketed trade name is Sumeta, with a specification of 0.5g (calculated as adenosylmethionine). It is used for intrahepatic cholestasis before and due to liver cirrhosis, and intrahepatic cholestasis during pregnancy.

[0004] Adenosylmethionine butanedisulfonate is very hygroscopic, and the moisture content of the product has a significant effect on its stability. Therefore, effective control of the moisture content of the product is an effective measure to improve the stability of this product.

[0005] CN114306266A discloses an enteric-coated composition of succinyl methionine disulfonate and a preparation method thereof, wherein the composition is prepared by tableting after dry granulation, removing moisture from the tablet by vacuum drying, coating with a moisture-proof isolation layer, and coating with an enteric coating. The enteric-coated tablets of succinyl methionine disulfonate produced by the above method have a complex process, and a large amount of organic solvents are used in the processes of coating with a moisture-proof isolation layer and coating with an enteric coating. In addition, the applicant has found that the level of related substances (especially adenine) in the released product produced according to the patented method is high, and the content of S,S isomers is low, resulting in an increased risk of stability.

[0006] CN 115998701 A discloses a production process of enteric-coated 1,4-butanedisulfonate adenosylmethionine tablets, comprising the following steps: (1) mixing microcrystalline cellulose and sodium carboxymethyl starch in a mixer to obtain a premix; (2) drying the premix in an electric heating oven, taking it out and setting it aside; (3) mixing the dried premix, 1,4-butanedisulfonate adenosylmethionine and magnesium stearate in a mixer to obtain a mixture; (4) adding the mixture into a dry granulator for dry granulation, and tableting with a rotary tablet press; (5) coating with an isolation layer coating agent; (6) coating with a coating liquid, drying, tableting and packaging to obtain enteric-coated 1,4-butanedisulfonate adenosylmethionine tablets. The production process uses dry granulation, followed by tableting, direct coating without drying, and then drying the coated enteric-coated tablets at a temperature of 42 to 47°C. The released products produced according to this patented method also have high levels of related substances (especially adenine) and low content of S,S isomers, resulting in increased stability risks.

[0007] Therefore, it is still necessary to develop a simple, effective and more environmentally friendly process to improve the stability of adenosylmethionine butanedisulfonate enteric-coated tablets. Summary of the invention

[0008] In the existing preparation process of enteric-coated ademethionine butane disulfonate tablets, most of the research focuses on the improvement of auxiliary materials and coating processes. The inventors found that even if the auxiliary materials and coating processes are strictly controlled, the obtained enteric-coated ademethionine butane disulfonate tablets still have the problems of degradation of S,S isomers and high levels of related substances, and the stability is difficult to ensure.

[0009] After extensive research, the applicant unexpectedly discovered that the main problem leading to the stability of adenosylmethionine butane disulfonate enteric-coated tablets is the degradation of S,S isomers and the increase of the related substance adenine during the drying process. The existing technology is to control the moisture content and generally use a vacuum drying temperature of 40°C. This condition is suitable for drying many other drugs, but when used for adenosylmethionine butane disulfonate enteric-coated tablets, it leads to the problem of a decrease in S,S isomers and an increase in adenine.

[0010] Based on the above findings, the inventors have effectively solved the above problems by improving the drying process, thereby improving the quality of the released products and improving the stability of the products.

[0011] The invention provides a method for preparing enteric-coated adenosylmethionine butanedisulfonate tablets, comprising the steps of direct tablet compression by powder mixing, vacuum drying of plain tablets, enteric coating, vacuum drying of coated tablets, blister packaging and the like. The method effectively increases the content of S,S isomers in the product, reduces the content of related substances in the product and improves the stability of the product.

[0012] Specifically, the technical solution of the present invention is as follows:

[0013] A method for preparing adenosylmethionine butanedisulfonate enteric-coated tablets comprises:

[0014] (1) uniformly mixing adenosylmethionine butanedisulfonate and a pharmaceutically acceptable additive;

[0015] (2) compressing the mixture into tablets;

[0016] (3) vacuum drying the tablets to remove moisture;

[0017] (4) Enteric coating the tablets after removing moisture to obtain enteric-coated tablets;

[0018] (5) vacuum drying the enteric-coated tablets to further remove moisture;

[0019] (6) the dried enteric-coated tablets are packaged in double aluminum blisters to obtain finished enteric-coated tablets;

[0020] The vacuum drying in step (3) and step (5) is carried out in a vacuum drying oven at a temperature below 25° C. and a vacuum degree below 100 Pa, and is dried until the moisture content of the tablets is less than 2.0%.

[0021] According to the preparation method provided by the present invention, the entire production process of the product is carried out in an environment with a relative humidity below 35%. According to the present invention, the vacuum drying of the tablet core and the enteric-coated tablet is carried out at a vacuum degree below 100 Pa and a temperature below 25°C.

[0022] According to conventional understanding, in order to control the moisture content of the product more quickly, a higher temperature and a lower vacuum degree are usually used to improve the drying efficiency of the product and obtain the lowest possible moisture content of the product. However, the inventors found in their research that under the same temperature conditions, in a vacuum environment below 100Pa, the drying efficiency of the product is very little affected by the vacuum degree. The pursuit of extreme vacuum not only increases the requirements for equipment performance, but also increases the energy consumption of equipment production. Therefore, it is not necessary to always control the vacuum degree at around 10Pa, but it is sufficient to control the vacuum degree below 100Pa according to the equipment performance.

[0023] On the other hand, although increasing the drying temperature improves the drying efficiency of the product to a certain extent, it will also increase the degradation of S,S isomers and the growth of related substances during the drying process. Controlling a reasonable drying temperature can maintain the stability of the product during the production process, improve product quality, and reduce the stability risk of the product during its shelf life.

[0024] According to the present invention, pharmaceutically acceptable additives include fillers, disintegrants, glidants and lubricants, wherein the filler is selected from microcrystalline cellulose and silicified microcrystalline cellulose; the disintegrant is selected from sodium starch glycolate and cross-linked sodium carboxymethyl cellulose; the glidant is selected from silicon dioxide and colloidal silicon dioxide; and the lubricant is selected from magnesium stearate and calcium stearate.

[0025] Furthermore, in step (1), the amount of the additive is as follows, in parts by weight:

[0026]

[0027] According to the present invention, the steps are specifically as follows:

[0028] (1) Weighing a prescribed amount of adenosine butane disulfonate, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate; and mixing the materials in a mixer;

[0029] (2) compressing the mixture into tablet cores;

[0030] (3) drying the tablet core under vacuum at 25°C or below and 100 Pa to remove moisture until the moisture content does not exceed 2.0%;

[0031] (4) coating the dehydrated tablet core with an aqueous suspension of an enteric coating material to obtain an enteric-coated tablet, and controlling the tablet bed temperature at 40-50° C. during the coating process;

[0032] (5) drying the enteric-coated tablets in a vacuum at a temperature below 25° C. and 100 Pa to remove moisture until the moisture content does not exceed 2.0%;

[0033] (6) The dried enteric-coated tablets are packaged in blisters, and the packaging materials are polyamide / aluminum / polyvinyl chloride cold-stamped solid medicinal composite hard tablets and medicinal aluminum foil, or polyamide / aluminum / polyethylene cold-stamped solid medicinal composite hard tablets and aluminum / polyethylene medicinal composite films.

[0034] Furthermore, the enteric coating of the present invention comprises the following coating materials in parts by weight:

[0035]

[0036] Furthermore, the coating weight gain range of the present invention is 5% to 10%.

[0037] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0038] The preparation method of the present invention avoids isolation layer coating, avoids the use of organic solvents, reduces the risk of organic solvent residues in tablets, and reduces production costs and safety and environmental protection pressures. The prepared enteric-coated adenosylmethionine butanedisulfonate tablets have a 0-day S,S isomer content of about 70%, an adenine content of less than 0.2%, and a total impurity content of no more than 1.0% by controlling the temperature and pressure of vacuum drying, and have better accelerated and long-term stability. DETAILED DESCRIPTION

[0039] In order to enable those skilled in the art to better understand the present invention, the present invention is further described in conjunction with specific embodiments. The following examples are examples of the present invention and should not be regarded as limiting the scope of protection of the present invention.

[0040] Example 1

[0041] Weigh the materials according to the following formula composition:

[0042]

[0043]

[0044] The preparation process is as follows:

[0045] (1) Weigh the prescribed amount of adenosine butane disulfonate, microcrystalline cellulose, sodium starch glycolate, and colloidal silicon dioxide, place in a mixing bucket and mix at 12 rpm for 10 min, then add magnesium stearate and mix at 12 rpm for 10 min;

[0046] (2) compressing the mixture into tablet cores with a tablet weight of 1100 mg, a weight difference of no more than 5%, and a tablet hardness of 250-500 N;

[0047] (3) Set the temperature of the vacuum drying oven to 25°C and the upper limit of the vacuum degree to 100Pa, and dry the tablet core to remove moisture. Dry until the moisture content does not exceed 2.0%. The drying time is 24 hours.

[0048] (4) methacrylic acid-ethyl acrylate copolymer is uniformly dispersed in purified water, sodium hydroxide solution is added dropwise, other coating ingredients are added, stirred and mixed uniformly to obtain a coating suspension, the tablet bed temperature is controlled at 40-50° C., the coating suspension is uniformly sprayed onto the surface of the tablet core and dried to obtain enteric-coated tablets;

[0049] (5) The temperature of the vacuum drying oven was set at 25°C and the upper limit of the vacuum degree was 100 Pa. The enteric-coated tablets were dried to remove moisture until the moisture content did not exceed 2.0% to obtain dried coated tablets. The drying time was 12 h.

[0050] Example 2

[0051] The products were prepared according to Example 1, and the dried coated tablets were packaged in different forms to conduct a stability comparison study. The packaging forms and materials are shown in the table below.

[0052]

[0053] The above-mentioned packaging samples were placed under accelerated conditions (temperature 40℃±2℃, relative humidity 75%±5%), intermediate conditions (temperature 30℃±2℃, relative humidity 65%±5%), and long-term conditions (temperature 25℃±2℃, relative humidity 60%±5%) to examine stability. The results are shown in the table below.

[0054]

[0055]

[0056] The results showed that the samples using polyamide / aluminum / polyvinyl chloride cold-stamped solid medicinal composite hard tablets and medicinal aluminum foil blister packaging, or polyamide / aluminum / polyethylene cold-stamped solid medicinal composite hard tablets and aluminum / polyethylene medicinal composite film blister packaging, had significantly slower growth in adenine and other impurities, which is expected to better ensure the stability of the product during the stability period and shelf life.

[0057] Example 3

[0058] Tablet cores were prepared according to the process of Example 1, and vacuum drying of the tablet cores was performed at different temperatures and vacuum degrees. The content, related substances, S,S-isomers, and moisture of the dried tablet cores were detected, and the effects of drying temperature and vacuum degree on drying efficiency and product quality were compared:

[0059]

[0060]

[0061] The inventors found in their research that the main impurity risk during the shelf life of this product is adenine, which will continue to grow during the shelf life. Therefore, controlling the initial level of adenine at a lower level and reducing the growth rate of adenine are effective strategies to reduce product stability risks.

[0062] From the experimental data in the above table, it can be found that when drying at 25°C or below and the vacuum degree is 10Pa or 100Pa, the effect of vacuum degree on drying efficiency is very limited, and the moisture content can be reduced to below 2.0% within 24h to 48h. In addition, when drying at 25°C or below, adenine hardly increases during the entire drying process. When drying at 40°C, although the drying efficiency is higher and the moisture content of the dried tablets is lower, adenine increases significantly during the drying process, which will eventually lead to a higher level of adenine in the newly produced finished product and increase the risk of excessive adenine impurities during the shelf life. When drying at 50°C, the drying efficiency is higher and the moisture content of the dried tablets is lower, but adenine increases significantly during the drying process and the S,S-isomer decreases significantly, which is not conducive to ensuring the quality of the 0-day product.

[0063] Therefore, choosing 25°C and below 100Pa for vacuum drying can better balance drying efficiency and product quality, which is conducive to obtaining products with lower impurity levels and reducing the risk of excessive impurities in products during the stability period and shelf life.

Claims

1. A method for preparing adenosylmethionine butanedisulfonate enteric-coated tablets, comprising: (1) uniformly mixing adenosylmethionine butanedisulfonate and a pharmaceutically acceptable additive; (2) compressing the mixture into tablets; (3) vacuum drying the tablets to remove moisture; (4) Enteric coating the tablets after removing moisture to obtain enteric-coated tablets; (5) vacuum drying the enteric-coated tablets to further remove moisture; (6) the dried enteric-coated tablets are packaged in double aluminum blisters to obtain finished enteric-coated tablets; The method is characterized in that the vacuum drying in step (3) and step (5) is carried out in a vacuum drying oven at a temperature below 25° C. and a vacuum degree below 100 Pa, and is dried until the moisture content of the tablets is less than 2.0%.

2. The preparation method according to claim 1, characterized in that: In step (3) and step (5), the temperature of the vacuum drying oven is 10 to 25°C.

3. The preparation method according to claim 1, characterized in that: In step (3) and step (5), the vacuum degree is 10 to 100 Pa.

4. The preparation method according to claim 1, characterized in that: In step (1), the additives include microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate.

5. The preparation method according to claim 4, characterized in that: In step (1), the amount of the additive is as follows, in parts by weight:

6. The preparation method according to claim 4, characterized in that: In step (1), firstly, adenosine disulfonate, microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide are placed in a mixing barrel and mixed at 10-12 rpm for 5-30 min, and then magnesium stearate is added and mixed at 10-12 rpm for 5-10 min.

7. The preparation method according to claim 1, characterized in that: The enteric coating comprises the following coating materials in parts by weight: The coating weight gain range is 5% to 10%.

8. The preparation method according to claim 1, characterized in that: In step (6), the packaging material of the double aluminum blister package is a cold-stamped solid medicinal composite hard tablet of polyamide / aluminum / polyvinyl chloride and a medicinal aluminum foil blister package.

9. The preparation method according to claim 1, characterized in that: In step (6), the packaging materials of the double aluminum blister packaging are polyamide / aluminum / polyethylene cold-stamped solid medicinal composite hard tablets and aluminum / polyethylene medicinal composite films.

10. Adenosylmethionine disulfate enteric-coated tablets obtained by the preparation method according to any one of claims 1 to 9.

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