JP5325490B2 - Preparation containing methylmethioninesulfonium chloride - Google Patents

Description

  The present invention relates to a preparation containing methylmethionine sulfonium chloride.

Methylmethionine sulfonium chloride (hereinafter also referred to as MMSC) has a protective action on the mucous membrane of the digestive tract. Therefore, improvement of subjective symptoms such as gastric ulcer, duodenal ulcer, gastritis and other objective findings, improvement of liver function in chronic liver disease, etc. Widely used for alleviation of various symptoms.
However, since MMSC is decomposed by moisture and generates an unpleasant odor, the formulation containing MMSC has a problem that the quality deteriorates with time.

As a means for preventing deterioration in the quality of the MMSC-containing preparation, for example, an uncoated tablet containing methylmethioninesulfonium chloride is protected and then coated with a sugar coating composition containing succinated gelatin. (Patent Document 1); Method using a mixed powder comprising a mixture obtained by mixing silicone with methyl methionine sulfonium chloride (Patent Document 2); Core material containing methyl methionine sulfonium chloride, and the core material A sugar-coating preparation having a sugar-coating layer to be coated, wherein at least one of the sugar-coating layers is a sugar-coating preparation containing 0.01 to 10% by weight of sugar and ethyl acrylate / methyl methacrylate copolymer (Patent Document 3) Etc. are known.
JP 2003-063953 A JP 2003-306431 A International Publication No. 08/013084 Pamphlet

However, the method of applying sugar coating to an uncoated tablet containing MMSC is highly effective in preventing moisture absorption, but has disadvantages such as a complicated manufacturing process and a long manufacturing time.
Accordingly, an object of the present invention is to provide an MMSC-containing preparation that can be produced by a simpler method than before and that maintains the stability of MMSC.

As a result of earnest research on the means for preventing the deterioration of the quality of the MMSC-containing preparation, the present inventor surprisingly surprisingly, when MMSC coexists with vitamin B ₁ species, the stability of MMSC is maintained and an unpleasant odor is obtained. The inventors have found that generation can be suppressed and completed the present invention.

That is, the present invention provides a pharmaceutical preparation containing methylmethionine sulfonium chloride and vitamin B ₁ or a derivative thereof or a salt thereof.

Further, the present invention is to provide a methyl methionine sulfonium chloride stabilization method characterized by blending the methyl methionine sulfonium chloride containing formulation, vitamin B ₁ or a derivative or a salt thereof.

  According to the present invention, it is possible to obtain a MMSC-containing preparation in which the stability of MMSC is maintained and the generation of unpleasant odor over time is suppressed. Moreover, since the preparation of the present invention does not require a complicated process such as a sugar coating process, it can be produced efficiently and simply.

The pharmaceutical preparation of the present invention is characterized in that vitamin B ₁ or a derivative thereof or a salt thereof is added to a preparation containing MMSC as an active ingredient.
The MMSC used in the present invention can be obtained according to a known production method. In addition, for example, “methyl methionine sulfonium chloride” (manufactured by Yonezawa Hamari Chemical Co., Ltd., manufactured by Alps Pharmaceutical Co., Ltd.) is commercially available.

  In the present invention, the content of MMSC is preferably 0.05 to 15% by mass, more preferably 0.1 to 10% by mass with respect to the total amount of the preparation, from the viewpoint of effectiveness and prevention of quality deterioration.

Examples of vitamin B ₁ or a derivative thereof or a salt thereof (hereinafter also referred to as vitamin B ₁ ) used in the present invention include thiamine, bisthiamine, bisbutiamine, bisbenchamine, thiamine disulfide, octothiamine, fursultiamine, Examples thereof include thiamine derivatives such as benfotiamine, bisthiamine, and dicetiamine, or salts thereof. The salt may be a pharmaceutically acceptable salt, for example, a mineral salt such as nitrate, hydrochloride, sulfate, etc .; acetate, propionate, tartrate, fumarate, maleate, malic acid Organic salts such as salts, citrate, methanesulfonate, p-toluenesulfonate, trifluoroacetate, etc., specifically thiamine hydrochloride, thiamine nitrate, fursultiamine hydrochloride, dicetiamine hydrochloride, etc. Can be mentioned. These can be used alone or in combination of two or more. In the present invention, as vitamin B ₁ , thiamine derivatives are preferable, and benfotiamine is particularly preferable.
Vitamin B ₁ is a known compound, and as a method for obtaining it, a commercially available product may be used, or it can be produced based on a known method.

In the present invention, the content of vitamin B ₁ is preferably 0.05 to 15% by mass, more preferably 0.1 to 10% by mass, based on the total amount of the preparation.

The blending ratio (mass ratio) of MMSC and vitamin B ₁ in the pharmaceutical preparation of the present invention is preferably 1: 0.1 to 10 from the viewpoint of suppressing the degradation of MMSC and suppressing the generation of unpleasant odor. 0.2 to 5 is more preferable, and 1: 0.5 to 2 is particularly preferable.

  The pharmaceutical preparation of the present invention is particularly useful as a drug for gastrointestinal tract due to the protective action of MMSC, which is an active ingredient, for gastrointestinal tract. For example, gastric ulcer, duodenal ulcer, gastritis etc. It can be applied to the improvement of liver function.

  The dosage form of the pharmaceutical preparation is not particularly limited as long as it is an oral solid preparation, and examples thereof include tablets, powders, granules, fine granules, pills, capsules, etc. Granules are particularly preferable.

The pharmaceutical preparation of the present invention can be produced by a conventional method. That is, using MMSC and vitamin B ₁ and a formulation additive that does not have a practical effect on the effect of the present invention, the known formulation method described in the 15th revised Japanese Pharmacopoeia General Formulation, etc. Can be manufactured based on.
The formulation additive is not particularly limited as long as it does not substantially affect the effects of the present invention. For example, excipients, binders, disintegrants, lubricants, coloring agents, taste masking agents are not limited. Agents, fragrances and the like can be used.
Examples of the excipient include lactose, starches, crystalline cellulose, sucrose, mannitol, xylitol, light anhydrous silicic acid, calcium hydrogen phosphate and the like.
Examples of the binder include hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol, pullulan methylcellulose, hydrogenated oil, and the like.
Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, crospovidone, corn starch, and low-substituted hydroxypropylcellulose.
Examples of the lubricant include magnesium stearate, talc, calcium stearate, silicon dioxide and the like.
Examples of the colorant include tar pigments and iron sesquioxide.
Examples of the corrigent include stevia and aspartame.
Examples of the fragrances include menthol, orange, caramel, mint oil, vanilla flavor, mint flavor and the like.
These formulation additives can be used alone or in combination of two or more, and the content of the formulation additive in the pharmaceutical formulation of the present invention may be determined by appropriate examination.

  The preparation of the present invention preferably contains one or more additives selected from hydroxypropylcellulose, carmellose calcium and hydrogenated oil among the above components. Here, the content of hydroxypropyl cellulose is preferably 0.5 to 5.0% by mass, more preferably 1.0 to 4.0% by mass with respect to the total amount of the preparation. Moreover, 5.0-40.0 mass% is preferable with respect to the formulation whole quantity, and, as for content of a carmellose calcium, More preferably, it is 10.0-30.0 mass%. The content of the hardened oil is preferably 5.0 to 50.0% by mass and more preferably 10.0 to 40.0% by mass with respect to the total amount of the preparation.

  In addition, for the purpose of enhancing the action of MMSC, the pharmaceutical preparation of the present invention includes a component that neutralizes gastric acid, a component that suppresses secretion of gastric acid (antacid component), a component that enhances stomach function (healthy stomach component), digestion It is preferable to further contain a component for assisting (digestive enzyme), a component for repairing the gastric mucosa (mucosal repair component) and the like.

  As the antacid component, for example, dried aluminum hydroxide gel, bismuth magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalsart, sodium hydrogen carbonate, magnesium oxide, aluminum hydroxide, magnesium hydroxide, Sodium bicarbonate coprecipitate, magnesium carbonate, precipitated calcium carbonate, precipitated magnesium carbonate, dihydroxyaluminum aminoacetate, magnesium metasilicate aluminate, funnel extract, ranitidine hydrochloride, loxatidine acetate hydrochloride, cimetidine, famotidine, nizatidine, lafutidine, omeprazole , Lansoprazole, Pantoprazole, Rabeprazole sodium, Leminoprazole, Esomeprazole, Pirenzepine hydrochloride, Proglumide, Tikiji bromide Beam, and the like.

  As a healthy stomach component, powdered red powder, powdered peanut, powdered powder, turmeric powder, powdered powder, powdered powder, powdered powder, powdered powder, powdered powder, powdered powder, powdered powder, powdered powder, powdered powder, powdered powder, powdered powder, powdered powder , Keihi powder, Ketsumeishi powder, Gennoshoko powder, Koujin powder, Koboku powder, Goshuyu powder, Gobaishi powder, Colombo powder, Chimpi powder, Hawthorn powder, Sansho powder powder, Sanna powder powder, Shokyo powder powder, Soshishi powder powder, Shukusha powder powder, Shozuk powder powder , Seihi powder, Sekishokon powder, Assembly powder, Sowjutsu powder, Soyou powder, Daio powder, Chikutsutsu carrot powder, Clove powder, Spruce powder, Nigaki powder, Nikuzuku powder, Carrot powder, Hikikoshi powder, Hihatsu powder, Sandalwood powder, Mokko Powder, Yakuchi powder, Yobai powder, mint oil, gentian powder, Ryokyo powder, anise , Aloe, Suisaiyou, star anise, Konzurango, processed garlic, calamus root, Sentauriumu grass, gentian extract, hop extract, Homikaekisu, dried yeast, carnitine chloride, glutamic acid hydrochloride, bethanechol and maleic acid trimebutine like chloride.

  Examples of the digestive enzyme include ursodeoxycholic acid, sugar-containing pepsin, diaspene, cellulase, cellulosin, takadiastase, bile powder, dehydrocol, neurase, pancreatin, biotamirase, biodiastase, prozyme, polypase, lipase and the like.

  Mucosal repair components include glycyrrhizic acid or its salt, licorice or its extract, sucrose sulfate aluminum salt (sucralfate), aldioxa, L-glutamine, magnesium metasilicate aluminate, sofalcone, copper chlorofin sodium, copper chloro Examples include fin potassium, cetraxate hydrochloride, gefarnate, trimebbutin maleate, sodium azulensulphonate and teprenone.

The dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the weight, age, sex, symptoms, etc. of the patient. In general, for adults, the MMSC is about 75.0 to 225.0 mg / day, particularly 150. It is preferable to administer about 0 to 225.0 mg / day, and the dosage of vitamin B ₁ can be determined according to the above-mentioned ratio according to the dosage.

  The pharmaceutical preparation of the present invention thus obtained is less susceptible to MMSC degradation due to moisture absorption and maintains its stability, so that odors are less likely to occur over time and there is almost no decrease in content during storage of the preparation. .

  EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Example 1
416.7 g of methylmethionine sulfonium chloride, 347.2 g of benfotiamine, 2000 g of hydrogenated oil, 150 g of hydroxypropylcellulose, 1250 g of carmellose calcium, 836.1 g of corn starch, and kneaded (500 g of ethanol), granulated and sized To obtain granules.

Comparative Example 1
416.7 g of methyl methionine sulfonium chloride, 2000 g of hydrogenated oil, 150 g of hydroxypropyl cellulose, 1250 g of carmellose calcium, and 1183.3 g of corn starch were mixed and kneaded (ethanol 500 g), granulated, and granulated to obtain granules.

[Odor evaluation]
The odor of each granule obtained in Example 1 and Comparative Example 1 was evaluated.
Occurrence of odor when 2 g of granules were put in a transparent glass bottle (3K bottle) and sealed and stored at 40 ° C. for 1 week, 2 weeks and 4 weeks was evaluated based on the following evaluation criteria. The evaluation was performed by five people, and the average value was calculated. The results are shown in Table 1.
<Score Evaluation Details>
0: No unpleasant odor derived from methyl methionine sulfonium chloride 1: No unpleasant odor derived from methyl methionine sulfonium chloride 2: Unpleasant odor derived from methyl methionine sulfonium chloride 3: Unpleasant odor derived from methyl methionine sulfonium chloride Feel strongly

In the granule of Example 1 containing benfotiamine, an unpleasant odor derived from MMSC was hardly felt even after a storage period of 4 weeks. On the other hand, in the granule of Comparative Example 1 in which no benfotiamine was added, an unpleasant odor of MMSC was clearly felt after 2 weeks of storage.
Also, the MMSC content stability over time of the granule of Example 1 blended with benfotiamine was good.
Therefore, it was confirmed that a MMSC-containing preparation with very excellent quality can be obtained by coexisting vitamin B ₁ such as benfotiamine with MMSC.

Claims (4)

Granules containing methylmethionine sulfonium chloride and benfotiamine . The granule of Claim 1 which contains a benfotiamine in the ratio of 0.1-10 mass parts with respect to 1 mass part of methylmethionine sulfonium chloride. The granule according to claim 1 or 2 , which is a gastrointestinal drug . A method for stabilizing methylmethionine sulfonium chloride, comprising adding benfotiamine to a preparation containing methylmethioninesulfonium chloride.