JP5491040B2 - Tablets containing acarbose - Google Patents

Description

  The present invention relates to a tablet containing acarbose which is a postprandial hyperglycemia improving agent.

  Acarbose has the effect of suppressing postprandial blood glucose increase by inhibiting the activities of α-amylase and α-glucosidase (such as sucrase and maltase) involved in carbohydrate digestion and absorption in the intestinal tract. It is used for the purpose of improving.

  Acarbose drug substance is known to have a strong hygroscopic property, and when it absorbs moisture, its content decreases and discolors, making it very difficult to handle. Therefore, in Japanese Patent Application Laid-Open No. 58-46013, a glycoside hydrolase inhibitor such as acarbose is mixed with starch and magnesium stearate to obtain a pharmaceutical preparation having a water content of 6% by weight or less of the preparation. Therefore, it is disclosed that the decomposition of acarbose is prevented and the storage stability is improved.

  However, when the tablets having the same composition as the above preparation were stored for 4 weeks under the conditions of 20 ° C., 75% relative humidity and 30 ° C. and 90% relative humidity, the content of the components did not change, but the discoloration of the tablets Has been reported (medicine and pharmacy 32 (3) 597-601, 1994).

  For this reason, tablets containing acarbose must avoid contact with moisture in the atmosphere as much as possible, and it is necessary to instruct not only the medical site but also the patient to be aware of moisture absorption during storage. was there.

JP 58-46013 A

Medicine and pharmacy 32 (3) 597-601, 1994

  As a result of intensive studies to solve the above problems, the present inventors have found that the above object can be achieved by adsorbing acarbose to a specific adsorbent.

  That is, the present invention includes (1) a tablet comprising a composition in which acarbose is adsorbed on one or more porous adsorbents having a specific surface area of 50 m 2 / g or more, (2) ratio A tablet comprising a composition obtained by adsorbing acarbose on a mixture of one or more porous adsorbents having a surface area of 50 m <2> / g or more and anhydrous calcium hydrogen phosphate; (3) specific surface area (1), the tablet according to (2), (4) specific surface area, wherein the porous adsorbent having a mass of 50 m 2 / g or more is selected from magnesium aluminate metasilicate, light anhydrous silicic acid, hydrous silicon dioxide and mixtures thereof In any one of (1)-(3) which contains 1 type, or 2 types or more of the porous adsorbent whose A is 50 m <2> / g or more in the ratio of 0.1-1 mass part with respect to 1 mass part of acarbose. Listed tablets, ( ) The mixing ratio of one or more porous adsorbents having a specific surface area of 50 m 2 / g or more and anhydrous calcium hydrogen phosphate is 1: 0.1 to 1:20 by weight (2) to The tablet according to (4), (6) a mixture of one or more porous adsorbents having a specific surface area of 50 m <2> / g or more and anhydrous calcium hydrogen phosphate with respect to 1 part by mass of acarbose, 0.3 It is related with the tablet in any one of (2)-(5) contained in the ratio of -2 mass parts.

  The tablet of the present invention containing a composition in which acarbose is adsorbed on one or more porous adsorbents having a specific surface area of 50 m2 / g or more prevents caking during production, and further, under high humidity conditions However, tablet discoloration, mutual adhesion, and container adhesion are improved and stable. Therefore, it is not necessary to give special consideration when storing.

  Furthermore, a tablet containing a composition in which acarbose is adsorbed to a mixture of one or more porous adsorbents having a specific surface area of 50 m <2> / g or more and anhydrous calcium hydrogen phosphate, each component in the mixture The desired tablet hardness can be obtained by adjusting the mixing ratio. For this reason, it becomes possible to apply to a split tablet or an orally disintegrating tablet.

  Hereinafter, embodiments of the present invention will be described.

  The acarbose used in the present invention may be produced according to a known method.

  The content of acarbose in the tablet of the present invention is 10 to 60% by weight, preferably 20 to 50% by weight in the tablet. Moreover, when using the tablet of this invention as a postprandial hyperglycemia improving agent, it is good to mix | blend acarbose so that it may become preferably 150 mg-300 mg as a daily dose of an adult.

  The porous adsorbent used in the present invention has a specific surface area of 50 m2 / g or more, preferably 100 m2 / g or more, more preferably 193 m2 / g or more, and an average particle size of 0.1 to 300 μm, preferably 0.5 to 250 μm, pH is 5.0 to 9.0, preferably 6.0 to 8.0, and one or more porous adsorbents included in the above range may be mixed. . Here, when a porous adsorbent having a specific surface area of less than 50 m <2> / g is used, if an attempt is made to produce a tablet having a size that does not hinder taking it, acarbose adsorption becomes insufficient, and the target tablet Can't get. In addition, when a grade in which the 4% slurry pH of the porous adsorbent is larger than 9.0 is used, acarbose may be decomposed, which is not preferable. The average particle diameter of the porous adsorbent is a value measured by a laser diffraction particle size distribution meter or a Coulter counter method, and the specific surface area is a value measured by a BET method using nitrogen gas.

  The porous adsorbent is not particularly limited as long as it is a pharmaceutically acceptable substance. Examples thereof include magnesium aluminate metasilicate, light silicic anhydride, hydrous silicon dioxide, and the like. You may mix.

  Furthermore, the present invention can also improve the stability against humidity by adsorbing acarbose to the mixture of the porous adsorbent and anhydrous calcium hydrogen phosphate, and in that case, by adjusting the mixing ratio of each component Desired tablet hardness can be obtained.

  In the present invention, any other adsorbent can be added to the porous adsorbent or the mixture. Here, the other arbitrary adsorbent is not particularly limited as long as it is a pharmaceutically acceptable substance. Specific examples thereof include crystalline cellulose, carmellose calcium, magnesium silicate, aluminum oxide, magnesium carbonate, dextrin, silicon dioxide and the like. Is mentioned.

  The porous adsorbent used in the present invention is added at a ratio of 0.1 to 1 part by mass, preferably 0.2 to 0.8 part by mass, with respect to 1 part by mass of acarbose. Here, if the addition amount is less than 0.1 parts by mass, the stability against humidity tends to be not improved, which is not preferable.

  The compounding ratio of the porous adsorbent and anhydrous calcium hydrogen phosphate used in the present invention is 1: 0.1 to 1:20, preferably 1: 1 to 1: 5, by weight. If it is in the range of said ratio, stability with respect to humidity can be improved and tablet hardness can be adjusted. This mixture is added in an amount of 0.3 to 2 parts by weight, preferably 0.4 to 1 part by weight, based on 1 part by weight of acarbose. Here, if the addition amount is less than 0.3 parts by mass, the stability against humidity tends to be not improved, which is not preferable.

  The method for adsorbing acarbose on the porous adsorbent is not particularly limited, and can be performed by a conventional method. For example, a method of spraying and adsorbing using a fluid bed granulator, a method of adsorbing by kneading, and the like can be mentioned.

  As a method of spraying and adsorbing using a fluidized bed granulator, for example, a porous adsorbent is put into a fluidized bed granulator (FL-MINI), air is fed from the lower part of the fluidized bed granulator, There is a method of obtaining a desired composition by suspending the adsorbent adsorbent and maintaining a fluid state, spraying a solution in which acarbose is dissolved thereto with a spray nozzle, adsorbing the solution, and drying in a fluidized bed granulator. Although the temperature of the fluid air at the time of spraying and adsorbing is not particularly limited, it is usually 50 to 80 ° C, preferably 60 to 70 ° C. Although the temperature at the time of drying is not specifically limited, It is preferable to dry at 60-70 degreeC. The solvent used in this method is not particularly limited as long as it dissolves acarbose and does not dissolve the porous adsorbent, but water, ethanol, or a mixed solvent of one or more of these is preferable.

  As a method of adsorbing by kneading, for example, a porous adsorbent is put in a commonly used apparatus such as a high speed mixer (LFS-GS-2J), Shinagawa mixer (5DM-r), and acarbose is added thereto. A method of obtaining a target composition by adding a dissolved solution and kneading and adsorbing these is mentioned. The solvent used in this method is not particularly limited as long as it dissolves acarbose and does not dissolve the porous adsorbent, but water, ethanol, or one or more mixed solvents thereof are preferable. Moreover, the removal of a solvent may be a normal drying means, for example, a shelf type dryer (40C), a fluidized bed dryer (MP-01) and the like. Although the temperature at the time of drying is not specifically limited, It is preferable to dry at 60-70 degreeC.

  The tablet of the present invention can be obtained by tableting the composition produced by the above method by a conventional method. For example, there is a method of obtaining a target tablet by tableting the composition produced by the above method with a commonly used apparatus such as a single tableting machine (manufactured by Kikusui Seisakusho) or a rotary tableting machine (VIRGO-512). Can be mentioned. The tableting pressure of the tablet in this case is not particularly limited as long as it does not hinder the production of the tablet, but it is 650 to 2200 kg / cm 2, preferably 1300 to 1800 kg / cm 2.

  It is preferable that the tablet of the present invention has a size that does not hinder the administration, the tablet weight is 90 to 500 mg, preferably 120 to 300 mg, and the size is 5 to 12 mm in diameter, preferably 6 to 10 mm. The thickness is 3.0 to 4.5 mm, preferably 3.1 to 4.2 mm. Further, the hardness of the tablet of the present invention is preferably such that the handling of the tablet and the disintegration property of the tablet are not hindered, and it is preferably 35 to 300N, preferably 40 to 150N.

  The tablet of this invention can contain an excipient | filler, a binder, a disintegrating agent, a lubricant agent, a solubilizing agent, etc. as needed. For example, excipients such as starches such as corn starch, lactose, sucrose, mannitol, xylitol, erythritol, sorbitol, maltitol, calcium citrate, calcium phosphate, crystalline cellulose, magnesium carbonate, calcium carbonate, magnesium aluminate metasilicate; Sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, carboxymethylcellulose, crystalline cellulose / sodium carboxymethylcellulose, dextrin, pullulan, tragacanth, sodium alginate, pregelatinized starch, etc. Agents: Carmellose sodium, croscarmellose sodium, carmellose Disintegrating agents such as calcium, carmellose, low-substituted hydroxypropylcellulose, crosslinked carmellose sodium, crosslinked polyvinylpyrrolidone; magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, hydrous silicon dioxide, sucrose fatty acid ester, hydrogenated oil, etc. Lubricants such as glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, sodium lauryl sulfate, polyoxyethylene polyoxypropylene glycol, etc .; , Fragrances, pigments and flavoring agents.

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

[Examples 1 to 6: When acarbose is adsorbed on a porous adsorbent used in the present invention or a mixture of the porous adsorbent and anhydrous calcium hydrogen phosphate to form tablets]
Based on the formulation shown in Table 1, tablets were produced by the following method.

(1) Magnesium aluminate metasilicate [Neusilin US2 (specific surface area: 300 m 2 / g): Fuji Chemical Co., Ltd.], light anhydrous silicic acid [Adsolider 101 (specific surface area: 300 m 2 / g): Freund Sangyo Co., Ltd.], hydrous silicon dioxide [Carplex # 67 (specific surface area: 429 m2 / g), Carplex # 80 (specific surface area: 193 m2 / g): Shionogi Pharmaceutical Co., Ltd.], anhydrous calcium hydrogen phosphate [Fujicalin ( Specific surface area: 40 m <2> / g): Fuji Chemical Co., Ltd.] is mixed in a mortar.
(2) Acarbose is dissolved in purified water, kneaded with (1) above and adsorbed.
(3) The adsorption powder of (2) is dried at 60 ° C. using a mini jet oven.
(4) After drying, the mixture is sized (No. 22 sieve), added with crystalline cellulose and carmellose calcium, and mixed in a plastic bag.
(5) After adding and mixing light anhydrous silicic acid and magnesium stearate to (4) above, tableting is performed with a single tableting machine (manufactured by Kikusui Seisakusho) using a 7 mm diameter, R-side punch, and the weight is 135 mg. A tablet with a thickness of 3.2 mm is obtained.

[Comparative Examples 1-3: When acarbose is tableted without adsorbing to the adsorbent]
Based on the formulation shown in Table 2, tablets were produced by the following method.

(1) In the formulation shown in Table 2, acarbose, corn starch (specific surface area: 0.4 m 2 / g), magnesium aluminate metasilicate (Neusilin US2: Fuji Chemical Co., Ltd.), anhydrous calcium hydrogen phosphate (Fujicalin: Fuji Chemical) Co., Ltd.) and crystalline cellulose (specific surface area: 1.1 m2 / g) are mixed in a plastic bag.
(2) Further, light anhydrous silicic acid and magnesium stearate were added and mixed, and then tableted with a single tableting machine (manufactured by Kikusui Seisakusho) using a 7 mm diameter, R-face punch, weight 135 mg, thickness 3 Obtain 2 mm tablets.

[Comparative Example 4: Adsorption of acarbose on anhydrous calcium hydrogen phosphate]
Based on the formulation shown in Table 2, tablets were produced by the following method.

  In the formulation shown in Table 2, acarbose was dissolved in purified water and kneaded with anhydrous calcium hydrogen phosphate [Fujicalin (specific surface area: 40 m 2 / g): Fuji Chemical Co., Ltd.] and adsorbed. Since the product caused caking, it could not be produced any more.

[Test Example 1]
The tablets obtained in Examples 1 to 6 and the tablets obtained in Comparative Examples 1 to 3 were left unpacked for 1 week or 2 weeks under the conditions of a temperature of 25 ° C. and a relative humidity of 75%. The color tone and adhesion to the container were observed. The color tone of the tablet was measured using a spectroscopic color difference meter (SE-2000), and the adhesion to the container was visually observed.

  Table 3 shows the color tone of the tablets obtained at the blending ratios in Tables 1 and 2 and the observation results of adhesion to the container. The symbols in the table are color differences that are hardly noticed in the JIS standard in the distance comparison, and those that meet or exceed Class A tolerance, which is generally considered to be the same color. In the case of non-conformity, x was described.

実施例１〜６については、湿度条件下、２週間後まで測定を行ったが、比較例１〜３については１週間で既に色調変化、容器への付着がみられたので、そこで試験を終了した。

For Examples 1-6, the measurement was carried out under humidity conditions until 2 weeks later, but for Comparative Examples 1-3, color change and adhesion to the container were already observed in 1 week, so the test was terminated there. did.

  As shown in Table 3, Examples 1 to 6 in which acarbose was adsorbed to the porous adsorbent used in the present invention or a mixture of the porous adsorbent and anhydrous calcium hydrogen phosphate were not Comparative Examples 1 It was confirmed that the color change of the tablet was improved as compared with ˜3, and there was no adhesion to the container. In Comparative Example 4 in which acarbose is adsorbed to anhydrous calcium hydrogen phosphate having a specific surface area of 40 m 2 / g, if a tablet having a size that does not hinder the use is produced, the adsorption becomes insufficient and caking occurs. Could not be manufactured. From this result, it was confirmed that the acarbose-containing tablet of the present invention is excellent in the stability of the preparation under high humidity conditions.

[Test Example 2]
About the tablet obtained in Examples 1-6, the tablet hardness was measured using the SHLEUNIGER hardness meter.

  Table 4 shows the hardness measurement results of the tablets obtained in Examples 1 to 6.

  Each tablet has a tablet hardness with no problem in handling, but as in Examples 5 to 6, when acarbose was adsorbed to the mixture of the porous adsorbent used in the present invention and anhydrous calcium hydrogen phosphate, The desired tablet hardness could be obtained by adjusting the mixing ratio.

Claims (3)

A composition in which acarbose is adsorbed on a mixture of a porous adsorbent having a specific surface area of 50 m 2 / g or more selected from magnesium aluminate metasilicate, light anhydrous silicic acid, hydrous silicon dioxide and a mixture thereof and anhydrous calcium hydrogen phosphate It is a tablet characterized by containing a thing , Comprising: The tablet whose compounding ratio of a porous adsorbent and anhydrous calcium hydrogenphosphate is 1: 0.1 to 1:20 by weight ratio here .   The tablet according to claim 1, comprising one or more porous adsorbents having a specific surface area of 50 m2 / g or more at a ratio of 0.1 to 1 part by mass with respect to 1 part by mass of acarbose. Claims containing a mixture of one or more porous adsorbents having a specific surface area of 50 m 2 / g or more and anhydrous calcium hydrogen phosphate in a proportion of 0.3 to 2 parts by mass with respect to 1 part by mass of acarbose. Item 3. The tablet according to any one of Items 1 and 2 .