JP2006342126A - Acarbose-containing tablet excellent in time stability - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an acarbose-containing tablet showing less time discoloration on the surface without removing oxygen at the inside of a hermetically closed container. <P>SOLUTION: This acarbose-containing tablet is obtained by coating the acarbose-containing naked tablet prepared under a dry condition with a film-coating composition containing a water soluble polymer by using an organic solvent. The two or more film coating layers containing the water soluble polymer are applied to the acarbose-containing naked tablet prepared under the dry condition is characterized by performing the film-coating of the first layer of the naked tablet side by using an organic solvent. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a tablet composition containing acarbose as an active ingredient and having excellent storage stability.

Acarbose is a substance that is isolated and purified from the culture solution of an amino sugar-producing bacterium belonging to the genus Actinoplanes, a type of radiobacteria. Α-amylase and α-glucosidase (sculase, which are involved in the digestion and absorption of carbohydrates in the human intestinal tract) It inhibits the activity of maltase and the like, delays the digestion and absorption of carbohydrates and suppresses postprandial blood glucose rise, and is widely used as a therapeutic agent for oral diabetes.
Acarbose has a strong hygroscopicity, and it is known that the water content greatly affects the storage stability of the acarbose-containing preparation, and it has been reported that the acarbose may cause discoloration or decrease in hardness depending on the storage condition.
In Japanese Examined Patent Publication No. 7-39340, when the water content of acarbose-containing tablets exceeds about 6% by weight, the acarbose content decreases during storage at a temperature of 60 ° C. for 6 weeks, causing discoloration. Are listed.
In addition, “Stability information in the non-packaging state of tablets and capsules, revised 3rd edition” (Pharmaceutical Journal), the result of storing tablets containing acarbose for 1 week at 25 ° C and 75% humidity, Although there is no change in the component content, it has been reported that a change in appearance (browning) was observed.
For this reason, when storing acarbose-containing tablets, it is necessary to keep them dry, and borrowing such as sealing in an aluminum laminate film in PTP packaging (material is polyvinyl chloride or polypropylene) is required. It has been.
Further, for the purpose of ensuring long-term storage stability, Japanese Patent Application Laid-Open No. 10-182687 discloses that acarbose or acarbose is contained by storing it in an atmosphere substantially free of oxygen under moisture resistance. It is disclosed that discoloration of the formulation can be prevented.
Specifically, the air inside a moisture-resistant container that is substantially gas impermeable, such as a metal container, a glass bottle, or an aluminum laminate film bag, is an inert gas that does not substantially contain oxygen such as nitrogen gas or carbon dioxide gas. Or a vacuum, or substantially remove oxygen from the air in the vessel. The simplest method among these is a method in which an oxygen scavenger is placed in the container and sealed.
However, the moisture-wrapping method using aluminum laminate film has insufficient storage stability, and the method of removing oxygen substantially inside the sealed container requires a work of adding an oxygen scavenger in the packaging operation. This complicates the process and increases costs.

Japanese Patent Publication No. 7-39340 Japanese Patent Laid-Open No. 10-182687

  An object of the present invention is to provide an acarbose-containing tablet with little discoloration of the tablet surface over time without removing oxygen inside the sealed container as described above.

The acarbose-containing tablet according to the present invention is characterized in that a film coating composition containing a water-soluble polymer is film-coated with an organic solvent on an acarbose-containing bare tablet formulated in a dry process.
When two or more film coating layers are used, two or more film coating layers containing a water-soluble polymer are applied to the acarbose-containing naked tablets formulated in a dry process, and at least the first coating on the naked tablet side. The layer is film-coated using an organic solvent.
Here, the formulation in a dry type means a direct compression method (direct tableting method), a dry granulation method, or the like, and it means not under a wet method.

Components contained in the water-soluble film coating layer include, in addition to water-soluble polymers, macrogols such as stearic acid and macrogol 6000, and, if necessary, talc, titanium oxide, and pigments in normal film coating layers. Components that can be added can be added.
Stearic acid has the effect of suppressing the moisture permeability of the coating film, and the macrogol imparts plasticity to the coating film.
As water-soluble polymers, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, polyvinylacetal diethylaminoacetate (trade name: AEA), fumaric acid / stearic acid / polyvinylacetal diethylaminoacetate / hydroxypropylmethylcellulose 2910 mixture Etc. are mentioned as examples.
Moreover, what dissolves in an organic solvent such as ethyl cellulose and aminoalkyl methacrylate copolymer E can be used by mixing with a water-soluble polymer.
Particularly preferred are hydroxypropylcellulose and hydroxypropylmethylcellulose.
It is desirable to use a solvent that dissolves the water-soluble polymer as the solvent used for coating. Specific examples include ethanol, methanol, acetone, a mixed solvent of alcohol / methylene chloride, a mixed solution of alcohol / water, and the like.
The film coating amount is important for ensuring storage stability, and is preferably 3% by weight or more with respect to the acarbose-containing bare tablet.
The upper limit is set in consideration of the dissolution rate of the active ingredient.

When two or more film coating layers are applied, an organic solvent can be used for forming the first film layer on the uncoated tablet side, and water can be used as the solvent for the second and subsequent layers. Thereby, the quantity of the organic solvent required at a coating process can be reduced, and manufacturing cost can be held down.
It is important that the coating amount of the first layer is an amount capable of preventing the purified water, which is the coating solvent of the second layer, from coming into contact with the naked tablet during spraying, and is 3 to 3 per unit surface area of the naked tablet. About 15 μg / mm ² is desirable (for example, about 0.5 mg to 2.0 mg in the case of a naked tablet having a diameter of 7 mm and a thickness of 3.38 mm).
This is because if it is less than 3 μg / mm ² , the moisture permeability of purified water in the second layer is weakly suppressed, and if it exceeds 15 μg / mm ² , the elution rate of the main drug acarbose is slowed.
Ingredients that can usually be incorporated into the film coating layer can be added as desired, for example, stearic acid, talc, titanium oxide, macrogol plasticizer, hydrous silicon dioxide, glycerin fatty acid ester, magnesium silicate, light anhydrous silica. Acid, magnesium oxide, dimethylpolysiloxane (for internal use), sucrose fatty acid ester, triethyl citrate, stearyl alcohol, magnesium stearate, cetanol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, triacetin, concentrated glycerin, propylene glycol, polysorbate 80, magnesium metasilicate aluminate.
As the production equipment that can be used in the present invention, an ordinary granulator, tablet press, and tablet coating machine can be used. The granulator used to obtain acarbose-containing tablets is, for example, a dry granulator roller compactor (Freund Sangyo), a small washing vacuum tableting machine (manufactured by Kikusui Seisakusho) as a tableting machine, and a high coater as a tablet coating machine. (Made by Freund Industries).

  As mentioned above, Acarbose is hygroscopic and has the property of absorbing moisture and changing over time. Therefore, when making uncoated tablets, use additives with low moisture content, and the working environment is also low humidity. It is more desirable to work.

  In order to ensure long-term storage stability of acarbose-containing tablets, conventionally, it has been necessary to put an oxygen scavenger in a sealed container, but according to the present invention, equivalent long-term stability can be achieved without performing these complicated operations. Secured tablets can be obtained.

(Manufacture example 1 of uncoated tablet)
Acarbose 50 parts, D-mannitol (trade name: Peeritol SD200, manufactured by roquetee) 43.25 parts, crystalline cellulose (trade name: Avicel PH102, manufactured by Asahi Kasei Chemicals), croscarmellose sodium (trade name: Ac-Di- sol, manufactured by FMC) 10 parts, and further, light anhydrous silicic acid (trade name: AdSorida 101, manufactured by Freund Sangyo) 0.25 part, magnesium stearate (trade name: magnesium stearate-S, manufactured by Nippon Oil & Fats) 1 After mixing 5 parts, 135 mg of uncoated tablets (diameter 7 mm, thickness 3.38 mm) were obtained with a rotary tableting machine.

  With respect to 135 parts of the bare tablet of Production Example 1, 0.8 parts of hydroxypropyl cellulose (trade name: HPC-L, manufactured by Nippon Soda) and 0.2 part of stearic acid (trade name: stearic acid, manufactured by NOF Corporation) are ethanol. The coating solution dissolved in 32 parts was sprayed using a tablet coating apparatus to provide the first water-soluble film layer. Furthermore, hydroxypropylmethylcellulose 2910 (trade name: TC-5RW, manufactured by Shin-Etsu Chemical Co., Ltd.) 3.5 parts, Macrogol 6000 (trade name: PEG6000P, manufactured by Nippon Oil & Fats) 0.5 parts, titanium oxide (trade name: A-100, Ishihara Sangyo Co., Ltd.) 0.6 parts, talc (trade name: Talkan Hayashi, Hayashi Kasei Co., Ltd. 0.4 parts) dissolved and dispersed in 70 parts of purified water, sprayed using a tablet coating machine, A water-soluble film-coated second layer was applied to make a film-coated tablet of 141 mg.

  With respect to 135 parts of the bare tablet of Production Example 1, 1.6 parts of hydroxypropylcellulose (trade name: HPC-L, manufactured by Nippon Soda) and 0.4 part of stearic acid (trade name: stearic acid, manufactured by NOF Corporation) are ethanol. The coating solution dissolved in 64 parts was sprayed using a tablet coating apparatus to provide the first water-soluble film layer. Furthermore, hydroxypropylmethylcellulose 2910 (trade name: TC-5RW, manufactured by Shin-Etsu Chemical Co., Ltd.) 3.5 parts, Macrogol 6000 (trade name: PEG6000P, manufactured by Nippon Oil & Fats) 0.5 parts, titanium oxide (trade name: A-100, Ishihara Sangyo Co., Ltd.) 0.6 parts, talc (trade name: Talkan Hayashi, Hayashi Kasei Co., Ltd. 0.4 parts) dissolved and dispersed in 70 parts of purified water, sprayed using a tablet coating machine, A second layer of water-soluble film coating was applied to make a 142 mg film-coated tablet.

(Comparative Example 1)
With respect to 135 parts of the bare tablet (135 mg of tablet weight) of Production Example 1, 3.5 parts of hydroxypropylmethylcellulose 2910 (trade name: TC-5RW, manufactured by Shin-Etsu Chemical), Macrogol 6000 (trade name: PEG6000P, manufactured by NOF Corporation) 0.5 parts, titanium oxide (trade name: A-100, manufactured by Ishihara Sangyo) 0.6 part, talc (trade name: Talkan Hayashi, Hayashi Kasei) 0.4 part are dissolved and dispersed in 70 parts of purified water. The resulting coating solution was sprayed using a tablet coating apparatus to form one film-coated tablet of 140 mg.

(Manufacture example 2 of uncoated tablet)
50 parts of acarbose and 43.25 parts of D-mannitol (trade name: Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd.) are mixed and dry granulated using a roller compactor. The granulated product is crushed and sieved and mixed with 30 parts of crystalline cellulose (trade name: Avicel PH102, manufactured by Asahi Kasei Chemicals) and 10 parts of croscarmellose sodium (trade name: Ac-Di-sol, manufactured by FMC). Furthermore, 0.25 parts of light anhydrous silicic acid (trade name: Adsolida 101, manufactured by Freund Industries) and 1.5 parts of magnesium stearate (trade name: magnesium stearate-S, manufactured by NOF Corporation) are mixed, and then subjected to rotary punching. A tablet of 135 mg was obtained with a tablet.

  With respect to 135 parts of the bare tablet of Production Example 2, 3.5 parts of hydroxypropylmethylcellulose 2910 (trade name: TC-5RW, manufactured by Shin-Etsu Chemical), 0.5 part of Macrogol 6000 (trade name: PEG6000P, manufactured by NOF Corporation), Titanium oxide (trade name: A-100, manufactured by Ishihara Sangyo) 0.6 part, talc (trade name: Talkan Hayashi, Hayashi Kasei Co., Ltd.) 0.4 part, ethanol / methylene chloride mixed solution (1: 1) 70 parts The coating solution dissolved and dispersed in was sprayed using a tablet coating machine to obtain one film-coated tablet of 140 mg.

  Hydroxypropylcellulose (trade name: HPC-L, manufactured by Nippon Soda) 0.8 parts, stearic acid (trade name: stearic acid, manufactured by Nippon Oil & Fats) 0 to 135 parts of the bare tablet (135 mg tablet weight) of Production Example 2 A coating solution prepared by dissolving 2 parts in 32 parts of ethanol was sprayed using a tablet coating apparatus to provide a first water-soluble film layer. Furthermore, hydroxypropylmethylcellulose 2910 (trade name: TC-5RW, manufactured by Shin-Etsu Chemical Co., Ltd.) 3.5 parts, Macrogol 6000 (trade name: PEG6000P, manufactured by Nippon Oil & Fats) 0.5 parts, titanium oxide (trade name: A-100, Ishihara Sangyo Co., Ltd.) 0.6 parts, talc (trade name: Talkan Hayashi, Hayashi Kasei Co., Ltd. 0.4 parts) dissolved and dispersed in 70 parts of purified water, sprayed using a tablet coating machine, A water-soluble film-coated second layer was applied to make a film-coated tablet of 141 mg.

  Hydroxypropylcellulose (trade name: HPC-L, Nippon Soda) 0.8 parts, Macrogol 400 (trade name: Macrogol 400, manufactured by Sanyo Chemical Industries) A coating solution in which 0.2 part was dissolved in 32 parts of ethanol was sprayed using a tablet coating apparatus to provide a first water-soluble film layer. Furthermore, hydroxypropylmethylcellulose 2910 (trade name: TC-5RW, manufactured by Shin-Etsu Chemical Co., Ltd.) 3.5 parts, Macrogol 6000 (trade name: PEG6000P, manufactured by Nippon Oil & Fats) 0.5 parts, titanium oxide (trade name: A-100, Ishihara Sangyo Co., Ltd.) 0.6 parts, talc (trade name: Talkan Hayashi, Hayashi Kasei Co., Ltd. 0.4 parts) dissolved and dispersed in 70 parts of purified water, sprayed using a tablet coating machine, A water-soluble film-coated second layer was applied to make a film-coated tablet of 141 mg.

  The above pharmaceutical formulation is summarized in Table 1 and Table 2 below.

(Experimental example 1)
Commercially available tablets of acarbose containing 50 mg, uncoated tablets of Production Examples 1 and 2 and each tablet obtained in Comparative Examples and Examples were placed in a sealed glass bottle of about 60 ml and stored at 60 ° C. One week, two weeks, and three weeks after the start of the test, the change in color tone of the tablets was measured using a color difference meter CM-3500d (Minolta). The results are shown in Table 3 and the graphs of FIGS.

実験例１の結果より、市販錠50mg、裸錠（製造例１、２）及び比較例１は、3週間でΔE値が上昇し、目視評価においても錠剤表面の微黄色化が確認された。一方、実施例１〜５の錠剤は開始時と比べΔE値の上昇は小さく、錠剤表面の色調にほとんど差は認められなかった。

From the results of Experimental Example 1, in the commercially available tablets 50 mg, uncoated tablets (Production Examples 1 and 2) and Comparative Example 1, the ΔE value increased in 3 weeks, and a slight yellowing of the tablet surface was also confirmed by visual evaluation. On the other hand, the increase in ΔE value of the tablets of Examples 1 to 5 was small compared to the beginning, and almost no difference was observed in the color tone of the tablet surface.

(Experimental example 2)
Example 4 and commercially available tablets 50 mg each 20 tablets (1) alone (2) together with a desiccant (3) air in the container was replaced with nitrogen, sealed in a glass bottle of about 60 ml, and stored at 60 ° C. One week, two weeks, and three weeks after the start of the test, changes in the color tone of the tablets were measured with a color difference meter. In addition, GEOLAM (manufactured by Shin-Etsu Chemical Co., Ltd.) was used as a desiccant. The results are shown in Table 4 and the graph of FIG.

実験例２の結果より、市販錠50mgは（１）単独で、（２）乾燥剤とともに保存した場合、3週間でΔEは７以上となり、明らかな色調変化が認められた。（３）容器内の空気を窒素置換して保存した場合は、ややΔE値は減少するが、錠剤表面の色調は開始時と比べやや微黄色を呈した。一方、実施例４の錠剤はいずれの保存形態においてもΔE値は小さく、差は認められなかった。
このことから、市販錠の変色を防止するには包装容器中の酸素を除いた状態を確保する必要があるが、実施例４の錠剤は通常の密閉容器中に保管することで、変色を防止することが可能であることが示唆された。

From the results of Experimental Example 2, when commercially available tablets (50 mg) were stored alone (1) and stored together with (2) desiccant, ΔE was 7 or more in 3 weeks, and a clear change in color tone was observed. (3) When the air in the container was stored after being purged with nitrogen, the ΔE value was slightly reduced, but the color of the tablet surface was slightly yellow compared to the start. On the other hand, the tablet of Example 4 had a small ΔE value in any storage form, and no difference was observed.
Therefore, to prevent discoloration of the commercially available tablets, it is necessary to ensure the state excluding oxygen in the packaging container. However, the tablet of Example 4 can be prevented from discoloring by storing it in a normal sealed container. It was suggested that it is possible.

The evaluation result of the time-dependent color difference change of a tablet is shown. The evaluation result of the time-dependent color difference change of a tablet is shown. The evaluation result of the time-dependent color difference change of a tablet is shown.

Claims (5)

  An acarbose-containing tablet characterized by film-coating a film coating composition containing a water-soluble polymer with an organic solvent on an acarbose-containing uncoated tablet formulated in a dry process.   It is characterized in that two or more film coating layers containing a water-soluble polymer are applied to an acarbose-containing uncoated tablet formulated in a dry manner, and at least the first layer on the uncoated tablet side is film-coated using an organic solvent. Acarbose-containing tablets.   The acarbose-containing tablet according to claim 1 or 2, wherein the water-soluble polymer is selected from hydroxypropylcellulose and hydroxypropylmethylcellulose.   The acarbose-containing tablet according to any one of claims 1 to 3, wherein the film coating layer containing the water-soluble polymer is 3% by weight or more based on the acarbose-containing uncoated tablet.   The acarbose-containing tablet according to any one of claims 1 to 4, wherein stearic acid or macrogol is blended in the film coating layer.

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