JP2013010798A - Colored sugar-coated tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a colored sugar-coated tablet capable of stabilizing medicines causing decomposition in high water content, having a masking property and a moisture resistance and clean surface.SOLUTION: In the sugar-coated tablet, the outermost layer of a sugar-coated layer is composed of sugar alcohols having low solubility, saccharides having high solubility and a coloring agent.

Description

  [Technical Field] The present invention relates to a colored dragee tablet having a clean surface and having a masking property and a moisture proof property in the field of foods and pharmaceuticals.

  Conventional sugar-coated tablets are generally produced by applying sugar coating of 70 to 110% of the weight of the uncoated tablet using a sugar-coating liquid composed of purified white sugar liquid. When the coating amount is large as described above, there is a drawback that the stability of the drug is deteriorated over time due to an increase in the size of the preparation and a high water content of the preparation (equilibrium relative humidity of about 55%).

  Patent Document 1 and Patent Document 2 disclose sugar-coated tablets with a coating amount reduced from that of conventional sugar coatings, both of which are sugar-coated tablets using only purified sucrose as a carbohydrate, and the disclosed methods However, even though the increase in size of the preparation could be solved, the drawbacks of deterioration in the stability of the drug over time due to high moisture content of the preparation and the disadvantage of long production time could not be solved.

Furthermore, as a method for producing a sugar-coated tablet that can solve the above-mentioned drawbacks, Patent Document 3 discloses a method for producing a thin-layer sugar-coated tablet using a sugar-coating liquid containing a sugar, an excipient, and a binder. However, when coloring sugar-coated tablets, the color tone differs depending on the sugar used, so it is necessary to combine two or more sugars according to the target color tone. The optimum combination and ratio when combining the qualities are not disclosed, and the surface may be rough and uneven in color.
JP 62-5910 A Japanese Patent Laid-Open No. 11-116467 JP 2002-179559 A

  An object of the present invention is to provide a colored sugar-coated tablet that can stabilize a drug that decomposes at high moisture, has masking properties and moisture-proof properties, and has a clean surface.

  As a result of intensive studies to achieve the above-mentioned object, the present inventors have surprisingly formed a sugar coating layer containing a sugar alcohol having a low solubility, a sugar having a high solubility, and a coloring agent as the outermost layer of the sugar coating. As a result, it was found that an unpleasant odor and taste masking, stabilization of a drug that decomposes with high moisture, and a colored dragee with a clean surface having moisture resistance were obtained, and the present invention was completed.

That is, the present invention
(1) a colored sugar-coated tablet, wherein the outermost layer of the sugar-coating layer comprises a sugar alcohol having a low solubility, a saccharide having a high solubility, and a colorant;
(2) Sugar-coated tablets according to the above (1), wherein the solubility of sugar alcohols with low solubility in water at 25 ° C. is 10 to 50%, and the solubility of sugars with high solubility in water at 25 ° C. is 60 to 250%,
(3) A sugar-coated tablet according to the above (1), wherein the sugar alcohol having low solubility is selected from the group consisting of erythritol, mannitol and reduced lactose,
(4) A sugar-coated tablet according to the above (1), wherein the highly soluble saccharide is selected from the group consisting of sucrose, purified sucrose, powdered reduced maltose water candy, trehalose and maltose,
(5) A sugar-coated tablet according to (1) above, wherein the colorant is selected from the group consisting of riboflavins such as riboflavin, riboflavin butyrate and riboflavin phosphate, yellow ferric oxide, ferric oxide, pigments and lakes,
(6) The sugar-coated tablet according to the above (1), wherein the mass ratio of the sugar alcohol having low solubility and the sugar having high solubility in the outermost layer is 1: 1 to 1: 9,
(7) The sugar-coated tablet according to the above (1), wherein the outermost layer is 3 to 30% of the uncoated tablet mass,
(8) The sugar-coated tablet according to the above (1), which has an equilibrium relative humidity of 40% or less.

  According to the present invention, it is possible to stabilize the drug in the uncoated tablet by reducing the moisture content of the tablet at an equilibrium relative humidity (ERH) of 40% or less, masking an unpleasant odor or taste, and having moisture resistance, and Thus, a colored sugar-coated tablet having an effect of preventing surface roughness and color unevenness of the tablet surface can be obtained.

As a general sugar-coated tablet, a three-layered sugar-coating layer is applied, in which one layer is kneaded (DC), two layers are kneaded (BC), three layers are syruped (SC), and further polished. There are various forms such as those having a sugar-coated layer having a two-layer structure in which the above-mentioned BC layer and SC layer are applied and polished, and those in which a poorly stable drug is blended in the sugar-coated layer .
As the sugar-coated layer structure of the sugar-coated tablet of the present invention, a sugar-coated layer containing a sugar alcohol with low solubility, a sugar with high solubility and a coloring agent may be formed as the outermost layer (that is, the top layer), and the others are particularly limited. Not. For example, any structure such as a three-layer structure composed of an undercoat layer, an intermediate cover layer and an overcoat layer, a two-layer structure composed of an undercoat layer and an overcoat layer, or a structure containing a drug in a sugar coating layer Also good.
Preferably, the sugar-coated layer of the sugar-coated tablet of the present invention has a three-layer structure, more preferably, the first layer is undercoated with a film base, the second layer is kneaded, the third layer is syruped, and then It is a three-layer structure that polishes.
Hereinafter, the case of a three-layer structure will be described.

The sugar used in the sugar-coating liquid for the overcoat layer of the sugar-coated tablet in the present invention consists of sugar alcohols having low solubility and sugars having high solubility.
The sugar alcohols having low solubility are preferably sugar alcohols having a solubility in water of 25 ° C. of 10 to 50% (% by weight, the same applies hereinafter), more preferably 15 to 40%.
Examples of the low-solubility sugar alcohols include erythritol, mannitol, and reduced lactose, and one or more of these can be used. Preferably, erythritol is used. The solubilities are 36 g / 100 g water 25 ° C. for erythritol, 18 g / 100 g water 25 ° C. for mannitol, and 25 g / 100 g water 25 ° C. for reduced lactose, respectively.

The saccharide having a high solubility is preferably a saccharide having a solubility in water of 25 ° C. of 60 to 250%, more preferably 65 to 220%.
Examples of the highly soluble saccharide include sucrose, purified sucrose, powdered reduced maltose syrup, trehalose, maltose, and the like, and one or more of these can be used. Preferably, purified sucrose, trehalose or maltose, more preferably purified sucrose is used. The solubilities of sucrose and purified sucrose are 215 g / 100 g water 25 ° C., powdered reduced maltose water candy 130 g / 100 g water 25 ° C., trehalose 68.9 g / 100 g water 20 ° C., maltose 81 g / 100 g water 25 ° C. is there.

The mixing ratio of the sugar alcohol having low solubility and the sugar having high solubility in the overlay layer is 1: 1 to 1: 9, preferably 1: 1.5 to 1: 4 in mass ratio.
The compounding quantity of the saccharide | sugar in a top sugar coating liquid is 20 to 80% as solid content in a sugar coating liquid, Preferably, it is 40 to 70%.

  The overlay layer further includes a colorant. Examples of the colorant include riboflavins such as riboflavin, butyric acid riboflavin, and sodium riboflavin phosphate, and yellow iron sesquioxide, iron sesquioxide, pigments, lakes, and the like. Used. The blending amount of the colorant is 0.1 to 0.5%, preferably 0.2 to 0.4%, based on the solid content of the upper layer.

As the sugar used in the sugar coating liquid for the intermediate layer of the sugar-coated tablet in the present invention, sugar alcohols having low solubility are used. The low-solubility sugar alcohols preferably have a solubility in water at 25 ° C. of 10 to 50%, preferably 15 to 40%, such as erythritol, mannitol, and reduced lactose. Preferably, erythritol is used.
The compounding quantity of the saccharide | sugar in a medium amount sugar coating liquid is 10 to 80% as solid content, Preferably, it is 35 to 65%.

The intermediate layer further includes an excipient and a binder.
Examples of the excipient include talc, precipitated calcium carbonate, crystalline cellulose and the like having a particle size of 100 μm or less, and preferably talc, precipitated calcium carbonate and crystalline cellulose are used. The compounding quantity of the excipient | filler in a medium amount sugar coating liquid is 10 to 60% as solid content, Preferably, it is 30 to 50%.
Examples of the binder include gum arabic powder, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl pyrrolidone, and copolyvidone. Preferably, gum arabic powder is used. The blending amount of the binder in the intermediate sugar coating liquid is 2 to 40%, preferably 4 to 25% as a solid content.

  As the component of the undercoat layer, at least one selected from gum arabic powder, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl pyrrolidone, talc, polyethylene glycol, precipitated calcium carbonate, crystalline cellulose and the like. Preferably, hydroxypropyl methylcellulose and talc are used.

  The ratio of the undercoat layer, the intermediate cover layer, and the upper cover layer in the sugar coating layer is 1 to 10% of the lower cover layer, 10 to 90% of the intermediate cover layer, and 3 to 30% of the upper cover layer. The covering layer is 1.5 to 6%, the middle covering layer is 40 to 80%, and the top covering layer is 5 to 25%.

The sugar-coated tablet of the present invention may have a two-layered sugar coating. In this case, the sugar-coated tablet may have a two-layer structure composed of the above-mentioned top layer and middle layer.
The sugar-coated tablet of the present invention may further have a polishing layer made of waxes such as carnauba wax and white wax.

What is necessary is just to prepare the uncoated tablet which gives sugar coating in this invention by a conventional method. For example, the drug is prepared by mixing, granulating, and tableting with an appropriate excipient, binder and the like. Further, according to a conventional method, a waterproof film may be applied to the uncoated tablet.
The drug used for the uncoated tablet is not particularly limited, and may be any drug such as a drug that is unstable under high moisture, or a drug that requires masking of smell or taste.

The top, middle or undercoat sugar coating liquid is prepared by dissolving or suspending each of the above components in purified water at the above ratio.
In order to produce the sugar-coated tablet of the present invention, according to a conventional method, the above-mentioned sugar-coating liquid is handled and / or sprayed to cover the uncoated tablet and to give a sugar-coated 30 to 90% of the uncoated tablet mass. . Preferably, as the outermost layer of the sugar-coated tablet of the present invention, 3 to 30%, more preferably 5 to 20%, sugar coating of the uncoated tablet mass is applied. Preferably, a sugar-coated tablet can be obtained in a short time by spraying.

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1
Fluidized bed granulator (Paulec Co., Ltd. FD-) containing 1544 g of tocopherol calcium succinate, 1400 g of pyridoxine hydrochloride, 143.1 g of gamma-oryzanol, 216.3 g of Cylysia (registered trademark) 320, and 554 g of crystalline cellulose (Asahi Kasei KG802) 5S type), and granulated by spraying 203 g of hydroxypropyl cellulose (6% solution) at a supply temperature of 70 ° C., an air volume of 2.5 m ³ / min, a spray volume of 2500 NL / min, and a spray liquid volume of 42 g / min. did. After drying, the particles were sized with a power mill (1.5 mmφ screen) to obtain Group E sized powder.
Furthermore, 2883 g of fursultiamine hydrochloride and 714.5 g of crystalline cellulose (Asahi Kasei PH101) were charged into a fluidized bed granulator (FD-5S type, manufactured by Pauleck Co., Ltd.), and a solution obtained by dissolving 40 g of cyanocobalamin in 3 L of purified water, Spray granulation was performed at a supply temperature of 70 ° C., an air volume of 2.5 m ³ / min, a spray volume of 2500 NL / min, and a spray liquid volume of 32 g / min, and further 112.5 g of hydroxypropylcellulose (6% solution) was sprayed. Spray granulation was performed at a liquid amount of 34 g / min. After drying, the particles were sized with a power mill (1.5 mmφ screen) to obtain a T group sized powder.
E group sized powder 3480g and T group sized powder 1800g, active ingredient calcium pantothenate type S (BASF product) 562.7g, silicia 320 66.6g, crystalline cellulose (Asahi Kasei KG802) 354.7g, low substitution 336 g of hydroxypropylcellulose and 60 g of magnesium stearate were mixed with a tumbler mixer, and 8.3 mmφ so as to be 185 mg per tablet using a rotary tablet press collect 19K (manufactured by Kikusui Seisakusho). Tableting was performed with a 2-stage R punch at a tableting pressure of 9 KN / 杵 to obtain an uncoated tablet. Table 1 shows the uncoated tablet formulation per three tablets.

3330 g of the obtained uncoated tablet was charged into Doria Coater DRC500 (manufactured by Pauleck Co., Ltd.), and 109.6 aqueous solution of hydroxypropylmethylcellulose (Shin-Etsu Chemical Co., Ltd.) 129.6 g and talc 14.4 g, rotation speed 10 rpm, air supply temperature 70 An undercoat layer of 4 mg per tablet was applied at 0 ° C., an air volume of 3.5 m ³ / min, a spray pressure of 0.4 Mpa, and a spray liquid volume of 12 g / min.
Next, spray solution with 1082 g of erythritol, 367.4 g of precipitated calcium carbonate, 204.1 g of talc, 40.82 g of titanium oxide, 102.1 g of crystalline cellulose (Asahi Kasei PH-F20) and 244.9 g of gum arabic powder. A 81 mg intermediate layer per tablet was applied under the same conditions as the underlayer except that the amount was 23 g / min.
Furthermore, 14,000 tablets with an intermediate layer were charged into a coating pan (triple-type coating pan manufactured by Kikusui Seisakusho Co., Ltd.), and 351.8 g of purified white sugar, 150.8 g of erythritol and 1.428 g of vitamin B2 were used as the outermost layer. A 66.6% solution was applied with a top layer of 15 ml / times, and further waxed to give 290 mg sugar-coated tablets per tablet. The resulting sugar-coated tablets had an equilibrium relative humidity of 26.0%.

Comparative Example 1
1 kg of uncoated tablets produced as described in Example 1 were charged into a 12-inch sugar-coated bread, and sugar-coated with a refined sucrose sugar-coating liquid containing talc and precipitated lime carbonate containing gum arabic as a binder. Thereafter, as the outermost layer, finishing is performed using an overcoat liquid having a purified sucrose / erythritol ratio of 10/0 (similar to the overcoat liquid used in Comparative Example 3 below), and further waxed. Polishing was performed to obtain sugar-coated tablets of 370 mg per tablet. The obtained sugar-coated tablets had an equilibrium relative humidity of 53.7%.

Examples 2-5, Comparative Examples 2 and 3
Sugar-coated tablets were produced by changing the blending ratio of erythritol and purified white sugar in the top layer of the sugar-coated tablets of Example 1 to the ratios shown in Table 2.

Test Example 1: Appearance evaluation of sugar-coated tablets The appearance of sugar-coated tablets in which the mixing ratio of sugar alcohol and sugar in the top layers of Examples 1 to 5 and Comparative Examples 2 and 3 was changed was evaluated by five panelists.
The results are shown in Table 2. The appearance of the refined sucrose / erythritol blending ratio of 5/5 to 9/1 was clean on the sugar coating surface.

糖衣面 〇：表面きれい、×：面荒れ、色むらあり

Sugar-coated surface 〇: Clean surface, ×: Surface roughness, uneven color

Test Example 2: Evaluation of drug stability in sugar-coated tablets The stability of the drug in the tablets of Example 1 and Comparative Example 1 was stored in tablets when stored at 60 ° C, 50 ° C, 40 ° C for 4 weeks to 3 months. The cyanocobalamin content was measured by HPLC method and evaluated by comparing the residual rate. The HPLC method was performed using the following test conditions. The results are shown in Table 3.
Test conditions:
Detector: UV-visible spectrophotometer (measurement wavelength: 550 nm)
Column: DAISOPAK SP-120-3-ODS-AP (3 mm ID. × 15 cm)
Moving layer: acetate buffer (pH 4.0) / acetonitrile mixture (89:11)
Injection volume: 30 μL
Flow rate: About 0.3 ml / min Sample solution preparation method:
0.29 g of tablet powder was dissolved in 50 mL of diluted methanol (1 → 10), shaken for 30 minutes, and then centrifuged to obtain a supernatant (sample solution).

従来からの知見どおり、高水分で糖衣した錠剤（比較例１）では、シアノコバラミンの安定性がかなり劣化したが、本発明の糖衣錠（実施例１）中のシアノコバラミンは安定であった。

As known from the past, the stability of cyanocobalamin deteriorated considerably in the tablet coated with high moisture (Comparative Example 1), but the cyanocobalamin in the sugar-coated tablet (Example 1) of the present invention was stable.

Example 6
1797 g of partially pregelatinized starch and 1.079 g of corn starch were charged into a fluidized bed granulator (FD-5S type, manufactured by Pauleck Co., Ltd.), and a cyanocobalamin solution obtained by dissolving 1.921 g of cyanocobalamin in 708 g of purified water was supplied at a supply temperature of 70 ° C. Granulation was carried out by spraying at an air volume of 2.5 m ³ / min, a spray volume of 2500 NL / min, and a spray liquid volume of 22 g / min. Subsequently, coating was performed with 180 g (12% solution) of hydroxypropylmethylcellulose, dried, and then sized with a power mill (1.5 mmφ screen) to obtain VB12 coated particles.
Furthermore, 1142 g of fursultiamine hydrochloride, 118.8 g of riboflavin, 200 g of pyridoxine hydrochloride, 1950 g of lactose, and 439.2 g of corn starch were charged into a fluidized bed granulator (FD-5S type, manufactured by Pauleck Co., Ltd.). 0 g (6% solution) was granulated by spraying at an air supply temperature of 70 ° C., an air volume of 2.5 m ³ / min, a spray volume of 2500 NL / min, and a spray liquid volume of 34 g / min. After drying, the particles were sized with a power mill (1.5 mmφ screen) to obtain a T group sized powder.
A tumbler containing 528 g of VB12 coated grain and 3216 g of T group sized powder, 189.4 g of calcium pantothenate type S (BASF product), 240.0 g of crystalline cellulose (Asahi Kasei KG802), 125.0 g of corn starch, and 21.6 g of magnesium stearate Using a rotary tablet press collect 19K (manufactured by Kikusui Seisakusho Co., Ltd.), the mixture is mixed with a blender, and the tableting pressure is 9 KN / 杵 with 8.0 mmφ, 2-stage R punch, so that 180 mg per tablet is obtained. Tableting was performed to obtain an uncoated tablet. Table 4 shows the uncoated tablet formulation per three tablets.
The obtained plain tablets were sugar-coated using the same sugar-coating method and conditions as in Example 1 to obtain 280 mg of sugar-coated tablets per tablet. The obtained sugar-coated tablets had an equilibrium relative humidity of 23.2%.

Comparative Example 4
1 kg of uncoated tablets produced as described in Example 6 were charged into a 12-inch sugar-coated bread, and sugar-coated using a talc-containing purified sucrose sugar-coating liquid containing gum arabic as a binder. Then, as the outermost layer, finishing is performed using an overcoat liquid having a refined sucrose / erythritol ratio of 10/0 (similar to the overcoat liquid used in Comparative Example 3), and further polished with wax. To obtain 320 mg sugar-coated tablets per tablet. The obtained sugar-coated tablets had an equilibrium relative humidity of 54.1%.

Test Example 3: Evaluation of drug stability in sugar-coated tablets Cyanocobalamin in tablets when stored in tablets of Example 6 and Comparative Example 4 at 60 ° C, 50 ° C and 40 ° C for 4 weeks to 3 months The content was measured by HPLC method and evaluated by comparing the residual ratio. The HPLC method was performed using the same test conditions as in Test Example 2. The results are shown in Table 5.

高水分で糖衣したもの（比較例４）において、ＶＢ１２の安定性はかなり劣化したが、本発明の糖衣錠（実施例６）中のシアノコバラミンは安定であった。

In the case of sugar coating with high moisture (Comparative Example 4), the stability of VB12 was considerably deteriorated, but the cyanocobalamin in the sugar-coated tablet of the present invention (Example 6) was stable.

Claims (8)

  A colored sugar-coated tablet, wherein the outermost layer of the sugar-coating layer comprises sugar alcohols having low solubility, sugars having high solubility, and a coloring agent.   The sugar-coated tablet according to claim 1, wherein sugar alcohols having low solubility have a solubility in water at 25 ° C of 10 to 50%, and sugars having high solubility in water at 25 ° C are 60 to 250%.   The sugar-coated tablet according to claim 1, wherein the sugar alcohol having low solubility is selected from the group consisting of erythritol, mannitol and reduced lactose.   The sugar-coated tablet according to claim 1, wherein the saccharide having high solubility is selected from the group consisting of sucrose, purified sucrose, powdered reduced maltose water candy, trehalose and maltose.   The sugar-coated tablet according to claim 1, wherein the colorant is selected from the group consisting of riboflavins such as riboflavin, riboflavin butyrate and riboflavin phosphate, yellow iron sesquioxide, iron sesquioxide, pigments and lakes.   The sugar-coated tablet according to claim 1, wherein the mass ratio of the sugar alcohol having low solubility and the sugar having high solubility in the outermost layer is 1: 1 to 1: 9.   The sugar-coated tablet according to claim 1, wherein the outermost layer is 3 to 30% of the uncoated tablet mass.   The sugar-coated tablet according to claim 1, wherein the equilibrium relative humidity is 40% or less.