KR100861444B1 - Process for producing stable enteric sugar-coated tablet - Google Patents

Abstract

A method for producing a stable enteric sugar-coated tablet comprising coating an enteric polymer on a bare tablet and forming a layer having a thickness of 20 to 300 µm of water-soluble polymer and / or water-soluble sugar, followed by forming a sugar-coated layer.

It is possible to produce stable enteric dragees without discoloration, puncture or cracking of dragees.

Enteric polymers, dragees, dragees, sun skin, medium skin, coloring, finishing, centrifugal tablets, uncoated tablets, polishing, sucrose

Description

Process for producing stable enteric sugar-coated tablet

The present invention relates to a method for preparing a stable enteric dragee, and more particularly, to a method for preparing an enteric dragee which prevents discoloration and puncture of the dragee over time.

The composition and prescription of dragees in dragees are various and know-how and many are not clear, but "coating of drug" (Nihon Kogyo Jutsurenmei) and "pharmaceutical development basic course 18 formulation engineering" (Chichijin Shokan) According to), film layer, subcoating layer and smooth layer are usually formed on the central tablet in order, and a dense sucrose layer is formed to prevent moisture permeation. It is produced by giving a gloss.

Manipulation of sugar is generally performed by the skin (usually gelatin as a sugar solution, gum arabic powder, aqueous solution of sucrose, a mixture of precipitated calcium carbonate, talc, sucrose and gum arabic powder) to give roundness to the central tablet. Medium for smoothing (usually, gelatin, gum arabic powder as sugar solution, precipitated calcium carbonate or talc added to a solution of white sugar), and coloring (usually, colorant and gelatinized sweet syrup) to create a smoother and more dense colored layer. Use thick liquids, starting with colored ones, finishing (usually, sweet syrups with colorants), and polishing polishes (usually white wax, carnauba wax). ]. Each of these operations is carried out by repeatedly coating the sugar solution (in the skin, an appropriate amount of the dispersant is mixed). The inhibitory effect of the air permeability and permeability of the sugar dragee layer depends on the dense colored layer of the white sugar crystals.

In general, enteric sugar-coated tablets are prepared by coating an enteric polymer dissolved in alkali in a central tablet and forming a sugar-coated layer consisting of a skin layer, a mesothelial layer, a colored layer and a finishing layer. Enteric preparations are drugs that are inactivated or reduced by gastric fluid, such as enzymes, or drugs that irritate the stomach, such as aspirin, which cause gastrointestinal digestive problems, or drugs that need to increase intestinal concentrations. Used as a formulation.

As the enteric coating agent, a polymer material which is substantially insoluble in acid but soluble in alkali, such as cellulose, vinyl or acrylic, is used. These enteric coating agents are dissolved and coated in an organic solvent, or cellulose polymers such as hydroxypropylmethylcellulose acetate succinate (HPMCAS) and carboxymethylethyl cellulose (CMEC) are dispersed and coated in water. In addition, latex type water based coatings, such as Eudragit L30D55, are often used. Recently, a method of dry coating hydroxypropylmethylcellulose acetate succinate (HPMCAS) while spraying a liquid plasticizer has also been developed.

However, the conventional dragees have a problem such as cracking, puncture, and change in color over time. These problems are mainly caused by the formation of each layer of sugars in the epidermal and mesothelial layers in which sugar solution obtained by dissolving or dispersing gelatin, gum arabic powder, sucrose, precipitated calcium carbonate, kaolin, and talc in water is added to uncoated tablets. The coating and drying steps are alternately coated. However, during the operation of the sugar, the moisture in the sugar liquid cannot be slightly infiltrated into the central well, and the colored layer, which is the last layer of the sugar layer, has very low water vapor permeability. This is due to the fact that water vapor from the outside is completely blocked, but cannot release the water that penetrates the central tablet, and thus, if the central tablet is a drug that is unstable in water, it promotes decomposition of the drug. This can also cause punk, cracking and discoloration of dragees. Particularly, since aqueous coatings and dry coatings use a lot of plasticizers, when the enteric dragees are prepared with these coating agents, plasticizers are also affected, causing problems such as cracking, puncture or discoloration of dragees.

As a countermeasure, it is conceivable to sufficiently dry the tablets during the formation of the skin layer, or to take a method of transferring the sugar film to the central tablet in advance and then proceeding to the sugar operation after the formation of the skin layer. Although the process of forming this waterproof film is called a protective coating, since the film to be used needs to be barrier-to-moisture, shellac and coatings which are insoluble in water are often used. Therefore, since the thickness of the film directly affects the disintegration and dissolution properties of the tablet, it requires difficulty in controlling the film thickness. Therefore, it is hard to be perfect as a preventive measure of cracking, puncture, and discoloration of dragees.

In addition, Japanese Patent Application Laid-Open No. 11-43430 discloses a method of adding a pigment or a binder to a colored layer or finishing layer to prevent peeling or cracking of a sugar layer. In Japanese Laid-Open Patent Publication No. 7-55898, a method of increasing the strength of dragees by providing a dragee with a membrane made of a polymer that is soluble in both water and lower alcohols, Japanese Patent Laid-Open No. 7-55898 uses a high-purity maltitol instead of sucrose as a dragee. ) And the method to increase the impact resistance using pullulan (pullulan) to prevent cracks, breakage, and changes over time, respectively. However, no method is perfect.

Therefore, there has been a strong demand for a method for producing a stable enteric dragee without discoloration of the dragee over time and puncture of the dragee.

Disclosure of the Invention

The present invention is a method for producing an enteric sugar-coated tablet, wherein after coating the enteric polymer in uncoated tablets, a layer having a thickness of 20 to 300 µm of a water-soluble polymer and / or a water-soluble sugar is formed, and then a sugar-coated layer is formed.

Best Mode for Carrying Out the Invention

Examples of enteric polymer coatings include cellulose polymers such as cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS) or carboxymethylethyl cellulose (CMEC); Vinyl polymers such as polyvinyl alcohol acetate phthalate (PVAP); An acrylic polymer such as a copolymer of methacrylic acid and ethyl acrylate (methacrylic acid copolymers L and S), such as a polymer material which is substantially insoluble in acid but soluble in alkali, can be used. Preferred enteric coatings are HPMCAS.

Enteric coating can be performed by dry-coating a fine powdery enteric polymeric material, spraying a liquid plasticizer in uncoated tablets. Furthermore, the enteric coating agent may be dissolved and coated in an organic solvent, coated by dispersing in water, or coated with a latex type liquid.

Examples of the water-soluble polymer of the water-soluble polymer and / or the water-soluble saccharide layer formed on the enteric polymer coating include hydroxypropyl cellulose (HPC), hydroxy film methyl cellulose (HPMC), methyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, Water-soluble cellulose polymers such as methyl hydroxyethyl cellulose; And pullulan, polyvinyl alcohol, etc. can be used. Of these, water-soluble cellulose polymers, in particular hydroxypropyl methyl cellulose (HPMC), are preferred.

Sucrose, mannitol, glucose, lactose and the like can be used as the water-soluble sugars. Of these, sucrose is preferred.

The above water-soluble polymers and water-soluble sugars may be used alone, or a mixture of both of them may be used, and a water-soluble sugar on a water-soluble polymer or a water-soluble polymer on a water-soluble sugar may be coated.

The film thickness of the layer of the water-soluble polymer and / or the water-soluble sugars is 20 µm to 300 µm, usually 22 to 300 µm, preferably 40 to 200 µm, particularly preferably 48 to 150 µm. Specifically, in the case of water-soluble sugars alone, the film thickness of the layer is usually 40 to 300 µm, preferably 48 to 200 µm, particularly preferably 60 to 150 µm. In the case of using the water-soluble polymer alone or in combination with the water-soluble polymer and the water-soluble sugars, the film thickness of the layer is usually 20 to 300 µm, preferably 22 to 200 µm, particularly preferably 50 to 150 µm. If it is less than 20 micrometers, sufficient puncture prevention and discoloration prevention effect will not be acquired. What is necessary is just to make the sum total of the film thickness of two layers into the said range, when coat | covering the layer of water-soluble polymer and the layer of water-soluble sugar separately.

The water-soluble polymers and water-soluble sugars are each coated on an enteric coated tablet in the form of an aqueous solution. For example, when a sugar such as sucrose is used, it may be used in the form of an aqueous solution of 10 to 80% by weight, and in the case of using a water-soluble polymer such as HPMC in the form of an aqueous solution of 1 to 30% by weight.

Formation of a sugar layer after forming a layer of water-soluble polymer and / or water-soluble sugars is usually carried out by manipulating sugars containing at least one of skin, skin, coloring and finishing, and then polishing (glossing) as necessary. Do it.

In particular, when the diameter of uncoated tablets is 7 mm or less, an enteric coating layer is formed, and then a layer of water-soluble sugars is formed, and a layer of water-soluble polymer (especially HPMC) is formed thereon, and finally, a colored layer is formed by using sucrose syrup. It is also possible.

Next, although an Example is given and this invention is demonstrated concretely, this invention is not limited to these.

Reference Example 1 [Production of Core Tablet]

The central tablet (uncoated tablet) of the composition shown in following Table 1 was produced by 55 mg per tablet with the diameter of 5.5 mm and a fine ball of 4.5R. The tablet hardness was 2.8 kg and the disintegration time (test solution: water) was 6-8 minutes.

4.7 kg of this tablet was filled in a ventilated fan coating apparatus (manufactured by Hicoater HCT-48 Freundt Sangyo Co., Ltd.) to triethyl citrate at an intake temperature of 50 ° C, a product temperature of 45 ° C, and a rotation speed of 16 rpm. Hydroxypropylmethylcellulose acetate succinate (brand name AS-MF Shin-Etsu Chemical Co., Ltd.) / talc ratio while spraying the plasticizer liquid of / glycerin fatty acid ester (35/20) at a spray rate of 20 g / min 10/6) was uniformly mixed with 58 g / min of powder to dry coat to obtain 67 mg of enteric film tablets.

Example 1

The enteric film tablet prepared in Reference Example 1 was a sucrose layer of 5 mg per tablet and a film thickness of 48 μm with a 65% sucrose syrup using an air-vented pancoating machine (manufactured by High Coater 48 Type Freundt Co., Ltd.) (film ) Was formed. In addition, a 35 mg per skin layer was formed per tablet with an aqueous suspension of 10% kaolin, 10% calcium carbonate, 5% talc, 5% titanium oxide, 4% gum arabic and 40% sucrose. Finally, 5 mg of colored layer was formed per tablet using 65% sucrose syrup added with tar pigment, and polished with wax to obtain enteric dragees.

Example 2

In the enteric film tablet prepared in Reference Example 1, a film having a sucrose 9 mg and a film thickness of 86 μm was formed with a 65% sucrose syrup using a ventilated fan coating machine (manufactured by HiCotter 48 Type Freundt Co., Ltd.). Furthermore, in the same manner as in Example 1, an intermediate skin layer and a colored layer were formed and polished to obtain an enteric dragee.

Example 3

In the enteric film tablet prepared in Reference Example 1, a film having a sucrose 13 mg and a film thickness of 124 μm was formed with a 65% sucrose syrup using a ventilated fan coating machine (manufactured by HiCotter 48 Type Freundt Co., Ltd.). Furthermore, in the same manner as in Example 1, an intermediate skin layer and a colored layer were formed and polished to obtain an enteric dragee.

Example 4

6% hydroxypropylmethylcellulose (HPMC) (TC-5R Shin-Etsu Chemical Co., Ltd.) was used for the enteric film tablet manufactured in Reference Example 1 using an air-permeable fan coating machine (manufactured by High Coater 48 Type Freundt Co., Ltd.). A water-soluble film having 3 mg of hydroxypropylmethylcellulose and a film thickness of 22 µm was formed with an aqueous solution of Gaku Kogyo Co., Ltd.). Furthermore, in the same manner as in Example 1, an intermediate skin layer and a colored layer were formed and polished to obtain an enteric dragee.

Example 5

6% hydroxypropylmethylcellulose (TC-5R Shin-Etsu Chemical Co., Ltd.) was used for the enteric film tablet manufactured in Reference Example 1 using an air-permeable fan coating machine (manufactured by High Coater 48 Type Freundt Co., Ltd.). Note) The aqueous solution was formed with 7 mg of hydroxypropylmethylcellulose and a film thickness of 52 µm with an aqueous solution. Furthermore, in the same manner as in Example 1, an intermediate skin layer and a colored layer were formed and polished to obtain an enteric dragee.

Example 6

6% hydroxypropylmethylcellulose (TC-5R Shin-Etsu Chemical Co., Ltd.) was used for the enteric film tablet manufactured in Reference Example 1 using an air-permeable fan coating machine (manufactured by High Coater 48 Type Freundt Co., Ltd.). Note) A water-soluble film having 10 mg of hydroxypropylmethylcellulose and a thickness of 75 µm was formed from an aqueous solution. Furthermore, in the same manner as in Example 1, an intermediate skin layer and a colored layer were formed and polished to obtain an enteric dragee.

Example 7

In the enteric film tablet prepared in Reference Example 1, a layer having a sucrose 3 mg, a film thickness of 28 μm was formed with a 65% sucrose syrup using an air-vented pancoating machine (manufactured by HiCotter 48 Type Freundt Co., Ltd.), Subsequently, a water-soluble film having 10 mg of hydroxypropylmethylcellulose and a thickness of 75 µm was formed from an aqueous 6% hydroxypropylmethyl cellulose (manufactured by TC-5R Shin-Etsu Chemical Co., Ltd.) solution. Furthermore, a 5 mg colored layer was formed per tablet with 65% sucrose syrup to which tar was added at the end and polished with wax to obtain an enteric sugar-coated tablet.

Example 8

In the enteric film tablet produced in Reference Example 1, a layer having a sucrose 6 mg and a film thickness of 57 μm was formed with a 65% sucrose syrup using an air-vented pancoating machine (manufactured by High Coater 48 Type Freundt Co., Ltd.), Subsequently, 10 mg of hydroxypropyl methyl cellulose and a water-soluble coating agent layer having a thickness of 75 μm were formed from an aqueous 6% hydroxypropyl methyl cellulose (manufactured by TC-5R Shin-Etsu Chemical Co., Ltd.) solution. Furthermore, a 5 mg colored layer was formed per tablet with 65% sucrose syrup to which tar was added at the end and polished with wax to obtain an enteric sugar-coated tablet.

Comparative Example 1

In the enteric film tablet prepared in Reference Example 1, a ventilated fan coating machine (manufactured by High Coater 48 Type Freundt Co., Ltd.) was used for 10% calcium carbonate, talc 5%, titanium oxide 5%, gum arabic powder 4%. And a suspension of 40% sucrose to form 35 mg of mesothelial layer per tablet. Subsequently, a 5 mg colored layer was formed per tablet with 65% sucrose syrup added with tar dye, and polished with wax to obtain an enteric dragee.

Comparative Example 2

In the enteric film tablet prepared in Reference Example 1, a layer having a sucrose 2 mg and a film thickness of 19 μm was formed with a 65% sucrose syrup using a ventilated fan coating machine (manufactured by HiCotter 48 Type Freundt Co., Ltd.). Furthermore, in the same manner as in Example 1, an intermediate skin layer and a colored layer were formed and polished to obtain an enteric dragee.

Comparative Example 3

6% hydroxypropylmethylcellulose (TC-5R Shin-Etsu Chemical Co., Ltd.) was used for the enteric film tablet manufactured in Reference Example 1 using an air-permeable fan coating machine (manufactured by High Coater 48 Type Freundt Co., Ltd.). Note) The aqueous solution layer of 2 mg of hydroxypropylmethylcellulose and a film thickness of 15 micrometers was formed by the aqueous solution. Furthermore, in the same manner as in Example 1, an intermediate skin layer and a colored layer were formed and polished with wax to obtain an enteric dragee.

Test Example

The enteric sugar-coated tablets obtained in Examples 1 to 8 and Comparative Examples 1 to 3 were stored under the conditions of 50 ° C, and the puncture and appearance change of the sugar-coated tablets were observed after one month. The results are shown in Table 2.

* DELTA E was the color difference meter SQ2000 (made by Nippon Denshoku Kogyo Co., Ltd.), The value which measured the sample of 50 degreeC and 1 month was made into the target at the time of manufacture of each sample.

ΔE = 3 or less: no change compared to the time of manufacture

ΔE = 3 to 5: slightly changed compared to the time of manufacture

ΔE = 5 to 10: clearly changed compared to the time of manufacture

According to the present invention, by coating the water-soluble polymer and / or water-soluble sugars on the enteric coating, it becomes possible to produce a stable enteric sugar-coated without discoloration and puncture of the sugar-coated.

Claims (4)

A method of producing an enteric sugar-coated tablet comprising forming a layer having a thickness of 20 to 300 µm of a water-soluble polymer, a water-soluble sugar, or a mixture thereof after coating the enteric polymer on uncoated tablets, and then forming a sugar-coated layer. The method of claim 1, wherein the layer of the water-soluble polymer, the water-soluble sugars, or a mixture thereof comprises hydroxypropylmethylcellulose or sucrose. The method for producing an enteric sugar-coated tablet according to claim 1 or 2, wherein the coating of the enteric polymer into uncoated tablets is carried out by a dry coating method in which a fine powder-type enteric polymer is dispersed and coated while spraying a plasticizer on the uncoated tablet. The method for producing an enteric sugar-coated tablet according to claim 1 or 2, wherein the film thickness of the layer of the water-soluble polymer, the water-soluble sugar, or a mixture thereof is 20 to 150 µm.