JPH0347246B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a process for preparing enteric capsules from an aqueous solution of an enteric base, particularly hydroxypropyl methyl cellulose acetate succinate. Enteric-coated capsules are used to enclose pharmaceuticals and are ingested. Conventionally, such capsules have been manufactured by coating gelatin capsules with enteric-coated polymeric substances, or by molding enteric-coated polymeric substances into an organic solvent solution. A method in which a pin is immersed and molded, and a method in which a molded pin is immersed in an aqueous solution of an alkali metal salt of gelatin and cellulose acetate phthalate or hydroxypropyl methyl cellulose phthalate and molded are known. However, the method of coating gelatin capsules with an enteric polymer substance tends to cause poor adhesion between the surface of the gelatin and the coating film, and the method of using an organic solvent solution does not contaminate the work environment during the solvent recovery process. , fire and explosion countermeasures are required, and there are concerns about solvent remaining in the product. Furthermore, when an aqueous solution of gelatin and an alkali metal salt of cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate is used, there are problems such as hydrolysis and brittle capsules. The present inventors investigated various methods of manufacturing capsules that are chemically stable and have excellent impact resistance by solving the above-mentioned drawbacks, and as a result, they were molded into an aqueous solution containing an alkali metal salt of hydroxypropyl methylcellulose acetate succinate and gelatin. After immersing the pin and molding it, by immersing it in an acid aqueous solution,
The inventors have discovered that it is possible to obtain extremely excellent enteric-coated capsules, and have completed the present invention. The present invention will be explained in detail below. Hydroxypropyl methyl cellulose acetate succinate (HPMC-
Unlike other enteric-coated bases, AS) is itself a very flexible base, so when used in combination with gelatin, the ratio of gelatin to enteric-coated base must be reduced. It is possible to produce capsules with excellent strength without becoming brittle, and by reducing the proportion of gelatin added, stability against gastric juices and water is improved, so there is no fear that the capsules will be destroyed before reaching the intestines. , can exhibit excellent enteric properties. In addition, while other bases require the addition of a large amount of plasticizer to impart flexibility, the method of the present invention does not require the addition of plasticizer at all or only requires the addition of a small amount. , there will be no problems such as plasticizer oozing out. The HPMC-AS used in the method of the invention is already known, for example by using a carboxylic acid such as acetic acid or propionic acid as the reaction medium;
A method of esterifying hydroxypropyl methylcellulose with acetic anhydride and succinic anhydride in the presence of an alkali metal salt catalyst of a carboxylic acid such as sodium acetate or potassium acetate, or a method of carrying out the esterification reaction in a suitable solvent such as acetone. It can be produced by a method in which it is carried out in the presence of a basic catalyst such as pyridine. For the purpose of the present invention, this HPMC-AS has an average number of substituents per glucose unit of 0.1 to 0.8 hydroxypropoxyl groups, 1.4 to 1.9 methoxyl groups,
Acetyl group 0.2~0.8, acidic succinoyl group 0.1~
A value of 0.7 is preferred. Gelatin is used to prevent the capsule from becoming uneven in thickness due to the dipping liquid flowing when the molding pin is immersed in the aqueous solution (immersion liquid) and pulled up. In order to achieve this, it is desirable to quickly cool the molding pin to below 20°C after pulling it out of the immersion liquid. Also, if the amount of gelatin added is too small, it will not be effective, and if it is too large, the enteric function will be impaired. In addition to being inhibited, the capsule becomes brittle after drying, so it is desirable that the amount be in the range of 0.05 to 0.5 parts by weight per 1 part by weight of HPMC-AS. The method of preparing an aqueous solution (immersion solution) is not particularly regulated, but in order to quickly dissolve HPMC-AS, first disperse HPMC-AS in water and then add an aqueous base solution while stirring. It's good to do that. Examples of bases used for this purpose include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and potassium carbonate. The amount of these bases used is equivalent to the acidic succinoyl group of HPMC-AS.
An equivalent weight of 60% or more is suitable. If the amount of base used is less than 60%, there is a risk that HPMC-AS will not be sufficiently dissolved in water, and there is a concern that the surface of the capsule may become rough. It is also possible to use an excess of more than 100% for the purpose of dissolving more quickly, but in this case,
In order to prevent the ester bonds in HPMC-AS from being hydrolyzed, it is desirable to neutralize them with acid to eliminate the harmful effects of excess alkali, or to manufacture capsules immediately after preparing the immersion liquid. . To dissolve gelatin, add gelatin to the above HPMC-AS solution and heat and dissolve while stirring, or mix gelatin aqueous solution separately dissolved in HPMC-AS solution while heating and stirring. This allows pin forming. As an immersion liquid
An aqueous solution consisting mainly of HPMC-AS and gelatin is obtained. To mold the capsule, a molding pin coated with a mold release agent such as liquid paraffin or carnauba wax is immersed in the dipping liquid made as described above, pulled up,
After cooling or further pre-drying,
This is carried out by immersing this in an acid aqueous solution to perform an acid treatment, then drying it, removing the molded body from the pin, and performing necessary post-processes such as cutting. The cooling temperature after immersion is set at 20°C to prevent the immersion liquid from flowing and making the capsule wall thickness uneven.
℃ or less, preferably 18℃ or less. In addition, the acid treatment mentioned above is an essential step, and if this treatment is not performed, the alkali metal salt of HPMC-AS is water-soluble, so the capsule will be destroyed before it reaches the stomach after ingestion, and enteric-coated There is a concern that the function of the product will be lost, but by acid treatment
Since the alkali metal salt of HPMC-AS returns to a free state that is insoluble in water, water resistance can be obtained and its functions can be fully demonstrated. Acids used for this purpose include hydrochloric acid, sulfuric acid, nitric acid,
Examples include inorganic acids such as phosphoric acid, monocarboxylic acids such as acetic acid, propionic acid, benzoic acid, and polyhydric carboxylic acids such as oxalic acid, malonic acid, succinic acid, adipic acid, maleic acid, fumaric acid, malic acid, and tartaric acid. be done. The above acid is used as an aqueous solution, and its concentration varies depending on the type of acid, but is usually in the range of 3 to 30%. Note that when mineral acids are used, mineral acids may remain in the capsule depending on the processing conditions.
Since decomposition and deterioration of HPMC-AS may occur, in such cases it is desirable to wash after acid treatment. The wall thickness of the capsule is HPMC− in the immersion liquid.
Although determined by the concentration of AS and gelatin and temperature, it is generally desirable to have a concentration of 15 to 40% by weight and a dipping temperature of 25 to 40°C. When the purpose is to obtain thin-walled capsules, it is desirable to use a low-concentration immersion liquid, and when the purpose is to obtain thick-walled capsules, it is desirable to use a high-concentration immersion liquid. Note that various additives such as colorants, flavoring agents, plasticizers, and fillers may be added to the immersion liquid as necessary. Next, specific examples will be given. Example 1 The average number of substitutions per glucose unit was 0.24 hydroxypropoxyl groups and 0.24 methoxyl groups.
1.87, an acetyl group of 0.44, and a succinoyl group of 0.24, 200 g of HPMC-AS was added to 920 g of water with stirring, and after being well dispersed, 78 g of a 10% aqueous sodium hydroxide solution was gradually added to form HPMC-AS.
An aqueous solution of was obtained. After adding 25 g of gelatin to this, the temperature was raised to 50°C and stirred for 3 hours to prepare an immersion liquid. This dipping solution is kept at 30°C, and a stainless steel molding pin coated with carnauba wax as a mold release agent is dipped in the liquid, pulled up and dried.The molded body is removed from the pin and subjected to the necessary post-processing to form capsules. Obtained. Separately, a molded pin was immersed, pulled out, air-dried for about an hour at room temperature, immersed in 10% hydrochloric acid aqueous solution at 15°C for 5 minutes, immersed in water for 20 seconds, rinsed with water, and immersed in 10% citric acid aqueous solution for 5 minutes. The dried product was dried and capsules were obtained in the same manner as above. The capsules thus obtained are filled with lactose powder,
The mating part of the body and cap is attached to the HPMC-AS above.
For those sealed with a 20% acetone solution,
When we observed the changes in the first solution (PH1.2), second solution (PH6.8) and tap water based on the 10th revision of the Japanese Pharmacopoeia, we obtained the results shown in the table below. .

[Table] Example 2 The HPMC-AS of Example 1 had an average particle size of 15μ,
200 g of this was added to 840 g of water with stirring, and after being well dispersed, 77 g of 10% potassium hydroxide was gradually added to obtain an aqueous solution of HPMC-AS. This liquid
The temperature was maintained at 40° C., and 100 g of a 30% gelatin aqueous solution at 40° C., which had been prepared separately, was added thereto, and stirring was continued for 3 hours to obtain an immersion liquid. Keep this immersion liquid at 40℃,
Capsules were obtained in the same manner as in Example 1 by immersing a stainless steel molding pin coated with liquid paraffin as a mold release agent. Separately, capsules treated with hydrochloric acid and capsules treated with 10% maleic acid aqueous solution for 3 minutes in the same manner as in Example 1 were obtained, and the capsules were tested according to the method of Example 1. The results were obtained.

【table】

Claims (1)

[Claims] 1. A method for producing enteric-coated capsules, which comprises immersing a molding pin in an aqueous solution containing gelatin and an alkali metal salt of hydroxypropyl methyl cellulose acetate succinate, molding the capsule, and then immersing the capsule in an acid aqueous solution. Method 3 for producing enteric-coated capsules according to claim 1 using an aqueous solution obtained by dispersing hydroxypropyl methylcellulose acetate succinate in water, adding and dissolving a base and gelatin while stirring Hydroxypropyl methylcellulose acetate succinate Method 4 for producing enteric capsules according to claim 1, characterized in that the ratio of gelatin to 1 part by weight of the alkali metal salt of hydroxypropyl methylcellulose acetate succinate is 0.05 to 0.5 parts by weight. 2. The method for producing enteric-coated capsules according to claim 1, wherein the amount of the alkali metal in the salt is 60% or more equivalent to the acidic succinoyl group of hydroxypropylmethylcellulose acetate succinate.