JPH0371414B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an aqueous enteric coating agent. In particular, the present invention relates to a method for producing an enteric coating agent comprising a polymer compound dispersed in a hydroalcoholic system. In recent years, solid medicines that are taken have become unstable in the gastric juices, irritate the gastric mucosa and cause side effects such as vomiting, or when it is desired to have a concentrated effect on the intestines. It is well known that it is widely practiced to coat drugs with an enteric coating agent so that they do not change in the stomach and are rapidly disintegrated once they reach the intestines. This enteric coating agent includes cellulose derivatives such as cellulose acetate phthalate (hereinafter abbreviated as CAP) and hydroxypropyl methylcellulose phthalate (hereinafter abbreviated as CAP).
(abbreviated as HPMCP), carboxymethylethyl cellulose (hereinafter abbreviated as CMEC, CMEC is a registered trademark owned by Kojin Co., Ltd.), etc.
Examples of synthetic polyvinyl resin derivatives include methyl methacrylate-methacrylic acid copolymer, methyl acrylate-methacrylic acid copolymer, and polyvinyl alcohol phthalate. Also, zein and shellac are known as natural enteric coating agents, but they are hardly used at present because they are difficult to obtain. When these enteric coating agents are coated on powders, granules, capsules, tablets, etc., they are dissolved in an organic solvent such as a halogenated hydrocarbon, alcohol, or ketone. However, with this method, it is difficult to completely remove the organic solvent impregnated into the tablet inside the coating agent or the organic solvent remaining in the coating film by drying, and this residual solvent deteriorates the quality of the tablet. Furthermore, there is a problem in terms of safety for users. Furthermore, although the organic solvent is recovered, a certain amount that cannot be completely recovered may be released into the atmosphere and cause environmental pollution. Furthermore, attention must be paid to the health of workers performing coating on site. In order to completely recover these solvents and to improve the working environment, sufficient exhaust must be provided, and the equipment required for this requires a large amount of cost. As described above, there is an increasing need and desire for water-based coatings without using organic solvents from the viewpoints of user safety, air pollution, working environment, and cost. Although no water-based enteric coating agent has been put to practical use so far, several attempts have been made. For example, JP-A-55-53215, JP-A-55-
This is the method shown in Japanese Patent Application Laid-Open No. 56-63925. To do this, a hydrosol or gel is prepared by neutralizing an alkaline solution of a polymer, which is then concentrated by centrifugal precipitation and then directly dispersed in water, or it is freeze-dried and taken out as a solid. Alternatively, the hydrosol or gel is heated and dehydrated to perform solid-liquid separation to remove the solid content. However, this method has extremely poor yield and poor productivity (freeze-drying cost). In addition, if desalination is insufficient, cracks may occur when coating due to the salt content. There is also a method shown in Japanese Patent Application Laid-Open No. 55-98120. This method involves mechanically pulverizing HPMCP and redispersing it in water, but the redispersibility is poor. As described above, various methods for producing water-based enteric coating agents have been attempted, but none of them have been put to practical use. In view of these circumstances, as a result of intensive studies, we have come up with a method for producing an aqueous enteric coating agent that does not have the problem of containing salt, has good operability, good dispersibility, and is safe. In other words, the number of carbon atoms is 1
60 lower alcohols having 1 to 3 carbon atoms which may contain up to 40% by weight of water;
This is a method for producing an aqueous enteric coating agent, which is characterized by adding water to a solution dissolved in ~100% by weight of a single solvent or a mixed solvent to form a dispersion. The lower alcohol having 1 to 3 carbon atoms used here may be methyl alcohol, ethyl alcohol, n-propyl alcohol, or i-propyl alcohol, but air pollution prevention regulations apply when it is released into the atmosphere. Ethyl alcohol is mainly used because it does not fall under the specified substances of the law and, more importantly, there is no toxicity problem due to ingestion of the solvent when it remains in the coating film. Examples of carboxyalkylalkyl cellulose that dissolve in lower alcohols having 1 to 3 carbon atoms include CMEC,
Carboxyethyl ethyl cellulose (CEEC)
), which dissolves in lower alcohols at room temperature or under heating. A carboxyl group-containing polymer compound that is soluble in a lower alcohol having 1 to 3 carbon atoms is dissolved in a lower alcohol having 1 to 3 carbon atoms to a concentration of 10 to 40% by weight, or in a solvent containing 40% by weight or less of water. Add and dissolve at room temperature or by heating (for example, reflux).
Or 10 to 20% by weight of a carboxyl group-containing polymer compound dissolved in a lower alcohol having 1 to 3 carbon atoms.
After dissolving the lower alcohol having 1 to 3 carbon atoms or a solvent containing 40% by weight or less of water at room temperature or by heating, for example under reflux, the amount of solvent is molecular compound concentration 20
~40% by weight) at normal pressure. After dissolving in this way at a predetermined concentration (the concentration of the polymer compound is 10 to 40% by weight, preferably 20 to 40% by weight), it is cooled and a predetermined amount of water is gradually added to obtain the desired composition. can get. If the water is too viscous and difficult to stir when adding it, heat it to about 40°C before adding the water. Lower alcohol/water polymerization ratio is 100/
When water is added to a carboxyalkylalkylcellulose solution dissolved in a 0 to 60/40 alcoholic solvent while stirring, the carboxyalkylalkylcellulose precipitates out to form a dispersion. When adding water, various emulsifiers and protective colloids may be added in an amount of 0.1 to 1.0% by weight based on the polymer compound. The composition obtained by the method of the present invention can be evaluated based on the minimum film forming temperature, viscosity, and intestinal fluid disintegration time. We obtained values that were almost the same as those obtained using conventional methods using organic solvents. Also, better results were obtained with no additives than with additives such as emulsifiers. As a result, compared to the water-based enteric coating agents known so far, there is no problem of salt content, and it is easy to operate, has good dispersibility, and has a high yield, and is extremely effective when the solvent used is ethyl alcohol. Since it is a safe substance, there is no problem of toxicity when taking it even if a trace amount remains. As described above, the composition obtained by the method of the present invention is excellent as an aqueous enteric coating agent. The present invention will be explained below with reference to Examples, but the present invention is not limited thereto. Example 1 CMEC (manufactured by Kojin Co., Ltd.; degree of carboxylmethyl group substitution = 0.4, degree of ethoxyl group substitution = 2.1, viscosity (ethyl alcohol/water = 8/2, 5% by weight, 25°C) =
11cp) was added to 425g of ethyl alcohol, heated to reflux temperature (78°C), and stirred to uniformly dissolve.
After dissolving, add ethyl alcohol at that temperature.
250g was distilled off to make the CMEC concentration 30%. Then, cool to 45℃ and add water while stirring at that temperature.
After gradually dropping 177g and stirring for 10 minutes, it was cooled to room temperature and stirred for 30 minutes (ethyl alcohol/water =
49.7/50.3). The evaluation results of the obtained dispersion are the first
Shown in the table. Example 2 A dispersion was obtained in the same manner as in Example 1 except that CEEC was used instead of CMEC. Example 3 In Example 1, instead of 177 g of water, a solution of 0.375 g (0.5% by weight relative to CMEC) of polyoxyethylene sorbitan monolaurate (HLB16.7) as an emulsifier dissolved in 177 g of water was used, and the other conditions were as follows. A dispersion liquid was obtained in the same manner. Example 4 In Example 1, instead of 177 g of water, a solution of 0.375 g (0.5% by weight of CMEC) of polyoxyethylene sorbitan monooleate (HLB10.0) as an emulsifier dissolved in 177 g of water was used, and other A dispersion liquid was obtained in the same manner. Example 5 In Example 1, the emulsifier sorbitan sesquioleate (HLB3.7) was used instead of 177 g of water.
A dispersion liquid was obtained using a solution in which 0.375 g (0.5% by weight based on CMEC) was dissolved in 177 g of water, and the other conditions were the same. Example 6 In Example 1, 0.075 g of hydroxypropylcellulose, a protective colloid, was used instead of 177 g of water.
(0.5% by weight based on CMEC) in 177 g of water was used, and the other conditions were the same to obtain a dispersion. Example 7 In Example 1, water containing 7.5 g of triacetin (10% by weight based on CMEC) was added to improve film-forming properties.
A dispersion liquid was obtained by adding 177 g dropwise and keeping the other things the same. Example 8 30 g of HPMCP (manufactured by Shin-Etsu Chemical Co., Ltd.; HP-55) was added to 70 g of ethyl alcohol, heated and stirred to reflux temperature (78° C.), and uniformly dissolved (HPMCP concentration = 30% by weight). Thereafter, the mixture was cooled to 45°C, and while stirring at that temperature, 28 g of water was slowly added dropwise, and after stirring for 10 minutes, it was cooled to room temperature and stirred for 30 minutes (ethyl alcohol/water = 71.4/28.6). The evaluation results of the obtained dispersion are shown in Table 1. Example 9 In Example 8, methyl acrylate-methacrylic acid copolymer (Tanabe Pharmaceutical Co., Ltd.) was used instead of HPMCP.
MPM-05), and use water instead of 28g of water.
100.7g was added dropwise (ethyl alcohol/water =
41.0/59.0). A dispersion liquid was obtained in the same manner as above. Example 10 75 g of CMEC was added to 425 g of ethyl alcohol, heated and stirred to reflux temperature (78° C.), and uniformly dissolved (CMEC concentration = 15% by weight). Thereafter, the mixture was cooled to 45°C, and while stirring at that temperature, 430 g of water was gradually added dropwise, and after stirring for 10 minutes, it was cooled to room temperature and stirred for 30 minutes (ethyl alcohol/water = 49.7/50.3).
The evaluation results of the obtained dispersion are shown in Table 1. Example 11 In Example 1, i instead of ethyl alcohol
- A dispersion was obtained using propyl alcohol and keeping the other conditions the same. Comparative Example CMEC (same quality as Example 1 5% by weight Methylene chloride i-propyl alcohol 89 parts by weight 11 parts by weight 95% by weight The above composition was stirred and dissolved at room temperature. Properties of dispersions according to each Example and Comparative Example) The first
Shown in the table. The coatings obtained from the dispersion according to the method of the invention are excellent as enteric coating agents. 【table】

Claims (1)

[Claims] 1 Carboxyalkylalkylcellulose that can be dissolved in a monohydric alcohol having 1 to 3 carbon atoms may be contained in an amount of 40% by weight or less of water and within a range where the mixed solvent can completely dissolve the carboxyalkylalkylcellulose. After dissolving in the alcohol to make a 10-40% by weight solution, in this solution,
1. A water-based enteric coating method characterized by using a liquid in which carboxyalkylalkylcellulose is precipitated and dispersed by adding water so that the alcohol concentration is in the range of 60 to 40% by weight.