JPS6379818A - Production of microcapsule agent - Google Patents

Abstract

PURPOSE:To obtain the titled formulation, by suspending a blend of a drug with an organic solvent and inorganic compound and further an acrylic resin derivative, etc., in a viscous liquid, adding water, etc., and obtaining a deposited microcapsules, etc., having a low production cost and capable of eluting the drug at a specific pH. CONSTITUTION:Water or a viscous liquid prepared by suspending water or both are added to a suspension obtained by suspending a blend of a drug, e.g. erythromycin, aspirin, vitamin E, etc., an organic solvent, e.g. ethanol, methanol, etc., and inorganic compound, e.g. talc, silicic acid anhydride, magnesium oxide, etc., and further an acrylic resin derivative, e.g. Eudragit L, etc., or hydroxypropyl methyl cellulose phthalate, in a viscous liquid, e.g. liquid paraffin, etc., to give deposited microcapsules, and produce the aimed microcapsule agent. The agent is capable of absorbing the drug in a part optimum for absorption and relieving the irritation given to other organs.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing microcapsules in the pharmaceutical industry.

[Prior Art and Problems] Generally, after administration, many oral pharmaceuticals reach the digestive organs such as the stomach, small intestine, and large intestine, are absorbed, and are distributed within the body.
It exhibits its medicinal effects.

In addition, formulations such as tablets, capsules, powders, granules, and fine granules have been devised for oral administration, and technological innovations are being made to enhance their functions.

Among these preparations, for drugs expected to be absorbed in the intestines, coated granules, coated fine granules, coated tablets, etc. coated with a film that does not dissolve in gastric acid are used.

By the way, when a drug is orally administered into a living body, it is preferable that each drug is absorbed at the most suitable absorption site. This is because some drugs may exhibit undesirable effects if absorbed at a site other than the intended absorption site.

Therefore, if the drug containing the drug is eluted before it reaches the target absorption site, the intended effect of the drug will not be fully achieved. For example, the pH in the human stomach is said to be 1 to 3.5, the small intestine usually has a pH of 5 to 7, and the large intestine has a pH of about 8. If the drug is degraded by gastric acid, or if the drug is to be absorbed in the small intestine, it is necessary to administer the drug in a dosage form that will not dissolve in the stomach. Currently, as a means of solving the above-mentioned problems, the above-mentioned film-coated chemicals are often used, but manufacturing equipment requires special specifications to manufacture this film-coated agent. Moreover, the running cost is also high, and it is difficult to say that the cost is fully justified from the viewpoint of productivity.

Therefore, it has been desired to develop an orally administered drug that is inexpensive to produce, elutes the drug at a specific pH.

[Means for Solving the Problems] As a result of intensive research in search of a drug that is low in manufacturing cost and that elutes the drug at a specific pH, the present inventors have found that the drug,
Adding water and/or a viscous liquid in which water is suspended to a suspension in which a mixture of an organic solvent and an inorganic compound, as well as an acrylic acid resin derivative or hydroxypropyl methylcellulose phthalate, is suspended in a viscous liquid; To obtain precipitated microcapsules, or to a suspension of a mixture of drug, organic solvent and inorganic compound as well as acrylic acid resin derivative or hydroxypropyl methylcellulose phthalate in a viscous liquid, add water and/or water. A suspended viscous liquid is added, and the precipitated microcapsules are added to the viscous liquid in which water is suspended, and a mixture of an organic solvent and an acrylic acid resin derivative or hydroxypropyl methylcellulose phthalate is added as is or The present invention was completed by discovering that by suspending and adding a drug to a viscous liquid to obtain precipitated microcapsules, it is possible to obtain microcapsules that elute drugs at a low manufacturing cost and at a specific pH.

The present invention will be explained in detail below.

As the drug used in the present invention, commonly used drugs can be used. Specific examples include erythromycin, aspirin, sennoside, theophylline, 5-
Examples include powdered drugs such as fluorouracil, nifedipine, and mercaptopurine, and oily drugs such as shogaol and vitamin E1 eicosapentaenoic acid.

Specific examples of organic solvents include ethanol, methanol,
Examples include propatool, hexane, chloroform, and dimethylmethane, where the weight percent of drug to organic solvent ranges from 1 to
An amount of about 30% by weight, preferably 3 to IO% by weight is used.

Specific examples of inorganic compounds include talc such as Talc 5W-AC (manufactured by Asada Seifun Co., Ltd.), Adsolider-101 (manufactured by Freund Sangyo Co., Ltd.), Cyroid 244 (manufactured by Fuji Davison Chemical Co., Ltd.), Aerosil 380 (Nippon Aerosil), etc. Co., Ltd.), magnesium oxide such as magnesium oxide (Kyowa Chemical Industry Co., Ltd.), magnesium oxide (Tomita Pharmaceutical Co., Ltd.), Kyowa Suimag (B3 Wa Chemical Co., Ltd.), magnesium hydroxide, etc. Magnesium hydroxide such as (manufactured by Tomita Pharmaceutical Co., Ltd.) is mentioned, and the amount of 50% to 2000% by weight based on the drug,
Particularly preferred is a proportion of 200% to 600% by weight.

Specific examples of acrylic acid resin derivatives include Eudragit, methacrylic acid-methyl methacrylate copolymers such as Eudragit S (manufactured by Rohm Pharma), and methacrylic acid such as Eudragit E (manufactured by Rohm Pharma). Ethyl methacrylate such as dimethylaminoethyl/methyl methacrylate copolymer, Eudragit RS, Eudragit RL (both manufactured by Rohm Pharma)
Trimethylammonium ethyl methacrylate copolymer may be mentioned, and examples of hydroxypropyl methylcellulose phthalate include commercially available HP-50, HP-55, H
P-55S (manufactured by Shin-Etsu Chemical Co., Ltd.) can be used. 50-50 based on the total weight of drug and inorganic compound
0% by weight, preferably 80-200% by weight.

Any means may be used to mix these, and they may be mixed in any order, but after dissolving the drug in a solvent and adding the inorganic compound, the acrylic acid resin derivative or hydroxypropyl methyl cellulose Preferably, the phthalate is added and stirred using conventional stirring equipment.

The mixture thus obtained is suspended in a viscous liquid, examples of which include liquid paraffin, glycerin, silicone oil, sesame oil, rapeseed oil,
Vegetable oils include camellia oil, soybean oil, cottonseed oil, olive oil, and castor oil.

Suspension can be carried out by a general stirring operation using a magnetic cooler or the like.

To this suspension is added water and/or a viscous liquid in which water is suspended. At this time, it is effective to add while stirring, and it is preferable to add a viscous liquid in which water is suspended, and then add water.

As a result, the acrylic acid resin derivative or hydroxypropyl methyl cellulose phthalate dissolved in the organic solvent becomes insolubilized, a film is formed on the surface of the inorganic compound that has adsorbed the drug, and microcapsules are precipitated. This is separated by normal fractionation operations such as suction filtration and sieving.
By drying, microcapsules can be obtained.

Furthermore, the precipitated microcapsules are added to a viscous liquid in which water is suspended, and a mixture of an organic solvent and an acrylic acid resin derivative or hydroxypropyl methyl cellulose phthalate is added to this as is or suspended in the viscous liquid. By adding it, microcapsules with double coatings can be obtained. Therefore, in this step, if a different type of acrylic acid resin derivative or hydroxypropyl methyl cellulose phthalate is used than in the previous step, microcapsules having a double coating consisting of two types of acrylic acid resin derivatives or hydroxypropyl methyl cellulose phthalate with different properties can be formed. can be obtained.

Also, among the specific examples of the acrylic acid resin derivatives described in Moe, for example, Eudragit S is pll6, Eudragit S is pll6, and Eudragit S is pll6.
In order to elute the drug at H7, by appropriately selecting and using a resin that elutes at a desired pH, it is possible to produce a microcapsule that elutes the drug at a desired specific pH.

[Effect of the invention] According to the present invention, the following effects can be obtained.

(2) Since the microcapsule according to the present invention elutes the drug at a specific pH, the drug can be absorbed at the site most suitable for absorption by utilizing the difference in l)H in each digestive organ.

(2) Since the microcapsules of the present invention can elute drugs in specific digestive organs, they can reduce irritation caused by drugs to other digestive organs.

■The manufacturing method of the present invention uses inexpensive solvents, etc.
Manufacturing costs are low because no special equipment is required for manufacturing.

(2) Drug elution can be controlled according to the pH of the secreted fluid in a specific digestive organ (for example, the pll of gastric acid in the case of the stomach).

Next, the ability of microcapsules produced by the method for producing microcapsules of the present invention to elute drugs at a specific pH will be explained using experimental examples.

[Experimental Examples] Experimental Example 1 The elution time of the erythromycin microcapsules obtained in Example 1 described later was measured by the elution test method (paddle method) of the 11th edition of the Japanese Pharmacopoeia. That is, 900It was placed in a glass tester of IOOODj having an inner diameter of 100mWl, a height of 160mi+, and a radius of 50n++n.
fl of pH 6.5 phosphate buffer and stirred at 1100 rpm with a paddle consisting of an acid-resistant stirring blade and a rotating shaft, and sampled the eluate over time. The elution time was defined as the time when % was reached.

As a result, the components were rapidly eluted with an elution time of 10 minutes. On the other hand, in the above dissolution test, except that the test solution was the 1st solution of the 11th revised Japanese Pharmacopoeia disintegration test method with pH 1 and 2,
When an elution test was conducted in the same manner as above, no elution of erythromycin was observed even after 2 hours had passed.

Table 1 summarizes the results of similar elution tests performed on various pl (buffer solutions).

Table 1 Buffer pH and Erythromycin Elution Index Experimental Example 2 Table 2 shows the results of measuring the elution time of the erythromycin microcapsules obtained in Example 2 described later in the same manner as in Example 1.

Table 2 Experimental Example 3 Acetylsalicylic acid microcapsules 200 R9 obtained in Example 3 described later were filled into No. 1 gelatin capsules to obtain acetylsalicylic acid hard capsules.

The elution time of the acetylsalicylic acid hard capsule prepared as described above was measured according to the elution test method of the 11th edition of the Japanese Pharmacopoeia. That is, the inner diameter is 100 mm and the height is I 60.
A 900 d test liquid was placed in a 10007 d glass tester with a semicircular bottom with a diameter of 50 mm, and an acid-resistant wire with a wire diameter of 1 mm was placed in an inner diameter of 12 mm and a length of 25 mm.
A hard capsule was placed in a sinker that was wound spirally with a winding interval of 3 mm, and 10 acid-resistant wires with a wire diameter of 1 mm were fixed in parallel at 3 mm intervals as supports around the outer periphery, and the capsule was submerged in the bottom of the tester. The eluate was sampled over time by stirring at 100 rpm using a paddle consisting of an acid-resistant stirring blade and a rotating shaft, and the time when acetylsalicylic acid in the sampled solution reached 75% of the complete elution time was defined as the elution time. . We summarized the results for buffer solutions of various pH,
It is shown in Table 3.

Table 3: pH of buffer solution and acetylsalicylic acid elution 1st, pH 1
The acetylsalicylic acid microcapsules from which no components were eluted in . Elution time was 16 minutes.

Experimental Example 4 Table 4 shows the results of measuring the elution time of the gingerol microcapsule obtained in Example 4 described later in the same manner as in Example 1.

From the results of Experimental Examples 1 to 4 in Table 4, it was confirmed that the microcapsule according to the present invention elutes the drug at a specific pl+.

The present invention will be explained in more detail below with reference to Examples, but the present invention is not limited thereto.

Example 1 1.0 g of erythromycin was dissolved in 257 d of ethanol, 5.0 g of light anhydrous silicic acid [trade name: Ad Solider 101, manufactured by Freund Sangyo Co., Ltd.] was added, and a magnetic stirrer (manufactured by Iuchi Seieido Co., Ltd., manufactured by Freund Sangyo Co., Ltd.) was added. The mixture was stirred and dispersed using a multi-cooler HS/49P). While stirring the dispersion, 5.09 g of methacrylic acid/methyl methacrylate copolymer (trade name: Eudragit, manufactured by Rohm Pharma) was gradually added. 10 g of the gel-like solution thus obtained was poured into 100 g of liquid paraffin (manufactured by Wako Pure Chemical Industries, Ltd.) and stirred to suspend it.

Stirring was performed using a magnetic stirrer (Multi-Scooler HS-48'P, manufactured by Iuchi Seieido Co., Ltd.). To this suspension, 50 g of a liquid paraffin/water suspension in which water was dispersed at a concentration of 5% was gradually added with stirring, and then 100 g of water was gradually added while stirring. After stirring for about 1 hour, the stirring was stopped, the mixture was allowed to stand, and the separated aqueous layer was separated using a separatory funnel and filtered with suction to collect particles in the aqueous layer. The particles were dried under reduced pressure (50°C, 10 mmHg
.

24 hours) to obtain 3 g of microcapsules.

Example 2 Erythromycin 1.09 was dissolved in 20 d of ethanol, 10.0 g of magnesium oxide [manufactured by Kyowa Chemical Industry Co., Ltd.] was added to this solution, and homogenized +J'- (manufactured by Fi Kiseiki Co., Ltd., EXCEL-AUTOlloMOG).
ENIZER) to stir and disperse. Do not stir the above dispersion until the methacrylic acid/methyl methacrylate copolymer [
Product name: Eudragit, manufactured by Rohm Pharma Co., Ltd.] 5
．． 0y was added gradually. The log of the gel-like solution thus obtained was poured into 100 g of soybean oil and stirred to suspend it. Stirring was performed using a magnetic stirrer (Multi-Scooler HS/4SP manufactured by Iuchi Seieido Co., Ltd.). Soybean oil/water suspension 509, in which water was dispersed at a ratio of 20%, was gradually added to this suspended liquid and stirred. After stirring for about 30 minutes, the stirring was stopped, the mixture was allowed to stand, and the separated aqueous layer was collected using a separatory funnel, followed by suction filtration to collect particles in the aqueous layer. Next, these particles were dispersed in 1009% soybean oil, and methacrylic acid/methyl methacrylate copolymer 2.09%
100g of soybean oil dispersed with ethanol solution containing TOG
was added and stirred. Furthermore, water 809 was gradually added without stirring, and the mixture was stirred for about 30 minutes. Stirring was stopped, and the aqueous layer was separated by standing still and separated using a separating funnel, and then the particles of the aqueous layer were collected by suction filtration. The particles were dried under reduced pressure (50°
C, 10 mmHg, 24 hours) to obtain 69 microcapsules.

Example 3 6.0 g of acetylsalicylic acid was dissolved in ethanol 100-, and light silicic anhydride [trade name: ADSOLYGOO 101.
209% of Co. manufactured by Freund Sangyo Co., Ltd. was added and stirred and dispersed. While stirring this dispersion, methacrylic acid/methyl methacrylate copolymer [trade name: Eudragit S, manufactured by Rohm Pharma Co., Ltd.] 259 was gradually added.

The gel-like solution 209 thus obtained was mixed with silicone oil [trade name: Silicone KF96. [manufactured by Shin-Etsu Silicone Co., Ltd.]] and stirred to suspend.

Stirring was performed using a laboratory stirrer (Chemistryler B-100, manufactured by Tokyo Rika Kikai Co., Ltd.). In this suspension,
100 g of water was gradually added with stirring. After the addition was completed, the aqueous layer was separated by standing and separated using a separating funnel.
Particles in the aqueous layer were separated using a sieve lined with a 00 mesh stainless steel wire mesh. Freeze-dry the particles (freezing temperature -40°C)
.

6 g of microcapsules were obtained.

Example 4 Shogaol 109 was dissolved in 500 d of n-hexane, and while stirring, light silicic anhydride [trade name: Ad Solider] was dissolved.
101, manufactured by Freund Sangyo Co., Ltd.] was gradually added and stirred for about 1 hour. For stirring, use a laboratory stirrer (
Manufactured by Tokyo Rika Kikai Co., Ltd.

Chemistler B-100) was used. While stirring this dispersion, add dimethylaminoethyl methacrylate.
Methyl methacrylate copolymer [trade name: Eudragit E, manufactured by Rohm Pharma Co., Ltd.] 709 was gradually added. 200 g of the gel-like solution thus obtained was poured into glycerin 5009 (manufactured by Wako Pure Chemical Industries, Ltd.) and suspended by stirring. Stirring was performed using a laboratory stirrer (Chemistryler B-100, manufactured by Tokyo Rika Kikai Co., Ltd.). 200 g of water was gradually added to this suspension while stirring. After the addition was completed, the aqueous layer was separated by standing and separated using a separatory funnel, and then the particles of the aqueous layer were separated using a sieve covered with a 200-mesh stainless wire mesh. The particles were dried under reduced pressure (506C, 10a+ml, 11g).

20 hours) to obtain microcapsules 359.

Example 5 In Example 3, methacrylic acid/methyl methacrylate copolymer [trade name: Eudragit S, manufactured by Rohm Pharma Co., Ltd.] was replaced with hydroxypropyl methylcellulose phthalate [trade name: [IP-553, Shin-Etsu]. Acetylsalicylic acid microcapsules 5.59 were obtained in the same manner as in Example 3, except for using [manufactured by Kagaku Kogyo Co., Ltd.].

Claims (2)

[Claims] (1) A viscous liquid made by suspending water and/or water in a viscous liquid suspension of a mixture of drugs, organic solvents, inorganic compounds, and acrylic acid resin derivatives or hydroxypropyl methyl cellulose phthalate. A method for producing microcapsules, which comprises adding a liquid to obtain precipitated microcapsules. (2) A viscous liquid made by suspending water and/or water in a viscous liquid suspension of a mixture of a drug, an organic solvent, an inorganic compound, and an acrylic acid resin derivative or hydroxypropyl methylcellulose phthalate. The precipitated microcapsules are added to a viscous liquid in which water is suspended, and a mixture of an organic solvent and an acrylic acid resin derivative or hydroxypropyl methylcellulose phthalate is added as is or suspended in the viscous liquid. A method for producing microcapsules, which comprises adding the microcapsules in a cloudy manner to obtain precipitated microcapsules.