JPS607492B2 - enteric-coated capsules - Google Patents

Description

[Detailed description of the invention] The present invention is a newly developed enteric-coated cell.

The present invention relates to an enteric-coated capsule made of a base material. Enteric-coated capsules, which are used to enclose and ingest pharmaceutical products, are stable and do not dissolve in the human stomach, but are required to dissolve quickly in the intestines. “Traditionally,
Capsules made of gelatin treated with formalin or coated with enteric polymeric substances are known.

However, such enteric port capsules are made by first making capsules using gelatin as a base material, and then making them enteric-coated by formalin treatment or coating, which makes the manufacturing process complicated. In the case of formalin treatment, it is not always easy to control the process so that it does not dissolve in the gastric fluid but dissolves in the phlegmatic fluid, and there is the difficulty that if the treatment is excessive, it will not dissolve even in the intestinal fluid. In addition, when coating with enteric-coated polymeric substances, poor adhesion between the surface of gelatin and the coating film tends to occur, and the coating film deteriorates due to the influence of water content in gelatin, resulting in enteric coating. There is a problem that the function may become inferior.

On the other hand, a method for manufacturing capsules using a polymeric material that is insoluble in gastric fluid but soluble in intestinal fluid as a base material has also been proposed.Currently, enteric-coated polymeric materials include
Carboxylic acid-based vinyl copolymers such as methacrylic acid-methyl methacrylate copolymers, cellulose derivatives such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methylcellulose phthalate, and cellulose acetate succinate are known. However, the above-mentioned carboxylic acid-based vinyl copolymer, hydrogen.

Kisif. In the case of propylmethylcellulose phthalate, methylcellulose phthalate, etc., it is essential to incorporate a large amount of plasticizer in order to improve the hardness and brittleness of the molded product (capsule). However, there are disadvantages and disadvantages in that there is a concern that the plasticizer may ooze out onto the surface of the molded product later on, and that it may have an unfavorable effect on the loaded pharmaceutical ingredients. In addition, over time, cellulose acetate phthalate, cellulose acetate succinate, etc. undergo hydrolysis reactions due to the influence of moisture (humidity) during storage.
Phthalic acid has the extremely unfavorable phenomenon of liberating acids such as succinic acid, and has the disadvantage that the solubility of the base material in intestinal fluid gradually decreases.The present invention exhibits excellent enteric properties and is safe for the human body. A new type of physically and chemically stable intestinal lagoon that is harmless, does not change over time and generate harmful substances, does not require the addition of L plasticizers, has excellent flexibility, and is physically and chemically stable. The present invention provides a pharmaceutical capsule based on an aliphatic cellulose derivative based on an acidic succinyl and aliphatic monoacyl hybrid ester of cellulose ether substituted with an alkyl group and/or a hydroxyalkyl group. It concerns capsules.

To explain this, the above-mentioned hybrid ester of cellulose ether used as a base material in the present invention was successfully developed as a result of intensive research by the present inventors (Tokukan Sho 52-
No. 127947 (see Japanese Unexamined Patent Application Publication No. 54-61282),
This is because {1) it forms a highly flexible film with almost no need for plasticizer, ■ the films do not stick to each other, and '3} chemical changes over time such as deterioration due to moisture during storage. , does not cause any physical change, {4
}The above-mentioned cellulose ether hybrid ester can be obtained as a pure product free of impurities because the purification operation after the completion of the esterification reaction can be easily performed in the manufacturing process without any difficulty. It has various advantages.

The acidic succinyl of the cellulose ether, that is, the group represented by the formula, and the aliphatic monoacyl, that is, the group represented by the general formula (
A hybrid ester with a group represented by the formula (R in the formula represents an aliphatic monovalent hydrocarbon group) can be easily obtained by subjecting cellulose to an esterification reaction of succinic anhydride and aliphatic monocarboxylic acid anhydride. can get.

The raw material cellulose ether must be substituted with an alkyl group and/or a hydroxyalkyl group. , hydroxyalkyl cellulose such as hydroxybutyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropylethyl cellulose, hydroxybutyl methyl cellulose, hydroxybutyl ethyl cellulose.

-su, and even hydroxyethyl hydroxyf. Lopyl cellulose, hydroxyethyl hydroxybutyl cellulose, hydroxyethyl hydroxypropyl methylcellulose. -su etc. are exemplified. These cellulose ethers are not particularly limited in their molecular weight or the number of moles of substituents, but in general, in the case of alkyl cellulose and hydroxyalkyl alkyl cellulose, when the number of molecules substituted with an alkyl group is greater than 2.5 per glucose unit,
Since the esterification reaction with the acid anhydride described above becomes difficult, it is desirable that the amount is less than this. As the succinic anhydride and aliphatic monocarboxylic anhydride to be subjected to the esterification reaction with the cellulose ether, commercially available ones may be used.
Examples of acetic acid include anhydrides such as propionic acid, lactic acid, and valeric acid.
In the presence of an alkali metal salt (catalyst) of a carboxylic acid such as sodium acetate or potassium acetate, using a carboxylic acid such as an acid as a reaction medium, cellulose ether, succinic anhydride, and aliphatic monocarboxylic anhydride are combined. Alternatively, cellulose ether is reacted with succinic anhydride and aliphatic monocarboxylic anhydride in the presence of a basic catalyst such as pyridine, Q-picoline, etc. in a suitable solvent such as acetone, dimethylformamide, etc. A method of esterification reaction may be used.

The average number of substitutions of acidic succinyl groups and aliphatic acyl groups per glucose unit varies depending on the performance required of the resulting product (hybrid ester) and the type of raw material cellulose ether, but in general acidic succinyl It is desirable that the number of substitutions of the group and the aliphatic monoacyl group is 0.1 or more and 0.05 or more, respectively, and if it is less than that, the flexibility and enteric properties will deteriorate.

Enteric-coated capsules can be produced using such a mixed ester by a dipping method using a molded pin.

That is, first, a hybrid ester is dissolved in an organic solvent or an organic solvent-water mixed solvent to prepare a dipping solution with a desired concentration, and after defoaming if necessary, a molded pin is immersed in this dipping solution, and then the pin is Capsules having the desired dimensions and shape are made into products by pulling up, drying the viscous film formed around the pins, removing the capsules thus formed from the pins, and applying finishing processing as necessary. can be obtained. Of course, the molding method is not limited to the dipping method, and other molding methods may be used. Examples of organic solvents used for preparing the infusion solution include methyl alcohol, ethyl alcohol, acetone, methyl cellosolve, ethyl cellosolve, and ethyl acetate. May be used together.

The dissolved concentration of the hybrid ester is determined by taking into account the compatibility with the molding operation using the pins placed above, but usually, if the purpose is to obtain capsules with thin meat, a low-concentration dissolving solution is used. In addition, if the purpose is to obtain thick capsules, it is desirable to use a highly concentrated viscous soaking liquid. Odor agents: Various additives such as fragrances and plasticizers may be added**, but the amounts added should be kept within a range that does not adversely affect the original characteristics and benefits of the hybrid ester.

Next, the present invention will be explained in more detail by referring to reference examples and examples.

Reference Example In a reaction vessel equipped with a stirrer, 100 parts of glacial acetic acid (parts indicate parts by weight, the same applies hereinafter), 20 parts of sodium acetate, and cellulose ether, succinic anhydride, and aliphatic monomers of the type and amount shown in Table 11 were added. Prepare each carboxylic acid anhydride, 8
The esterification reaction was carried out at 5o0 for 3 hours.

Then, water was added to the reaction solution to precipitate the reaction product, which was washed with water and dried to obtain a hybrid ester containing an acidic succinyl group and an aliphatic monoacyl group as shown in Table 11.

However, the abbreviations used in Table 11 have the following meanings.

HPC: Hydroxypropylcellulose "Number of hydroxypropoxyl group substitutions per glucose unit: 3.
0 HFMC: hydroxypropyl methyl cellulose, number of hydroxypropoxyl group substitutions per glucose unit: 0.27, number of methoxy group substitutions: 1.82 HEHPC: hydroxyethyl hydroxyf.

Lopylcellulose, Number of hydroxyethoxy group substitutions per glucose unit 2"5 Number of hydroxypropoxyl group substitutions 0.32 DS: Table of moles of substituents per glucose unit
-1 Next, the hydrolytic stability and elongation rate when made into films were investigated for Samples Nos. 1, 2, and 3 obtained above and Samples Nos. 4 and 5 below for comparison, and the results are shown in Table 1. It was as shown in -2.

Sample No. 4: Cellulose acetate phthalate "Number of acetyl group substitutions per glucose unit: 184; Number of phthaloyl group substitutions: Q.

76 Sample No. 5: Hydroxypropyl methylcellulose phthalate, the number of hydroxypropoxyl group substitutions per glycose unit is 02, and the number of methoxy group substitutions is 0.

72 "The number of phthaloyl group substitutions is 0.

68 [Hydrolytic stability test method] A measurement sample of free aliphatic carboxylic acid was incubated at 60°C and 100% relative humidity for a certain number of days (
After thinning (6 days and 12 days), this was extracted using ethyl ether in a Soxhlet extractor for 5 hours, and the aliphatic monocarboxylic acid extracted into ethyl ether was quantified by gas chromatography.

'60 samples of free acids other than aliphatic monocarboxylic acids
°C for a certain number of days (6 days, 1 hour under conditions of 100% relative humidity)
After standing for 2 days), it was dissolved in a mixed solvent of methylene chloride and methanol (volume ratio 1:1), added with t-hexane, extracted with water, and titrated with 0.1N NaOH using a soil trowel. Quantify the amount of free acid. Next, the amount of free acids other than aliphatic monocarboxylic acids is determined from the difference between this value and the amount of free aliphatic monocarboxylic acids. [Measurement method of film elongation rate] A film prepared by dissolving a sample in a mixed solvent of methylene chloride and methanol (volume ratio 1:1) and casting was measured using a Tensilon UTM-m model (manufactured by Toyo Balduin Co., Ltd.). The elongation rate is measured at 2500.

Table-2 Example 1 Sample No. in Reference Example. Completely dissolve 2,109 tons of ethanol (volume ratio: 634) in an acetone dish and leave to stand at room temperature to degas, creating a homogeneous viscous solution.

Immerse a pre-lubricated molded pin (mold for cap and body) in this solution and slowly pull it up to form a film of viscous liquid around the pin. After drying, the molded body was removed from the pin and subjected to necessary post-processing to obtain capsules.

This capsule was transparent and had excellent flexibility.
The capsules obtained in this way were filled with lactose powder and
Regarding the mating part of the cap and body sealed with the above-mentioned viscous solution, "1st liquid (pH 7.5) containing 1st liquid (pH 7.5) based on the 9th revision of the Japanese Pharmacopoeia, and 4.
When we observed the change in pH 5.05.5 and 6.0 in McIlven buffer solution, we obtained the results shown in Table 3. Table 3 Test solution Change in capsule pH 1, Solution 2 Stable for more than 2 hours (first solution) pH 4.5 solution Same as above Solution pH 5.0 Solution with pH 5.5, which releases the dissolved contents of the capsule in 20 to 25 minutes pH 6, which releases the dissolved contents of the capsule in 12 to 18 minutes .0 liquid Capsule dissolution contents are released in 8 to 10 minutes pH 7.5 liquid Capsule dissolution contents are released in 6 to 9 minutes (second liquid) Example 2 Sample No. in Reference Example.

Capsules were made in the same manner as in the previous example, except that a viscous steel solution obtained by melting 20 minutes of ethanol-water (volume ratio 8:2) mixed solvent was used.The capsules were transparent. The product had excellent flexibility.

Regarding the capsule obtained in this way, the first
The solubility in the liquid and the second liquid was investigated and the results were as follows.

Solubility in first solution (pHI.2): Not dissolved for over 2 hours.

Solubility in second liquid (PH7.5): Dissolves in 15 to 2 drops and releases contents.

Example 3 Sample No. 3 in Reference Example. Acetone-methyl cellosolve (volume ratio (131) mixed solvent 75%)
Capsules were made according to Example 1 except that the clayey rice solution obtained by sawdusting was used, and the capsules were transparent and had excellent flexibility.

The solubility of the thus obtained capsules in the first liquid and the second liquid was examined using the same machine as in Example 1, and the results were as follows. Solubility in the first solution (pHI.2): No dissolution for more than 2 hours. Second liquid (PH7.5)
Solubility in: Dissolves in 15-2 powders and releases contents.

Claims (1)

[Claims] 1. An enteric capsule comprising as a base material an acidic succinyl and aliphatic monoacyl mixed ester of cellulose ether substituted with an alkyl group and/or a hydroxyalkyl group.