JPH0128043B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel compounds, acidic succinoyl and acidic phthaloyl mixed esters of cellulose ethers. Conventionally, cellulose acetate phthalate, cellulose acetate succinate, methyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, methyl cellulose succinate, hydroxypropyl methyl cellulose succinate, etc. are known as carboxylic acid esters of cellulose or cellulose ether.
These are applied as enteric coating agents and the like. However, among the above-mentioned cellulose acetate phthalate and cellulose acetate succinate, cellulose acetate phthalate and cellulose acetate succinate have the disadvantage that they tend to gradually decompose under the action of water and release acetic acid, phthalic acid, or succinic acid, and their solubility in intestinal fluids gradually decreases. be. In addition, methylcellulose phthalate and hydroxypropyl methylcellulose phthalate take too long to dissolve in intestinal fluid, or have poor flexibility when formed into a coating, so it is necessary to use a large amount of plasticizer when used as a coating. However, while the use of such plasticizers forms a highly flexible film, there is a risk that the plasticizers may later migrate to the film surface or gradually volatilize from the surface. There are concerns that it may have an adverse effect on medicines if it is applied as an enteric coating agent, etc.
Another drawback is that the physical properties of the coating change over time. Additionally, methylcellulose succinate and hydroxypropyl methylcellulose succinate form flexible films that do not require the use of plasticizers; however, the coatings of these succinates tend to stick to each other. , it also has a serious drawback of being easily sticky. The present invention aims to provide a novel compound free from such drawbacks, which is a glycose ether of cellulose ether substituted with an alkyl group having 1 to 3 carbon atoms and/or a hydroxyalkyl group having 2 to 4 carbon atoms. The average number of substitutions of acidic succinoyl groups and acidic phthaloyl groups per unit is 0.1 to 2.0, respectively, and the weight average molecular weight is 10,000 to 300,000.
The invention relates to acidic succinoyl and acidic phthaloyl mixed esters. The above hybrid ester of cellulose ether is (1)
Forms a highly flexible and strong film with almost no need for plasticizer; (2) When used as a coating film, the film surface is not sticky and does not stick to each other; (3) ) It has various advantages such as not undergoing chemical or physical changes over time such as deterioration due to moisture during storage, and is especially suitable for use in the production of enteric coated tablets. . The present invention will be explained in detail below. Acidic succinoyl of the above cellulose ether i.e. formula The group represented by and acidic phthaloyl, that is, the general formula A hybrid ester with a group represented by the above has an average number of substitutions of acidic succinoyl group and acidic phthaloyl group per glucose unit of 0.1 to 2.0, respectively, and a weight average molecular weight of 10,000 to 300,000. It is obtained by esterifying an acid and phthalic anhydride. When the weight average molecular weight of this mixed ester is larger than the above range, the viscosity of the organic solvent solution used to manufacture coated tablets may become too high and become difficult to handle, or a large amount of solvent may be used to reduce the viscosity. If the amount is smaller than this range, the polymeric properties will be lost and the coating film will become brittle. This cellulose ether includes an alkyl group having 1 to 3 carbon atoms and/or
or substituted with a hydroxyalkyl group having 2 to 4 carbon atoms, including alkylcelluloses such as methylcellulose, ethylcellulose, and propylcellulose; Examples include alkylcellulose, hydroxyalkylalkylcellulose such as hydroxyethylmethylcellulose, hydroxyethylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, hydroxybutylmethylcellulose, and hydroxybutylethylcellulose, and further hydroxyethylhydroxypropylmethylcellulose. The weight average molecular weight of these cellulose ethers is approximately 7,000 to 7,000 in order to make the weight average molecular weight of the resulting hybrid ester 10,000 to 300,000.
250,000, and the number of moles of the substituents is not particularly limited, but generally in the case of alkyl cellulose and hydroxyalkylalkyl cellulose, when the number of molecules substituted by the alkyl group is larger than 2.5 per glucose unit, the above-mentioned Since the esterification reaction with the acid anhydride becomes difficult, it is desirable that the amount is less than this. Generally commercially available succinic anhydride and phthalic anhydride to be used in the esterification reaction with the cellulose ether may be used. In the esterification reaction, a carboxylic acid such as acetic acid, propionic acid, or laconic acid may be used as the reaction medium. , a method of esterifying cellulose ether with succinic anhydride and phthalic anhydride in the presence of an alkali metal salt (catalyst) of a carboxylic acid such as sodium acetate or potassium acetate, or a suitable solvent such as acetone or dimethylformamide. Among them, a method may be used in which cellulose ether is subjected to an esterification reaction with succinic anhydride and phthalic anhydride in the presence of a basic catalyst such as pyridine or α-picoline. Note that the two types of acid anhydrides may be charged into the reactor at the same time, or one of them may be charged first and reacted, and then the other may be charged and reacted. After the esterification reaction is complete, a large amount of water is added to the reaction solution to precipitate the reaction product (mixed ester), which is thoroughly washed with water for purification and then dried to obtain a powdery, highly pure product. It will be done. Such mixed esters provide flexible and strong coatings that are readily soluble in alkaline liquids such as artificial intestinal fluid and photographic developers. Therefore, the acidic succinoyl and acidic phthaloyl mixed ester of cellulose ether of the present invention can be dispersed or dissolved in water or an organic solvent to form a coating liquid, which is used to coat tablets, pills, granules, capsules, etc. Enteric-coated pharmaceuticals can be manufactured by this method. In this case, the organic solvents include acetone, methylene chloride, ethyl acetate, 1,
1,1-trichloroethane, methyl alcohol,
One or more mixed solvents such as ethyl alcohol are used. Incidentally, various additives such as colorants, taste and odor agents, fragrances, plasticizers, etc. may be added to the coating liquid. The coating means may be a conventionally known method using a pan coating device, a drum type coating device, a fluid coating device, or the like.
There are no particular restrictions on the coating operation itself. On the other hand, it is also possible to produce capsules from the cellulose hybrid esters of the invention. This may be accomplished by a dipping method in which a molding pin is immersed in the coating liquid, pulled up and dried, or a molding method in which a film or sheet material is formed and then heated and pressure molded. Next, specific examples will be given. Example In a reaction vessel equipped with a stirrer, 100 parts by weight of glacial acetic acid,
20 parts by weight of sodium acetate, cellulose ether, succinic anhydride, and phthalic anhydride in the types and amounts shown in Table 1 were charged, and an esterification reaction was carried out at 85°C for 3 hours. Next, water was added to the reaction solution to precipitate the reaction product, which was washed with water and then dried to obtain a mixed ester having an acidic succinoyl group and an acidic phthaloyl group as shown in Table 1. However, table -
The abbreviations used in 1 are as follows. MC: Methylcellulose, number of moles of methoxy group substitution per glucose unit: 1.80. HPMC: Hydroxypropyl methylcellulose, number of moles substituted with hydroxypropoxy group per glucose unit: 0.27, number of moles substituted with methoxy group: 1.82. HPC: Hydroxypropylcellulose, 3.00 moles of hydroxypropoxyl group substitution per glucose unit. DS: moles of substituents per glucose unit.

【table】

[Physical property test]

(1) Solubility in organic solvents: 9 g of organic solvent was added to 1 g of sample and observed at room temperature. Those that dissolved were indicated as ○, those that swelled were indicated as △, and those that did not dissolve at all were indicated as ×. (2) Tensile properties: Dissolve the sample in acetone, manufacture a film by casting, and autograph IS-
5000 (manufactured by Shimadzu Corporation). (3) Stability over time: Samples were stored at 60℃ and 100% relative humidity2.
After leaving it for a week, it was dissolved in a mixed solvent of methylene chloride/methanol (1:1), added with n-hexane, extracted with water, and a portion of it was subjected to UV measurement to determine the amount of free phthalic acid. .
Next, the remaining amount was titrated with 0.1N-NaOH to determine the total amount of free acid, and the amount of free succinic acid was determined from the difference between this and the above amount of free phthalic acid. (4) Adhesion: A film test piece (20
×20×0.1mm) stacked, load 10g/cm ² , temperature
Pressed for 24 hours at 60℃ and 81% relative humidity.
I checked to see if the films were attached to each other.

[Coating operation conditions]

Coating liquid temperature: 24°C Coating liquid supply rate: 30ml/min Drying air temperature: 40°C Spray air flow rate: 100/min Coating time: 180 min By coating in this way, each tablet can be coated with approx.
Enteric coated tablets with a coating of 20 mg were obtained. When this coated tablet was tested according to the disintegration test method for enteric-coated preparations according to the Ninth Edition Japanese Pharmacopoeia, the results were as follows. Disintegration property with the first liquid: No change for over 2 hours Disintegration property with the second liquid: Disintegrated in 12 to 14 minutes (Disintegration time of the bare tablet was 9 to 10 minutes.) Covering test 2 Sample No. 2 Dissolve the substance in acetone to a concentration of 20% by weight, leave it at room temperature to defoam,
A homogeneous viscous solution was created. A molding pin (cap and body mold) for manufacturing half of the capsule is immersed in this solution, slowly pulled up to form a viscous liquid film around the pin, and then thoroughly dried. After that, the molded body was removed from the pin and subjected to necessary processing to obtain a capsule. This capsule was transparent, flexible, and strong. The capsules thus obtained are filled with lactose powder,
The mating area between the cap and the body was sealed with a viscous solution prepared in this test. When this filled capsule was examined for solubility in the first and second liquids using a disintegration tester based on the Ninth Edition Japanese Pharmacopoeia, the results were as follows. Solubility in the first liquid: Does not dissolve for more than 2 hours Solubility in the second liquid: Dissolves in 15 to 20 minutes Content release coating test 3 Sample No. 3 was added to acetone to a concentration of 10% by weight. An enteric coating was obtained under the same operating conditions as in Example 1. When this coated tablet was tested according to the disintegration test method for enteric-coated preparations according to the Ninth Edition Japanese Pharmacopoeia,
The results were as follows. Disintegration in the first liquid: No change for over 2 hours Disintegration in the second liquid: Disintegrated in 11 to 12 minutes (Disintegration time of the bare tablet was 9 to 10 minutes).

[Brief explanation of drawings]

The drawing shows the infrared absorption spectrum of sample No. 2 shown in Table 1 of Examples.

Claims (1)

[Claims] 1 The average number of substitutions of acidic succinoyl groups and acidic phthaloyl groups per glucose unit of the cellulose ether substituted with an alkyl group having 1 to 3 carbon atoms and/or a hydroxyalkyl group having 2 to 4 carbon atoms is 0.1 to 0.1, respectively. 2.0, an acidic succinoyl and acidic phthaloyl mixed ester with a weight average molecular weight of 10,000 to 300,000.