JP2879905B2 - Composition for oral administration containing ibuprofen - Google Patents

Description

The present invention relates to a composition for oral administration containing ibuprofen widely used as an antipyretic analgesic. In particular, the present invention relates to an orally administered composition that masks the unpleasant taste and mucosal irritation of ibuprofen and is easy to take.

(B) Conventional technology and problems to be solved It is known that ibuprofen and its salt such as its sodium salt have an unpleasant taste and mucosal irritation. As an attempt to remedy such a defect, a composition containing aluminum hydroxide has been proposed (JP-A-63-1).
01321). However, this is applicable to the production of suspensions and tablets, and is not applied to fine granules or granules.

As a technique for masking a drug having an unpleasant taste, a method of kneading a polymer compound or a lipid (Japanese Patent Application Laid-Open No. 64-31721) and a method of encapsulating in a microcapsule (US Pat. No. 3,922,379) It has been known. Further, a method of coating droplets of a solution or suspension of a drug with particles of a gastrosoluble polymer compound is known (JP-A-63-277616).
issue). These latter methods require special equipment compared to the method of compounding aluminum hydroxide,
The operation is complicated, the yield is poor, and there are various problems.

Therefore, it has been desired that ibuprofen or a salt thereof can be masked by a simple method to provide fine granules or granules.

(C) Means for Solving the Problems According to the present invention, ibuprofen or a pharmaceutically acceptable salt thereof as an active ingredient, gastric solubility in an amount sufficient to mask the unpleasant taste and irritation of the active ingredient Provided are an ibuprofen-containing composition for oral administration obtained by kneading and granulating a polymer compound, a disintegrant, and optionally a pharmaceutically acceptable excipient or carrier, and a method for producing the same.

Pharmaceutically acceptable salts of ibuprofen of the present invention include, but are not limited to, the sodium salts that exhibit an unpleasant taste.

The gastric-soluble polymer compound used in the present invention refers to a polymer compound having a property of dissolving in gastric juice. Various kinds of such polymer compounds are known in the art mainly as coating agents, and any of them can be used. For example, polyvinyl acetal diethylaminoacetate (Japanese Patent Publication No. 40-3786), copolymer of alkyl methacrylate and dialkylaminoalkyl methacrylate (US Pat. No. 3,070,509), copolymer of alkylvinylpyridine with other monomers (Japanese Patent Publication No. 40-786) 2055
And JP-B-37-12936, JP-B-37-12936), and cellulose acetate N, N-di-n-butylhydroxyether (JP-B-40-26358). Among them, polyvinyl acetal diethylaminoacetate (available as AEA “Sankyo” from Sankyo Co., Ltd.) or ethyl acrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer (Eudragit E) is preferred.

The composition of the present invention preferably contains a disintegrant. Since disintegrants affect the release of active ingredients and granulation properties, it is desirable to select and use those that have a favorable effect. From such a viewpoint, it has been found that it is preferable to use low-substituted hydroxypropylcellulose (for example, those having grades of LH-11, 20, 21, 22, 23, and 31). In particular, the degree of substitution with a hydroxypropyl group in cellulose is about 10.0 to 13.0% (particularly, the grade is LH-31
Are preferred.

On the other hand, pharmaceutically acceptable excipients or carriers can be added. Such excipients or carriers are preferably solid and non-acidic. For example, lactose is most preferably used (the amount used is 150 mg ibuprofen)
Is usually 30 to 150 mg, preferably 37 to 43 mg). However, there is no particular limitation.

The composition of the present invention may contain a flavoring agent, a flavoring agent, a coloring agent, and the like in addition to the above essential components and optional components. As another optional ingredient, the addition of sorbitol will provide a refreshing sensation upon oral administration.

The content of the active ingredient ibuprofen or a pharmaceutically acceptable salt thereof in the composition of the present invention is 1 to 90% by weight,
Preferably it is 5 to 70% by weight. The gastric-soluble polymer compound is used in an amount sufficient to mask the unpleasant taste and mucosal irritation of the active ingredient. According to experiments performed by the inventors of the present invention, generally, 1 to 2 parts
It has been found that the addition of 0 parts by weight, preferably 3 to 10 parts by weight is effective. The disintegrant can be used generally in an amount of 2 to 50 parts by weight, preferably 20 to 40 parts by weight, based on 100 parts by weight of the active ingredient. In addition, the excipient or carrier can be used in an amount sufficient to adjust the content of the active ingredient in the presence of a gastrosoluble polymer compound, an optional disintegrant, and the like.

The composition of the present invention can be easily obtained by simply kneading the active ingredient, the gastric-soluble polymer compound and other optional ingredients according to a conventional method, granulating and, if necessary, drying. Therefore, there is no need to perform complicated processing such as film coating or microcapsule as in the conventional method.

In the above method, the active ingredient is preferably used as a powder having an average particle size of 50 μm or less. Other optional ingredients may be used as a powder with a small average particle size similar to the active ingredient. The gastric-soluble polymer compound is preferably used as a solution in which a lower alcohol (for example, ethanol), acetone, or a mixture thereof and water is used as a solvent for uniform blending. When used as a solution, drying is required after granulation. Granulation can be performed by a method known per se in order to obtain predetermined particles as fine granules and granules. The obtained fine granules and granules can be used as they are as oral administration agents. However, they can also be made into tablets, capsules and the like. The ibuprofen-containing preparation for oral administration thus obtained can be used in the same manner as a conventional oral preparation of ibuprofen.

(D) Action According to the present invention, the unique taste and mucous membrane irritation possessed by ibuprofen are masked by simple blending of a gastrosoluble polymer compound without using a coating method, and are easy to take. The present invention provides fine granules or granules having the same, and can be produced efficiently on an industrial basis.

(E) Examples Hereinafter, the present invention will be described specifically with reference to Examples and Test Examples.

Example-1 6,000 g of ibuprofen having an average particle diameter of 50 μ or less and lactose 1
750g and low-substituted hydroxypropylcellulose (hereinafter
L-HPC), grade LH-31, 2,000 g were uniformly mixed with a mixer. Next, the mixture was put into a kneading machine, a solution of 250 g of polyvinyl acetal diethylaminoacetate (hereinafter, AEA) uniformly dissolved in 1,800 g of ethanol was poured, kneaded for about 3 minutes, and then granulated by passing through a # 20 mesh. . The granulated product was blow-dried for 1 hour and then dried at 40 ° C. for 4 hours. The dried product was classified using a # 32 sieve to obtain 9,724 g of fine granules and standard-compliant products.

Example-2 Ibuprofen 60.0% by weight Lactose 17.5% by weight L-HPC 20.0% by weight AEA 2.5% by weight The above-mentioned composition other than AEA was mixed uniformly, and 7.
Five times the amount of ethanol was added, and the mixture was kneaded using a uniformly dissolved AEA ethanol solution, and then granulated by a basket-type extrusion granulator having a diameter of 0.8 mm. Further, the extruded granules were blow-dried for 1 hour and then dried at 40 ° C. for 4 hours.
The dried product was classified with a # 42 sieve to obtain granules.

Example-3 To 2,500 g of the fine granules obtained in Example 1, 7,500 g of sorbitol separately granulated was added and mixed to prepare a fine granule containing 150 mg of ibuprofen in 1 g.

Example-4 7,500 g of sorbitol granulated separately into granules was mixed with 2,500 g of the granules obtained in Example 2, and 1 g of ibuprofen was added.
It was adjusted to a granule containing 150 mg.

Control Example The same operation was carried out using hydroxypropylcellulose instead of AEA used in Example 1 to obtain a fine granule. In addition, sorbitol 7,50 separately granulated in 2,500 g of fine granules
0 g was added and mixed to obtain fine granules containing 180 mg of ibuprofen in 1 g.

Test Example-1 The fine granules obtained in Example-3 of the present invention, the granules obtained in Example-4, and the fine granules obtained in the control example were 150 mg each as ibuprofen for 10 healthy adult men. A considerable amount was taken and a unique taste and mucosal irritation evaluation test was performed. The evaluation was made at two points: immediately after taking and 10 minutes after taking.
In the evaluation, the degree of specific taste and mucosal irritation was unbearable, but there were specific taste and mucosal irritation. Has a unique taste and mucosal irritation that can be tolerated. No peculiar taste or mucous membrane irritation. And above three points.

 The results are shown in Table 1.

From the results shown in Table 1, it is clear that the oral preparation of the present invention has almost no peculiar unpleasant taste and irritation to mucous membrane of ibuprofen and is extremely easy to take as compared with the conventional preparation.

Test Example-2 Eve (SS Pharmaceutical Co., Ltd.) was used as the fine granule and the control preparation of Example 3 of the present invention 150 m each as ibuprofen.
g equivalent was administered to 12 subjects, and the blood concentrations of both preparations were measured. Table 2 shows the parameters related to the bioavailability, and Figure 1 shows the changes in blood concentration.

[Brief description of the drawings]

FIG. 1 is a graph showing the time course of the mean blood concentration of ibuprofen of a composition according to the present invention (Example-3) and a control preparation.

──────────────────────────────────────────────────続 き Continuation of front page (56) References JP-A-63-277616 (JP, A) JP-A-64-13033 (JP, A) JP-A-63-258809 (JP, A) JP-A-54-107515 (JP, A) JP-A-49-133513 (JP, A) JP-A-49-101521 (JP, A) JP-A-49-94821 (JP, A) JP-A-49-81526 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 31 / 19,9 / 16 A61K 47 / 32,37 / 38 CA (STN)

Claims (11)

(57) [Claims] 1. Ibuprofen or a pharmaceutically acceptable salt thereof as an active ingredient, a gastric-soluble polymer compound in an amount sufficient to mask the unpleasant taste and irritation of the active ingredient, a disintegrant, and optionally a pharmaceutical. An ibuprofen-containing composition for oral administration obtained by kneading and granulating a chemically acceptable excipient or carrier. 2. The composition according to claim 1, wherein the gastric-soluble polymer compound is polyvinyl acetal diethylaminoacetate or a copolymer of methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate. 3. The composition according to claim 1, wherein the disintegrant is low-substituted hydroxypropylcellulose. 4. The composition according to claim 1, wherein the ratio of the active ingredient, the disintegrant and the gastrosoluble polymer compound is 100: 2 to 50: 1 to 20 parts by weight. 5. The composition according to claim 1, wherein the active ingredient or a salt thereof is a powder having an average particle size of 50 μ or less. 6. The composition according to claim 1, which is in the form of fine granules or granules. 7. An active ingredient containing ibuprofen or a pharmaceutically acceptable salt thereof, polyvinyl acetal diethylaminoacetate and low-substituted hydroxypropylcellulose, and optionally a pharmaceutically acceptable excipient or carrier. A composition for oral administration containing ibuprofen obtained by granulation. 8. The composition according to claim 7, wherein the ratio of the active ingredient, polyvinyl acetal diethylaminoacetate and low-substituted hydroxypropylcellulose is from 100: 3 to 10:20 to 40 parts by weight. 9. The composition according to claim 7, wherein the proportion of the active ingredient, polyvinyl acetal diethylaminoacetate and low-substituted hydroxypropylcellulose is 24: 1: 8 parts by weight. 10. A solution of a gastric-soluble polymer compound is added to a mixture of ibuprofen or a pharmaceutically acceptable salt thereof, a disintegrant and a pharmaceutically acceptable excipient or carrier, and the mixture is kneaded, granulated, A method for producing an ibuprofen-containing composition for oral administration comprising drying. 11. A solution of polyvinyl acetal diethylaminoacetate in a mixture of ibuprofen or a pharmaceutically acceptable salt thereof, low-substituted hydroxypropylcellulose and a pharmaceutically acceptable excipient or carrier, and kneading, A method for producing an ibuprofen-containing composition for oral administration, comprising granulating and drying.