JPH10152439A - Ketotifen fumarate-containing medicinal composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition useful for treatment of bronchial asthma and allergic rhinitis, etc., by including ketotifen fumarate and glycyrrhizic acid or its salt. SOLUTION: This medicinal composition is obtained by mixing 1 pts.wt. 4,9-dihydro-4-(1-methyl-4piperidinylidene)-1-OHbenzo[4,5]-cyclopenta[1 ,22- b]thiophen-10-one-fumarate with 0.1-30 pts.wt. 20β-carboxyl-11-oxo-30norolean-12- ene3β-yl 2-0-β-D-glucopyran-uronosylα-D-glucopyranosiduronic acid. The composition is remarkably improved in stability of keotifen fumarate to various pharmaceutical auxiliary (usually 30-500 pts.wt. of e.g. mannitol).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a pharmaceutical composition having improved storage stability of ketotifen fumarate.

[0002]

BACKGROUND OF THE INVENTION AND PRIOR ART Ketotifen fumarate is
It is a medicine having an antihistamine action, an anti-anaphylaxis action and the like, and is widely used as a therapeutic agent for bronchial asthma, allergic rhinitis, eczema, dermatitis, urticaria and the like. On the other hand, in the case of administering a drug, studies on a dosage form for improving the taste and prolonging the action time to reduce the burden on the patient have been studied.

[0003]

[0007] Ketotifen fumarate interacts with many formulation aids, excipients, additives, etc., and causes coloration, decomposition, etc., so that it is difficult to formulate it.
The present inventor has conducted intensive studies to solve this problem,
The inventors have found that the problems can be solved by the following means, and have completed the present invention.

[0004]

SUMMARY OF THE INVENTION The present invention is a pharmaceutical composition containing ketotifen fumarate and glycyrrhizic acid or a salt thereof. According to the present invention, the stability of ketotifen fumarate to various formulation aids is improved. Therefore, the present invention is also a pharmaceutical composition containing ketotifen fumarate, a formulation aid and glycyrrhizic acid or a salt thereof, and further contains ketotifen fumarate, a formulation aid and glycyrrhizic acid or a salt thereof. It is a pharmaceutical composition in which ketotifen fumarate is stabilized.

In the present invention, ketotifen fumarate is defined as 4,9-dihydro-4- (1-methyl-4-piperidinylidene) -1
0H-benzo [4,5] cyclopenta [1,2-b] -thiophen-10-one fumarate, and glycyrrhizic acid is 20β-carboxyl-11-oxo-30-norolean-12-ene-3β-
Il-2-O-β-D-glucopyran uronosyl-α-D-glucopyranoside uronic acid, and salts of glycyrrhizic acid are dipotassium glycyrrhizinate, diammonium glycyrrhizinate, disodium glycyrrhizinate and the like. is there.

In the present invention, the ratio of ketotifen fumarate to glycyrrhizic acid is usually 0.1 to 30 parts by weight of glycyrrhizic acid or a salt thereof per 1 part by weight of ketotifen fumarate, and preferably 1 to 30 parts by weight of ketotifen fumarate. Glycyrrhizic acid or a salt thereof is 1 to 20 parts by weight, more preferably 3 to 11 parts by weight, based on parts by weight. The ratio of ketotifen fumarate to the formulation aid is 30 to 500 parts by weight, preferably 50 to 300 parts by weight, more preferably 60 to 200 parts by weight, based on 1 part by weight of ketotifen fumarate. Parts by weight. In other words, when the dose of ketotifen fumarate in a single administration is 1 mg, glycyrrhizic acid or a salt thereof is 0.1 to 30 mg, and the other is a formulation aid.
A dose of 100 mg to 300 mg is administered as tablets, capsules or granules.

[0007] Glycyrrhizic acid or a salt thereof has an antiallergic effect and is used as a therapeutic agent for allergic conjunctivitis and the like. In the present invention, it acts as a stabilizer for ketotifen fumarate. The method for producing the pharmaceutical composition according to the present invention is not particularly limited, and it can be produced by a usual method by mixing ketotifen fumarate, a formulation aid and glycyrrhizic acid or a salt thereof. For example, 1 g of ketotifen fumarate and 5 g of dipotassium glycyrrhizinate are mixed, and 260 g of mannitol is further added as a formulation aid, and while mixing, a solution obtained by dissolving 3 g of polyvinylpyrrolidone in ethanol is gradually added and granulated. After drying, 1 g of calcium stearate is mixed and tableted to produce a tablet.

[0008]

According to the pharmaceutical composition of the present invention,
The stability of ketotifen fumarate when formulated with a formulation aid is significantly improved. Next, experimental examples will be given to show the effects of the composition according to the present invention.

Experimental Example 1 Ketotifen fumarate 138 m
g, 28 mg to 500 mg of various formulation aids, 1 g of dipotassium glycyrrhizinate, and 28 g of mannitol were mixed and stored for one month under the conditions of 55 ° C. and 40 ° C. and 75% humidity, and changes before and after storage were observed. The results are shown in Table 1.
As is clear from Table 1, ketotifen fumarate reacts with many formulation aids, and the mixture is colored yellow. However, by adding dipotassium glycyrrhizinate, no coloration is observed or recognized. Was also mild.

[0010]

[Table 1] In the table,-means not colored, ± means slightly yellow, + means yellow, ++ means yellow to yellow-orange, and +++ means marked yellow-orange. The control is a mixture of ketotifen fumarate and mannitol.

EXPERIMENTAL EXAMPLE 2 Tablets obtained in Comparative Example 1 and Examples 1 to 3 shown below were used at 55.degree.
It was stored for one month under the condition of%. As a result, while the tablets obtained by the control example were colored yellow, Examples 1 to
No color was observed in the tablets obtained in No. 3.

[0012]

【Example】

Example 1 0.69 g of ketotifen fumarate, 2.5 g of dipotassium glycyrrhizinate, 100 g of mannitol and 35.4 g of crystalline cellulose were mixed, granulated while adding 1.4 g of polyvinylpyrrolidone dissolved in an appropriate amount of water, and dried, after drying, 0.7 g of calcium stearate And tableting, the average weight of one tablet is 280
mg tablets were produced. Example 2 Using 0.69 g of ketotifen fumarate, 5 g of dipotassium glycyrrhizinate, 100 g of mannitol, 32.9 g of crystalline cellulose, 1.4 g of polyvinylpyrrolidone and 0.7 g of calcium stearate, the average weight of one tablet was 280 mg in the same manner as in Example 1. Tablets were manufactured. Example 3 Using 1.38 g of ketotifen fumarate, 15 g of dipotassium glycyrrhizinate, 200 g of mannitol, 59.4 g of crystalline cellulose, 2.8 g of polyvinylpyrrolidone, and 1.4 g of calcium stearate, the average weight of one tablet was 280 mg in the same manner as in Example 1. Tablets were manufactured.

Example 4 Ketotifen fumarate 2.76 g,
173.2 g mannitol, 20 g dipotassium glycyrrhizinate
Was charged into a fluidized-bed granulator, and sprayed with purified water containing 20 g of hydroxypropylcellulose to prepare granules. Example 5 Ketotifen fumarate 0.138 g, lactose 9.3 g, corn starch 4.5 g, dipotassium glycyrrhizinate 1 g were granulated with purified water containing polyvinyl pyrrolidone 0.61 g, dried, mixed with calcium stearate 0.03 g, and then tableted. 1
Tablets An average of 150 mg tablets were produced.

Example 6 Ketotifen fumarate 3.45 g,
Using 37.5 g of dipotassium glycyrrhizinate, 600 g of lactose, 59 g of crystalline cellulose, 6 g of methylcellulose and 3 g of calcium stearate, a tablet having an average weight of one tablet of 280 mg was produced in the same manner as in Example 1. Comparative Example 1 Ketotifen fumarate 0.69 g, mannitol
A tablet having an average weight of one tablet of 280 mg was produced in the same manner as in Example 1 using 137.9 g, polyvinylpyrrolidone 1.4 g and calcium stearate 0.7 g.

Claims (5)

[Claims] 1. A pharmaceutical composition comprising ketotifen fumarate and glycyrrhizic acid or a salt thereof. 2. The pharmaceutical composition according to claim 1, wherein 1 part by weight of ketotifen fumarate and 0.1 to 30 parts by weight of glycyrrhizic acid or a salt thereof are contained. 3. A pharmaceutical composition comprising ketotifen fumarate, a formulation aid and glycyrrhizic acid or a salt thereof. 4. The pharmaceutical composition according to claim 1, wherein the glycyrrhizic acid or a salt thereof is glycyrrhizic acid, dipotassium glycyrrhizinate, diammonium glycyrrhizinate, or disodium glycyrrhizinate. 5. A pharmaceutical composition comprising ketotifen fumarate stabilized, comprising ketotifen fumarate, a formulation aid and glycyrrhizic acid or a salt thereof.