JP5644167B2 - Solid preparation containing ketotifen or its salt with improved dissolution - Google Patents

Description

  The present invention relates to a solid preparation containing ketotifen or a salt thereof, and more particularly to an improvement in dissolution of ketotifen or a salt thereof from the solid preparation.

  When a pharmaceutical product is produced as a solid preparation, rapid dissolution of the active ingredient from the solid preparation is required. In general, the disintegration of the solid preparation and the elution of the active ingredient are in a correlation, and therefore, the dissolution of the active ingredient is accelerated by adding a disintegrant to accelerate the disintegration of the solid preparation. According to the Japanese Pharmacopoeia, for example, in the case of an uncoated tablet, the disintegration time is considered to be within 30 minutes, and it is necessary to add a disintegrant to achieve this value. Often becomes.

  On the other hand, ketotifen is an antiallergic agent having an antihistaminic action, an anti-inflammatory action, etc., but ketotifen fumarate is known to adsorb to croscarmellose sodium, which is a typical disintegrant ( Non-patent document 1). However, it is desired to provide a solid preparation containing ketotifen or a salt thereof.

International J. of Pharmaceutics, 149 (1997) 115-121

  When the present inventors manufactured a tablet containing ketotifen fumarate without using a disintegrant such as croscarmellose sodium, the disintegration time exceeded 60 minutes, which complies with the Japanese Pharmacopoeia standards. It wasn't something to do. On the other hand, when disintegrants such as croscarmellose sodium are added, the disintegration time is shortened, but the dissolution of ketotifen fumarate deteriorates. Couldn't get.

  Therefore, an object of the present invention is to provide a solid preparation containing ketotifen or a salt thereof having good disintegration and dissolution properties.

  As a result of various studies, the present inventors have found that the dissolution of ketotifen or a salt thereof can be improved by adding an organic acid or a salt thereof to a solid preparation containing ketotifen or a salt thereof and a disintegrant. The headline and the present invention were completed.

That is, the present invention
(1) A solid preparation comprising a) ketotifen or a salt thereof, b) a disintegrant, and c) an organic acid or a salt thereof.
(2) The solid preparation according to (1), wherein the disintegrant is croscarmellose sodium, crospovidone, or low-substituted hydroxypropylcellulose.
(3) The solid preparation according to (1), wherein the organic acid is citric acid, malic acid, tartaric acid, ascorbic acid, or succinic acid.
(4) The solid preparation according to (1), wherein the salt of ketotifen is ketotifen fumarate.
(5) The solid preparation according to (1), comprising ketotifen fumarate, croscarmellose sodium, and citric acid.
(6) The solid preparation according to any one of (1) to (5), which is a tablet.
(7) When producing a solid preparation containing a) ketotifen or a salt thereof, and b) a disintegrant, c) an organic acid or a salt thereof is blended, and ketotifen from the solid preparation is characterized. Or a method for improving the elution of the salt thereof.

  According to the present invention, it is possible to ensure sufficient dissolution of ketotifen or a salt thereof while maintaining the disintegration property of a solid preparation containing ketotifen or a salt thereof.

It is the graph which showed the elution rate of ketotifen fumarate, and the elution liquid collection time (min) was shown for the average elution rate (%) on the vertical axis | shaft.

  As ketotifen or a salt thereof used in the present invention, those commercially available can be used, and ketotifen fumarate is preferably used. The blending amount of ketotifen or a salt thereof varies depending on the blending purpose. Generally, about 2 mg per day is required as ketotifen, so the blending ratio in the solid preparation may be adjusted according to the type of solid preparation and the number of administrations.

  The disintegrant is a component that promotes rapid disintegration of the solid preparation after internal use. Examples of the disintegrant used in the present invention include croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, carboxymethyl starch sodium. , Carmellose, carmellose calcium and the like. Of these, croscarmellose sodium, crospovidone, and low-substituted hydroxypropylcellulose are preferred. The blending amount is generally 0.5 to 50% by mass with respect to the entire solid preparation, but taking into account the type of solid preparation, the disintegration required for the solid preparation, other compounding ingredients, etc. The trader can make an appropriate decision.

  A commercially available product can be used as the disintegrant, and examples of croscarmellose sodium include Ac-di-sol (trade name, Asahi Kasei Chemicals). Examples of crospovidone include Kollidon CL (trade name, BASF Japan), and examples of low-substituted hydroxypropylcellulose include L-HPC (trade name, Shin-Etsu Chemical Co., Ltd.).

  The organic acid means an acidic substance having a carbon atom, and examples thereof include citric acid, malic acid, tartaric acid, ascorbic acid, succinic acid, fumaric acid, and acetic acid. Preferred organic acids are citric acid, malic acid, tartaric acid, ascorbic acid, and succinic acid, with citric acid being more preferred. The blending amount is generally 1 to 10% by mass with respect to the whole solid preparation, and 5 to 10% by mass is preferable from the viewpoint of elution of ketotifen or a salt thereof.

  Examples of the salt of an organic acid include a salt of an organic acid and an alkali metal or alkaline earth metal. A sodium salt of an organic acid is preferable. As the blending amount, it is preferable to add 5% or more based on the whole solid preparation, and it is preferable to add more than the amount added as a free organic acid in order to ensure sufficient dissolution.

  In the present invention, the dissolution property of ketotifen or a salt thereof from a solid preparation is deteriorated by adding a disintegrant, but the dissolution property is improved by adding an organic acid or a salt thereof. Therefore, if the amount of the disintegrant is increased, the required amount of the organic acid or its salt is also increased. From this viewpoint, in the present invention, it is preferable to blend 0.2 parts by mass or more of an organic acid or a salt thereof with respect to 1 part by mass of the disintegrant.

  The solid preparation of the present invention contains a) ketotifen or a salt thereof, b) a disintegrant, and c) an organic acid or a salt thereof, and if necessary, other known additives such as excipients, Granules, powders, tablets, dry syrups, etc. that can be produced by conventional methods using binders, lubricants, antioxidants, coating agents, coloring agents, flavoring agents, surfactants, plasticizers, etc. Also included are capsules obtained by capsule filling. When the present invention is used, both the disintegration property of the solid preparation and the dissolution property of ketotifen or a salt thereof can be improved, so that the present invention is particularly effective when producing tablets. However, by using the present invention for other solid preparations, further improvement in disintegration and dissolution can be achieved, so that the present invention is not prevented from being used for other solid preparations other than tablets.

  Tablets can be produced by known methods. For example, a direct compression method in which the ingredients to be blended are mixed and compressed as it is, or a granulated product of the ingredients to be blended is produced and then the granulated product is tableted. Is mentioned. Examples of the method for producing the granulated product include wet granulation methods such as fluidized bed granulation, kneading granulation, and stirring granulation, and dry granulation methods.

  In the present invention, “improvement of dissolution of ketotifen or a salt thereof from a solid preparation” means that the dissolution of ketotifen or a salt thereof from a solid preparation is accelerated, and / or ketotifen or a salt thereof dissolved from a solid preparation after a certain period of time. Means increasing the amount.

Hereinafter, the present invention will be described in more detail with reference to examples and test examples.
Example 1
2.76 g of ketotifen fumarate, 565 g of lactose, 566.2 g of crystalline cellulose, 60 g of hydroxypropyl cellulose and 6 g of magnesium stearate were mixed, passed through a sieve, and further 60 g of croscarmellose sodium and 66 g of citric acid were added and mixed. . Using a hydraulic manual pump type tableting machine (HAND TAB-200, Ichihashi Seiki Co., Ltd.), the compression pressure was 15 kN, and tableting was performed at 331.5 mg per tablet to obtain tablets with a diameter of 9.0 mm. Table 1 shows the formulation of this tablet. The citric acid content in the tablet of Example 1 is 5.0% by mass.

Comparative Examples 1-2
A formulation excluding citric acid and croscarmellose sodium from Example 1 and a formulation excluding only citric acid were produced in the same manner as in Example 1 with the weight of one tablet shown in Table 1, and a tablet with a diameter of 9.0 mm was prepared. Obtained.

Test example 1
The tablets obtained in Example 1 and Comparative Examples 1 and 2 were subjected to disintegration time measurement and ketotifen fumarate dissolution test. The disintegration time was measured using a disintegration tester (Toyama Sangyo Co., Ltd.) based on the disintegration test method of the 15th revision Japanese Pharmacopoeia using 37 ° C./900 mL of purified water. The dissolution test was performed at a rotation speed of 75 rpm using 37 ° C / 900 mL of purified water based on the 15th revision Japanese Pharmacopoeia dissolution test method paddle method. The results are shown in Table 1 and FIG.

In Comparative Example 1 containing no disintegrant, the tablet did not disintegrate even after 60 minutes. Further, the dissolution of ketotifen fumarate was slow, and the dissolution rate showed a gentle curve as shown in FIG.
On the other hand, in Comparative Example 2 in which croscarmellose sodium was added as a disintegrant, the disintegration time was shortened to 3 minutes, but the result was that ketotifen fumarate elution remained at 24%.
On the other hand, in Example 1 of the present invention in which croscarmellose sodium and citric acid were blended, a tablet capable of rapid disintegration and rapid dissolution of ketotifen fumarate could be produced.

Examples 2-4
Tablets were obtained in the same manner as in Example 1 with the formulation in which the amount of citric acid in Example 1 was changed to 1.0, 2.0, and 10.0% by mass. Table 2 shows the formulation and the weight of one tablet.

Test example 2
Tests were performed on Examples 2 to 4 in the same manner as in Test Example 1. The results are shown in Table 2.

  As is clear from the results in Table 2, the dissolution rate was improved when the citric acid content was 1.0, 2.0, or 10.0% by mass.

Examples 5-9
Tablets were obtained in the same manner as in Example 1, except that the citric acid in Example 1 was replaced with an organic acid other than citric acid or a salt thereof. Table 3 shows the formulation and the weight of one tablet.

Test example 3
Tests were performed on Examples 5 to 9 in the same manner as in Test Example 1. The results are shown in Table 3.

  As is clear from the results in Table 3, the elution rate was improved even when the organic acid other than citric acid or its salt was replaced.

Examples 10-11
Tablets were obtained in the same manner as in Example 1, except that croscarmellose sodium in Example 1 was replaced with crospovidone or low-substituted hydroxypropylcellulose. The formulation and the weight of one tablet are shown in Table 4.

Comparative Examples 3-4
Tablets were obtained in the same manner as in Example 1 except that citric acid was removed from Examples 10-11. The formulation and the weight of one tablet are shown in Table 4.

Test example 4
Tests were performed on Examples 10 to 11 and Comparative Examples 3 to 4 in the same manner as Test Example 1. The results are shown in Table 4.

  From the results in Table 4, 60 minutes compared with Comparative Example 1 in which crospovidone or low-substituted hydroxypropylcellulose was used as a disintegrant other than croscarmellose sodium, compared to Comparative Example 1 in which no disintegrant was blended. It was found that the elution rate of ketotifen fumarate later decreased. On the other hand, in Examples 10 and 11 in which citric acid was added to Comparative Examples 3 and 4, the elution rate of ketotifen fumarate was improved.

  The present invention can be used for producing a solid preparation containing ketotifen or a salt thereof.

Claims (6)

A solid preparation comprising a) ketotifen or a salt thereof, b) croscarmellose sodium, crospovidone, or low-substituted hydroxypropylcellulose, and c) an organic acid or a salt thereof. The solid preparation according to claim 1, wherein the organic acid is citric acid, malic acid, tartaric acid, ascorbic acid, or succinic acid. The solid preparation according to claim 1, wherein the salt of ketotifen is ketotifen fumarate. The solid preparation according to claim 1, comprising ketotifen fumarate, croscarmellose sodium, and citric acid. It is a tablet, The solid formulation of any one of Claims 1-4. When a solid preparation containing a) ketotifen or a salt thereof, and b) croscarmellose sodium, crospovidone, or low-substituted hydroxypropylcellulose is produced, c) an organic acid or a salt thereof is added. A method for producing a solid preparation, wherein the dissolution property of ketotifen or a salt thereof from the solid preparation is improved .

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