JPH11209305A - Mequitazine combination solid preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a mequitazine combination solid preparation for internal use which can prevent biological usability of mequitazine in stomach from decreasing. SOLUTION: This mequitazine combination solid preparation for internal use includes at least one kind selected from hydroquinone, dibutyl hydroxytoluene, butyl hydroxyanisole, gallic acid or its salt or ester, tocopherol or its ester, benzoic acid or its salt, inositol, salicylic acid or its salt or ester, p-hydroxybenzoic acid ester, sulfite, hydrogensulfite, pyrosulfite, lecithin, ascorbic acid or its salt or ester and erythorbic acid or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an oral solid preparation containing an antihistamine drug mequitazine.

[0002]

2. Description of the Related Art Mequitazine is an antihistamine having a phenothiazine skeleton and has been applied to urticaria, pruritus associated with skin diseases, allergic rhinitis and the like. However, since mequitazine is easily decomposed in a low pH aqueous solution, its stability in the stomach is very poor, and bioavailability may be impaired. In particular, an oral solid preparation is considered to be more susceptible to the effects of stomach acid, since it has a longer residence time in the stomach and usually does not have a buffering capacity as compared to an oral liquid preparation. For this reason, in developing a solid oral preparation containing mequitazine, prevention of a decrease in the bioavailability of mequitazine was an important issue.

[0003]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a solid oral preparation containing mequitazine, in which a decrease in bioavailability of mequitazine in the stomach is prevented.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies on the formulation of components that prevent a decrease in the bioavailability of mequitazine, and as a result, have found that an oral solid preparation containing mequitazine as an active ingredient. In addition, it has been found that the incorporation of a specific stabilizer enhances the stability of mequitazine in the stomach, so that a decrease in bioavailability can be prevented, and the present invention has been completed.

That is, the present invention relates to hydroquinone, dibutylhydroxytoluene, butylhydroxyanisole, gallic acid or a salt or ester thereof, tocopherol or an ester thereof, benzoic acid or a salt thereof, inositol,
Salicylic acid or a salt or ester thereof, paraoxybenzoate, sulfite, bisulfite, pyrosulfite, lecithin, ascorbic acid or a salt or ester thereof and erythorbic acid or a salt thereof, This is an internal solid preparation containing mequitazine.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Among the additives used in the present invention to improve the stability of mequitazine in the stomach (hereinafter referred to as "mequitazine stabilizer"), gallate is pharmaceutically acceptable. The salt is not particularly limited as long as it is a salt with an alkali metal salt such as potassium or sodium. Examples of gallic esters include C _1-5 alkyl esters such as propyl esters, preferably propyl gallate.

As tocopherol, for example, dl-α
-Tocopherol, natural vitamin E (d-form). Examples of the tocopherol ester include tocopherol acetate. The benzoate is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include a sodium salt. The salicylate is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include a sodium salt. Examples of the salicylate include aromatic esters such as C _1-5 alkyl esters and phenyl esters, and preferably phenyl salicylate.

Examples of the paraoxybenzoate include C _1-5 alkyl esters such as methyl ester, ethyl ester, propyl ester and butyl ester, aromatic esters and aralkyl esters. The sulfite is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include a sodium salt. The bisulfite is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include a sodium salt. The pyrosulfite is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include a sodium salt.

Examples of lecithin (phosphatidylcholine) include soybean lecithin and purified soybean lecithin. Ascorbate is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include a sodium salt and a calcium salt. Ascorbic acid esters include:
For example, fatty acid esters such as ascorbic acid stearate and the like can be mentioned. Erythorbate is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include a sodium salt. As the mequitazine stabilizer, hydroquinone, in particular, from the viewpoint of the mequitazine stabilizing effect,
Dibutylhydroxytoluene, propyl gallate and tocopherol are preferred. The mequitazine stabilizer,
They may be used alone or in combination of two or more.

[0010] The content of mequitazine in the solid preparation containing mequitazine of the present invention is not particularly limited, and the compounding amount per adult daily dosage unit is usually 1 to 4 mg. The amount of the mequitazine stabilizer to be added to mequitazine varies depending on the type thereof. The effective and particularly preferred amounts of the mequitazine stabilizer to 1 mg of mequitazine are as shown in Table 1.

[0011]

[Table 1]

The mequitazine-containing internal solid preparation of the present invention comprises:
It can be formulated into various solid dosage forms such as tablets, capsules, granules, fine granules, powders, chewables, drops and dissolving agents in the mouth. These preparations can be prepared according to a conventional method according to each dosage form except that the above-mentioned mequitazine stabilizer is added. Carriers used in the preparation of formulations include lactose, starch, sugar, mannitol,
There are excipients such as crystalline cellulose, disintegrants such as hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, PVP, and lubricating agents such as magnesium stearate, hydrogenated castor oil and talc. And flavoring agents can be used.

[0013] The solid preparation containing mequitazine of the present invention may contain, if necessary, besides mequitazine, acetaminophen, ibuprofen, clofezone, phenylbutazone, alclofenac, flurbiprofen, bucolome, ketoprofen, tiaprofenic acid and the like. Antipyretic analgesic and anti-inflammatory agents; antitussives such as dihydrocodeine phosphate, dextromethorphan hydrobromide, noscapine, guaifenesin; antihistamines such as chlorpheniramine maleate; bronchodilators such as dl-methylephedrine hydrochloride;
Inflammatory enzyme agents such as lysozyme chloride; bromhexine hydrochloride,
An expectorant such as potassium guaiacol sulfonate; a drug such as a central nervous system stimulant such as anhydrous caffeine can be appropriately compounded.

[0014]

The present invention will be described below in more detail with reference to examples and test examples, which do not limit the scope of the present invention. (Example 1) (Formulation) Dihydrocodeine phosphate 24 g dl-methylephedrine hydrochloride 60 g Mequitadine 4 g Guaifenesin 250 g Hydroquinone 3 g Lactose 300 g Microcrystalline cellulose 239 g Magnesium stearate 10 g Hardened castor oil 10 g The above components and amounts are uniformly mixed and weighed. After that, the obtained mixed powder was tableted by a direct compression method so that the weight of one tablet became 100 mg, and 9000 tablets were obtained.

(Example 2) (Formulation) Dihydrocodeine phosphate 24 g dl-methylephedrine hydrochloride 60 g Mequitadine 4 g Guaifenesin 250 g Dibutylhydroxytoluene 3 g Lactose 300 g Microcrystalline cellulose 239 g Magnesium stearate 10 g Hardened castor oil 10 g After weighing and mixing uniformly, 9000 100 mg tablets were obtained according to Example 1.

(Example 3) (Formulation) Dihydrocodeine phosphate 24 g dl-Methylephedrine hydrochloride 60 g Mequitadine 4 g Guaiphenesin 250 g Butylhydroxyanisole 0.3 g Lactose 300 g Microcrystalline cellulose 241.7 g Magnesium stearate 10 g Hardened castor oil 10 g After the components and amounts were weighed and uniformly mixed, 9000 100 mg tablets were obtained according to Example 1.

Example 4 (Formulation) Ibuprofen 450 g Mequitazine 4 g Dextromethorphan hydrobromide 48 g Noscapine 48 g dl-methylephedrine hydrochloride 60 g Anhydrous caffeine 150 g Propyl gallate 5 g Lactose 500 g Microcrystalline cellulose 515 g Magnesium stearate 10 g Castor oil 10 g After weighing the above components and amounts, and mixing them uniformly, 9000 200 mg tablets were obtained according to Example 1.

Example 5 (Formulation) Ibuprofen 450 g Mequitazine 4 g Dextromethorphan hydrobromide 48 g Noscapine 48 g dl-methylephedrine hydrochloride 60 g Anhydrous caffeine 150 g dl-α-tocopherol 5 g Lactose 500 g Microcrystalline cellulose 515 g Stearate 10 g of hydrogenated castor oil 10 g After weighing and uniformly mixing the above-mentioned components and amounts, 9000 tablets of 200 mg were obtained according to Example 1.

Example 6 (Formulation) Ibuprofen 450 g Mequitazine 4 g Dextromethorphan hydrobromide 48 g Noscapine 48 g dl-methylephedrine hydrochloride 60 g Anhydrous caffeine 150 g Sodium benzoate 900 g Lactose 50 g Microcrystalline cellulose 70 g Magnesium stearate 10 g Castor oil 10 g After weighing the above components and amounts, and mixing them uniformly, 9000 200 mg tablets were obtained according to Example 1.

(Example 7) (Formulation) Dihydrocodeine phosphate 24 g dl-methylephedrine hydrochloride 60 g Mequitadine 4 g Guaifenesin 250 g Inositol 20 g Lactose 300 g Microcrystalline cellulose 222 g Magnesium stearate 10 g Hardened castor oil 10 g The above components and amounts are weighed. After uniform mixing, 9000 100 mg tablets were obtained according to Example 1.

Example 8 (Formulation) Dihydrocodeine phosphate 24 g dl-Methylephedrine hydrochloride 60 g Mequitadine 4 g Guaifenesin 250 g Sodium salicylate 40 g Lactose 300 g Microcrystalline cellulose 202 g Magnesium stearate 10 g Hardened castor oil 10 g The above components and amounts are weighed. Then, according to Example 1, 9000 tablets of 100 mg were obtained.

(Example 9) (Formulation) Dihydrocodeine phosphate 24 g dl-methylephedrine hydrochloride 60 g Mequitadine 4 g Guaifenesin 250 g Ethyl paraoxybenzoate 60 g Lactose 300 g Microcrystalline cellulose 182 g Magnesium stearate 10 g Hardened castor oil 10 g After weighing and uniformly mixing, 9000 tablets of 100 mg were obtained according to Example 1.

Example 10 (Formulation) Ibuprofen 450 g Mequitazine 4 g Dextromethorphan hydrobromide 48 g Noscapine 48 g dl-methylephedrine hydrochloride 60 g Anhydrous caffeine 150 g Sodium sulfite 200 g Lactose 500 g Microcrystalline cellulose 320 g Magnesium stearate 10 g 10 g of oil After weighing the above components and amounts and mixing them uniformly, 9000 tablets of 200 mg were obtained according to Example 1.

Example 11 (Prescription) Ibuprofen 450 g Mequitazine 4 g Dextromethorphan hydrobromide 48 g Noscapine 48 g dl-methylephedrine hydrochloride 60 g Anhydrous caffeine 150 g Sodium bisulfite 150 g Lactose 500 g Microcrystalline cellulose 270 g Magnesium stearate 10 g Castor oil 10 g After weighing the above components and amounts, and mixing them uniformly, 9000 200 mg tablets were obtained according to Example 1.

(Example 12) (Formulation) Ibuprofen 450 g Mequitazine 4 g Dextromethorphan hydrobromide 48 g Noscapine 48 g dl-methylephedrine hydrochloride 60 g Anhydrous caffeine 150 g Sodium pyrosulfite 20 g Lactose 500 g Microcrystalline cellulose 400 g Magnesium stearate 10 g Castor oil 10 g After weighing the above components and amounts, and mixing them uniformly, 9000 200 mg tablets were obtained according to Example 1.

(Example 13) (Formulation) Dihydrocodeine phosphate 24 g dl-methylephedrine hydrochloride 60 g Mequitadine 4 g Guaifenesin 250 g Soybean lecithin 200 g Lactose 300 g Microcrystalline cellulose 42 g Magnesium stearate 10 g Hardened castor oil 10 g The above components and amounts are weighed. Then, according to Example 1, 9000 tablets of 100 mg were obtained.

Example 14 (Prescription) Ibuprofen 450 g Mequitazine 4 g Dextromethorphan hydrobromide 48 g Noscapine 48 g dl-methylephedrine hydrochloride 60 g Anhydrous caffeine 150 g Ascorbic acid 500 g Lactose 200 g Microcrystalline cellulose 220 g Magnesium stearate 10 g 10 g of oil After weighing the above components and amounts and mixing them uniformly, 9000 tablets of 200 mg were obtained according to Example 1.

Example 15 (Prescription) Dihydrocodeine phosphate 24 g dl-Methylephedrine hydrochloride 60 g Mequitadine 4 g Guaifenesin 250 g Sodium erythorbate 200 g Lactose 300 g Microcrystalline cellulose 42 g Magnesium stearate 10 g Hardened castor oil 10 g After weighing and mixing uniformly, 9000 100 mg tablets were obtained according to Example 1.

(Comparative Example 1) (Formulation) Dihydrocodeine phosphate 24 g dl-methylephedrine hydrochloride 60 g Mequitadine 4 g Guaifenesin 250 g Lactose 300 g Microcrystalline cellulose 242 g Magnesium stearate 10 g Hardened castor oil 10 g The above components and amounts are weighed and uniform. After mixing, 9000 100 mg tablets were obtained according to Example 1.

Comparative Example 2 (Prescription) Ibuprofen 450 g Mequitadine 4 g Dextromethorphan hydrobromide 48 g Noscapine 48 g dl-methylephedrine hydrochloride 60 g Anhydrous caffeine 150 g Lactose 500 g Microcrystalline cellulose 420 g Magnesium stearate 10 g Hardened castor oil 10 g After weighing each component and the amount thereof and mixing them uniformly, 9000 tablets of 200 mg were obtained according to Example 1.

Test Example 1 The oral solid preparations of Examples 1 to 15 and Comparative Examples 1 and 2 were each heated to 40 ° C.
After being dissolved in the solution (pH 1.2), the solution was stored in a dark place. After 3 hours, mequitazine remaining in the first solution was quantified by high performance liquid chromatography. Table 2 shows the test results.
In an internal solid preparation containing mequitazine, in a formulation containing at least one of the mequitazine stabilizers according to the present invention (Examples 1 to 15), almost no decrease in mequitazine at 40 ° C. for 3 hours was observed. Was.
On the other hand, a formulation containing no mequitazine stabilizer (Comparative Example 1)
In (2) and (2), a decrease of about 10% in mequitazine was confirmed under the same conditions. From these results, it has been proved that the combination of the mequitazine stabilizer has an excellent effect in preventing the decrease in the bioavailability of mequitazine in the mekitazine-containing internal solid preparation.

[0032]

[Table 2]

[0033]

Industrial Applicability According to the present invention, since the stability of mequitazine, an antihistamine drug, in stomach acid is improved, it has become possible to develop an internal solid preparation containing mequitazine which ensures sufficient bioavailability.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 47/16 A61K 47/16 J 47/20 47/20 J 47/22 47/22 J (72) Inventor Yuji Ito Tokyo 3-24-1, Takada, Toshima-ku Taisho Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. Hydroquinone, dibutylhydroxytoluene, butylhydroxyanisole, gallic acid or a salt or ester thereof, tocopherol or an ester thereof, benzoic acid or a salt thereof, inositol, salicylic acid or a salt or ester thereof, a paraoxybenzoate, a sulfite A mequitazine-containing internal solid preparation comprising at least one selected from a group consisting of bisulfite, pyrosulfite, lecithin, ascorbic acid or a salt or ester thereof, and erythorbic acid or a salt thereof.