JPH1045595A - Antitussive - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a safe medicine composition high in antitussive effect, useful as an antitussive by mixing an antitussive selected from codeine (salt) and/or dihydrocodeine (salt) with a specific medicine. SOLUTION: This medicine composition is obtained by mixing (A) at least one selected from codeine, dihydrocodeine and their salts with (B) ibuprofen and/or acetaminophen and (C) at least one selected from ketotifen, mequitazine and their salts. Preferably, the amounts of these compounds blended are 0.1-10wt.% of codeine, 0.2-20wt.% of dihydrocodeine, 3-75wt.% of ibuprofen, 5-90wt.% of acetaminophen and 0.05-5wt.% of ketotifen or mequitazine. Generally, the total dose of the active ingredient is 250-2,000mg daily and the antitussive can be orally administered once to several times dividedly.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an antitussive having an enhanced antitussive effect.

[0002]

2. Description of the Related Art At present, treatment for the cause of the cold syndrome is incomplete, and symptomatic treatment is mainly used.

[0003] Here, it is considered that cough symptoms that mainly appear in the late to late stages of the cold illness consume a lot of energy and prolong the entire cold symptoms.

[0004] However, most of the cough medicines for colds that respond to cough symptoms are mainly narcotic or central respiratory depressants, and these drugs suffer from side effects such as drug dependence due to repeated use. Had become.

[0005]

An object of the present invention is to provide an effective and safe antitussive.

[0006]

DISCLOSURE OF THE INVENTION The present inventors have conducted studies with the aim of providing a drug having a strong antitussive effect. As a result, the present inventors have found that by combining an antitussive selected from the group consisting of codeine and dihydrocodeine with a specific drug. The present inventors have found that they show excellent antitussive effects which are unexpected from the case where each drug is used alone, and completed the present invention. That is, the present invention provides (a) at least one selected from the group consisting of codeine, dihydrocodeine and salts thereof, (b)
A pharmaceutical composition comprising one or two selected from the group consisting of ibuprofen and acetaminophen, and (c) at least one selected from the group consisting of ketotifen, mequitazine and salts thereof.

[0007]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the present invention, the amount of codeine is preferably 0.1 to 10% by weight, and the amount of dihydrocodeine is preferably 0.2 to 20% by weight. The amount of ibuprofen is 3 to 75% by weight, and the amount of acetaminophen is 5 to 75% by weight.
90% by weight is preferred. The amount of ketotifen or mequitazine is preferably 0.05 to 5% by weight, respectively.

In the present invention, the salt means phosphoric acid, fumaric acid, hydrochloric acid,
It is a salt with a physiologically acceptable acid such as nitric acid or tartaric acid. Preferred examples include phosphate for codeine or dihydrocodeine and fumarate for ketotifen.

The antitussive according to the present invention comprises, in addition to the above essential components, other antipyretic analgesics (aspirin or a salt thereof, etenzamide, sazapyrine, isopropylantipyrine, ketoprofen, naproxen, loxoprofen or a salt thereof, diflunisal, planopro) Fen,
Flurbiprofen, fenbufen, fenoprofen or its salts, diclofenac or its salts, alclofenac, ampfenac or its salts, flufenamic acid, tolfenamic acid, mefenamic acid, tenoxicam, piroxicam, etc.), other antihistamines / antiallergic drugs (Carbinoxamine maleate, chlorphenimine maleate (including d-form and dl-form), diphenhydramine or salts thereof, promethazine hydrochloride, isotipendyl hydrochloride, clemastine fumarate, iproheptin hydrochloride, cyproheptadine hydrochloride, diphenylpyraline or salts thereof, dimethindene maleate, Triprolidine hydrochloride, homochlorcyclidine hydrochloride, azelastine hydrochloride, ibudilast, sodium cromoglycate, oxatomide, amlexanox, trani Last, repirinast, emedastine fumarate, ozagrel hydrochloride, tazanolast, pemirolast potassium, suplatast tosilate, etc., other antitussives (dextromethorphan hydrobromide, noscapine or its salts, dimemorphan or its salts, cloperastine or its Salts, eprazinone hydrochloride, clobutinol hydrochloride, oxeradine or its salts, isoaminyl citrate, pentoxyberine citrate, sodium dibnate, hydrocotarnine, etc., anti-inflammatory drugs and anti-inflammatory drugs (lysozyme chloride, serrapeptase, bromelain, semi-alkaline proteinase) , Pronase, tranexamic acid, glycyrrhizic acid and related substances), bronchodilators (methylephedrine hydrochloride (d-isomer, dl
Ephedrine hydrochloride, methoxyphenamine hydrochloride, trimethoquinol hydrochloride, theophylline, aminophylline, diprofylline, proxifylline, orciprenaline hydrochloride, chlorprenaline hydrochloride, isoprenaline hydrochloride, hexoprenaline sulfate, salbutamol sulfate, formoterol fumarate, tulobtenol hydrochloride , Fenoterol hydrobromide, procaterol hydrochloride, clenbuterol hydrochloride, probuterol hydrochloride, mabuterol hydrochloride, terbutaline sulfate, pyrbuterol hydrochloride), central nervous stimulants (caffeine, etc.), other expectorants (potassium guaiacol sulfonate, L hydrochloride) -Methylcysteine, L-ethylcysteine hydrochloride, carbocysteine, acetylcysteine, etc.), anticholinergics (belladonna (total) alkaloids, iodide Puropamido, ipratropium bromide, flutropium, such as oxitropium bromide), vitamins (vitamin B ₁ or a derivative or their salts, vitamin B ₂ or derivatives thereof, or their salts, vitamin C, etc.), antacid Medicines (magnesium carbonate, magnesium oxide, magnesium silicate,
Magnesium hydroxide, synthetic aluminum silicate, aluminum sulfate, dihydroaluminum / aminoacetate, aluminum hydroxide gel, magnesium metasilicate aluminate, aluminum hydroxide / sodium hydrogencarbonate coprecipitate, synthetic hydrotalcite, sucralfate, etc.),
Crude drugs (kakkon, mao, cinnamon bark (branch), saiko, licorice, bellflower, senega, enshi, carrot, chen, gomiko, (purple) soba, ginger, yellow bonito, midsummer, spicy, spicy, kawakyu , Peony, syrup, forsythia, apricot kernel, peach kernel, germ winter, etc. and their extracts, etc.), and these can be used alone or in combination of two or more.

[0010] The antitussive of the present invention can be prepared in the form of tablets,
It can be prepared into oral dosage forms such as granules, fine granules, powders, capsules, chewables, drops, foams, dissolving agents in the mouth, dry syrups, and oral liquids.

Carriers used in the preparation of a solid preparation include lactose, starch, sugar, mannitol, crystalline cellulose, and other excipients, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin,
There are binders such as PVP, disintegrators such as carboxymethylcellulose calcium and low-substituted hydroxypropylcellulose, and lubricants such as magnesium stearate, hydrogenated castor oil, and talc. , Preservatives, flavors, pigments, flavoring agents and the like can be used.

[0012] Carriers used in the preparation of preparations for internal liquids include surfactants such as sucrose fatty acid esters, polyoxyl stearate, polyoxyethylene polyoxypropylene glycols and polyoxyethylene mono fatty acid esters. , Synthetic aluminum silicate,
Thickeners such as magnesium silicate, magnesium carbonate, magnesium oxide, magnesium metasilicate aluminate,
There are organic acid-based and inorganic acid-based pH adjusters such as citrate buffer and phosphate buffer. In addition, use dissolution aids, buffers, preservatives, flavors, pigments, sweeteners, etc. as necessary. can do.

The antitussive of the present invention can be generally orally administered to adults in an amount of 250 to 2000 mg per day as a total amount of the active ingredient once or several times a day. This dose can be appropriately adjusted depending on the age, weight, and medical condition.

[0014]

According to the present invention, it has become possible to provide a drug which is extremely useful for improving cough symptoms.

[0015]

The present invention will be described in more detail with reference to the following Examples and Test Examples.

Example 1 450 g of ibuprofen 18 g of codeine phosphate 2 g of ketotifen fumarate 2 g of bromhexine hydrochloride 12 g of lactose 100 g of microcrystalline cellulose 100 g of talc 18 g Hard capsules were filled at 100 mg each to obtain capsules.

Example 2 900 g of acetaminophen 900 g of dihydrocodeine phosphate 24 g of mequitazine 4 g of ambroxol hydrochloride 45 g of lactose 90 g of low-substituted hydroxypropylcellulose 90 g of talc 32 g of hydrogenated castor oil 15 g After weighing and uniformly mixing the above components and amounts, The resulting mixed powder was tableted by a direct compression method so that the weight of one tablet became 200 mg to obtain tablets.

Example 3 Ibuprofen 400 g Dihydrocodeine phosphate 24 g Ketotifen fumarate 2 g Ambroxol hydrochloride 45 g Noscapine 48 g Methylephedrine hydrochloride 60 g Vitamin B ₁ nitrate 8 g Vitamin B ₂ 4 g Anhydrous caffeine 50 g Lactose 65 g Low substituted hydroxypropyl cellulose 65 g 19 g hydrogenated castor oil 10 g After weighing and uniformly mixing the above components and amounts, 200 mg tablets were obtained according to Example 2.

Example 4 450 g of ibuprofen 18 g of codeine phosphate 2 g of ketotifen fumarate 2 g of methylephedrine hydrochloride 60 g of bromhexine hydrochloride 12 g of anhydrous caffeine 50 g of sucrose fatty acid ester 15 g of sweetener, suitable amount, preservative, appropriate amount, flavoring agent, appropriate pH adjuster (phosphate buffer) Preservatives, sweeteners and flavors were added to the aqueous solution obtained by dissolving the liquid) to completely dissolve it. After uniformly dispersing the sucrose fatty acid ester in the solution, another drug was added and dissolved, and then the solution was made up to 1000 ml with purified water to obtain a liquid.

Test Example 1 A male Hartley guinea pig (body weight 35) was used as a test animal.
0g). As for the number of cough symptoms, a large change in temporary respiratory volume was determined as a cough symptom by a volume fluctuation recorder.
It was measured. Cough symptoms were induced by inhaling capsaicin (30 μM).

As a test method, capsaicin was inhaled for 5 minutes 15 minutes before application of the test drug, and the number of cough symptoms during that time was measured. 60 minutes after application of the test drug, capsaicin was again inhaled for 5 minutes, during which the number of cough symptoms was measured. From these measurement results, the rate of suppression of cough symptoms was determined.
All drugs were dissolved in purified water and applied orally. Table 1 shows the results of the test drug and the antitussive effect.

[0022]

[Table 1]

Test Example 2 [Effect of Combination Formulation on Cough] Among 38 adult men and women suffering from cold syndrome, 32 patients with particularly remarkable cough symptoms were subjected to 1 in 2 groups of A group and B group.
The test drug was divided into 6 patients and given the test drug prescribed in Table 2 three times a day.
After oral administration for one day, the effects on cough symptoms were compared. It should be noted that, based on the degree of symptoms before administration, the progress of the improvement was determined after 1 day, 2 days, and 3 days.

[0024]

[Table 2]

The symptom evaluation was markedly improved: no coughing,
Improvement: Slight coughing, mild improvement: Coughing decreased compared to the original condition, unchanged: unchanged from the original condition, worsened:
The cough was increased from the original condition. The test results are shown in Table 3 as the rate of improvement (more than mild improvement) for cough symptoms.
It was shown to.

[0026]

[Table 3]

As shown in the results, it was confirmed that the test drug had an excellent antitussive effect as compared with the control drug.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Takafumi Ohashi 3-24-1, Takada, Toshima-ku, Tokyo Inside Taisho Yaku Co., Ltd.

Claims (2)

[Claims] 1. (a) at least one selected from the group consisting of codeine, dihydrocodeine and salts thereof,
A pharmaceutical composition comprising (b) one or two selected from the group consisting of ibuprofen and acetaminophen, and (c) at least one selected from the group consisting of ketotifen, mequitazine and salts thereof. 2. The pharmaceutical composition according to claim 1, which is an antitussive.