JP2004123712A - Medicinal composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for improving antipyretic activity of para-aminophenol derivatives represented by acetaminophen, and also to obtain a medicinal composition having an excellent antipyretic effect. <P>SOLUTION: The medicinal composition having no adverse effect such as gastrointestinal disorder, while having the excellent anti-pyretic effect is provided by using glycine having an antipyretic activity-improving effect and a high safety simultaneously with a para-aminophenol derivative to improve the anti-pyretic activity of the para-aminophenol derivative. <P>COPYRIGHT: (C)2004,JPO

Description

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a novel antipyretic agent. The present invention also relates to a method for improving the antipyretic effect of a paraaminophenol derivative and a pharmaceutical composition having an excellent antipyretic effect.
[0002]
[Prior art]
Many antipyretics or antipyretic analgesics containing acetaminophen, a typical para-aminophenol derivative, have been commercially available. However, the antipyretic effect was not enough.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to provide a method for improving the antipyretic effect of a paraaminophenol derivative represented by acetaminophen, and to provide a pharmaceutical composition having an excellent antipyretic effect.
[0004]
[Means for Solving the Problems]
The present inventors have conducted intensive studies to achieve the above-mentioned object, and found that glycine has an antipyretic effect-improving effect on para-aminophenol derivatives, and that the combined use of glycine and para-aminophenol derivatives improves the antipyretic effect. It has been found that the pharmaceutical composition of the present invention can be obtained, and the present invention has been completed.
[0005]
That is, the present invention is an antipyretic action improver or a pharmaceutical composition or method described in the following (1) to (8).
(1) an antipyretic action improver containing glycine,
(2) a pharmaceutical composition comprising the antipyretic effect-improving agent according to (1) and a para-aminophenol derivative;
(3) a method for improving the antipyretic effect of a pharmaceutical composition, which comprises using glycine together with a para-aminophenol derivative;
(4) The method for improving the antipyretic effect according to (3), wherein glycine is used in a proportion of 0.1 to 100 parts by weight based on 1 part by weight of the paraaminophenol derivative.
(5) a pharmaceutical composition comprising a paraaminophenol derivative and glycine, wherein the method of (3) or (4) has an improved antipyretic effect;
(6) a method for improving the antipyretic action of a para-aminophenol derivative, which comprises using glycine together with the para-aminophenol derivative;
(7) The method for improving the antipyretic effect according to (6), wherein glycine is used in an amount of 0.1 to 100 parts by weight based on 1 part by weight of the paraaminophenol derivative.
(8) A pharmaceutical composition containing a paraaminophenol derivative and glycine, and having an improved antipyretic effect by the method according to (6) or (7).
[0006]
In this specification, unless otherwise specified,% means w / v%.
[0007]
BEST MODE FOR CARRYING OUT THE INVENTION
Para-aminophenol derivatives that can be used in the present invention are typical compounds having an antipyretic effect, and include acetaminophen (N-acetyl-p-aminophenol), lactylphenetidine and the like. In particular, acetaminophen is preferable from the viewpoint of improving the antipyretic effect of glycine. The amount of the paraaminophenol derivative to be used is not particularly limited as long as the effect of the present invention can be obtained, but the amount of the drug is adjusted so as to be 50 mg to 4000 mg, preferably 50 mg to 2000 mg, more preferably 100 to 1500 mg per adult day. The compounding amount in the composition and the method of using the pharmaceutical composition can be appropriately selected and used, and can be appropriately increased or decreased according to the patient's age, body weight, symptoms, and the like. For example, the amount of the paraaminophenol derivative in the pharmaceutical composition is usually 0.01% to 1%, preferably 0.06 to 6%, and 0.06% to 3% based on the whole pharmaceutical composition. The pharmaceutical composition can be administered once or several times a day. As the paraaminophenol derivative, a water adduct (hydrate) may be used, and any of an optically active substance and a racemic form (dl form, 1 form, d form) may be used.
[0008]
Glycine, which can be used in the present invention, is also called aminoacetic acid, and is used as a pharmaceutical additive as a stabilizer, buffer, sweetener, flavoring agent, suspending agent, excipient, solubilizer, It is a component that is used as an antacid in combination with gastrointestinal drugs, and has high safety without fear of gastrointestinal disorders. The amount of glycine to be added to the pharmaceutical composition of the present invention is usually 0.001% to 25%, preferably 0.01% to 15%, more preferably 0.01% to It is 10%, particularly preferably 0.1% to 5%. The mixing ratio of glycine to the paraaminophenol derivative is usually 0.1 to 100 parts by weight, preferably 0.1 to 50 parts by weight, more preferably 0.1 to 50 parts by weight, based on 1 part by weight of the paraaminophenol derivative. It is 1 to 25 parts by weight, particularly preferably 0.5 to 25 parts by weight. As glycine, a water adduct (hydrate) may be used, and any of an optically active substance and a racemic form (dl form, 1 form, d form) may be used.
[0009]
Examples of the use form of the pharmaceutical composition of the present invention include pharmaceuticals and quasi-drugs. The use of the pharmaceutical composition of the present invention is not particularly limited as long as it utilizes the antipyretic action of the paraphenol derivative, and examples thereof include a drug for treating inflammation accompanied by fever and cold. Specifically, for antipyretic analgesia during inflammation, antipyretic during chills and fever, rheumatoid arthritis, rheumatic fever, osteoarthritis, ankylosing spondylitis, periarthritis, fibrositis (internal use), postoperative pain・ Toothache, neuralgia, joint pain, back pain, muscle pain, sprain pain, bruise pain, gout pain, headache, menstrual pain (menstrual pain), stiff shoulder pain, sore throat pain, pain after tooth extraction, ear pain, bone fracture pain, outside As an antipyretic at the time of cold, such as a medicine for treating pain, it can be used as a medicine for treating various symptoms of a cold (throat pain, fever, chills, headache, joint pain, muscle pain, etc.).
[0010]
The pharmaceutical composition of the present invention can be combined with various components as necessary in addition to the glycine and para-aminophenol derivatives as long as the effects of the present invention are not impaired. The types of such components are not particularly limited. For example, antipyretic analgesic components, sedative-hypnotic components, anti-inflammatory components, antihistamine components, antiallergic components, antitussive components, bronchodilator components, or sympathetic nerves Examples include at least one component selected from stimulant components, expectorant components, crude drug components, antacid components, and vitamins. Examples of suitable components in the present invention include the following components.
[0011]
Antipyretic analgesic components: for example, aspirin, ethenzamide, sodium salicylate, aspirin aluminum and the like.
Sedative-hypnotic components: for example, bromvalerylurea, allylisopropylacetylurea and the like.
Anti-inflammatory drug components: for example, ketoprofen, indomethacin, diclofenac, pranoprofen, piroxicam, epsilon-aminocaproic acid, berberine, glycyrrhizic acid, lysozyme, allantoin, azulene and pharmacologically acceptable salts (eg berberine chloride, sulfate Berberine, diclofenac sodium, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, lysozyme chloride).
Antihistamine drug components: for example, clemastine, diphenhydramine, iproheptin, isotipendyl, dipheterol, diphenylpyrazine, triprolidine, tripelenamine, tondiamine, promethazine, methdilazine, carbinoxamine, alimedine, promethazine, mebuhydroline, phenetazine, methadine, medastin, ezidazine, ezedine , Terfenadine, epinastine, astemizole, ebastine, cetirizine, levocabastine, olopatadine and pharmacologically acceptable salts thereof (for example, diphenhydramine hydrochloride, ketotifen fumarate, emedastin fumarate, clemastine fumarate, azelastine hydrochloride, levocabastine hydrochloride) Such.
Antiallergic component: for example, cromoglycic acid, tranilast, amlexanox, ibudilast, pemirolast, tazanolast and pharmacologically acceptable salts thereof (for example, sodium cromoglycate and the like).
Antitussive ingredients: achloramide, cloperastine, pentoxiverine (carbetapentane), tipepidine, dibnate, codeine, dihydrocodeine, noscapine and their pharmacologically acceptable salts (eg, cloperastine hydrochloride, tipepidine hibenzate, codeine phosphate) , Dihydrocodeine phosphate, noscapine hydrochloride, etc.).
Bronchodilator or sympathomimetics components: ephedrine, methylephedrine, pseudoephedrine, and pharmacologically acceptable salts thereof (eg, ephedrine hydrochloride, methylephedrine hydrochloride, pseudoephedrine hydrochloride, etc.).
Expectorant components: licorice, sodium guaiacol sulfonate, guaifenesin, etc.
Crude drug ingredients: Kikyo, Fennel, Chamomile, Keihi, Kakkonto etc.
Antacid component: dried aluminum hydroxide gel, magnesium aluminate silicate, magnesium aluminate metasilicate, aluminum silicate, hydrotalcite, magnesium aluminate hydroxide, aluminum hydroxide gel, coprecipitation of aluminum hydroxide and sodium hydrogen carbonate Product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / calcium carbonate / magnesium carbonate co-precipitated product, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium silicate, magnesium hydroxide / aluminum potassium sulfate Magnesium-based antacids such as coprecipitated products, calcium-based antacids such as anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, calcium lactate and calcium hydroxide, sodium bicarbonate , Sodium citrate, sodium-based antacids such as sodium acetate, anion exchange resins such as polyamino methylene resins, famotidine, H2 receptor antagonists, such as ranitidine and cimetidine, proton pump inhibitors, such as scopolia extract.
Vitamins: Examples of vitamins A include vitamin B, such as retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene, and pharmaceutically acceptable salts thereof (eg, retinol acetate, retinol palmitate, etc.). Examples include, for example, thiamine, thiamine disulfide, dicetiamine, octiamine, sicotiamine, bisibutiamine, bisbenthamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, hydroxocobalamin , Cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folic acid, tetrahydrofolate, dihydrofolate, nicotinic acid, nicotinamide, nicotinic alcohol, pantothene , Panthenol, biotin, choline, inositol or a pharmaceutically acceptable salt thereof (for example, thiamine hydrochloride, thiamine nitrate, dicetiamine hydrochloride, fursultiamine hydrochloride, riboflavin butyrate, riboflavin sodium phosphate, flavin adenine dinucleotide) Vitamin Cs such as sodium, pyridoxine hydrochloride, pyridoxal phosphate, calcium pyridoxal phosphate, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, calcium pantothenate, sodium pantothenate), such as ascorbic acid, erythorbic acid, and derivatives thereof Vitamin Ds such as pharmacologically acceptable salts thereof (eg, sodium ascorbate, sodium erythorbate, etc.) include, for example, ergocalciferol Examples of vitamin Es such as cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotaxerol and pharmaceutically acceptable salts thereof) include tocopherol and its derivatives, ubiquinone derivatives and its pharmacology Other vitamins such as chemically acceptable salts (tocopherol acetate, tocopherol nicotinate, tocopherol succinate, calcium tocopherol succinate, etc.) include, for example, hesperidin, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin , Eriocitrin and pharmacologically acceptable salts thereof (such as carnitine chloride), and the like, and preferred are vitamins B, vitamin Cs, hesperidin and derivatives thereof and salts thereof.
[0012]
In the pharmaceutical composition of the present invention, various additives can be arbitrarily selected and used as needed as long as the effects of the present invention are not impaired. For example, in solid preparations, binders (hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc.), excipients (sucrose, lactose, starch, corn starch, crystalline cellulose, light anhydrous cellulose) For example, silicic acid, a lubricant (eg, polyethylene glycol, magnesium stearate), a disintegrant (eg, methylcellulose, polysorbate 80, croscarmellose sodium), and a foaming agent (eg, sodium hydrogen carbonate) can be used. In the liquid preparation, a solvent or water as a base, an oily base, a solubilizer, a suspending agent or an emulsifier, an isotonic agent, a buffer and the like can be used. In addition, preservatives, antioxidants, sweeteners, sour agents, coloring agents, flavors, flavors, and the like may be added to these compositions as necessary.
[0013]
In the present invention, the dosage form or use form of the preparation is not particularly limited, and various dosage forms or use forms can be adopted depending on the use or kind of the preparation.
Examples of the dosage form include a solid dosage form, a semi-solid dosage form or a liquid dosage form, preferably a solid dosage form or a liquid dosage form. Specifically, tablets (including oral quick disintegrating tablets, chewable tablets, effervescent tablets, troches, jelly-shaped drops, etc.), granules, fine granules, powders, hard capsules, soft capsules, Examples thereof include liquids, gels, liposomes, extracts, tinctures, lemonades, syrups, jellies, suspensions and the like, and particularly preferably tablets, granules, fine granules, powders, hard capsules or soft capsules. Capsules and liquids. These compositions are prepared by a conventional method, and in this case, in addition to the above-mentioned components, conventional additives according to the preparation can be used.
[0014]
The pharmaceutical composition of the present invention can exhibit a sufficient antipyretic effect even in a liquid preparation because the antipyretic action of the paraaminophenol derivative is improved by using glycine in combination. The range of the viscosity of such a liquid agent is usually from 1 to 150 mPa · S, preferably from 1 to 100 mPa · S. The viscosity can be measured in accordance with a method using a cone-plate type rotational viscometer (cone-plate viscometer) among the fourteenth revised Japanese Pharmacopoeia viscosity measurement methods. Further, when the pharmaceutical composition of the present invention is a liquid preparation, it is preferable to adjust the pH, and the pH range of the liquid preparation is 3.0 to 6.5, preferably 3.0 to 5.0, and more preferably. Is 3.5 to 4.5.
[0015]
The present invention also provides a method for improving the antipyretic effect of a para-aminophenol derivative, which comprises using glycine together with the para-aminophenol derivative. Furthermore, the present invention also includes a method for improving the antipyretic effect of a pharmaceutical composition, which comprises using glycine together with a paraaminophenol derivative. In such a method for improving the antipyretic effect, the amounts and proportions of the paraaminophenol derivative and glycine can be achieved by making them the same as those described for the pharmaceutical composition.
[0016]
【The invention's effect】
In the present invention, glycine has an excellent effect of improving the antipyretic action of a paraaminophenol derivative, and can provide an antipyretic action improver containing glycine. The present invention also provides a method for improving the antipyretic action of a paraaminophenol derivative by using glycine and a paraaminophenol derivative in combination. Furthermore, the pharmaceutical composition of the present invention is a composition containing a paraaminophenol derivative together with a fever reducing agent containing glycine and having an improved fever reducing effect.
According to the method or the pharmaceutical composition of the present invention, the amount of the paraaminophenol derivative used can be reduced by improving the antipyretic effect of the paraaminophenol derivative, and glycine used in combination has an antacid action, which causes gastrointestinal disorders. It is possible to provide an extremely safe composition that does not generate.
[0017]
【Example】
Hereinafter, the present invention will be described in detail with reference to Test Examples and Examples, but the present invention is not limited to these Examples.
[0018]
Test Example The antipyretic effect of the pharmaceutical composition of the present invention was tested. As a test animal, SD male rats (body weight: 200 to 300 g) were used, and after measuring the rectal body temperature of each test animal, 20% of dry yeast (product name “Dry yeast” manufactured by Wako Pure Chemical Industries) as a pyrogen was measured. The solution (suspended in a 0.5% sodium carboxymethylcellulose aqueous solution) was subcutaneously administered at 10 ml / kg. Then, 16 hours after the administration of the pyrogen, the rectal body temperature was measured. Rats that had a fever of 2.0 ° C. or higher from the rectal body temperature before the administration of the pyrogen were selected and divided into six groups, each group comprising five rats. Examples 1-4 and Comparative Examples 1-2 in which acetaminophen and / or glycine were dissolved in a 0.5% aqueous solution of sodium carboxymethylcellulose in rats of each group, and a comparative example using only a 0.5% aqueous solution of sodium carboxymethylcellulose. 3 was orally administered at 10 ml / kg, and the rectal body temperature was measured 1 hour after administration. The difference in the rectal body temperature between the time of fever (16 hours after administration of the pyrogen) and the administration of Example or Comparative Example was determined, and the antipyretic effects were compared. The results are shown in FIG.
Formula for calculating the difference in rectal body temperature: Difference in rectal body temperature (degree) = Rectal body temperature 16 hours after administration of pyrogen-Rectal body temperature 1 hour after administration of test preparation Example 1 1% acetaminophen (w / v), glycine 0.50% (w / v)
Example 2 Acetaminophen 1% (w / v), glycine 0.83% (w / v)
Example 3 Acetaminophen 1% (w / v), glycine 2.50% (w / v)
Example 4 Acetaminophen 1% (w / v), Glycine 8.30% (w / v)
Comparative Example 1 Acetaminophen 1% (w / v)
Comparative Example 2 Glycine 8.30% (w / v)
Comparative Example 3 0.5% aqueous solution of sodium carboxymethylcellulose
As is clear from the results of the test shown in FIG. 1, it was found that glycine did not have an antipyretic effect (Comparative Example 2), but had an effect of improving the antipyretic effect of acetaminophen (Example 1). 4). In addition, comparing Examples 1 to 4 in which glycine was used together at a ratio of 0.5 to 8.3 parts by weight with respect to 1 part by weight of acetaminophen, the effect of improving the antipyretic effect of glycine was less than the mixing ratio of glycine. It was found to be higher with increasing.
[0020]
Example 5 Syrup 300 mg acetaminophen
Dextromethorphan hydrobromide 16 mg
1.16 mg of d-chlorpheniramine maleate
Glycine 250 mg
5000 mg of purified sucrose
Fructose glucose liquid sugar 4000 mg
Glycerin 2000 mg
Erythritol 250 mg
48 mg of citric anhydride
Trisodium citrate dihydrate 45 mg
Tartaric acid 24 mg
DL-malic acid 8 mg
Sodium chloride 15 mg
25 mg caramel
Methyl paraoxybenzoate 2.82 mg
Propyl paraoxybenzoate 0.56 mg
Perfume micro-purified water qs total 30 mL
A syrup having a content of 30 ml / bottle of the above formulation was produced according to the production method of the 14th revised Japanese Pharmacopoeia General Rules for Preparations of Syrups. The pH of the syrup was 4.2 (20 ° C.), and the viscosity was 3.2 mPa · S.
[0021]
Example 6 Chewable Tablets Acetaminophen 900 mg
Glycine 500 mg
200 mg of ascorbic acid
Mannit appropriate amount of crystalline cellulose 120 mg
Aspartame 10 mg
Hydroxypropyl cellulose 72 mg
Magnesium stearate 28 mg
Fragrance trace total 3600 mg
According to the manufacturing method of the 14th revised Japanese Pharmacopoeia General Rules for Preparations “Tablets”, chewable tablets of 1.2 g / tablet having a daily dosage of 3 tablets as described above were prepared.
[0022]
Example 7 　 Dry syrup <br/> acetaminophen 900 mg
Glycine 900 mg
500 mg of ascorbic acid
Dextromethorphan hydrobromide 48 mg
dl-Chlorpheniramine maleate 7.5 mg
Guaifenesin 250 mg
1200 mg of citric anhydride
Trisodium citrate dihydrate 220 mg
Carmellose sodium 1100 mg
Fragrance Micro-purified white sugar Appropriate amount Total 36000 mg
According to the manufacturing method of the 14th revised Japanese Pharmacopoeia General Rules for Preparations "Powder", 12 g of a dry syrup preparation having the above-mentioned formulation in three packets per day was prepared.
[0023]
Example 8 　 Capsule <br/> acetaminophen 900 mg
Glycine 500 mg
500 mg of ascorbic acid
Dextromethorphan hydrobromide 48 mg
dl-Chlorpheniramine maleate 7.5 mg
dl-methylephedrine hydrochloride 60 mg
75 mg of anhydrous caffeine
Crystalline cellulose suitable amount of magnesium stearate 10 mg
2220 mg in total
According to the manufacturing method of the 14th revised Japanese Pharmacopoeia General Rules for Preparations “Capsules”, capsules of 370 mg (contents) were prepared, each of which had the above-mentioned formulation in 6 capsules per day.
[0024]
Example 9 　 Granules acetaminophen 450 mg
Ethenzamide 750 mg
Glycine 900 mg
Ascorbic acid 100 mg
Dextromethorphan hydrobromide 48 mg
dl-Chlorpheniramine maleate 7.5 mg
dl-methylephedrine hydrochloride 60 mg
75 mg of anhydrous caffeine
Riboflavin phosphate 5 mg
Hesperidin 18 mg
Mannit appropriate amount crystalline cellulose 400 mg
Hydroxypropyl cellulose 60 mg
Light silicic anhydride trace fragrance trace total 3600 mg
According to the manufacturing method of the 14th revision Japanese Pharmacopoeia General Rules for Preparations “Granules”, 1.2 g of granules were prepared per package, in which the prescription in three packets per day was as described above.
[0025]
Example 10 Tablets Acetaminophen 450 mg
Ethenzamide 750 mg
Glycine 350 mg
Bromvalerylurea 600 mg
75 mg of anhydrous caffeine
Lactose Suitable amount of crystalline cellulose 300 mg
Hydroxypropyl cellulose 50 mg
Fragrance trace total 2700 mg
According to the manufacturing method of the 14th revised Japanese Pharmacopoeia General Rules for Preparations “Tablets”, a tablet of 300 mg per tablet having a daily dose of 9 tablets as described above was prepared.
[0026]
Example 11 Powder Acetaminophen 300 mg
Ethenzamide 960 mg
Glycine 900 mg
Allyl isopropyl urea 120 mg
Caffeine 240 mg
400 mg of ascorbic acid
Thiamine nitrate 1 mg
Riboflavin phosphate 12 mg
Hespericin 18 mg
Synthetic hydrotalcite 200 mg
Aspartame 10 mg
Cornstarch qs perfume trace magnesium stearate trace total 3600 mg
According to the manufacturing method of the 14th revision Japanese Pharmacopoeia General Rules for Preparations “Powder”, 1.2 g of a powder was prepared in which 3 packets per day had the above formulation.
[0027]
[Brief description of the drawings]
FIG. 1 is a graph showing the results of a comparison between the antipyretic effect of acetaminophen and the antipyretic effect of a composition containing glycine together with acetaminophen in a test example.

Claims (5)

Antipyretic action improver containing glycine. A pharmaceutical composition comprising the antipyretic agent according to claim 1 and a para-aminophenol derivative. A method for improving the antipyretic effect of a para-aminophenol derivative, comprising using glycine together with the para-aminophenol derivative. The method according to claim 3, wherein glycine is used in an amount of 0.1 to 100 parts by weight per 1 part by weight of the paraaminophenol derivative. A pharmaceutical composition comprising a para-aminophenol derivative and glycine, wherein the antipyretic effect is improved by the method for improving antipyretic effect according to any one of claims 3 to 4.

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