JP7163014B2 - cold medicine - Google Patents

Description

More specifically, the present invention relates to cold medicines, and more specifically, as OTC medicines (over-the-counter medicines), anti-inflammatory, antipyretic, analgesic, anti-nasal, antitussive, and expectorant effects are further improved compared to conventional medicines. To provide a cold medicine which is easy to administer, manage one's health by oneself, is easy to use for relieving symptoms of mild illness, is suitable for self-medication, is easy to handle during distribution, and is excellent in safety and stability.

The common cold is said to be the most common disease with an average of 5 to 6 cases per person per year. This common cold is said to develop when upper respiratory tract infections such as rhinoviruses, parainfluenza viruses, and adenoviruses are added to short-term autonomic dysfunction such as exposure to the cold.

At present, no drugs have been found that suppress the infection and proliferation of viruses that cause colds, except those effective against influenza A and/or B viruses such as Tamiflu, Relenza, Inavir, Rapiacta, and Symmetrel. do not have. For this reason, symptomatic therapy, which aims to prevent physical exhaustion, is the main treatment.

As a symptomatic remedy to relieve cold symptoms, it is effective in alleviating various symptoms of the so-called cold syndrome (common cold) such as headache, fever, sore throat and muscles, cough, sneezing, runny nose, and stuffy nose. Designed cold remedies have been developed and marketed as OTC drugs.

This cold medicine is a non-steroidal anti-inflammatory drug ( Anti-inflammatory analgesics such as NSAIDs) are active ingredients that alleviate the symptoms of runny nose, nasal congestion (nasal congestion), and sneezing. Antitussives are often blended as active ingredients to alleviate phlegm, and expectorants are often blended as active ingredients to alleviate sputum symptoms.

Conventionally, in OTC drugs, ibuprofen and acetaminophen have been mainly used as anti-inflammatory analgesics with anti-inflammatory, antipyretic, and analgesic effects (Patent Documents 1 to 4, etc.), and ethenzamide, aspirin, and isopropylantipyrine are also used. It is found here and there (Patent Document 5). Furthermore, cold remedies containing loxoprofen (Patent Document 6, etc.) have been actively developed, and many patent applications have been filed.

However, considering the balance between efficacy and safety, these drugs are not satisfactory in their therapeutic and alleviating effects on cold symptoms. For example, it has been pointed out that a drawback of conventional cold remedies containing non-steroidal anti-inflammatory analgesics is that the anti-inflammatory and analgesic effects start up slowly. was sought.

JP 2008-143807 A Japanese Patent Application Laid-Open No. 2003-081821 JP 2005-187328 A JP-A-2001-233765 JP-A-06-287144 JP 2013-151486 A

Accordingly, the present invention provides a cold medicine that has improved therapeutic and alleviating effects on cold symptoms as compared with conventional cold medicines.

The inventor of the present invention has conducted intensive research on cold medicines that are more effective. It has been found that an excellent anti-inflammatory and analgesic effect can be obtained from the initial stage of administration, and that a cold medicine with medicinal effects can be obtained by combining it with other cold medicine components. Further, by further blending a cellulose-based water-swellable polymer with this product, it was found that even in the case of a solid formulation, it becomes a cold medicine that provides an excellent anti-inflammatory and analgesic effect from the initial stage of administration. completed the invention.

That is, the present invention is a cold medicine containing naproxen or a pharmaceutically acceptable salt thereof and a pharmaceutical ingredient selected from an antinasal ingredient, an antitussive ingredient and an expectorant ingredient.

Further, the present invention is the above-mentioned cold medicine further containing a basic component.

Furthermore, the present invention is a cold medicine further containing a crude drug component and/or a central nervous system stimulant.

Furthermore, the present invention is a solid cold medicine containing a cellulose-based water-swellable polymer.

The cold remedy of the present invention using naproxen or a pharmaceutically acceptable salt thereof as an anti-inflammatory analgesic can enhance the effects of other cold medicine components such as antinasal, antitussive and expectorant components. In particular, when free naproxen and a basic substance are combined, the excellent anti-inflammatory and analgesic effect of naproxen can be obtained from the initial stage of administration, and the medicinal effects of other cold medicine components can be felt.

In addition, a solid formulation further containing a cellulose-based water-swellable polymer has enhanced disintegration properties in the oral cavity and the like when orally ingested, and can obtain more rapid efficacy. Furthermore, a pharmaceutical composition containing naproxen or a salt thereof, bromhexol or ambroxol or a salt thereof and a basic substance has the effect of being able to prevent coloration caused by the combination of the former two.

The cold medicine of the present invention is a drug selected from naproxen or a pharmaceutically acceptable salt thereof (hereinafter sometimes collectively referred to as "naproxen or a salt thereof"), an antinasal ingredient, an antitussive ingredient and an expectorant ingredient. components.

Naproxen ((2S)-2-(6-Methoxynaphthalen-
2-yl)propanoic acid) is an anti-inflammatory analgesic already known as a propionic acid-based nonsteroidal anti-inflammatory analgesic, and is effective for rheumatoid arthritis, osteoarthritis, gout attack, ankylosing spondylitis, lumbago, shoulder joint Anti-inflammation, analgesia, antipyretic for peri-inflammation, cervico-omo-brachial syndrome, tendon/tenosynovitis, dysmenorrhoea, herpes zoster, anti-inflammation and analgesia after trauma and surgery, anti-inflammation after tooth extraction and minor surgery in dental and oral surgery. is widely used for pain relief.

In the present invention, pharmaceutically acceptable salts of naproxen such as sodium salt, potassium salt, ammonium salt, meglumine salt, tris salt, salts of basic amino acids, etc. may be used, but free naproxen is used. is more preferable.

In the cold medicine of the present invention, the amount of naproxen or its salt in the formulation is not particularly limited, but for efficacy and safety as an OTC drug, the daily dose for adults is usually in the range of 10 to 1200 mg. , preferably about 15-900 mg, more preferably about 20-600 mg.

On the other hand, in the cold remedy of the present invention, in addition to naproxen or a salt thereof, one or more medicinal ingredients selected from antinasal inflammation ingredients, antitussive ingredients and expectorant ingredients are blended.

Among these, anti-rhinitis active ingredients include drugs generally called antihistamines, vasoconstrictors, and parasympatholytic agents.

Examples of such anti-nasal ingredients include mequitazine, clemastine fumarate, ketotifen fumarate, oxatomide, fexofenadine hydrochloride, epinastine hydrochloride, ebastine, cetirizine hydrochloride, levocetirizine hydrochloride, bepotastine becil. emedastine fumarate, olopatadine hydrochloride, loratadine, chlorpheniramine maleate, 5,d-chlorpheniramine maleate, carbinoxamine maleate, carbinoxamine diphenyldisulfonate, isothibenzyl hydrochloride, diphenhydramine, tannin diphenhydramine acid, diphenhydramine hydrochloride, diphenhydramine salicylate, dipheterol hydrochloride, tripelennamine hydrochloride, tonjilamine hydrochloride, phenetazine hydrochloride, methdilazine hydrochloride, diphenylpyraline hydrochloride, diphenylpyraline teorate, arimemazine tartrate, triprolidine hydrochloride hydrate, mebhydrine napadilcylate , promethazine methylene disalicylate, promethazine hydrochloride, diferol phosphate, pseudoephedrine hydrochloride, belladonna total alkaloids, isopropamide iodide and the like. These may be used singly or in combination.

Although there are no particular restrictions on the amount of these anti-rhinitis active ingredients in the formulation, the daily dose for adults is about 0.05 to 200 mg, and even 0 mg, depending on the type, from the viewpoint of efficacy and safety. It is preferable to prepare a formulation so that the dosage is about 1 to 135 mg.

Among these, particularly preferred anti-nasal ingredients include mequitazine, clemastine fumarate, ketotifen fumarate, oxatomide, fexofenadine hydrochloride, epinastine hydrochloride, emedastine fumarate, olopatadine hydrochloride, loratadine, and chlor. pheniramine maleate, d-chlorpheniramine maleate, carbinoxamine maleate, carbinoxamine diphenyldisulfonate, pseudoephedrine hydrochloride, belladonna total alkaloids, isopropamide iodide and the like.

The daily doses of the above-mentioned particularly preferred anti-nasal inflammation active ingredients are as follows. That is, mequitazine is 0.2-8 mg, further 0.4-4 mg, clemastine fumarate is 0.1-2 mg as clemastine, further 0.2-1 mg, ketotifen fumarate is 0 as ketotifen. 2-4 mg, further 0.4-2 mg, oxatomide 6-80 mg, further 12-60 mg, fexofenadine hydrochloride 6-240 mg, further 12-120 mg, epinastine hydrochloride 1- 30 mg, further 21-20 mg, emedastine fumarate, 0.2-8 mg, further 0.4-4 mg, olopatadine hydrochloride, 0.5-20 mg, further 1-10 mg, loratadine, 0.5-20 mg, further 1-10 mg, for chlorpheniramine maleate, 0.75-100 mg, further 1.5-7.5 mg, d-chlorpheniramine maleate, 0.3- 10 mg, more preferably 0.7-3.5 mg, carbinoxamine maleate preferably 0.7-10 mg, more preferably 1.5-7.5 mg, carbinoxamine diphenyldisulfonate 0.7-10 mg, more preferably 0.75 ~7.5 mg preferably, pseudoephedrine hydrochloride 10-150 mg, further 27-135 mg, belladonna total alkaloids 0.1-1 mg, further 0.12-0.3 mg, isopropamide iodide 0.5 A daily dose of up to 12 mg, more preferably 1.5 to 6 mg, is preferred, and preparations may be prepared to achieve these doses.

Furthermore, among the pharmaceutical ingredients blended in the general cold remedies of the present invention, commonly used and known antitussive ingredients can be mentioned.

Examples of this antitussive component include aloclamide hydrochloride, cloperastine hydrochloride, pentoxyverine citrate, dibunate sodium, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalate, cloperastinfen. Dizoate, Codeine Phosphate Hydrate, Dihydrocodeine Phosphate, Noscapine, Noscapine Hydrochloride Hydrate, Dimemorphan Phosphate, Eprazinone Hydrochloride, Nantenjitsu, Tipepidine Citrate, Tipepidine Hibenzate, dl-Methyl Examples include ephedrine hydrochloride, dl-methylephedrine saccharin salt, and the like. These may be used singly or in combination.

The amount of the antitussive component of the present invention in the formulation is not particularly limited, but from the viewpoint of efficacy and safety, the daily dose for adults is about 1 to 12000 mg, further 2.4 to 10000 mg. It is preferable to prepare the formulation as follows.

Among these antitussive ingredients, particularly preferred ones are dextromethorphan hydrobromide hydrate, codeine phosphate hydrate, dihydrocodeine phosphate, noscapine, noscapine hydrochloride hydrate, dimemorphan phosphate, and tipepidine. citrate, tipepidine hibenzate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt and the like.

The daily dosage of each of the above-mentioned particularly preferred antitussive components is as follows. That is, dextromethorphan hydrobromide hydrate is 4.8-60 mg, further 9.6-48 mg, codeine phosphate hydrate is 4.8-72 mg, further 9.6-48 mg, dihydrocodeine Phosphate, 2.4-48 mg, further 4.8-24 mg, Noscapine, 4.8-60 mg, further 9.6-48 mg, Noscapine hydrochloride hydrate, 4.8-60 mg, further 9.6-48 mg dimemorphan phosphate 3-60 mg further 6-30 mg tipepidine citrate 6-80 mg further 12-60 mg tipepidine hibenzate 7.5-100 mg , 6-90 mg for dl-methylephedrine hydrochloride, 12-60 mg for dl-methylephedrine hydrochloride, 6-90 mg for dl-methylephedrine saccharin salt, and 12-60 mg for each daily dose, such as The formulation should be prepared so that the amount of

Furthermore, commonly used known expectorant ingredients can be used as pharmaceutical ingredients for the general cold remedies of the present invention.

Examples of the expectorant component include potassium guaiacolsulfonate, guaifenesin, bromhexine hydrochloride, L-ethylcysteine hydrochloride, L-carbocysteine, potassium cresol sulfonate, ambroxol hydrochloride, tipepidine citrate, and tipepidine hibenzate. , dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, Ephedra, Ephedra, Onji, Glycyrrhiza, Bellflower, Shazenshii, Shazensou, Garlic, Senega, Fritillaria and the like. These may also be used singly or in combination.

The amount of these expectorant ingredients in the formulation is not particularly limited, but it is preferable to prepare the formulation so that the daily dose for adults is 2 to 12,000 mg, more preferably 4.5 to 10,000 mg.

Among the above expectorants, particularly preferred are potassium guaiacolsulfonate, guaifenesin, bromhexine hydrochloride, L-ethylcysteine hydrochloride, L-carbocysteine, ambroxol hydrochloride, tipepidine citrate, and tipepidine hibenzate. , dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, Ephedra, Ephedra, Onji, Glycyrrhiza, Bellflower, Shazenshii, Chazensou, Sargassum, Senegal and the like.

Preferred daily doses of expectorant components in the cold remedies of the present invention are as follows: That is, potassium guaiacolsulfonate is 25-500 mg, further 50-250 mg, guaifenesin is 25-500 mg, further 50-250 mg, bromhexine hydrochloride is 4-24 mg, further 8-12 mg, L-ethylcysteine. Preferably, hydrochloride is 30 to 450 mg, preferably 60 to 300 mg, L-carbocysteine is 75 to 1000 mg, preferably 150 to 750 mg, ambroxol hydrochloride is preferably 4.5 to 60 mg, preferably 9 to 45 mg, tipepidine citrate is 6 to 80 mg, preferably 12 to 60 mg; tipepidine hibenzate is 5 to 100 mg, preferably 15 to 75 mg; The dl-methylephedrine saccharin salt is preferably 6 to 90 mg, more preferably 12 to 60 mg, respectively, and preparations may be prepared to achieve such amounts. In addition, Ephedra is 0.4 to 8 g, and further 0.8 to 4 g in terms of crude drug, Ephedra is 0.4 to 8 g, and further 0.8 to 4 g in terms of crude drug, Onji is in terms of crude drug Glycyrrhiza is 0.15 to 10g, further 1 to 5g in terms of crude drug, Bellflower is 0.2 to 8g in terms of crude drug, further 0.8 to 4g, 0.5 to 10g, 1 to 5g, 1 to 15g, 2 to 10g, 1 to 15g, 2 to 10g, and 0.08g, respectively. ~2g, more preferably 0.16~0.8g, and for Senega, 0.15~8g, preferably 0.4~4g in terms of crude drug, respectively. Good luck.

In the cold remedy of the present invention, in addition to the components described above, if necessary, various formulation components and other pharmaceutical components may be blended.

In the cold remedy of the present invention containing naproxen or a salt thereof as an active ingredient, a basic component, also known as an antacid, which neutralizes gastric acid, can be added as a formulation component, thereby enhancing the anti-inflammatory and analgesic effect of naproxen. can accelerate the rise of

Examples of such basic components include magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel, dried aluminum hydroxide gel. , aluminum hydroxide-magnesium carbonate mixed dry gel, aluminum hydroxide-sodium hydrogen carbonate co-precipitation product, aluminum hydroxide-calcium carbonate-magnesium carbonate co-precipitation product, magnesium hydroxide-aluminum potassium sulfate co-precipitation product substances, magnesium carbonate, magnesium aluminometasilicate, magnesium aluminosilicate, magnesium alumina hydroxide, magnesium hydroxide, sodium hydrogen carbonate, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate and the like. These may be used singly or in combination of two or more.

Among these, more preferred are inorganic compounds containing divalent or trivalent metals, and specific examples thereof include magnesium silicate, aluminum silicate, hydrotalcite, magnesium oxide, and dihydroxyaluminum aminoacetate. , (dry) aluminum hydroxide gel, aluminum hydroxide/sodium hydrogen carbonate coprecipitate, aluminum hydroxide/magnesium carbonate mixed dry gel, aluminum hydroxide/magnesium carbonate/calcium carbonate coprecipitate, magnesium hydroxide/aluminum potassium sulfate , magnesium carbonate, magnesium aluminometasilicate, and the like.

Although the above-mentioned basic component varies depending on its type, it is preferable to design a formulation so that the daily dose for adults is 10 to 5000 mg, more preferably 16 to 4000 mg.

More specifically, the daily dose of the basic component for adults is 30 to 900 mg, magnesium silicate, synthetic aluminum silicate and aluminum hydroxide/magnesium carbonate for the coprecipitation product of aluminum hydroxide/sodium hydrogen carbonate. 100 to 3000 mg for mixed dry gel, 133 to 4000 mg for synthetic hydrotalcite, 16 to 500 mg for magnesium oxide, dihydroxyaluminum aminoacetate, coprecipitation product of aluminum hydroxide, calcium carbonate and magnesium carbonate, metasilicon 50 to 1500 mg for magnesium aluminate and precipitated calcium carbonate, 33 to 1000 mg as dry aluminum hydroxide gel for aluminum hydroxide gel and dry aluminum hydroxide gel, and 60 mg for coprecipitation product of magnesium hydroxide and potassium aluminum sulfate. 1800 mg, 66 to 2000 mg for magnesium carbonate and magnesium aluminosilicate, and 40 to 1200 mg for magnesium hydroxide.

In addition, when the cold medicine of the present invention is made into solid preparations such as tablets, capsules, and granules, in order to improve disintegration and solubility in the oral cavity and the like during oral administration, cellulose-based water-swelling It is desirable to incorporate a flexible polymer into the formulation.

This cellulose-based water-swellable polymer swells when it comes into contact with water, promoting disintegration of the formulation. Preferred examples of cellulosic water-swellable polymers include low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, crystalline cellulose, pregelatinized starch, sodium carboxymethylstarch, and the like. be done.

Among these cellulose-based water-swellable polymers, preferred ones include low-substituted hydroxypropyl cellulose, croscarmellose sodium, crystalline cellulose, and the like.

When low-substituted hydroxypropyl cellulose is used as the cellulosic water-swellable polymer, the hydroxypropoxy group content is 5.0 to 16.0 from the standpoint of ease of processing into an oral solid composition with excellent shape and particle size. A content of 0% by mass is preferable, and a content of 7.0 to 13.0% by mass is more preferable. Examples of such low-substituted hydroxypropyl cellulose include Shin-Etsu Chemical Co., Ltd. LH-31 (hydroxypropoxy group: 10.0 to 12.9% by mass), NBD-022 (hydroxypropoxy group: 7.0 to 9.9% by mass). 9% by mass). Furthermore, the average particle size of the low-substituted hydroxypropyl cellulose is preferably about 60 µm or less, more preferably 55 µm or less.

Croscarmellose sodium, which is used as a cellulose-based water-swellable polymer, is a white to yellowish white powder. Such croscarmellose sodium includes Kikkolate (Asahi Kasei Chemicals).

Furthermore, when crystalline cellulose is used as the cellulosic water ^- swellable polymer, there are various grades of crystalline cellulose. It is preferred to use highly moldable crystalline cellulose exhibiting a particle size of 300 μm. More preferably, the bulk density is 0.10-0.43 g/ml and the average particle size is 20-170 μm. Commercially available products such as Ceorus KG-1000, Ceorus UF-711, and Ceorus KG-802 (trade name) (Asahi Kasei Chemicals) can be used.

The content of the cellulose-based water-swellable polymer is about 1 to 99%, preferably 5 to 85%, in the formulation.

On the other hand, examples of other medicinal ingredients that can be arbitrarily blended in the cold remedies of the present invention include central nervous system stimulants such as anhydrous caffeine, caffeine, sodium caffeine benzoate; ctothiamin, prosultiamine, fursultiamine. , fursultiamine hydrochloride, bisbentiamine, benf, thiamine, disetiamine hydrochloride, sicothiamine, cocarboxylase, thiamine disulfide, thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine dicetyl sulfate, bisivtiamine and other vitamin _B1 and its derivatives and their salts, vitamin B2 such as riboflavin, riboflavin butyrate, riboflavin sodium phosphate, flavin adenine dinucleotide sodium and its derivatives and their salts, vitamin _C such as ascorbic acid, sodium ascorbate, calcium ascorbate and Its derivatives and their salts, hesperidin and its derivatives and their salts, vitamin A such as vitamin F, retinol acetate, retinol palmitate and its derivatives and their salts, tocopherol succinate, tocopheryl calcium succinate, tocopherol acetate, tocopherol and vitamins such as vitamin E, derivatives thereof, and salts thereof.

Of these, the amount of central nervous system stimulants varies depending on the type, but one or more of them should be added to the preparation so that the daily dose for adults is 15 to 1200 mg, and further 5 to 300 mg. preferably prepared. More specifically, it is preferable to add sodium caffeine benzoate to a dosage of 30 to 300 mg and caffeine or anhydrous caffeine to a dosage of 5 to 150 mg per day for an adult in the formulation.

In addition, although the amount of vitamins to be added varies depending on the type, it is preferable to prepare preparations so that the daily dose for adults of one or more of them is 0.5 to 3000 mg, more preferably 1 to 2000 mg.

More specifically, vitamin _B1 is preferably blended so that the daily dose for adults is 0.1 to 100 mg, _more preferably 0.5 to 50 mg, particularly 1 to 25 mg. The daily dose of 0.1 to 45 mg, preferably 1 to 30 mg, particularly 2 to 12 mg, is preferably blended. It is preferable to add 50 to 500 mg of hesperidin, and hesperidin is preferably added to the preparation so that the daily dose for adults is 1 to 270 mg, more preferably 9 to 180 mg, particularly 18 to 90 mg.

In addition to the antacids that neutralize gastric acid described as basic components, antacids that suppress gastric acid secretion and gastric mucosa protective agents may be added to the cold medicine of the present invention.

Examples of antacids that suppress gastric acid secretion include omeprazole, lansoprazole, rabeprazole sodium, esomeprazole, famotidine, ranitidine, cimetidine, roxatidine, nizatidine, lafutidine, pirenzepine, tikidium, and proglumi.

These gastric acid secretion-suppressing antacids may be used singly or in combination of two or more. The amount is preferably 2 to 1600 mg, more preferably 5 to 1200 mg.

More specifically, the daily dose is 5-20 mg for omeprazole, 7.5-30 mg for lansoprazole, 5-20 mg for rabeprazole sodium, and 5-20 mg for esomeprazole (as magnesium hydrate). , famotidine 10-40 mg, ranitidine (as hydrochloride) 75-300 mg, cimetidine 200-800 mg, roxatidine (as acetate hydrochloride) 30-150 mg, nizatidine 75-300 mg, lafutidine , 5 to 20 mg, pirenzepine (as hydrochloride hydrate) 30 to 100 mg, tikididium (as hydrate) 5 to 30 mg, and proglumide 300 to 1600 mg.

Furthermore, examples of gastric mucosal protective agents include teprenone, aldioxa, sucralfate, cetraxate, azulene, rebamipide, etc., and mucopolysaccharides. These gastric mucosal protective agents may be used singly or in combination of two or more.

The amount of the gastric mucosal-protecting agent to be added varies depending on the type of the gastric mucosal-protecting agent, but it is preferable that the dosage for adults is 0.5 to 3600 mg, more preferably 1 to 1200 mg per day. More specifically, the daily dosage is 15-150 mg for teprenone, 40-400 mg for aldioxa, 150-3600 mg for sucralfate (as hydrate), 60-800 mg for cetraxate (as hydrochloride), and 60-800 mg for azulene (as sulfone). It is preferable to add 0.5 to 6 mg (as sodium salt) and 15 to 300 mg of rebamipide in the formulation.

Furthermore, the cold remedy of the present invention can also be blended with an anti-inflammatory/antipyretic/analgesic agent other than naproxen or a pharmaceutically acceptable salt thereof. Examples of such ingredients include acetaminophen, lactylphenetidine, aspirin, aspirin aluminum, ethenzamide, sazapyrin, salicylamide, sodium salicylate, isopropylantipyrine, ibuprofen, aluminoprofen, loxoprofen, glycyrrhizic acid and its salts, tranexam. acids and the like. These may be used singly or in combination of two or more.

Although the amount of the above anti-inflammatory/antipyretic/analgesic agent varies depending on the type, it may be blended into the formulation so that the daily dose for adults is 3 to 4500 mg, more preferably 6 to 3000 mg.

More specifically, the daily doses are 30-1500 mg for acetaminophen, 20-600 mg for lactylphenetidine, 75-1500 mg for aspirin, 100-2000 mg for aspirin aluminum, 50-1500 mg for ethenzamide, and 100-1500 mg for sazapirin. 3000 mg Salicylamide 100-3000 mg Sodium Salicylate 100-3000 mg Isopropylantipyrine 15-450 mg Ibuprofen 15-600 mg and a salt thereof (as glycyrrhizic acid) in an amount of 3 to 39 mg, and tranexamic acid in an amount of 10 to 750 mg.

Furthermore, examples of other medicinal ingredients include crude drug ingredients other than those described in each of the medicinal ingredients.

Examples of these herbal ingredients include herbal medicines such as fennel, Phellodendron bark, coptis, zedoary, chamomile, cinnamon bark, gentian, bitter gourd, animal bile (including tonga), sage, sojutsu, chowaji, pyakujutsu, chiksettsu ginseng and carrot, or their extracts. , Kakkonto, Kakkonto Kakikyo, Keikoto, Kososan, Saikokeishito, Shosaikoto, Shoseiryuto, Bakumondo, Hangekobokuto, and Maoto. These crude drug components can be used singly or in combination of two or more.

Although the above-mentioned crude drug components differ depending on the type, it is preferable to incorporate them into the formulation so that the daily dose for an adult is about 0.002 to 30 g (converted crude drug amount). More specifically, the daily dosage in terms of crude drugs is 0.5 to 6 g, further 1 to 3 g for fennel, 0.5 to 6 g, further 1 to 3 g for Phellodendron bark, and 0.1 to 0.1 g for coptis. 6g, further 0.5-3g, zedoary 0.5-6g, further 1-3g, chamomile 1-15g, further 2-10g, cinnamon 0.2-10g, further 0.5- 5g, 0.05-1g for gentian, 0.1-0.5g, 0.002-0.04g for Chinese gourd, 0.01-0.02g for animal bile (including Utan), 0.05g 0.1-0.5g, 0.25-10g, 0.5-5g, ginger 0.1-5g, 0.2-3g, sojutsu 0 0.5-10g, further 1-5g, Chowaji 0.1-3g, further 0.2-2g, Chimpi 0.5-6g, further 1-5g, Pyakujutsu 0.2-6g, further 1-5g, 0.2-6g, further 0.4-3g for Jiryu, 0.3-9g, further 0.6-6g for Chikusetsu carrots, 0.3-9g, further 0.6g for carrots. Since 6 to 6 g is preferable, it may be blended in the formulation so as to achieve such an amount.

Kakkonto is 5-50g, further 10-25g, Kakkonto Kakikyo is 5-58g, further 9-29g, Keikousan is 3-30g, further 6-15g, Kososan is 1.5-22g, further 3-11g, Saiko-keishito 4-48g, 8-24g, Shosaikoto 4-48g, 8-24g, Shoseiryuto 4-48g, 8-24g, Bakumondo 5-5g. 60 g, further 12 to 30 g, hangekobokuto 2 to 32 g, further 3 to 16 g, and maoto 1 to 26 g, further 3 to 13 g.

The general cold medicine of the present invention comprises the above naproxen or a salt thereof, an anti-nasal inflammation component, an antitussive component, an expectorant component, and, if necessary, other pharmaceutical ingredients and formulation additives commonly used in the pharmaceutical field. are combined and formulated by a known method.

Examples of formulation additives used include excipients, binders, disintegrants, lubricants, various carriers, stabilizers, surfactants, plasticizers, lubricants, soluble (chemical) agent, reducing agent, buffering agent, sweetener, base, adsorbent, flavoring agent, suspending (chemical) agent, antioxidant, brightening agent, coating agent, shell, wetting agent, moisture control agent , fillers, antifoaming agents, cooling agents, coloring agents, flavoring agents, fragrances, sugar coating agents, isotonizing agents, softening agents, emulsifiers, thickening agents, thickening agents, foaming agents, pH adjusters, Diluents, dispersants, disintegration aids, disintegration extenders, fragrances, moisture-proof agents, preservatives, preservatives, solubilizers, solubilizers, solvents, fluidizers, antistatic agents, bulking agents, humectants, attachments Formulation additives such as wetting agents may be included. Specific examples of these additives include the PFSB Notification No. 1204 No. 1 (Pharmaceutical Affairs Administrative Law), Pharmaceutical Excipients Encyclopedia 2016 (edited by the Japan Pharmaceutical Excipients Association, Yakuji Nippo) and the 8th Edition Food Additives Standards (Japan Japan Food Additives Association).

The cold medicine of the present invention includes tablets, caplets, hard capsules, soft capsules, orally disintegrating tablets, chewable tablets, lozenges, effervescent tablets, fine granules, granules, powders, dry syrups, and other solid solids for internal use. It is provided in the form of formulations, oral liquids, and syrups. Also, if necessary, film coating or sugar coating can be applied to prepare a coated formulation of the above formulation. For these dosage forms, a commonly used formulation method (Kyosuke Tsuda and Hisashi Ueno, "Drug Development Basic Course XI Drug Manufacturing Method (1) (2)", Chijin Shokan, 1971); Yu Nakai Nori, "Pharmaceutical Engineering Handbook", Chijin Shokan, 1983; Yoshinobu Nakai, "Development of Pharmaceuticals 11 Unit Operations and Machines for Formulations", Hirokawa Shoten, 1989; Mitsuru Hashida, "Oral Administration Preparations" Design and Evaluation, Yakugyo Jihosha, 1995; Mitsuru Hashida, "Prescription Design of Orally Administered Formulation," Yakugyo Jihosha, 1995). Microparticles such as microcapsules, nanocapsules, microspheres, nanospheres and liposomes may also be used.

Furthermore, in the cold remedy of the present invention, if desired, a part of the active ingredient may be subjected to a sustained-release treatment to prepare a twice-daily or once-daily dosage formulation.

The cold medicine of the present invention produced as described above can be stored in a sealed container such as a glass bottle, a plastic bottle, a PTP package, or an aluminum heat seal package. A desiccant may be enclosed.

The cold remedy of the present invention obtained in this way is usually divided into 2 to 3 times a day, and it is preferable to take it with water or lukewarm water, avoiding fasting as much as possible, with a maximum of 3 times a day. When divided into 2 doses, the interval between doses should be 6 hours or more, and when divided into 3 doses, the interval between doses should preferably be 4 hours or more.

Hereinafter, the present invention will be specifically described with reference to Formulation Examples, Examples, and Test Examples, but the present invention is not limited to these.

Formulation example 1
(tablet)
For each tablet, an immediate-release portion and a sustained-release portion were prepared according to the following formulation according to a conventional method. These were then used to manufacture tablets as bilayer tablets.

Formulation example 2
(tablet)
For each tablet, an immediate-release part and a sustained-release part were prepared according to the following formulation according to a conventional method. These were then used to manufacture tablets as bilayer tablets.

Formulation example 3
(granules)
Granules were produced according to a conventional method according to the following formulation per packet.

Formulation example 4
(granules)
Granules were produced according to a conventional method according to the following formulation per packet.

Formulation example 5
(granules)
Granules were produced according to a conventional method according to the following formulation per packet.

Formulation example 6
(tablet)
Powders blended so as to have the following formulation per tablet were tableted according to a conventional method to obtain tablets. The tablets were coated with 10 mg of hypromellose per tablet to produce film-coated tablets.

Formulation example 8
(hard capsule)
A rapid-release portion and a sustained-release portion were prepared according to a conventional method so that each capsule had the following formulation, and these were filled into hard capsules to produce hard capsules.

Formulation example 9
(granules)
Granules were produced according to a conventional method according to the following formulation per packet.

Formulation example 10
(tablet)
For each tablet, an immediate-release portion and a sustained-release portion were prepared according to the following formulation according to a conventional method. These were then used to manufacture tablets as bilayer tablets.

Test example 1
Allergic Rhinitis Suppression Test:
Suppression of increased nasal resistance by naproxen (NPX), chlorpheniramine maleate (CF), combination of NPX and CF, dl-methylephedrine hydrochloride (MF), and combination of NPX and MF using an allergic rhinitis model examined the effects. As an allergic rhinitis model, guinea pigs were actively sensitized with an antigen (ovalbumin, OVA) and intranasally administered with the antigen to induce a rhinitis reaction.

The study included a control group, a naproxen group (NPX 60 mg/kg), a chlorpheniramine maleate group (CF 0.75 mg/kg), a combined NPX and CF group (NPX 60 mg/kg + CF 0.75 mg/kg), MF group (MF 6 mg/kg), NPX, MF combination group (NPX 60 mg/kg + MF 6 mg/kg), a total of 6 groups, 8 subjects each, were set up. A 0.5 w/v % aqueous solution of methyl cellulose) was administered by forced oral administration. A control group received vehicle only.

Before and 2 hours after the induction of rhinitis reaction, nasal resistance was measured in conscious guinea pigs, and the rate of increase in nasal resistance before and after the induction of rhinitis was calculated. Nasal resistance was measured using a comprehensive respiratory function measurement system (Pulmos-I, MIPS), and nasal resistance (nasal airway resistance, nRaw) was measured for 100 breaths or more once at each measurement point, and 100 breaths were taken. was taken as the nRaw of the individual at each measurement time. From this nRaw, the rate of increase in nRaw (%) after 2 hours of induction is calculated using the formula below.
was calculated.

nRaw increase rate (%) = nRaw(2) - nRaw(0) / nRaw(0) × 100
nRaw(0); nRaw value before induction
nRaw(2); nRaw value 2 hours after induction

Furthermore, based on the nRaw increase rate obtained as described above, the difference between the nRaw increase rate of the control group and the nRaw increase rate of each other group 2 hours after induction was calculated as the rhinitis suppression rate by the following formula, made an evaluation. The results are shown in Tables 10 and 11.

Rhinitis suppression rate (%) = ΔnRaw(con.) - ΔnRaw(2) / ΔnRaw(con.) × 100
ΔnRaw(con.); nRaw increase rate of control group ΔnRaw(2); nRaw increase rate of each sample 2 hours after induction

Test example 2
Investigation of the interaction between naproxen and expectorant components in the presence of basic components:
Naproxen, expectorant component (ambroxol hydrochloride), basic component (magnesium oxide, magnesium hydroxide, potassium hydrogen carbonate, sodium hydrogen carbonate) were weighed in the amounts shown in Table 12, and 10% of the total weight of purified water was added. and kneaded to prepare a mixture of 1 to 30. These mixtures were placed in glass bottles and stored at 50° C. After 60 days, the state of the mixtures was evaluated to confirm the presence or absence of discoloration. The results are shown together in Table 12.

<Evaluation Criteria>
(Evaluation) (Content)
-: No discoloration ±: Almost no discoloration +: Some discoloration

<Test results>
As shown in Table 12, blending of naproxen and ambroxol hydrochloride, an expectorant component, caused a blending change, suggesting that cold remedies blended with them are less effective and significantly lower in commercial value. . On the other hand, by blending naproxen and ambroxol hydrochloride, and further blending a basic component, no blending change occurred. It was suggested that the combinational change of naproxen and the expectorant component could be prevented by the basic component, and that the effect as a cold medicine could be fully exhibited.

The cold remedy of the present invention using naproxen or a pharmaceutically acceptable salt thereof as an anti-inflammatory analgesic can enhance the effects of other cold medicine components such as antinasal, antitussive and expectorant components. In particular, when free naproxen and a basic substance are combined, the excellent anti-inflammatory and analgesic effect of naproxen can be obtained from the initial stage of administration, and the medicinal effects of other cold medicine components can be felt.

Further, a solid formulation further containing a water-swellable polymer compound has enhanced disintegration properties in the oral cavity and the like when orally ingested, so that more rapid efficacy can be obtained.

Therefore, the cold medicine of the present invention can be advantageously used as an OTC preparation.

Claims (5)

Naproxen or a pharmaceutically acceptable salt thereof and ambroxol or a pharmaceutically acceptable salt thereof as pharmaceutical ingredients, and further from the group consisting of magnesium oxide, magnesium hydroxide, potassium hydrogen carbonate and sodium hydrogen carbonate A cold remedy characterized by containing one or more selected basic components. The cold remedy according to claim 1, further comprising a cellulose-based water-swellable polymer. The cellulosic water-swellable polymer was selected from the group consisting of low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, microcrystalline cellulose, pregelatinized starch and sodium carboxymethylstarch. The cold medicine according to claim 2, which is a The cold medicine according to any one of claims 1 to 3, which is a solid preparation. In a pharmaceutical composition containing naproxen or a pharmaceutically acceptable salt thereof and ambroxol or a pharmaceutically acceptable salt thereof as pharmaceutical ingredients, magnesium oxide, magnesium hydroxide, potassium hydrogen carbonate and sodium hydrogen carbonate A method for preventing discoloration of a pharmaceutical composition, which comprises blending one or more basic components selected from the group consisting of: