JP2018076305A - Pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition containing naproxen, in which an analgesic-antipyretic antiphlogistic effect of the naproxen is improved.SOLUTION: The present invention provides a pharmaceutical composition that contains naproxen or a pharmaceutically acceptable salt thereof, and a medical component selected from a central nervous system stimulant, a sedative, a gastric mucosa protection agent, an antispasmodic agent, a muscle relaxant and a migraine agent. The pharmaceutical composition may further contain a basic component.SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition, and more specifically, as an OTC drug (general drug), the anti-inflammatory action, analgesic action and antipyretic action are further improved as compared with the conventional one, and handling is easy. The present invention relates to a pharmaceutical composition containing naproxen, which is suitable for self-medication and is easy to use for relief of symptoms of mild illness, and is easy to handle at the time of distribution and excellent in safety and stability.

  Naproxen is a non-steroidal antipyretic analgesic / antiinflammatory agent of propionic acid type, and has anti-inflammatory, analgesic, and antipyretic effects by suppressing biosynthesis of prostaglandins that cause fever and inflammation.

  Naproxen has the pharmacological action as described above, and further attempts have been made to increase the drug efficacy of naproxen itself. For example, it has been reported that a complex of naproxen and zinc (naproxen-zinc complex) increases the anti-inflammatory effect of naproxen (Patent Document 1).

  However, in order to obtain this naproxen-zinc complex, first, naproxen and zinc are reacted in an aqueous solvent, and then the obtained precipitate is washed and dried, which requires time and effort in the production process. There was a problem.

Japanese Patent Laid-Open No. 10-298072

  Therefore, an object of the present invention is to provide a pharmaceutical composition in which the antipyretic analgesic / anti-inflammatory effect of naproxen is further enhanced by simple means.

  The inventors of the present invention have been diligently researching to solve the above-mentioned problems. By combining naproxen or a pharmaceutically acceptable salt thereof with a specific pharmaceutical ingredient, the antipyretic analgesic / anti-inflammatory effect of naproxen is enhanced. And found that a more effective pharmaceutical composition can be obtained. In particular, it has been found that an excellent antipyretic analgesic and anti-inflammatory effect can be obtained from the initial stage of oral administration by adding a basic component to naproxen and the above-mentioned pharmaceutical component, and a pharmaceutical composition that works quickly and well can be obtained. In addition, by adding a cellulose-based water-swellable polymer to this, it has been found that a pharmaceutical composition with good disintegration and quick action can be obtained even when a solid preparation is obtained. Was completed.

  That is, the present invention relates to a medicament comprising naproxen or a pharmaceutically acceptable salt thereof and a pharmaceutical ingredient selected from a central nervous stimulant, a sedative, a gastric mucosa protective agent, an antispasmodic agent, a muscle relaxant and a migraine agent. It is a composition.

  Moreover, this invention is the said pharmaceutical composition which contains a basic component further.

  Furthermore, the present invention is the above pharmaceutical composition further comprising a cellulosic water-swellable polymer.

  The pharmaceutical composition of the present invention combines naproxen or a pharmaceutically acceptable salt thereof with a pharmaceutical ingredient selected from a central nervous stimulant, a sedative, a gastric mucosal protective agent, an antispasmodic agent, a muscle relaxant and a migraine agent. Thus, the antipyretic analgesic / anti-inflammatory effect of naproxen is enhanced.

  Further, the pharmaceutical composition of the present invention further containing a basic component is one in which naproxen has an excellent antipyretic analgesic and anti-inflammatory action from the initial stage of oral administration. Furthermore, even when the pharmaceutical composition of the present invention containing a cellulose-based water-swellable polymer is a solid preparation, the disintegration in the oral cavity or the like at the time of oral administration is enhanced, and a quicker drug effect can be obtained. Was made.

It is drawing which showed the result of the analgesic effect enhancement test. A shows the result of the first day, and B shows the result of the second day.

  The pharmaceutical composition of the present invention contains naproxen or a pharmaceutically acceptable salt thereof and a pharmaceutical ingredient selected from a central nervous stimulant, a sedative, a gastric mucosal protective agent, an antispasmodic agent, a muscle relaxant and a migraine agent. Is.

Naproxen used in the pharmaceutical composition of the present invention has the chemical name (2S) -2- (6-methoxynaphthalen-2-yl) propanoic acid ((2S) -2- (6-Methoxynaphthalen-2-yl). propanoic acid), the molecular formula is C ₁₄ H ₁₄ O ₃ and its molecular weight is 230.26. Naproxen is an anti-inflammatory analgesic that is already known as a propionic non-steroidal anti-inflammatory analgesic, including rheumatoid arthritis, osteoarthritis, gout attacks, ankylosing spondylitis, low back pain, periarthritis, cervical shoulder-arm syndrome , Tendon / tendonitis, dysmenorrhea, herpes zoster disease, analgesia, antipyretic, post-traumatic and post-operative anti-inflammatory, analgesia, tooth extraction in dental / oral surgery field, anti-inflammatory, analgesia after minor surgery, etc. It is widely used.

  Examples of the pharmaceutically acceptable salt of naproxen in the pharmaceutical composition of the present invention include sodium salt, potassium salt, ammonium salt, meglumine salt, tris salt, basic amino acid salt and the like.

  The blending amount of naproxen or a pharmaceutically acceptable salt (hereinafter also simply referred to as “naproxen”) in the pharmaceutical composition of the present invention may be appropriately determined depending on the sex, age, symptoms, etc. of the user. For example, for the effectiveness and safety as an OTC pharmaceutical, the daily dose for an adult is usually 10 to 1200 mg, preferably 15 to 900 mg, more preferably 20 to 600 mg in the pharmaceutical composition of the present invention. It is preferable to blend in. In addition, the content of naproxen with respect to the total mass of the pharmaceutical composition of the present invention is, for example, preferably 1 to 99% by mass (hereinafter referred to as “%”), and more preferably 5 to 95%.

  On the other hand, in the pharmaceutical composition of the present invention, in addition to the above-mentioned naproxen, one or more pharmaceutical components selected from central nervous stimulants, sedatives, gastric mucosal protective agents, antispasmodics, muscle relaxants and migraine drugs are blended. .

  Among these, examples of the central nervous stimulant include sodium benzoate caffeine, caffeine, and anhydrous caffeine, and these can be used alone or in combination of two or more. Among these, caffeine and anhydrous kaphene are preferable.

  The compounding amount of the central nervous stimulant varies depending on the type of central nervous stimulant, but in the pharmaceutical composition of the present invention, the daily dose for an adult is about 15 to 1200 mg, preferably about 50 to 300 mg. It is preferable to blend in. Moreover, it is preferable to mix | blend caffeine and anhydrous caffeine in the pharmaceutical composition of this invention so that it may become 50-250 mg as a daily dose of each central nervous stimulant.

  Examples of the sedative used in the pharmaceutical composition of the present invention include allyl isopropyl acetyl urea and bromovaleryl urea, and these can be used alone or in combination of two kinds.

  The amount of the sedative varies depending on the type of sedative, but it may be formulated in the pharmaceutical composition of the present invention so that the daily dose for an adult is about 15 to 1200 mg, preferably about 30 to 600 mg. preferable. Moreover, as a daily dose of each sedative, it is preferable to mix | blend in the pharmaceutical composition of this invention so that allyl isopropyl acetyl urea may be 30-180 mg and bromovaleryl urea may be 100-600 mg.

  Furthermore, examples of the gastric mucosa protective agent used in the pharmaceutical composition of the present invention include teprenone, aldioxa, sucralfate, cetraxate, azulene, rebamipide and the like, and these can be used alone or in combination of two or more. it can. Among these, teprenone and azulene are preferable.

  The compounding amount of the gastric mucosa protective agent varies depending on the type of the gastric mucosa protective agent, but the pharmaceutical composition of the present invention is about 0.5 to 3600 mg, preferably about 1 to 1200 mg as a daily dose for an adult. It is preferable to mix in. Moreover, it is preferable to mix | blend the pharmaceutical composition of this invention so that it may become 15-150 mg of teprenone and 0.5-6 mg of azulene (as sodium sulfonate) as the compounding quantity of each gastric mucosa protective agent. .

  Furthermore, examples of the antispasmodic agent used in the pharmaceutical composition of the present invention include, for example, butyl scopolamine or a salt thereof, timepidium bromide, papaverine hydrochloride, ethyl aminobenzoate, funnel extract, and the like. Two or more types can be used in combination. Among these, butyl scopolamine or a salt thereof and funnel extract are preferable.

  The compounding amount of the antispasmodic agent varies depending on the type of antispasmodic agent, but may be formulated in the pharmaceutical composition of the present invention so that the daily dose for an adult is about 0.5 to 600 mg, preferably about 1 to 400 mg. preferable. Moreover, it is preferable to mix | blend in the pharmaceutical composition of this invention so that a butyl scopolamine (as a bromide) may be 1-100 mg and a funnel extract will be 3-90 mg as a compounding quantity of each antispasmodic agent.

  Examples of the muscle relaxant used in the pharmaceutical composition of the present invention include metcarbamol, tolperisone, chlorzoxazone, pridinol mesylate, chlorphenesine carbamate, eperisone hydrochloride, afroqualone, tizanidine, baclofen and the like. These may be used alone or in combination of two or more. Among these, metcarbamol and eperisone hydrochloride are preferable.

  The compounding amount of the muscle relaxant varies depending on the type of the muscle relaxant, but the pharmaceutical composition of the present invention is such that the daily dose for an adult is about 0.05 to 2000 mg, preferably about 0.1 to 1500 mg. It is preferable to mix in. Moreover, as a compounding quantity of each muscle relaxant, it is preferable to mix | blend in the pharmaceutical composition of this invention so that a methocarbol may be 50-1500 mg and an eperisone hydrochloride may be 5-150 mg.

  Examples of migraine drugs used in the pharmaceutical composition of the present invention include zolmitriptan, sumatriptan, naratriptan, rizatriptan, eletriptan, lomelidine hydrochloride, dimethothiazine mesylate, dihydroergotamine, and the like. Can be used alone or in combination of two or more. Among these, zolmitriptan and sumatriptan are preferable.

  The compounding amount of the migraine drug differs depending on the type of the migraine drug, but the pharmaceutical composition of the present invention is such that the daily dose for an adult is about 0.05 mg to 40 g, preferably about 0.1 mg to 25 g. It is preferable to mix in. Moreover, as a compounding quantity of each migraine drug, it is preferable to mix | blend in the pharmaceutical composition of this invention so that solmitriptan will be 0.25-10 mg and sumatriptan will be 5-200 mg.

  In the pharmaceutical composition of the present invention, in addition to the above-described respective pharmaceutical ingredients, a pharmaceutical ingredient and other pharmaceutical ingredients other than those described above may be blended as necessary.

  As a pharmaceutical ingredient, a basic ingredient, also known as an antacid that neutralizes gastric acid, can be blended in the pharmaceutical composition of the present invention, whereby the onset of the anti-inflammatory analgesic effect of naproxen can be accelerated.

  Examples of such basic components include magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel, dry aluminum hydroxide gel , Aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / calcium carbonate / magnesium carbonate coprecipitation product, magnesium hydroxide / potassium aluminum sulfate coprecipitation product , Magnesium carbonate, Magnesium aluminate metasilicate, Magnesium aluminate silicate, Magnesium aluminate hydroxide, Magnesium hydroxide, Sodium hydrogen carbonate, Precipitated calcium carbonate, Calcium hydrogen phosphate anhydrous, Phosphoric acid Containing calcium and the like. These can be used alone or in combination of two or more.

  The above basic component varies depending on the type, but is preferably blended in the pharmaceutical composition of the present invention so that the daily dose for an adult is 10 to 5000 mg, more preferably 16 to 4000 mg.

  More specifically, as the daily dose of each basic component for adults, the coprecipitation product of aluminum hydroxide / sodium bicarbonate is 30 to 900 mg, magnesium silicate, synthetic aluminum silicate and aluminum hydroxide / carbonate. Magnesium mixed dry gel is 100 to 3000 mg, synthetic hydrotalcite is 133 to 4000 mg, magnesium oxide is 16 to 500 mg, co-precipitated product of dihydroxyaluminum / aminoacetate, aluminum hydroxide / calcium carbonate / magnesium carbonate, Magnesium aluminate metasilicate, precipitated calcium carbonate and calcium hydrogen phosphate are 50 to 1500 mg, aluminum hydroxide gel and dry aluminum hydroxide gel are 33 to 1000 mg as dry aluminum hydroxide gel, magnesium hydroxide 60-800 mg of coprecipitation product of aluminum potassium potassium sulfate, magnesium carbonate, magnesium aluminate silicate and magnesium aluminate 66-2000 mg, magnesium hydroxide and anhydrous calcium hydrogen phosphate 40-1200 mg, It is preferable to mix | blend sodium hydrogencarbonate in the pharmaceutical composition of this invention so that it may become 83-2500 mg.

  Among these, more preferable examples include inorganic compounds containing divalent or trivalent metals. 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 / potassium aluminum sulfate And coprecipitation products, magnesium carbonate, magnesium aluminate metasilicate, and the like.

  Moreover, it is desirable to mix a cellulose-based water-swellable polymer in the pharmaceutical composition of the present invention as the preparation component. Disintegration and dissolution in the oral cavity during oral administration when the pharmaceutical composition of the present invention is made into an internal solid preparation such as tablets, capsules, granules, etc. Can increase the sex.

  This cellulosic water-swellable polymer swells when contacted with water and promotes the disintegration of the preparation. Examples of preferred cellulosic water-swellable polymers include low-substituted hydroxypropylcellulose, carmellose calcium, croscarmellose sodium, carboxymethylcellulose sodium, carboxymethylcellulose, crystalline cellulose, pregelatinized starch, carboxymethyl starch sodium, and the like. It is done. These can be used alone or in combination of two or more.

  Among these cellulose-based water-swellable polymers, preferred are low-substituted hydroxypropylcellulose, carmellose calcium, croscarmellose sodium, crystalline cellulose and the like.

  When low-substituted hydroxypropylcellulose is used as the cellulosic water-swellable polymer, the hydroxypropoxy group has a molecular weight of 5.0 to 16 in terms of manufacturability, which is easy to process into an oral solid composition having an excellent shape and particle size. What is 0 mass% is preferable, and what is 7.0-13.0 mass% is more preferable. Examples of such low-substituted hydroxypropylcellulose include, for example, LH-31 (hydroxypropoxy group 10.0 to 12.9% by mass), NBD-022 (hydroxypropoxy group 7.0 to 0.05%) manufactured by Shin-Etsu Chemical Co., Ltd. 9.9% by mass). Furthermore, the average particle size of the low-substituted hydroxypropyl cellulose is preferably about 60 μm or less, and more preferably 55 μm or less.

  Moreover, as carmellose calcium used as a cellulosic water-swellable polymer, for example, ECCG-505 (Gotoku Pharmaceutical) is mentioned.

  Furthermore, croscarmellose sodium used as the cellulose-based water-swellable polymer is a white to yellowish white powder. Examples of such croscarmellose sodium include kikkolate (Asahi Kasei Chemicals).

Furthermore, when crystalline cellulose is used as the cellulose-based water-swellable polymer, there are various grades, but the bulk density of the powder is from 0.10 to 0.55 g / cm ³ , and the average particle size is It is preferable to use highly moldable crystalline cellulose exhibiting 20 to 300 μm. More preferably, the bulk density is from 0.10 to 0.43 g / ml, and the average particle size is from 20 to 170 μm. As commercially available products, for example, Theolas KG-1000, Theolas UF-711, Theolas KG-802 (trade name) (Asahi Kasei Chemicals) and the like can be used.

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

  On the other hand, examples of other pharmaceutical ingredients that can be optionally blended in the pharmaceutical composition of the present invention include other anti-inflammatory / antipyretic / analgesic drugs other than naproxen or pharmaceutically acceptable salts thereof, herbal medicines, vitamins, Examples include mucopolysaccharides.

  Other anti-inflammatory / antipyretic / analgesic agents other than naproxen or pharmaceutically acceptable salts thereof include, for example, acetaminophen, lactylphenetidine, aspirin, aspirin aluminum, etenzamide, sazapyrine, salicylamide, sodium salicylate, isopropylantipyrine , Ibuprofen, aluminoprofen, loxoprofen, tranexamic acid and the like. These central nervous stimulants can be used alone or in combination of two or more.

  The amount of anti-inflammatory / antipyretic / analgesic drug other than naproxen or its pharmaceutically acceptable salt varies depending on the type of anti-inflammatory / antipyretic / analgesic drug, but it is about 3-4500 mg per day for adults. It is preferable to blend in the pharmaceutical composition of the present invention so as to be about 6 to 3000 mg. More specifically, the daily dose for adults is 30 to 1500 mg acetaminophen, 20 to 600 mg lactylphenetidine, 75 to 1500 mg aspirin, 100 to 2000 mg aspirin aluminum, 50 to 1500 mg ethenamide, 100-3000 mg, salicylamide 100-3000 mg, sodium salicylate 100-3000 mg, isopropylantipyrine 15-450 mg, ibuprofen 15-600 mg, aluminoprofen 20-600 mg, loxoprofen (as an anhydride) 6-180 mg, It is preferable to mix tranexamic acid in the pharmaceutical composition of the present invention so as to be 10 to 750 mg.

  Examples of the herbal medicine include earth dragons, licorice, kehi, peony, buttonpi, valerian, salamander, ginger, chimpi and the like. These herbal medicines can be used alone or in combination of two or more.

  The blending amount of the crude drug varies depending on the type of the crude drug, but it is preferably blended in the pharmaceutical composition of the present invention so that the daily dose for an adult is about 0.05 to 9 g in terms of the crude drug equivalent. More specifically, the daily dose of the raw material equivalent amount is 0.2 to 4.5 g, preferably 0.4 to 3 g for ground dragon, and 0.05 to 7.5 g for liquorice, preferably Is 0.1 to 5 g, Keihi is 0.1 to 7.5 g, preferably 0.2 to 5 g, and peony is 0.2 to 7.5 g, preferably 0.4 to 5 g. , Button pin is 0.2-9g, preferably 0.4-6g, valerian is 0.2-9g, preferably 0.4-6g, sanshuyu is 0.1-3g, preferably 0.2 to 2 g, and 0.05 to 4.5 g, preferably 0.1 to 3 g of the pepper, and 0.15 to 7.5, preferably 0.3 to 5 g of the chimney. Thus, it is preferable to mix in the pharmaceutical composition of the present invention.

  Furthermore, examples of vitamins include vitamin B1, vitamin B2, vitamin C, hesperidin and the like, and these vitamins may be derivatives or salts thereof. Specifically, vitamin B1 and derivatives thereof and salts thereof include thiamine, thiamine chloride hydrochloride, thiamine nitrate, thiamine disulfide nitrate, thiamine disulfide, thiamine dicetyl sulfate, dicetiamine hydrochloride hydrate, full Examples include sultiamine hydrochloride, fursultiamine, octothiamine, chicotiamine, bisbutiamine, bisbenchamine, prosultiamine, benfotiamine, cocarboxylase, and dibenzoylthiamine. Examples of vitamin B2 and derivatives thereof and salts thereof include riboflavin, riboflavin butyrate, riboflavin sodium phosphate, and flavin adenine dinucleotide. Furthermore, examples of vitamin C and its derivatives and salts thereof include ascorbic acid, metal ascorbate (sodium ascorbate, potassium ascorbate, calcium ascorbate, magnesium ascorbate, aluminum ascorbate, etc.) and the like. Further, examples of hesperidin and its derivatives and salts thereof include hesperidin and αG hesperidin. These vitamins can be used alone or in combination of two or more.

  The blending amount of these vitamins may vary depending on the type, but it may be blended in the pharmaceutical composition of the present invention so that the daily dose for an adult is about 0.1 to 3000 mg, preferably about 1 to 2000 mg. . More specifically, vitamin B1 may be formulated in the composition of the present invention so that the daily dose for an adult is 0.1 to 100 mg, preferably 0.5 to 50 mg, more preferably 1 to 25 mg. preferable. B2 is preferably blended in the composition of the present invention so that the daily dose for an adult is 0.1 to 45 mg, preferably 1 to 30 mg, more preferably 2 to 12 mg. Furthermore, it is preferable to mix vitamin C in the composition of the present invention so that the daily dose for an adult is 5 to 2000 mg, preferably 25 to 1000 mg, more preferably 50 to 500 mg. Furthermore, hesperidin is preferably added to the composition of the present invention so that the daily dose for an adult is 1 to 270 mg, preferably 9 to 180 mg, more preferably 18 to 90 mg.

  Examples of the mucopolysaccharide include glucosamine, chondroitin and the like. These mucopolysaccharides can be used alone or in combination of two or more. The amount of mucopolysaccharide blended varies depending on the type of mucopolysaccharide, but the daily dose for an adult is about 0.01 mg to about 40 g, more preferably about 0.1 mg to about 25. It is preferable to mix in the composition. As the compounding amount of each mucopolysaccharide, glucosamine (as glucosamine hydrochloride) is preferably compounded in the composition of the present invention so as to be 10 to 1000 mg and chondroitin (as sodium chondroitin sulfate) to 20 to 900 mg.

  Moreover, you may add to the pharmaceutical composition of this invention the antacid which suppresses secretion of a stomach acid besides the type of antacid which neutralizes the stomach acid demonstrated as a basic component.

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

  These gastric acid secretion suppression type antacids may be used alone or in combination of two or more, and the amount of the antacid varies depending on the type of antacid, but it is 2 to 1600 mg as a daily dose for an adult, It is preferable to mix | blend in this invention composition so that it may become 5-1200 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 is 10 to 40 mg, ranitidine (as hydrochloride) is 75 to 300 mg, cimetidine is 200 to 800 mg, roxatidine (as acetate hydrochloride) is 30 to 150 mg, nizatidine is 75 to 300 mg, and lafutidine is 5-20 mg, pirenzepine (as hydrochloride hydrate) is 30-100 mg, thikikidium (as hydrate) is 5-30 mg, and proglumide is 300-1600 mg. Is preferred.

  The pharmaceutical composition of the present invention comprises a medicinal component selected from naproxen, central nervous stimulants, sedatives, gastric mucosal protective agents, antispasmodic agents, muscle relaxants and migraine drugs, and various preparation components as described above and other It is prepared by combining a pharmaceutical ingredient and a pharmaceutical additive generally used in the pharmaceutical field and formulating it by a known method.

  Examples of formulation additives used include excipients, binders, disintegrants, lubricants, various carriers, stabilizers, surfactants, plasticizers, lubricants, soluble agents (Chemical) agent, reducing agent, buffering agent, sweetener, base, adsorbent, taste-masking agent, suspension (chemical) agent, antioxidant, brightener, coating agent, skin, wetting agent, wetting regulator , Fillers, antifoaming agents, cooling agents, coloring agents, flavoring agents, fragrances, dragees, isotonic agents, softeners, emulsifiers, thickening agents, thickening agents, foaming agents, pH adjusting agents, Diluent, Dispersant, Disintegration aid, Disintegration extender, Fragrance, Dehumidifier, Preservative, Preservative, Solubilizer, Dissolving aid, Solvent, Fluidizer, Antistatic agent, Bulking agent, Moisturizer There may be mentioned formulation additives such as wetting agents. Specific examples of these additives are: Yakushoku 1204 No. 1 (Pharmaceutical Administration Law), Pharmaceutical Additives Encyclopedia 2016 (edited by Japan Pharmaceutical Additives Association, Yakuji Nippo) and Eighth Edition Food Additives Official (Japan) (Food Additives Association).

  The pharmaceutical composition of the present invention includes tablets, caplets, hard capsules, soft capsules, orally disintegrating tablets, chewable tablets, troches, effervescent tablets, fine granules, granules, powders, and dry syrups. It is provided as solid dosage forms, oral solutions, and syrup dosage forms. In addition, if necessary, film coating or sugar coating can be applied to form a coating preparation of the above preparation. These dosage forms include the usual formulation methods (Yusuke Tsuda and Toshi Ueno, “Pharmaceutical Development Basic Course XI Pharmaceutical Production Method (top) (bottom)”, Jinshokan, 1971; Yu Nakai Nobu, “Formulation Engineering Handbook”, Jinshokan, published in 1983; Nakano, Yoshinobu, “Pharmaceutical Development 11 Unit Operation and Machine of Drugs”, Yodogawa Shoten, 1989; Hashida, Mitsuru, “Oral Preparations” ”Design and Evaluation”, published by Yakuho Jihosha, 1995; Mitsuru Hashida, “Prescription Design of Orally Administered Drugs”, Yakuho Jihosha, 1995). Further, microparticles such as microcapsules, nanocapsules, microspheres, nanospheres, and liposomes may be used.

  Furthermore, in the pharmaceutical composition of the present invention, if desired, a part of the active ingredient can be subjected to a sustained release treatment to obtain a preparation that can be taken twice a day or once a day.

  The pharmaceutical composition of the present invention produced as described above can be stored in a closed container such as a glass bottle, a plastic bottle, PTP packaging, and aluminum heat seal packaging, and in that case, if necessary, silica gel, activated carbon, etc. The desiccant may be enclosed.

  The pharmaceutical composition of the present invention thus obtained is preferably divided into 2 to 3 times a day, and preferably taken with water or lukewarm water as much as possible, avoiding fasting as much as possible 3 times. If divided into two doses, the dose interval should be 6 hours or more, and if divided into three doses, the interval should be set to 4 hours or more.

  EXAMPLES Hereinafter, although a test example, an Example, and a formulation example are shown and this invention is demonstrated concretely, this invention is not restrict | limited at all by these.

Test example 1
Analgesic enhancement test:
The comparative effect 1 shown in Table 1 shows the effect of enhancing the analgesic effect of naproxen blended with anhydrous caffeine (Invention product 1) and naproxen blended with anhydrous caffeine and allylisopropylacetylurea (Invention product 2). And 2 and 2. In the test, each sample was administered to a morphine withdrawal hypersensitive model mouse (hereinafter referred to as “model mouse”), and the latency of pain reaction was measured by the following hot plate method. The model mouse was prepared by giving a morphine solution to the mouse as drinking water and stopping the morphine treatment on the 15th day from the start of the morphine treatment. Pain response latency was measured using model mice on the day (day 1) and day 2 when morphine treatment was stopped.

<Hot plate method>
When a model mouse is placed on a hot plate type analgesic effect measuring device (HOTPLATE ANALGESIA METER MK-350D, manufactured by Muromachi Kikai Co., Ltd.) set at 52 ° C, the push button of the device is pressed (or the foot switch is depressed) Measurement started. When the model mouse showed a pain response (foot licking, escape behavior), the push button was pressed (or the foot switch was stepped on), and the displayed number of seconds in 0.1 second was defined as the latency (seconds). For the first day of morphine stoppage, the latency was measured after 0.5, 1, 2, and 4 hours from the administration of the sample shown in Table 1, and for the second day of morphine stoppage, The latency was measured after 0.5, 1, 2, 4 and 6 hours from the administration of the sample described in 1.

  Subsequently, the change time with the latency time (seconds) before the test as zero was plotted, a graph was created, and the area (latency change value-area under the time curve) was obtained. Since model mice that became hypersensitive to morphine withdrawal showed a pain response in a shorter time than before the test, in the area under the latency change-time curve, the more negative the area, the more likely it is to feel pain. Represented. The area under the latency change value-time curve on the first day is shown on the right side of FIG. 1, and that on the second day is shown on the left side of FIG. As shown in FIG. 1, on the first day of measurement, naproxen blended with anhydrous caffeine (Invention product 1) and naproxen blended with anhydrous caffeine and allyl isopropylacetylurea (Invention product 2) were naproxen alone (comparison). Inventive product 1 which exhibited a remarkable analgesic effect than product 1), in particular, anhydrous caffeine in naproxen was confirmed to have a significant analgesic effect.

  In addition, even on the second day of measurement, which seems to have escaped from the state of hypersensitivity to pain, invention product 1 in which anhydrous caffeine was added to naproxen rather than naproxen alone (comparative product 1) and anhydrous caffeine and allyl isopropyl in naproxen It was confirmed that the invention product 2 containing acetylurea has a higher analgesic effect. In addition, on the second day of measurement, Invention 2 was better in analgesic effect than Invention 1.

Preparation Example 1
(Tablet)
Each component was blended and mixed to give the following formulation per tablet and tableted according to a conventional method to produce a tablet.

Product example 2
(Granules)
Each component was blended and mixed so that the following formulation was obtained, and this was kneaded and granulated by drying according to a conventional method to produce granules.

Product example 3
(Tablet)
Each component was blended and mixed so that each tablet had the following formulation, and this was tableted according to a conventional method to produce a tablet.

Product example 4
(Granules)
Each component was blended and mixed so that the following formulation was obtained, and this was kneaded and granulated by drying according to a conventional method to produce granules.

Product example 5
(Tablet)
Each component was blended and mixed to give the following formulation per tablet, and tableted according to a conventional method to obtain an uncoated tablet. This uncoated tablet was coated with 10 mg of hypromellose per tablet to produce a film-coated tablet.

Product example 6
(Tablet)
Each component was blended and mixed so that the following formulation was obtained per tablet, and tableted according to a conventional method to obtain an uncoated tablet. This uncoated tablet was coated with 10 mg of hypromellose per tablet to produce a film-coated tablet.

Product example 7
(Powder)
Each ingredient was blended and mixed according to a conventional method so that the following prescription per packet was produced.

Product Example 8
(Hard capsule)
Each capsule was blended and mixed so that the following formulation was obtained per capsule, and granules were obtained according to a conventional method. The granules were filled into hard capsules to produce hard capsules.

Product example 9
(Tablet)
Each component was blended and mixed to give the following formulation per tablet, and tableted according to a conventional method to produce a tablet.

Product example 10
(Granules)
Each ingredient was blended and mixed so as to have the following formulation per packet, and granulated according to a conventional method to produce a granule.

Preparation Example 11
(Tablet)
Each component was blended and mixed to give the following formulation per tablet, and tableted according to a conventional method to produce a tablet.

Product example 12
(Tablet)
Each component was blended and mixed to give the following formulation per tablet, and tableted according to a conventional method to obtain an uncoated tablet. This uncoated tablet was coated with 10 mg of hypromellose per tablet to produce a film-coated tablet.

Product example 13
(Tablet)
Each component was blended and mixed to give the following formulation per tablet, and tableted according to a conventional method to produce a tablet.

Product example 14
(Tablet)
Each component was blended and mixed to give the following formulation per tablet and tableted according to a conventional method to produce a tablet.

Product example 15
(Tablet)
Each component was blended and mixed so that the following formulation was obtained per tablet, and tableted according to a conventional method to obtain an uncoated tablet. This uncoated tablet was coated with 10 mg of hypromellose per tablet to produce a film-coated tablet.

  According to the pharmaceutical composition of the present invention, by using naproxen in combination with a pharmaceutical ingredient selected from a central nervous stimulant, a sedative, a gastric mucosa protective agent, an antispasmodic agent, a muscle relaxant and a migraine agent, The antipyretic analgesic and anti-inflammatory effect can be further enhanced. In particular, when naproxen and a basic component are combined, naproxen's excellent antipyretic analgesic and anti-inflammatory effect can be obtained from the initial stage of administration.

  In addition, an internal solid preparation containing a water-swellable polymer compound further increases the disintegration property in the oral cavity or the like when taken orally, and can obtain a quicker drug effect.

Therefore, the pharmaceutical composition of the present invention can be advantageously used as an OTC preparation.

Claims (13)

  A pharmaceutical composition comprising naproxen or a pharmaceutically acceptable salt thereof and a pharmaceutical ingredient selected from a central nervous stimulant, a sedative, a gastric mucosa protective agent, an antispasmodic agent, a muscle relaxant and a migraine agent.   The pharmaceutical composition according to claim 1, wherein the central nervous stimulant is at least one selected from sodium benzoate caffeine, caffeine and anhydrous caffeine.   The pharmaceutical composition according to claim 1 or 2, wherein the sedative is allyl isopropyl acetyl urea and / or bromovaleryl urea.   The pharmaceutical composition according to any one of claims 1 to 3, wherein the gastric mucosa protective agent is one or more selected from teprenone, aldioxa, sucralfate, cetraxate, azulene and rebamipide.   The pharmaceutical composition according to any one of claims 1 to 4, wherein the antispasmodic agent is at least one selected from butyl scopolamine or a salt thereof, timepidium bromide, papaverine hydrochloride, ethyl aminobenzoate and funnel extract.   The muscle relaxant is at least one selected from metcarbamol, tolperisone, chlorzoxazone, pridinol mesylate, chlorphenesin carbamic acid ester, eperisone hydrochloride, afroqualone, tizanidine and baclofen. A pharmaceutical composition according to claim 1.   The migraine drug is one or more selected from zolmitriptan, sumatriptan, naratriptan, rizatriptan, eletriptan, romeridine hydrochloride, dimethothiazine mesylate and dihydroergotamine. Pharmaceutical composition.   Furthermore, the pharmaceutical composition in any one of Claims 1-7 containing a basic component.   Basic components are magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel, dry aluminum hydroxide gel, aluminum hydroxide / carbonic acid Magnesium mixed dry gel, coprecipitation product of aluminum hydroxide / sodium bicarbonate, coprecipitation product of aluminum hydroxide / calcium carbonate / magnesium carbonate, coprecipitation product of magnesium hydroxide / potassium aluminum sulfate, magnesium carbonate, metasilica Magnesium aluminate, magnesium aluminate, magnesium aluminate, magnesium hydroxide, sodium bicarbonate, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate and calcium hydrogen phosphate The pharmaceutical composition of claim 8 which is a compound selected from the group consisting.   Furthermore, the pharmaceutical composition in any one of Claims 1-9 containing a cellulosic water-swellable polymer.   The cellulosic water-swellable polymer was selected from the group consisting of low-substituted hydroxypropylcellulose, carmellose calcium, croscarmellose sodium, carboxymethylcellulose sodium, carboxymethylcellulose, crystalline cellulose, pregelatinized starch, and sodium carboxymethyl starch The pharmaceutical composition according to claim 10.   The pharmaceutical composition according to any one of claims 1 to 11, which is a solid preparation for internal use. A pharmaceutical composition comprising naproxen or a pharmaceutically acceptable salt thereof, one or more compounds selected from sodium caffeine benzoate, caffeine and anhydrous caffeine, and allylisopropylacetylurea and / or bromovalerylurea.

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