JP6580897B2 - Pharmaceutical composition for cold - Google Patents

Description

  The present invention relates to a pharmaceutical composition for colds, and more particularly to a pharmaceutical composition for colds that suppresses discoloration of ibuprofen and ambroxol hydrochloride and has excellent dissolution properties.

  Switch OTC cold medicine containing ibuprofen and a medical expectorant ingredient ambroxol hydrochloride was released on December 26, 2007 as Estac Eve Fine (manufactured by SS Pharmaceutical Co., Ltd.). Various symptoms that make you feel a cold, such as “sore throat / swell”, “samuke / chills”, “nasal mucus”, “fever”, “sore throat”・ Exhibits excellent effects on “well” and “cough / tan”. According to the results of general clinical trials, the degree of improvement by symptom was “nasal mucus: 85%”, “nasal congestion: 78.3%”, “sneezing: 88%”, “cough: 76.8%”, “headache 92 .5% "," sore throat: 75.4% "," difficulty in spitting vaginal discharge: 71.9% "," joint pain: 100% "," muscle pain: 90.3% "," fever: 77 .9% "and" Chill: 96.2% ", and is generally used as a cold medicine with an improvement rate of 100% or more.

  By the way, since OTC medicines such as cold medicine are stored in the home, they may be exposed to environments of various temperatures and humidity from low temperature to high temperature and from low humidity to high humidity. For this reason, discoloration may occur under extremely severe conditions, and a change in appearance such as discoloration may cause a reduction in commercial value even if there is no change in the quantitative value of the active ingredient. In particular, it is known that when ibuprofen and ambroxol hydrochloride are blended in the same preparation, stability is lost over time and discoloration occurs. The following attempts have been reported in order to prevent changes in the combination of ibuprofen and ambroxol hydrochloride, which are unstable active pharmaceutical ingredients, as described above.

  For example, polyethylene glycol, BHT (dibutylhydroxytoluene), BHA (dibutylhydroxyanisole), benzoic acid or its salts, propyl gallate, hydroquinone, dl-α-tocopherol, d-α-tocopherol, tocopherol acetate, sodium hydrogen sulfite A reducing agent such as sodium sulfite, sodium pyrosulfite and lecithin (Patent Document 1), an amino acid such as aspartic acid, glutamine and taurine, or a peptide such as aspartame (Patent Document 2), It has been reported that ibuprofen granules and ambroxol hydrochloride granules film-coated with a coating solution containing talc are separately prepared and blended (Patent Document 3). In this way, each active pharmaceutical ingredient is made into separate granules, etc., and further, the coating change is applied as necessary, and then a single formulation is added and additives are prevented from being changed by additives. However, these methods are often ineffective when exposed to very harsh environments, and when sufficient coatings are applied to prevent discoloration, the elution of active pharmaceutical ingredients It was delayed, and the onset of effects could be delayed or inadequate.

Japanese Patent Laid-Open No. 10-101581 JP-A-2005-350448 JP 2007-55924 A

  Accordingly, an object of the present invention is to provide a common cold pharmaceutical composition that suppresses a change in formulation and has excellent dissolution properties in a common cold pharmaceutical composition containing ibuprofen and ambroxol hydrochloride.

  The inventors of the present invention have been diligently researching to solve the above-mentioned problems, and for the cold pharmaceutical composition containing ibuprofen and ambroxol hydrochloride, by further containing magnesium oxide, ibuprofen and ambrox Not only suppresses changes in the composition of sole hydrochloride, but also improves the dissolution properties of ibuprofen and ambroxol hydrochloride, reducing the effect as a cold medicine, and thus the effects of ibuprofen and ambroxol hydrochloride. The present invention was completed by finding out that the onset can be accelerated and the onset of the effect as a cold medicine can be made stronger.

  That is, the present invention is a cold pharmaceutical composition characterized by containing ibuprofen, ambroxol hydrochloride and magnesium oxide.

  According to the present invention, the compounding change of ibuprofen and ambroxol hydrochloride can be suppressed, and further, the onset of the effect of the common cold medicine can be ensured quickly. The product value of the used medicine can be increased.

  The pharmaceutical composition for cold according to the present invention contains ibuprofen, ambroxol hydrochloride and magnesium oxide (hereinafter referred to as “the composition of the present invention”). You may contain a thing.

The chemical name of ibuprofen contained in the composition of the present invention is (2RS) -2- [4- (2-methylpropyl) phenyl] propanoic acid (English name: (2RS) -2- [4- (2-Methylpropyl). Phenyl] propanoic acid), a molecular formula of C ₁₃ H ₁₈ O ₂ , a molecular weight of 206.28, a melting point of 75-77 ° C., a non-steroidal anti-inflammatory drug of the phenylpropionic acid type, It exerts anti-inflammatory, analgesic, and antipyretic effects by inhibiting the action of glandin biosynthesis.

The chemical name of ambroxol hydrochloride contained in the composition of the present invention is trans-4-[(2-amino-3,5-dibromobenzyl) amino] cyclohexanol hydrochloride (English name: trans-4). - a [(2-amino-3, 5-dibromobenzyl) amino] cyclohexanol hydrochloride), molecular _formula, with _{C 13 H 18 Br 2 N 2} O · HCl, and its molecular weight, 414.56, melting point about 235 An expectorant at ℃, secretion of lung surface active substance, airway fluid secretion, ciliary motility, acute bronchitis, bronchial asthma, chronic bronchitis, bronchiectasis, pulmonary tuberculosis, pneumoconiosis, surgery It is used for expectoration of diseases such as later exudation and drainage of chronic sinusitis.

  Further, magnesium oxide (English name: Magnesium Oxide) contained in the composition of the present invention is an antacid with a molecular formula of MgO and a molecular weight of 40.30, gastric / duodenal ulcer, acute / chronic gastritis, drug-induced gastritis It is used for antacid action and symptom improvement in diseases such as upper gastrointestinal dysfunction such as gastritis, anorexia nervosa, so-called gastric ptosis and hyperacidity.

  As described above, the composition of the present invention contains ibuprofen, ambroxol hydrochloride and magnesium oxide in a unit preparation. In the composition of the present invention, ibuprofen: ambroxol hydrochloride: magnesium oxide is preferably contained in the unit preparation at a mass ratio of 10 to 70: 1 to 5: 2 to 60, and 4 to 27: 1 to 2. : It is more preferable to contain by the mass ratio of 2-23, and it is still more preferable to mix | blend by the mass ratio of 20-27: 1-2: 4-23. Specifically, for example, in a tablet or capsule dosage form, one tablet or one capsule contains 33 to 167 mg of magnesium oxide with respect to 150 to 200 mg of ibuprofen and 15 mg of ambroxol hydrochloride. Further, 16 to 84 mg of magnesium oxide is contained for 75 to 100 mg of ibuprofen and 7.5 mg of ambroxol hydrochloride in one tablet or capsule, and 50 to 66.7 mg of ibuprofen and ambrox in one tablet or capsule. 11-56 mg of magnesium oxide is contained with respect to 5 mg of sole hydrochloride. Further, for example, in a packaged preparation such as a granule, 33-167 mg of magnesium oxide is contained in one package with respect to 150-200 mg of ibuprofen and 15 mg of ambroxol hydrochloride.

  In addition to ibuprofen, ambroxol hydrochloride, and magnesium oxide, the composition of the present invention may further contain components that are usually added to cold medicines. Examples of such components include anti-inflammatory / antipyretic analgesics, antihistamines, antiallergic agents, antitussive expectorants, central nervous stimulants, antacids, vitamins and herbal medicines.

  Specific examples of anti-inflammatory / antipyretic analgesics that can be further added to the composition of the present invention include aspirin, aspirin aluminum, acetaminophen, enanthamide, sazapyrine, salicylamide, lactylphenetidine, isopropylantipyrine, loxoprofen sodium hydrate Glycyrrhizin, glycyrrhizin, ammonium glycyrrhizinate, potassium glycyrrhizinate, dipotassium glycyrrhizinate, and related substances or salts thereof, tranexamic acid, and the like. In addition, you may add these 1 type or in mixture of 2 or more types.

  Specific examples of antihistamines and antiallergic agents that can be further added to the composition of the present invention include azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, epinastine hydrochloride, ebastine, emedastine fumarate Acid salt, oxatomide, carbinoxamine diphenyl disulfonate, carpinoxamine maleate, clemastine fumarate, chlorpheniramine maleate, d-chlorpheniramine maleate, dipheterol hydrochloride, dipheterol phosphate Salt, carbinoxamine diphenyldisulfonate, diphenylpyraline hydrochloride, diphenylpyraline theocrylate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, cetirizine hydrochloride, triplicate Lysine hydrochloride hydrate, tripelenamine hydrochloride, tondilamine hydrochloride, fexofenadine, phenetadine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, bepotastine besylate, homochlorcyclidine hydrochloride, mequitazine, methodilazin hydrochloride Salt, mebhydroline napadisilate and the like. You may add these 1 type or in mixture of 2 or more types.

  Specific examples of the antitussive expectorant that can be further added to the composition of the present invention include aloclamide hydrochloride, tipepidine citrate, cloperastine hydrochloride, cloperastine phendizoate, codeine phosphate hydrate, dihydrocodeine phosphate water Japanese hydrate, dibutate sodium, tipepidine hibenzate, dextromethorphan hydrobromide, dextromethorphan / phenolphthalin salt, pentoxyberine citrate, dimemorphan phosphate, noscapine, noscapine hydrochloride hydration Dl-methyl ephedrine hydrochloride, dl-methyl ephedrine saccharin salt, guaifenesin, potassium guaiacol sulfonate, potassium cresol sulfonate, bromhexine hydrochloride, L-carbocysteine, L-ethylcysteine hydrochloride, belladonna total alkaloid Isopropamide iodide include eprazinone hydrochloride salt. You may add these 1 type or in mixture of 2 or more types.

  Specific examples of central nervous stimulants that can be further added to the composition of the present invention include sodium benzoate caffeine, anhydrous caffeine, and caffeine hydrate. You may add these 1 type or in mixture of 2 or more types.

  Specific examples of antacids that can be further added to the composition of the present invention include glycine, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel , Dried aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate coprecipitate, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitate, magnesium hydroxide / potassium aluminum sulfate co-precipitate Precipitated products, magnesium carbonate, magnesium aluminate metasilicate and the like can be mentioned. You may add these 1 type or in mixture of 2 or more types.

  Vitamins that can be further added to the composition of the present invention include vitamin B1 and derivatives thereof and salts thereof, vitamin B2 and derivatives thereof, salts thereof, vitamin C and derivatives thereof, salts thereof, hesperidin and derivatives thereof, and Examples of herbal medicines include mao, nantenjitsu, baboons, onji, licorice, citrus, shrimp, shazensou, sexan, senega, baimo, fennel, autaku, auren, cajutsu, chamomile, keihi, gentian, Gooh, Beast, Shajin, Shokyo, Sojutsu, Clove, Chinpi, Sandalwood, Giryu, Chiksetsu Carrot, Carrot, Kakkonyu, Kakkonyu Kakikyo, Keishiyu, Kososan, Saiko Katsueyu, Shosaikoto, Small Seiryu-yu, Mumon Fuyu-yu, Semi-summer Koboku-yu, Mention may be made of a yellow hot water and the like. You may add these 1 type or in mixture of 2 or more types.

  Common cold drugs using the composition of the present invention include ibuprofen, ambroxol hydrochloride and magnesium oxide, the above anti-inflammatory / antipyretic analgesics, antihistamines and antiallergic drugs, antitussive expectorants, central nervous stimulants Add pharmaceutical ingredients such as antacids, vitamins and herbal medicines as needed, and add formulation additives such as excipients, binders, disintegrants, lubricants, etc. that can be generally used in the pharmaceutical field. Manufactured with addition. Formulation additives that can be used at that time 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 Mention may be made of formulation additives such as wetting agents. Examples of such additives are: Yakushoku 1204 1 (Pharmaceutical Administration Law), Pharmaceutical Additives Encyclopedia 2007 (edited by Japan Pharmaceutical Additives Association, Yakuji Nippo) and 8th edition Food Additives Official (Japan Food Additives) (Association of Things).

  Among the above preparation additives, examples of the excipient include lactose, starch, corn starch, pregelatinized starch, partially pregelatinized starch, crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, purified sucrose, and sugar alcohols. , Light anhydrous silicic acid, calcium silicate, titanium oxide, precipitated calcium carbonate and the like. These excipients can be used alone or in combination of two or more.

  Examples of the binder include gelatin, gum arabic powder, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl Alcohol / polyethylene glycol / graft copolymer, pullulan, dextrin, carboxymethylcellulose calcium, sodium carboxymethylcellulose, acrylic acid derivatives such as methacrylic acid copolymer, shellac, carboxyvinyl polymer, sodium carboxymethyl starch, carboxymethylethylcellulose, cellulose acetate phthalate, etc. Can be mentioned. These binders can use 1 type (s) or 2 or more types.

  Furthermore, examples of the disintegrant include croscarmellose sodium, crospovidone, cross-linked insoluble polyvinylpyrrolidone, carmellose calcium, sodium carboxymethyl starch, potato starch, corn starch, pregelatinized starch and the like. These disintegrants can be used alone or in combination of two or more.

  Furthermore, examples of the lubricant include talc, stearic acid, magnesium stearate, sucrose fatty acid esters, polyethylene glycol and the like. These lubricants can be used alone or in combination of two or more.

  Common cold preparations using the composition of the present invention described above include tablets, caplets, hard capsules, soft capsules, orally disintegrating tablets, chewable tablets, fine granules, granules, and dry syrups. Or as an oral solution. 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). Moreover, you may use microparticles, such as a microcapsule, a nanocapsule, a microsphere, and a nanosphere. Moreover, it can preserve | save in airtight containers, such as a glass bottle, a plastic bottle, PTP packaging, and aluminum heat seal packaging, In that case, you may enclose desiccants, such as a silica gel, as needed.

  The common cold medicine using the composition of the present invention is usually preferably taken three times a day with water or lukewarm water. Depending on the case, a sustained release treatment may be applied to a part of the active ingredient to provide a cold medicine to be taken twice a day or once a day.

  The cold medicine using the composition of the present invention thus obtained is a product because it prevents changes in appearance such as discoloration even though ibuprofen and ambroxol hydrochloride are blended in the same preparation. It is possible to provide drugs that do not lose value. Further, by adding magnesium oxide, not only the elution of ibuprofen and ambroxol hydrochloride is promoted, but also the elution of other components is promoted, and it is possible to provide a pharmaceutical product that is effective quickly.

  EXAMPLES Next, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited at all by these Examples.

Example 1
Discoloration test:
According to the formulation shown in Table 1, ibuprofen, ambroxol hydrochloride and magnesium oxide were weighed, and 10% of purified water was added and kneaded. Each of the obtained mixtures was prepared, placed in a glass bottle and stored at 70 ° C., and the state of the mixture after 24 hours was evaluated according to the following evaluation criteria to confirm the presence or absence of discoloration. The results are also shown in Table 1.

<Evaluation criteria>
(Evaluation) (Content)
-: No discoloration ±: Little discoloration +: Discoloration

  Invention products 1 to 11 in which magnesium oxide was further blended with ibuprofen and ambroxol hydrochloride did not cause any blending change. On the other hand, Comparative Product 1 and Comparative Product 2 that did not contain magnesium oxide caused a change in formulation. Therefore, it was shown that the compounding change of ibuprofen and ambroxol hydrochloride can be prevented by magnesium oxide.

Example 2
Dissolution test:
(Cold medicine 1 containing ibuprofen, ambroxol hydrochloride and magnesium oxide)
300 g of ibuprofen, 30 g of ambroxol hydrochloride, 200 g of magnesium oxide, 5 g of chlorpheniramine maleate, 16 g of dihydrocodeine phosphate, 40 g of dl-methylephedrine hydrochloride, 50 g of anhydrous caffeine, 4 g of isopropamide iodide, low substituted hydroxy Purified water (1380 g) was added to propyl cellulose (454 g), D-mannitol (197 g), corn starch (40 g), and lactose hydrate (4 g). After wet granulation by a conventional method, drying and granulating were performed to obtain a granulated powder. To 1273 g of this granulated powder, 228 g of crystalline cellulose, light anhydrous silicic acid, 7.6 g, 15.2 g of talc and 405 g of magnesium stearate were added and mixed uniformly to obtain a tableting powder. This tableting powder was compression-molded by a conventional method with a rotary tableting machine to obtain 405 mg per tablet using a 9.5 mmφ mortar to obtain a plain tablet. A film coating agent composed of hypromellose, titanium oxide, macrogol, talc and purified water (8.6: 1.5: 1.45: 4.5: 88) is sprayed on the uncoated tablets with a ventilated coating apparatus, Invention 12 was obtained as a film-coated tablet at 425 mg / tablet.

(Cold medicine containing ibuprofen and ambroxol hydrochloride and no magnesium oxide)
300 g of ibuprofen, 30 g of ambroxol hydrochloride, 5 g of chlorpheniramine maleate, 16 g of dihydrocodeine phosphate, 40 g of dl-methylephedrine hydrochloride, 50 g of anhydrous caffeine, 4 g of iodopropamide, 454 g of low-substituted hydroxypropylcellulose, Purified water (1380 g) was added to D-mannitol (197 g), corn starch (40 g), and lactose hydrate (204 g). After wet granulation by a conventional method, drying and granulating were performed to obtain a granulated powder. To 1273 g of this granulated powder, 228 g of crystalline cellulose, light anhydrous silicic acid, 7.6 g, 15.2 g of talc and 405 g of magnesium stearate were added and mixed uniformly to obtain a tableting powder. This tableting powder was compression-molded by a conventional method with a rotary tableting machine to obtain 405 mg per tablet using a 9.5 mmφ mortar to obtain a plain tablet. The film coating agent similar to the above was sprayed on this uncoated tablet with a breathable coating apparatus to obtain Comparative Product 3 as a film-coated tablet of 425 mg / tablet.

  The dissolution test of Invention Product 12 and Comparative Product 3 was performed according to the dissolution test method of the 16th revision of the Japanese Pharmacopoeia. The test conditions were the paddle method, rotation speed 50 rpm, test solution volume 500 mL, the first dissolution test solution as the test solution, ibuprofen, ambroxol hydrochloride, chlorpheniramine maleate 30 minutes after the start of the test, The elution rates of dihydrocodeine phosphate, dl-methylephedrine hydrochloride, anhydrous caffeine, and isopropamide iodide were measured. The results are shown in Table 2. Inventive product 12 was superior not only to ibuprofen but also all of the components as compared with comparative product 3.

Example 3
(Cold medicine 2 containing ibuprofen, ambroxol hydrochloride and magnesium oxide)
400 g of ibuprofen, 30 g of ambroxol hydrochloride, 200 g of magnesium oxide, chlorpheniramine maleate, 5 g, 16 g of dihydrocodeine phosphate, 40 g of dl-methylephedrine hydrochloride, 50 g of anhydrous caffeine, 4 g of iodopropamide, low substitution degree 1420 g of purified water was added to 452 g of hydroxypropyl cellulose, 197 g of D-mannitol, 40 g of corn starch and 4 g of lactose hydrate. After wet granulation by a conventional method, drying and granulating were performed to obtain a granulated powder. . To 1368 g of this granulated powder, 228 g of crystalline cellulose, light anhydrous silicic acid, 7.6 g, 15.2 g of talc and 405 g of magnesium stearate were added and mixed uniformly to obtain a tableting powder. This tableting powder was compression-molded by a conventional method with a rotary tableting machine so as to obtain 430 mg per tablet using a 9.5 mmφ mortar to obtain an uncoated tablet. This uncoated tablet was sprayed with a film coating agent similar to the above using a ventilating coating apparatus to obtain Invention 13 as a film-coated tablet of 450 mg / tablet.

Example 4
(Cold medicine 3 containing ibuprofen, ambroxol hydrochloride and magnesium oxide)
200 g of ibuprofen, 15 g of ambroxol hydrochloride, 100 g of magnesium oxide, 2.5 g of chlorpheniramine maleate, 8 g of dihydrocodeine phosphate, 20 g of dl-methylephedrine hydrochloride, 25 g of anhydrous caffeine, 2 g of isopropamide iodide, low substitution To 1460 g of hydroxypropylcellulose, 368.6 g of carmellose calcium, and 35 g of tartaric acid, 1880 g of purified water was added, and after wet granulation by a conventional method, drying and granulating were performed to obtain a granulated powder. Add saccharin sodium 57g, light anhydrous silicic acid 1.235g, talc 1.235g and fragrance 1.235g to this granulated powder 1174.3g and mix evenly, with aluminum three-side seal to 1300mg per package The product was packaged to obtain Invention Product 14 as a granule.

  According to the present invention, in the pharmaceutical composition for colds containing ibuprofen and ambroxol hydrochloride, by further containing magnesium oxide, discoloration due to a change in formulation is suppressed, and further the dissolution of the active ingredient is improved. Can do.

Accordingly, since the present invention can easily prevent discoloration, it is possible to prevent a decrease in commercial value and can be widely used in the manufacture of cold medicines. Furthermore, since the effect of each active ingredient is improved and the effect appears surely and quickly, it is possible to provide a cold medicine that can make the most of the pharmacological effect.

Claims (3)

A solid preparation for internal use comprising a pharmaceutical composition for colds containing ibuprofen, ambroxol hydrochloride and magnesium oxide. Cold pharmaceutical composition, ibuprofen, ambroxol hydrochloride and magnesium oxide, respectively mass ratio 10-70: 1 to 5: oral solid preparation according to claim 1, wherein those containing at a ratio of 2 to 60. Those cold pharmaceutical composition further anti-inflammatory, antipyretic analgesics, antihistamines, antiallergic agents, antitussive expectorants, central nervous system stimulants, antacids, containing one or more selected from vitamins and herbal oral solid preparation according to one claim 1 or 2.