JP2007031285A - Stabilized preparation containing epinastine with reduced bitter taste - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a preparation having a reduced bitter taste of epinastine and a salt thereof and exhibiting enhanced stability. <P>SOLUTION: In an oral preparation containing epinastine or a pharmaceutically acceptable salt thereof, a sweetening agent (for example, aspartame, erythritol, xylitol, and D-sorbitol) and an acidulant, the ratio of the acidulant is caused to be 10-1,000 pts.wt. based on 100 pts.wt. of the sweetening agent thereby effectively reducing the bitter taste of epinastine and the salt thereof while enhancing stability. Such a preparation does not suffer from discoloration or the like for long terms and exhibits markedly enhanced stability against light, pH or the like. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a novel oral preparation and bitterness reducing agent that reduce the bitterness of epinastine and its pharmaceutically acceptable salts (hereinafter also referred to as medicinal ingredients), a method for producing the oral preparation, and the bitter taste of the medicinal ingredients. Relates to a method of reducing

  Epinastine having a chemical structure represented by 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine and a pharmaceutically acceptable salt thereof are disclosed in -139484 (Patent Document 1), which is a compound having antiallergic, antihistamine and antiserotonin activities. Epinastine hydrochloride is also a medical drug marketed in Japan as “Aresion” (registered trademark), and is widely used as an effective drug for treating diseases such as bronchial asthma and allergic rhinitis.

  Epinastine hydrochloride is a white to slightly yellow powder and does not smell, but has a strong bitter taste. On the other hand, it is important to improve the patient's compliance at the time of taking by improving the taste of pharmaceuticals, and various bitter taste improvements have been attempted so far in the epinastine hydrochloride preparation. For example, “Alesion” is sold in various dosage forms (eg, tablets, dry syrups, internal liquids, etc.), and these preparations contain a sweetener to mask the bitter taste of epinastine, for example, dry syrup. The drug contains aspartame and erythritol. JP-A-2005-82594 (Patent Document 2) discloses a preparation that masks bitterness by coating epinastine with a mixture of a surfactant and oil, fat, wax, fatty alcohol or fatty acid. (Especially powders) are disclosed.

  JP-T-2005-508364 (Patent Document 3) discloses a powder preparation containing epinastine, a component for masking the bitterness of epinastine with an immediate effect and a component for masking the bitterness with a sustained effect. Saccharin sodium, erythritol, and aspartame are disclosed as ingredients for masking the bitter taste of food (fast-acting sweet ingredients), and glycyrrhizinate or glycyrrhizic acid is disclosed as an ingredient for masking persistent bitter taste (persistent sweet ingredients) Yes. Furthermore, in this document 3, a pH adjusting agent is added to adjust the pH of the liquid to 5 to 8, and as the pH adjusting agent, citric acid, succinic acid, tartaric acid, hydrochloric acid, sodium hydroxide, buffer (phosphoric acid) It is described that disodium etc.) can be used. These pH adjusters are used in a proportion of 100 to 600 parts by weight with respect to 100 parts by weight of epinastine.

  In JP-A-2001-81033 (Patent Document 4), in order to prevent discoloration due to light, a polymer film layer containing no titanium oxide pigment is provided between the titanium oxide pigment-containing film and the epinastine hydrochloride-containing bare tablet. Providing is disclosed.

However, with these methods, it is difficult to improve the stability of epinastine and its pharmaceutically acceptable salts while reducing strong bitterness.
JP-A-56-139484 (Example 1) Japanese Patent Laying-Open No. 2005-82594 (Claims) JP 2005-508364 A (Claims) JP 2001-81033 A (Claims)

  Accordingly, an object of the present invention is to provide an oral preparation capable of effectively reducing the bitter taste of epinastine and pharmaceutically acceptable salts thereof (particularly epinastine hydrochloride) and a method for producing the same.

  Another object of the present invention is to provide a highly stable oral preparation containing epinastine and a pharmaceutically acceptable salt thereof (particularly epinastine hydrochloride) and a method for producing the same.

  Still another object of the present invention is to provide an oral preparation capable of improving the stability of epinastine and a pharmaceutically acceptable salt thereof and a method for producing the same without causing coloring or the like over a long period of time.

  Another object of the present invention is to provide an oral preparation in which the stability of epinastine and a pharmaceutically acceptable salt thereof is greatly improved against heat, moisture (moisture), light, pH, and the like, and a method for producing the same. It is in.

  Still another object of the present invention is to provide a bitterness reducing agent and a bitterness reducing method capable of effectively reducing the bitterness of epinastine and a pharmaceutically acceptable salt thereof and enhancing the compliance.

  As a result of intensive investigations to achieve the above-mentioned problems, the present inventors have found that the bitterness of medicinal ingredients is reduced when at least one sweetener selected from a synthetic sweetener and a sugar alcohol and a sour agent are used at a specific ratio. The present invention has been completed by finding that not only it can be effectively reduced but also coloring and the like do not occur over a long period of time, and the stability to light, pH, etc. is remarkably improved.

That is, the oral preparation of the present invention comprises epinastine or a pharmaceutically acceptable salt thereof, at least one sweetener selected from synthetic sweeteners and sugar alcohols, and a sour agent, and the proportion of the sour agent is It is 10-1000 weight part (for example, 10-750 weight part) with respect to 100 weight part of sweetening agents. As the sweetener, at least one selected from aspartame, erythritol, xylitol and D-sorbitol may be used. Further, as the sour agent, at least one selected from saturated carboxylic acid, unsaturated carboxylic acid, oxycarboxylic acid and salts thereof may be used, for example, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, Examples thereof include at least one selected from gluconic acid, fumaric acid, maleic acid, ascorbic acid and salts thereof. The proportion of the sweetener may be about 0.1 to 200 parts by weight and the proportion of the sour agent is about 1 to 150 parts by weight with respect to 1 part by weight of epinastine or a pharmaceutically acceptable salt thereof. Also good.
The oral preparation of the present invention may further contain a fragrance, and examples of the fragrance include at least one selected from strawberry essence, nicki essence, white grape essence, banana essence and drink essence. Further, the oral preparation of the present invention may further contain a sweetness enhancer, and as the sweetness enhancer, for example, at least one selected from sodium chloride, potassium chloride, organic acid salt and phosphate is used. be able to. The oral preparation of the present invention may be a liquid or syrup. The range of 3-7 may be sufficient as the pH of the oral formulation (solution) of this invention.

  The oral preparation of the present invention can be produced using epinastine or a pharmaceutically acceptable salt thereof as a medicinal ingredient, the specific sweetener, and a sour agent. The ratio of the sour agent to 100 parts by weight of the sweetener is about 10 to 750 parts by weight.

  The present invention is a bitterness reducing agent for reducing the bitter taste of epinastine or a pharmaceutically acceptable salt thereof, which is a medicinal ingredient, comprising the specific sweetener and a sour agent, and a sweetener of 100 weight The bitterness reducing agent which contains a sour agent in the ratio of 10-750 weight part with respect to a part is also included. Furthermore, this invention also includes the method of reducing the bitter taste of a medicinal ingredient by adding the said bitterness reducing agent to epinastine or its pharmaceutically acceptable salt as a medicinal ingredient.

  In this invention, since a specific sweetener and a sour agent are used in a specific ratio, the bitter taste of epinastine and its pharmaceutically acceptable salt can be effectively reduced, and patient ingestion can be greatly improved. In addition, it is possible to provide an oral preparation with improved stability against heat, moisture, light, pH, etc. without causing coloration over a long period of time, which can greatly improve the storage stability of the oral preparation. it can.

[Oral preparation]
Epinastine (chemical name: 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine), which is a medicinal component of the oral preparation of the present invention, is bronchial asthma, allergic It is an effective drug for treating rhinitis, urticaria, eczema, dermatitis, pruritus dermatosis, prurigo, pruritus vulgaris, etc. Epinastine does not smell but has a bitter taste. Therefore, it is important to effectively mask the bitter taste of epinastine.

  As the pharmaceutically acceptable salt of epinastine, various physiologically or pharmaceutically acceptable salts can be used, and the acid or base forming the salt can be selected according to the type of the component, for example, inorganic Acid salts (eg, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); organic acid salts (eg, carboxylates (eg, monocarboxylic acid salts (eg, acetic acid, trichloroacetic acid, trifluoro) Salt with acetic acid), polyvalent carboxylate (eg, salt with oxalic acid, succinic acid, maleic acid, fumaric acid, etc.), oxycarboxylate (eg, tartaric acid, citric acid, lactic acid, gluconic acid) , Salts with salicylic acid, phenolphthaline, tannic acid, etc., amino acid salts (such as salts with aspartic acid), organic sulfonates (eg, alkane sulfonic acids (eg, methane sulfonic acid, Salts with tansulfonic acid, etc.), arenesulfonic acid salts (for example, salts with benzenesulfonic acid, toluenesulfonic acid, diphenyldisulfonic acid salts, etc.)); salts with inorganic bases (for example, alkali metal hydroxides) Salts (eg, salts with sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonates, salts with alkaline earth metal hydroxides (eg, salts with calcium hydroxide, magnesium hydroxide, etc.) Alkaline earth metal carbonate, aluminum salt, ammonium salt, etc .: salt with organic base (alkylamine salt (eg trimethylamine salt, triethylamine salt etc.), alkanolamine salt (eg monoethanolamine salt, triethanolamine) Salts), polyamine salts such as alkylene diamines, tertiary amines such as pyridine salts Etc.), and others. A particularly preferred salt is epinastine hydrochloride.

  The content of the above-mentioned medicinal ingredient (epinastine and / or a pharmaceutically acceptable salt thereof) can be selected according to the kind of the preparation, for example, 0.1 to 10% by weight of the whole preparation, preferably 0.1 It can be selected from a range of about 5% by weight, more preferably about 0.1-1% by weight.

  In addition, if necessary, epinastine may be used in combination with other active ingredients (pharmacological activity or physiologically active ingredients), and the other active ingredients may have a bitter taste. Examples of the other active ingredients include analgesics, antipyretic analgesics, antitussives, expectorants, sedatives, antisedatives, antihistamines, antiallergic agents, bronchodilators, diabetes treatment agents, liver disease treatment agents, ulcers It may be a therapeutic agent, a gastric digestive agent, a blood pressure lowering agent, a hormone agent, an antibiotic, a sulfa agent, a neuropsychiatric agent, an intraocular pressure lowering agent, a vitamin agent, amino acids, minerals and the like. These components can be used alone or in combination of two or more.

  Examples of the other active ingredients having a bitter taste include, for example, aminopyrine, antipyrine, phenacetin, theophylline, anhydrous caffeine, acetaminophen, choline salicylate, dextromethorphan hydrobromide, trimethquinol hydrochloride, allobarbital, and cyclobarbital. , Barbital, phenobarbital, N-methyl scopolamine, methyl sulfate, furopropion, diclofenac sodium, chlorpheniramine maleate, cyclopeptazine hydrochloride, tolbutamide, grubuzole, acetohexamide, chlorbropamide, hydrazinophthalazine hydrochloride, reserpine, polythiazide , Dexamethasone, betamethasone, aminobenzylpenicillin, cephalexin, tetracycline hydrochloride, doxycycline hydrochloride, chloramf Examples include nicole, sulfisomezole, sulfisoxazal, hydroxyzimbamoate, primidone, isosorbide, nicotinic acid, nicotinamide, ascorbic acid, pantothenic acid, thiamine, fursultiamine and their salts, lysine hydrochloride, etc. It is done. Herbal medicine ingredients as bitter active ingredients include, for example, icarius, seisei, guarana, kokushi, jiou, touki, eucommia, carrot, ogon, pteridophyllum, ouren, gadju, calacon, kyouko, yellowfin, kengoshi, gentian, kobushi, koboku, Extracts from herbal raw materials such as garlic, psycho, saffron, sand squirrel, safflower, cormorant, senbou, sardine, daiou, chimpi, spruce, oyster, peony, mugwort, mugwort, hops, wolf, mao, ryutan, gentian, forsythia Can be illustrated.

[Sweetener]
The oral preparation and bitterness reducing agent of the present invention effectively reduce the bitter taste of epinastine, do not cause coloring or the like over a long period of time, and improve the stability to light, pH, etc. including. Sweetening agents include synthetic sweeteners [saccharin or salts thereof (such as saccharin sodium), aspartame, sucralose, acesulfame or salts thereof (such as acesulfame potassium)] and sugar alcohols [mannitol (D-mannitol), sorbitol (D-sorbitol). ), Erythritol, xylitol, reduced palatinose, maltitol, lactitol, etc.]. These sweeteners can be used alone or in combination of two or more. Preferred sweeteners are aspartame and / or sugar alcohols (such as erythritol, xylitol, D-sorbitol). Synthetic sweeteners and sugar alcohols may be suitably combined.

  When using a plurality of sweeteners, the amount of each sweetener used can be selected according to the degree of sweetness and the like. For example, the ratio of sugar alcohol to 1 part by weight of a synthetic sweetener (eg, aspartame) is usually 0-50. It can be selected from the range of about parts by weight (for example, 0.1 to 50 parts by weight), 0.5 to 40 parts by weight (for example, 0.7 to 35 parts by weight), preferably 1 to 30 parts by weight (for example, 2 About 25 parts by weight), more preferably about 3-20 parts by weight.

  The proportion of the sweetener is usually 0.1 to 200 parts by weight, preferably 0.5 to 100 parts by weight, more preferably about 1 to 75 parts by weight with respect to 1 part by weight of the medicinal component (for example, epinastine hydrochloride). (For example, 3 to 60 parts by weight).

  The proportion of the synthetic sweetener (for example, aspartame) in the sweetener is usually 0.1 to 100 parts by weight, preferably 0.3 to 50 parts by weight, per 1 part by weight of the medicinal component (for example, epinastine hydrochloride). More preferably, it may be about 0.5 to 25 parts by weight (for example, 1 to 10 parts by weight). The amount of sugar alcohol used in the sweetener may be a ratio obtained by subtracting the amount of artificial sweetener used from the total amount of the sweetener.

  The amount of these sweeteners used may be about 0.1 to 20% by weight, preferably 0.5 to 15% by weight, more preferably about 0.5 to 13% by weight of the whole preparation.

  Moreover, as the usage-amount of each sweetener, synthetic sweeteners (for example, aspartame) are 0.1 to 10 weight% with respect to the whole preparation, Preferably it is 0.1 to 5 weight%, More preferably, it is 0.8. About 5 to 1 weight% may be sufficient. The sugar alcohol is 1 to 20% by weight, preferably 2 to 15% by weight, more preferably about 3 to 10% by weight. In addition, erythritol and xylitol may each be 1 to 20% by weight, preferably 2 to 15% by weight, more preferably about 3 to 10% by weight, and D-sorbitol is the whole preparation. 1 to 20% by weight, preferably 2 to 10% by weight, more preferably about 3 to 7% by weight.

  Moreover, when the sweetness degree of sucrose is set to 100, the oral formulation and bitterness reducing agent of this invention may contain saccharides (sugars other than the said sweetener) of sweetness degree 200 or less.

  Examples of such saccharides include sugar (sucrose, glucose, fructose, lactose, brown sugar, honey, trehalose, maltose (malt sugar), xylose, mannose, raffinose, galactose, fructose, rhamnose, isomerized sugar (high fructose). Syrup), palatinose, etc.), oligosaccharides (starch sugar (starch saccharified product), maltooligosaccharide, fructooligosaccharide, galactooligosaccharide, coupling sugar, etc.) and the like. These saccharides can be used alone or in combination of two or more.

  The saccharide may be a non-reducing type (trehalose type) or a reducing type (maltose type). The type of reducing sugar is not particularly limited as long as it has a free aldehyde group or a ketone group and exhibits reducibility. For example, free monosaccharides; reduced maltose or maltose, isomaltose, lactose, palatinose, etc. Examples include oligosaccharides or oligosaccharides. These reducing sugars can also be used alone or in combination of two or more. As reducing sugar, reduced maltose (such as syrup or powdered sugar) or maltose is often used.

[Sour agent]
Furthermore, the oral preparation and the bitterness reducing agent of the present invention effectively reduce the bitterness of epinastine, do not cause coloring or the like over a long period of time, and significantly improve the stability to light, pH, etc. including. The kind of acidulant is not particularly limited as long as it exhibits acidity, and various organic acid components can be used. Examples of sour agents include saturated carboxylic acids (eg, saturated monocarboxylic acids such as acetic acid, saturated dicarboxylic acids such as malonic acid, succinic acid, succinic anhydride, glutaric acid) and unsaturated carboxylic acids (eg, maleic acid, Unsaturated polycarboxylic acids such as fumaric acid). These saturated and unsaturated carboxylic acids also include oxycarboxylic acids (eg, hydroxy monocarboxylic acids such as lactic acid and gluconic acid, and hydroxypolycarboxylic acids such as malic acid, tartaric acid and citric acid). These saturated and unsaturated carboxylic acids also include lactones (eg, ascorbic acid). These acidulants can be used alone or in combination of two or more. Of these acidulants, oxycarboxylic acids (for example, lactic acid, malic acid, tartaric acid, citric acid, etc.), fumaric acid, ascorbic acid and the like are often used, and at least oxycarboxylic acid is often used.

  The sour agent may be used as a salt (an alkali metal salt such as sodium salt or potassium salt). When the sour agent is an optically active substance, the optically active substance may be a d, l, dl form or a racemic form. When a plurality of sour agents are used, it may be effective for bitter taste.

  The ratio of the sour agent can be selected according to the kind and quantitative ratio of the sweetener, and for example, 1 to 150 parts by weight per 1 part by weight of epinastine or a pharmaceutically acceptable salt thereof (medicinal ingredient) Preferably, it may be about 2 to 100 parts by weight, more preferably about 5 to 75 parts by weight (for example, 10 to 50 parts by weight). The amount of the sour agent used relative to the whole preparation may be, for example, about 1 to 20% by weight, preferably about 2 to 10% by weight, and more preferably about 3 to 7% by weight.

  In order to effectively reduce the bitterness of the medicinal component, in the present invention, the acidulant is 10 to 1000 parts by weight (for example, 10 to 750 parts by weight), preferably 20 to 600 parts by weight with respect to 100 parts by weight of the sweetener. (For example, 25 to 550 parts by weight), more preferably 30 to 500 parts by weight (for example, 35 to 450 parts by weight). When bitterness reducing agents containing sweeteners and sour agents are used in such proportions, the bitterness of the medicinal ingredients can be effectively reduced, not only the compliance associated with taking can be improved, but also the stability of medicinal ingredients and oral preparations can be increased. It can be improved and stable even when heat, moisture (humidity), light is applied, or the pH fluctuates, and it is possible to effectively prevent coloring and generation of impurities.

[Sweet enhancer]
It is preferable that the oral preparation and the bitterness reducing agent further include a sweetness enhancer (or a savory agent) having a savory taste (salt taste). Examples of such sweetness enhancers include sodium chloride, sodium chloride, potassium chloride, organic acid salts (sodium or potassium salts such as sodium oxycarboxylate such as sodium malate, sodium gluconate, potassium glutamate, etc.), phosphoric acid Examples of the salt include potassium hydrogen phosphate and sodium hydrogen phosphate. Sweetness enhancers (or flavoring agents) are often neutral salts, for example, salts that dissociate as sodium ions and / or chloride ions. These sweetness enhancers can also be used alone or in combination. A preferred sweetness enhancer is sodium chloride.

  The amount of the sweetness enhancer (or flavoring agent) used can be selected according to the type of sweetener and the quantitative ratio thereof. For example, 0.1 to 50 parts by weight, preferably 0. It may be about 5 to 40 parts by weight, more preferably about 1 to 30 parts by weight.

  The amount of the sweetness enhancer used may be about 0.01 to 1% by weight, preferably about 0.05 to 0.5% by weight, based on the whole preparation.

  In addition, when a compound that can act not only as a sour agent but also as a sweet taste enhancer (for example, malate) is added to an oral preparation in an amount larger than the amount used as the sour agent, malate, for example, It acts as a sour agent and a sweetness enhancer.

[Fragrance]
The oral preparation and the bitterness reducing agent may contain a fragrance. As the fragrance, natural fragrance, for example, fruit fragrance (essence or oil such as strawberry, blueberry, apple, ume, lime, vanilla, pepper, etc.), skin fragrance (essence or oil such as orange, white grape, grapefruit, lemon) ), Bark fragrance (essence or oil such as Nikki), root fragrance (essence or oil such as ginger), branch and leaf fragrance (essence or oil such as mint, peppermint, spearmint, rosemary), floral fragrance (jasmine, Essence or oil such as lavender, rose, rosemary, hyacinth), brown sugar flavor, drink essence, etc .; synthetic fragrances such as benzyl acetate, linalyl acetate, citral, citronellal, citronellol, cisjasmine 3-hexenol, menthol and others. These fragrance | flavors can also be used individually or in combination of 2 or more types. As the fragrance, fruit-based fragrance, bark-based fragrance, fruit-based fragrance, and drink essence are preferable, and strawberry essence, Nikki essence, white grape essence, and drink essence are particularly preferable. The drink essence is a mixture of strawberry and nicki.

  The quantitative ratio of the fragrance is 0.01 to 2 parts by weight, preferably 0.05 to 1.5 parts by weight, and more preferably 0.1 to 1 part by weight with respect to 1 part by weight of the medicinal component (for example, epinastine hydrochloride). It may be about parts by weight.

  The amount of these fragrances used may be about 0.01 to 1% by weight, preferably about 0.05 to 0.5% by weight, based on the whole preparation.

  The above oral preparations include solid preparations (eg, tablets, granules, powders, hard capsules, soft capsules, troches, dry syrups, etc.), liquid preparations (eg, syrups, liquids, suspensions, etc.), etc. Any preparation suitable for oral administration may be used. The present invention is preferably applied to a preparation that tends to feel a bitter taste, particularly a liquid (liquid, syrup, etc.).

  The oral preparation of the present invention is physiologically acceptable in addition to the above-mentioned medicinal ingredients, sweeteners, sour agents, fragrances and sweetness enhancers, and impairs the taste-masking of medicinal ingredients depending on the dosage form of the preparation. Various additives (carriers) that are not present can be used for formulation. Examples of the formulation additive include additives usually used for producing pharmaceuticals of the dosage forms mentioned in the pharmaceutical formulation. For example, excipients, binders, disintegrants, disintegration aids, lubricants listed in the Pharmacopoeia and “Pharmaceutical Additives Encyclopedia 2000” (Pharmaceutical Daily Inc., published on March 25, 2002, second edition) , Brighteners, colorants, antioxidants (antioxidants), moisture-proofing agents, coating agents, sugar-coating agents, thickening agents, cooling agents, flavoring agents (for example, fragrances, etc.), wetting agents, solvents or Liquid, solubilizer, surfactant, dispersant, suspending agent, adsorbent, antifoaming agent, stabilizer, preservative, preservative, solubilizer, softener, plasticizer, foaming agent, pH adjuster, buffer An agent suitable for each dosage form is selected.

  As the above solid preparation, the medicinal component and the carrier component are granulated, and the resulting granule is compression-molded by adding additives as necessary, and then, if necessary, imparting taste masking, enteric properties or sustainability itself It is manufactured by coating by a known method, and capsules can be prepared by filling capsules with granules. In the solid preparation, the sweetener and sour agent may be added at an appropriate stage of the production process, such as a granulation process or an additive addition process. As a carrier for a solid preparation, at least one carrier selected from excipients, binders and disintegrants is often used, and additives such as lipids may be used.

  Examples of the excipient include sugars such as lactose, sucrose, glucose, sucrose, mannitol, sorbitol or sugar alcohols; starch such as corn starch; polysaccharides such as crystalline cellulose (including microcrystalline cellulose); Examples thereof include silicon oxides such as acids and synthetic aluminum silicates or silicates. Binders include soluble starch such as pregelatinized starch and partially pregelatinized starch; polysaccharides such as agar, gum arabic, dextrin, sodium alginate, tragacanth gum, xanthan gum, hyaluronic acid, sodium chondroitin sulfate; polyvinylpyrrolidone, polyvinyl alcohol, carboxy Synthetic polymers such as vinyl polymer, polyacrylic acid polymer, polylactic acid, and polyethylene glycol; and cellulose ethers such as methyl cellulose, ethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. . Examples of the disintegrant include calcium carbonate, carboxymethylcellulose or a salt thereof (carmellose, carmellose sodium, carmellose calcium, etc.), polyvinylpyrrolidone (polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone (crospopidone), etc.), low-substituted hydroxypropylcellulose, etc. It can be illustrated. These carriers can be used alone or in combination of two or more.

Lipids include waxes (beeswax, carnauba wax, lanolin, paraffin, petrolatum, etc.), long chain fatty acid esters (saturated or unsaturated fatty acid alkyl esters, fatty acids and polyhydric alcohols (poly C _2-4 alkylene glycol, glycerin or Polyglycerin, etc.) and esters (such as glycerides), hydrogenated oils, higher alcohols (saturated fatty alcohols such as stearyl alcohol, unsaturated fatty alcohols such as oleyl alcohol), higher fatty acids (stearic acid, oleic acid, etc.) ), Metal soaps (for example, fatty acid metal salts such as coconut oil fatty acid sodium and calcium stearate) and the like.

  Examples of additives include lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000), disintegration aids, antioxidants or antioxidants, and emulsifiers (eg, nonionic surfactants). Surfactants), dispersants, suspensions, solubilizers, thickeners (water-soluble polymers such as carboxyvinyl polymer, polyvinyl alcohol, carrageenan, gelatin; cellulose ethers such as carboxymethylcellulose), pH adjustment Agents or buffers (citric acid-sodium citrate buffer, etc.), preservatives or preservatives (parabens, such as methylparaben and butylparaben), bactericides or antibacterial agents (benzoic acids, such as sodium benzoate), charging Inhibitors, flavoring agents or masking agents (for example, sweeteners), coloring agents (Bengara) What colorant etc.), etc. flavoring or perfume (fragrance), fresheners, defoamers, isotonic agents, soothing agents. These additives can be used alone or in combination of two or more.

  The liquid preparation may be in the form of a solution, suspension, emulsion, etc., as long as it is liquid, or it may be a liquid preparation such as a drink, extract, elixir, syrup, or limonade. Of course, various drinks such as health drinks may be used.

  The liquid uses a medicinal component, the sweetener and sour agent in a specific ratio, and mixes liquid carrier components (oil solvent, aqueous solvent such as purified water, alcoholic solvent such as ethanol, etc.) and additives as necessary. And can be sterilized if necessary. Additives include conventional ingredients such as carriers, surfactants (emulsifiers or dispersants), solubilizers, solubilizers, suspending agents, thickeners, etc. Sugars (for example, pectin, locust bean gum, gum arabic, tragacanth gum, sodium alginate, agar, carrageenin, hyaluronic acid, chondroitin sulfate, etc.), cellulose derivatives (methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, etc.) , Synthetic polymers (polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, methacrylic acid copolymer, carboxyvinyl polymer, etc.), colorants, dietary fiber, preservatives or preservatives (eg, sodium benzoate) And paraoxybenzoic acid alkyl esters, methylparaben, propylparaben, etc.), antioxidants (antioxidants), cooling agents, bactericides, antibacterial agents, isotonic agents, pH adjusters, buffering agents (generally buffering action) As long as it has (resisting to pH change), for example, an organic acid buffer (sodium acetate, citric acid, sodium citrate, potassium hydrogen tartrate, sodium hydrogen tartrate, etc.), phosphate-based Examples include buffers (phosphate salts such as sodium dihydrogen phosphate and potassium dihydrogen phosphate), boric acid buffers (boric acid, borax, etc.), flavoring agents, antifoaming agents, and the like. In many cases, the liquid is usually sterilized by mixing each component with purified water, adjusting the pH as necessary.

  The oral preparation (solution) has excellent stability in a wide pH range. For example, the oral preparation has a pH of 3 to 7, preferably pH 3.5 to 7, and more preferably about pH 4 to 6. The pH of the preparation of the present invention may be adjusted with a pH adjuster. Examples of pH adjusters include inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, etc.), organic acids (acetic acid, etc.), inorganic bases (sodium hydroxide, sodium bicarbonate, ammonia, etc.), organic bases (amines, etc.), etc. A buffer may be used.

  Epinastine is useful for the treatment of diseases such as bronchial asthma; allergic rhinitis; urticaria, eczema / dermatitis, pruritus pruritus, prurigo vulgaris and pruritus vulgaris. It can be determined appropriately depending on the symptoms, age, weight, etc. For example, in the case of allergic rhinitis, the dosage is usually converted to the amount of the medicinal component, usually once a day, about 10 to 20 mg once, in the case of other diseases once a day once. About 20 mg.

  INDUSTRIAL APPLICABILITY The present invention can reduce the bitter taste of medicinal ingredients and also improve the stability of the preparation over a long period of time. Therefore, the present invention is useful for improving the feeling of administration during oral administration or taking, and for preventing deterioration of the preparation during long-term storage.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

Examples 1 to 19 (Liquids) and Comparative Examples Table 1 shows the weight ratios (%) in the formulation components and the whole preparation. In the purified water heated to 40 ° C., the ingredients shown in Tables 1 and 2 except the fragrance were dissolved, allowed to cool to room temperature, and if necessary, the fragrance was added and mixed. Thereafter, purified water was added to make a total amount to obtain a preparation (solution) (epinastine hydrochloride concentration 0.2 wt%). As a comparative example, a commercially available epinastine hydrochloride preparation (hereinafter also referred to as a commercial product) was used.

Test example 1. Sensory test The sensory test was conducted on the preparation of Example 19 and a commercial product of 23 men and women (15 males and 8 females). As a result, in 21 persons (male: 14 persons, females: 7 persons), the bitterness of the preparation of Example 19 was sufficiently suppressed as compared with the commercially available product, and it was easy to drink. From the above, it was confirmed that the preparation feeling of Example 19 was greatly improved in the ingestion feeling by improving the unique taste of the commercial product where sweetness and bitterness coexisted.

2. Stability test [Method]
The preparations of Examples and commercial products filled in glass bottles were stored at 60 ° C. for 3 weeks, and the degree of coloration (APHA color) was measured every week. The difference between the measured APHA color value and the APHA color value before storage (ΔAPHA = (APHA color value measured after storage for 1 to 3 weeks) − (APHA color value before storage)) is shown in Tables 1-2.

[APHA color measurement method]
Based on the JOCS 3.2.1.2-1996 reference oil analysis test method, an APHA standard color stock solution at a wavelength of 450 nm was prepared, a calibration curve was obtained, and calculated from the following formula.

U _APHA = U _ABS × 140 / 0.0383
[result]
As shown in Tables 1 and 2, the ΔAPHA of the commercial product (pH 3.5) increased to 516.2 in 3 weeks, whereas the change in ΔAPHA in the preparations of the examples (pH 3.0 to 6.5) It was found to be very small or not fluctuating. That is, it was confirmed that the preparations of Examples were stable in a wide pH range of pH 3.0 to 6.5.

3. Stability test (effect of heat and light)
[Method]
The preparations of Examples 12, 13, 14 and 15 filled in glass bottles were stored at 60 ° C. for 3 weeks, and the remaining ratio of epinastine hydrochloride and the amount of related substances (impurities) in the preparation were changed for each week. Pharmacopoeia Part 1 General test method 2. It measured according to the liquid chromatograph method. Furthermore, the stability of the preparations of Examples 13 and 15 to light (temperature 25 ° C., D60 fluorescent lamp, 1,200,000 Lux · h) was evaluated by measuring the amount of related substances produced (impurity amount). The results are shown in Tables 3-4.

[result]
As shown in Table 3, after 3 weeks, the commercial product had a large change in ΔAPHA (about 516), a decrease in the residual ratio of epinastine hydrochloride (95.2%), and an increase in the amount of related substances produced (1.78%). showed that. Furthermore, as shown in Table 4, the amount of related substances produced in the commercial product was greatly increased (5.43%) in terms of light stability.

  On the other hand, as shown in Table 3, the preparations of Examples 12, 13, 14 and 15 not only have very small fluctuations in ΔAPHA, but also show little decrease in the residual ratio of epinastine hydrochloride and increase in the amount of related substances produced. Furthermore, in the stability to light, as shown in Table 4, the preparations of Examples 13 and 15 hardly generated any related substances. From the above, it was confirmed that the example preparations were markedly superior in terms of stability as compared with the commercial products.

4). Stability test (effect of pH)
[Method]
Each formulation of Example 19 having a pH adjusted to 3.5 to 6.5 was filled in a glass bottle and stored at 60 ° C. for 3 weeks, and the coloration degree (APHA color) of the formulation every week, the residual ratio of epinastine hydrochloride and The amount of related substances produced was measured. The results are shown in Table 5.

[result]
As shown in Table 5, as compared with the commercially available product (pH 3.5), the formulation of Example 19 was colored (APHA color), epinastine hydrochloride residual rate at any pH (3.5 to 6.5). It was also observed that the amount of production of related substances was small and excellent stability was exhibited in a wide pH range.

  As described above, as apparent from the results of Test Examples 1 to 4, by blending the medicinal component, sweetener and sour agent, the bitterness of the medicinal component can be effectively suppressed, and further, its stability in a wide pH range. (Long-term storage stability) can also be effectively improved.

Claims (14)

  An oral preparation comprising epinastine or a pharmaceutically acceptable salt thereof, at least one sweetener selected from synthetic sweeteners and sugar alcohols, and a sour agent, wherein the ratio of the sour agent is a sweetener 100. The oral formulation which is 10-1000 weight part with respect to a weight part.   The oral preparation according to claim 1, wherein the sweetener is at least one selected from aspartame, erythritol, xylitol and D-sorbitol.   The oral preparation according to claim 1, wherein the sour agent is at least one selected from saturated carboxylic acid, unsaturated carboxylic acid, oxycarboxylic acid and salts thereof.   The oral preparation according to claim 1, wherein the sour agent is at least one selected from succinic acid, lactic acid, malic acid, tartaric acid, citric acid, gluconic acid, fumaric acid, maleic acid, ascorbic acid and salts thereof.   The oral preparation according to claim 1, comprising 0.1 to 200 parts by weight of a sweetener and 1 to 150 parts by weight of a sour agent with respect to 1 part by weight of epinastine or a pharmaceutically acceptable salt thereof.   The oral preparation according to claim 1, further comprising a fragrance.   The oral preparation according to claim 6, wherein the fragrance is at least one selected from strawberry essence, nikki essence, white grape essence, banana essence and drink essence.   The oral preparation according to claim 1, further comprising a sweetness enhancer.   The oral preparation according to claim 8, wherein the sweetness enhancer is at least one selected from sodium chloride, potassium chloride, organic acid salts and phosphates.   The oral preparation according to any one of claims 1 to 9, which is a liquid or syrup.   The oral preparation according to claim 10, wherein the pH is in the range of 3-7.   A method for producing an oral preparation using epinastine or a pharmaceutically acceptable salt thereof as a medicinal ingredient, the sweetener according to claim 1 and a sour agent, wherein the sour agent is added to 100 parts by weight of the sweetener. A method for producing an oral preparation using an agent at a ratio of 10 to 750 parts by weight.   A bitterness reducing agent for reducing the bitter taste of epinastine or a pharmaceutically acceptable salt thereof as a medicinal component, comprising the sweetening agent according to claim 1 and a sour agent, wherein 100 parts by weight of the sweetening agent is added. The bitterness reducing agent which contains a sour agent in the ratio of 10-750 weight part with respect to it.   A method for reducing the bitterness of a medicinal ingredient by adding the bitterness reducing agent according to claim 13 to epinastine or a pharmaceutically acceptable salt thereof as the medicinal ingredient.