WO2009022674A1 - Medical composition containing rebamipide - Google Patents

Medical composition containing rebamipide Download PDF

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Publication number
WO2009022674A1
WO2009022674A1 PCT/JP2008/064385 JP2008064385W WO2009022674A1 WO 2009022674 A1 WO2009022674 A1 WO 2009022674A1 JP 2008064385 W JP2008064385 W JP 2008064385W WO 2009022674 A1 WO2009022674 A1 WO 2009022674A1
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WO
WIPO (PCT)
Prior art keywords
medical composition
rebamipide
acid
granules
arginine
Prior art date
Application number
PCT/JP2008/064385
Other languages
French (fr)
Inventor
Yoshio Hara
Original Assignee
Otsuka Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Otsuka Pharmaceutical Co., Ltd. filed Critical Otsuka Pharmaceutical Co., Ltd.
Priority to JP2010519618A priority Critical patent/JP5328789B2/en
Priority to CN200880102776.7A priority patent/CN101778626B/en
Publication of WO2009022674A1 publication Critical patent/WO2009022674A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to a medical composition containing rebamipide.
  • Rebamipide or a salt thereof (hereunder, this may be simply referred to as “rebamipide”) is known as a medicine for alleviating subjective and objective symptoms of gastric ulcer, gastritis and like diseases.
  • Rebamipide is naturally very bitter; therefore, when used in an orally administered pharmaceutical preparation, a coating is provided around the rebamipide in order to reduce the bitter taste in the mouth.
  • the rebamipide thus takes the form of film-coated tablets, film-coated granules, etc. (Japanese Patent No. 3466921).
  • rebamipide can be used to treat stomatitis (Japanese Patent No. 2839847).
  • Japanese Patent No. 2839847 Japanese Patent No. 2839847
  • a pharmaceutical preparation that is less of an irritant to the mucosa in the oral cavity, and is free from bitterness even when containing rebamipide in a high concentration is desired.
  • corrigents, sweeteners and like additives have been widely used.
  • some corrigents may reduce the stability of the pharmaceutical compositions with the passage of time.
  • corrigents cannot be added in an amount that would sufficiently suppress the bitterness of the preparation and facilitate its administration.
  • merely increasing the amount of sweetener would not satisfactorily suppress the bitterness, and some artificial sweeteners may undesirably increase unpleasant tastes, such as bitterness, acridity, etc.
  • no corrigent or sweetener has been developed that can satisfactorily suppress the intensive long-lasted bitterness of rebamipide.
  • the present invention relates to a technique to reduce the bitterness of a medical composition containing rebamipide .
  • the present inventors conducted extensive research to achieve the above object, and found that bitterness of rebamipide can be reduced by adding L-arginine or a salt thereof (hereunder may be referred to as "L-arginine”) to a medical composition containing rebamipide.
  • L-arginine L-arginine
  • the present inventors also found that by adding L-arginine along with an acidic substance to a medical composition containing rebamipide, irritation of the mucous membrane can be suppressed while the bitterness reduction effect is maintained.
  • the present inventors also found that the addition of specific sweeteners can reduce the bitterness of rebamipide . Furthermore, the present inventors found that by adding L-arginine and a sweetener, in particular thaumatin, to rebamipide, reduction of bitterness and ease of taking can be enhanced .
  • the present invention has been accomplished by these findings .
  • the present invention provides the medical compositions of Items 1 to 31 below:
  • Item 1 A medical composition comprising rebamipide or a salt thereof and L-arginine or a salt thereof.
  • Item 2 The medical composition according to Item 1, wherein the content of the L-arginine or a salt thereof is 0.001 to 300 parts by weight per 100 parts by weight of rebamipide or a salt thereof.
  • Item 3 The medical composition according to Item 1 or 2 , which comprises at least one sweetener selected from the group consisting of thaumatin, stevia and luohan fruit extracts.
  • Item 4 The medical composition according to Item 3, wherein the sweetener is thaumatin.
  • Item 5 The medical composition according to any one of Items 1 to 4, which further comprises an acidic substance.
  • Item 6 The medical composition according to Item 5 , wherein the content of the acidic substance is such that the pH becomes 3 to 11 when suspended or dissolved in water.
  • Item 7 The medical composition according to Item 5 or 6 , wherein the acidic substance is an organic acid or an inorganic acid.
  • Item 8 The medical composition according to any one of Items 5 to 7 , wherein the acidic substance is at least one member selected from the group consisting of hydrochloric acid, phosphoric acid, tartaric acid, malic acid, ascorbic acid, succinic acid, citric acid, maleic acid, acetic acid, and oxalic acid.
  • the acidic substance is at least one member selected from the group consisting of hydrochloric acid, phosphoric acid, tartaric acid, malic acid, ascorbic acid, succinic acid, citric acid, maleic acid, acetic acid, and oxalic acid.
  • Item 9 The medical composition according to Item 8, wherein the acidic substance is at least one member selected from the group consisting of citric acid, ascorbic acid, tartaric acid and succinic acid.
  • Item 10 The medical composition according to Item 9, wherein the acidic substance is citric acid.
  • Item 11 The medical composition according to any one of Items 1 to 10 , which further comprises a flavoring agent .
  • Item 12 The medical composition according to any one of Items 1 to 11 , which takes the form of tablets or granules without coating, tablets or granules with coating, orally disintegrating tablet, oral liquid medicine, gargle, intraoral sprays or intraoral film agents.
  • Item 13 The medical composition according to Item 12, which takes the form of granules without coating or granules with coating.
  • Item 14 The medical composition according to Item 12, which takes the form of granules with coating.
  • Item 15 The medical composition according to Item 14, wherein the core particles of the granules with coating comprise rebamipide or a salt thereof, L-arginine or a salt thereof, an acidic substance, and at least one sweetener selected from the group consisting of thaumatin, stevia and luohan fruit extracts.
  • Item 16 The medical composition according to Item 15, which further comprises soybean lecithin in the coating.
  • Item 17 A medical composition comprising rebamipide or a salt thereof , and at least one sweetener selected from the group consisting of thaumatin, stevia and luohan fruit extracts.
  • Item 18 The medical composition according to Item
  • Item 19 The medical composition according to Item 17 or 18, which further comprises an acidic substance.
  • Item 20 The medical composition according to Item 19, wherein the content of the acidic substance is such that the pH becomes 3 to 11 when suspended or dissolved in water.
  • Item 21 The medical composition according to Item 19 or 20, wherein the acidic substance is an organic or inorganic acid.
  • Item 23 The medical composition according to Item 22, wherein the acidic substance is at least one member selected from the group consisting of citric acid, ascorbic acid, tartaric acid and succinic acid.
  • Item 24 The medical composition according to Item 23, wherein the acidic substance is citric acid.
  • Item 25 The medical composition according to any one of Items 17 to 24, which further comprises an flavoring agent.
  • Item 26 The medical composition according to any one of Items 17 to 25, which takes the form of tablets or granules without coating, tablets or granules with coating, orally disintegrating tablet, oral liquid medicine, gargle, intraoral sprays or intraoral film agents.
  • the core particles of the granules with coating comprise rebamipide or a salt thereof, an acidic substance, and at least one sweetener selected from the group consisting of thaumatin, stevia and luohan fruit extracts.
  • Item 31 A method for reducing bitterness of rebamipide, which comprising a step of adding L-arginine or a salt thereof, citric acid and thaumatin to the rebamide- containing composition.
  • the medical composition of the present invention contains rebamipide and L-arginine.
  • this composition is referred to as Medical Composition A.
  • the rebamipide (chemical name:
  • rebamipide salts can be used as the pharmaceutically acceptable rebamipide salts .
  • Specific examples thereof include salts formed with generally used bases, such as sodium hydroxide, potassium hydroxide, trometamol ( tris (hydroxymethyl ) aminomethane ) , monoethanolamine , diethanolamine , triethanolamine , diisopropanolamine, meglumine, etc.
  • bases such as sodium hydroxide, potassium hydroxide, trometamol ( tris (hydroxymethyl ) aminomethane )
  • monoethanolamine diethanolamine
  • triethanolamine diisopropanolamine
  • meglumine etc.
  • the amount of the rebamipide contained in the Medical Composition A of the present invention is generally about 0.01 to 99 wt.% and preferably about 0.1 to 90 wt.%.
  • salts of L-arginine include salts between L-arginine and an acid (such as hydrochloric acid, sulfuric acid, methanesulfonic acid, etc.).
  • the content of L-arginine is generally 0.001 to 300 parts by weight, preferably 0.01 to 200 parts by weight, and more preferably 0.1 to 100 parts by weight per 100 parts by weight of rebamipide . In the case of granules , it is particularly preferable that 1 to 10 parts by weight of L-arginine be added per 100 parts by weight of rebamipide. This provides a medical composition having excellent properties , such as free from smeariness in a granulation step, and thereby can be easily produced.
  • the Medical Composition A contain a sweetener.
  • usable sweeteners include thaumatin, stevia and luohan fruit extracts. These sweeteners may be used singly or in combination.
  • the content the sweetener is generally 0.0001 to 300 parts by weight, preferably 0.001 to 200 parts by weight, and more preferably 0.01 to 100 parts by weight per 100 parts by weight of rebamipide .
  • 0.1 to 10 parts by weight of sweetener be added per 100 parts by weight of rebamipide.
  • a medical composition contains 0.1 to 1.5 parts by weight of thaumatin per 100 parts by weight of rebamipide, it can be easily taken, because the sweetness of thaumatin and the bitterness of rebamipide are well balanced therein.
  • Stevia sweeteners which are collectively called as stevia, include, for example, stevia extracts (an extract containing stevioside at the greatest percentage among the sweetener components contained therein; an extract containing rebaudioside at the greatest percentage; etc.), stevioside, rebaudioside, dulcoside, stevia powder, glycosyl stevia, enzyme-treated stevia, etc., and these stevia sweeteners may be used singly or in combination. Among these stevioside is particularly preferable.
  • the Medical Composition A of the present invention further contain an acidic substance.
  • an acidic substance By adding an acidic substance, the pH after dissolving or suspending the Medical Composition A in water can be controlled, so that irritation of the mucous membrane can be reduced.
  • Examples of acidic substances include various known organic acids and inorganic acids .
  • Examples of organic acids include tartaric acid, malic acid, ascorbic acid, succinic acid, citric acid, maleic acid, acetic acid, oxalic acid, etc.
  • Examples of inorganic acids include hydrochloric acid, phosphoric acid, etc. These acidic substances may be used singly or in combination.
  • citric acid, ascorbic acid, tartaric acid, and succinic acid are preferable, and citric acid is particularly preferable.
  • the acidic substance is added in such a manner that the pH, when the medical composition of the present invention is suspended or dissolved in water, generally becomes 3 to 11, preferably 4 to 10, more preferably 5 to 9, and particularly preferably 6 to 8. Specifically, generally 0.01 to 100 mol, preferably 0.1 to 50 mol, and more preferably 0.2 to 10 mol of acidic substance is added per mol of L-arginine .
  • the medical composition A further contain a flavoring agent .
  • flavoring agents include lemons, grapefruits, oranges, pineapples, peaches, yogurt, chocolate, coffee, wine, powdered tea, gin, etc. These flavoring agents may be used singly or in combination.
  • the content of the flavoring agent is generally 0.0001 to 300 parts by weight, preferably 0.001 to 200 parts by weight, and more preferably 0.01 to 100 parts by weight per 100 parts by weight of rebamipide . In the case of granules , content of the flavoring agent is preferably 0.1 to 10 parts by weight per 100 parts by weight of rebamipide.
  • the Medical Composition A of the present invention may be taken as orally administered pharmaceutical preparations, such as tablets, granules, fine particles, powdered medicines , liquid medicines , suspension pharmaceuticals, orally disintegrating tablets, intraoral film agents, intraoral sprays, gargle, etc. These tablets, granules and fine particles may be coated.
  • ком ⁇ онент In order to prepare the oral administration preparation, various kinds of carriers can be added.
  • usable carriers include those used in this field, such as excipients, lubricants, disintegrants , binders, surfactants, plasticizers, acidulant , diluents, etc.
  • excipients include crystalline cellulose, potato starch, dextrin, cornstarch, lactose, saccharose, mannitol, talc, calcium carbonate , etc.
  • lubricants include magnesium stearate, calcium stearate, aluminum stearate, etc.
  • disintegrants include sodium carboxymethyl starch, sodium carboxymethylcellulose, low substituted hydroxypropylcellulose, calcium carboxymethylcellulose, sodium cros ⁇ armellose, hydroxypropyl starch, potato starch, polyvinyl pyrrolidone, agar, etc.
  • binders include gum arable, hydroxypropylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, gelatin, etc.
  • surfactants include sodium lauryl sulfate etc.
  • plasticizers include Polysorbate 80, hydrogenated soya oil, hydrogenated castor oil, Japan tallow, hydrogenated beef tallow and like oils and fats; carnaubawax, beeswax and like waxes ; paraffin, ceresin, microcrystalline wax and like higher hydrocarbons; and mixtures thereof.
  • acidulants include ascorbic acid, tartaric acid, malic acid, succinic acid, citric acid, maleic acid, acetic acid, oxalic acid and like acidulants.
  • diluents include cetyl alcohol, stearyl alcohol and like higher alcohols; myristic acid, palmitic acid, stearic acid, behenic acid and like higher fatty acids or glycerine fatty acid esters thereof; esters between acetic acid, citric acid, succinic acid and like organic acids, and mono- or di-higher fatty acid esters.
  • various film coating bases used in this field may be added in such an amount that does not adversely affect the effects of the present invention.
  • usable film coating bases include saccharose, fructose and like sugars; mannitol, sorbitol, xylitol and like sugar alcohols ; cetyl alcohol, stearyl alcohol and like higher alcohols; myristic acid, palmitic acid, stearic acid, behenic acid and like higher fatty acids or glycerin esters thereof; esters of acetic acid, citric acid, succinic acid and like organic acids with glycerin mono- or di-higher fatty acid esters; hydrogenated soya oil, hydrogenated castor oil, Japan tallow, hydrogenated beef tallow and like oils and fats; carnaubawax, beeswax and like waxes ; paraffin, ceresin, microcrystalline wax and like higher hydrocarbons; hydroxypropylmethylcellulose , ethyl
  • the amount of the coating may be suitably selected depending on the type of solid preparation. For example, in the case of granules, generally 1 to 200 wt.%, preferably 1 to 100 wt.%, and more preferably 5 to 100 wt.% per total weight of the core granules .
  • the oral pharmaceutical preparation of the present invention can be prepared by a generally known method.
  • the Medical Composition A of the present invention is preferably in the form of tablets without coating, orally disintegrating tablets, oral liquid medicines, gargle, intraoral sprays or intraoral film agents, which contain rebamipide, L-arginine, and an acidic substance.
  • the acidic substance is preferably at least one member selected from the group consisting of citric acid, tartaric acid and succinic acid.
  • the Medical Composition A of the present invention is also preferably in the form of tablets or granules that contain rebamipide and L-arginine, for which a coating is provided.
  • the Medical Composition A of the present invention is also preferably in the form of film-coated tablets or film-coated granules that contain rebamipide , L-arginine, and an acidic substance.
  • the medical composition A of the present invention is also preferably in the form of orally disintegrating tablets , oral liquid medicines, intraoral sprays and intraoral film agents, which contain rebamipide or a salt thereof, L-arginine or a salt thereof, an acidic substance, a sweetener, and a flavoring agent.
  • the sweetener is at least one member selected from the group consisting of thaumatin, stevia and luohan fruit extracts .
  • a particularly preferable example of the Medical Composition A is that contains rebamipide, L-arginine, an acidic substance and at least one sweetener selected from the group consisting of thaumatin, stevia and luohan fruit extracts .
  • the Medical Composition A takes the form of granules without coating or granules with coating (particularly preferably, granules with coating) .
  • the core particles of granules with coating contain rebamipide, L-arginine, an acidic substance, and at least one sweetener selected from the group consisting of thaumatin, stevia, and luohan fruit extracts.
  • Such granule also contains soybean lecithin in the coating.
  • the content of soybean lecithin in the coating is generally 0.1 to 50 wt.%, and preferably 1 to 10 wt.%.
  • the medical composition of the present invention comprises rebamipide or a salt thereof, and at least one sweetener selected from the group consisting of thaumatin, stevia and luohan fruit extracts (preferably, thaumatin) .
  • Such medical composition is hereunder referred to as Medical
  • Composition B is Composition B.
  • the content of the sweetener is generally 0.0001 to 300 parts by weight, preferably 0.001 to 200 parts by weight, and more preferably 0.001 to 100 parts by weight per 100 parts by weight of rebamipide.
  • the acidic substance is added in such a manner that the pH, when the medical composition B is suspended or dissolved in water, generally becomes 3 to 11, preferably 4 to 10, more preferably 5 to 9, and particularly preferably 6 to 8.
  • the administration amount of the oral pharmaceutical preparation of the present invention depends on usage, gender, age and other conditions of the patient , the degree of the disease, etc.; however, a rebamipide, which is the active ingredient, is generally administered in a dosage of 0.001 to 100 mg, preferably 0.001 to 50 mg, per kg of body weight per day, in such a manner that the aforementioned amount is taken once per day, or divided into several dosages during the day.
  • the administration amount changes depending on various conditions; an administration amount less than the above-mentioned range may therefore be sufficient at times, while an administration amount exceeding the above range may also at times be necessary.
  • the present invention provides a medical composition in which the bitterness of rebamipide or a salt thereof is reduced.
  • the present invention also provides a medical composition by which irritation to the mucous membrane is reduced.
  • the medical composition of the present invention is effectively usable not only in the form of tablets, granules and like solid preparations, but also in the form of liquid agents , gargles , intraoral sprays and intraoral film agents .
  • the bitterness reduction effect can be maintained even after the coating is broken; this provides medical compositions that can be taken more easily.
  • the following effects can be achieved.
  • Such preparations can be easily taken, patient compliance can be improved, and the pharmacological action inherent in the medicine can be satisfactorily expressed.
  • the medical composition of the present invention can be taken as tablets, orally disintegrating tablets which do not require a coating, oral liquid medicines, intraoral film agents, intraoral sprays and like orally administered medicines .
  • the present invention provides various pharmaceutical preparations that can be easily taken, improving patient compliance and widening the number of diseases the invention is applicable to.
  • a mixture of 1010 g of rebamipide, 1845 g of lactose, 510 g of corn starch, 140 g of crystalline cellulose, 680 g of dextrin, 150 g of carboxymethyl starch sodium and 90 g of croscarmellose sodium was kneaded with a combining liquid of 20 g of L-arginine, 838 g of purified water, and 140 g of polysorbate 80 using a vertical granulator.
  • the resulting mixture was granulated using an extruding granulator equipped with a 0.6 mm diameter screen (TDG-80, provided by Fuji Paudal Co., Ltd.), and then formed in spherical shape using a Marumerizer (QJ-400, provided by Fuji Paudal Co. , Ltd. ) .
  • the granules thus obtained are dried, and the granules having a particle size of 0.355-1 mm are collected to give core granules .
  • Citric and Fatty Acid Esters of Glycerol (SunSoft 621G, provided by Taiyo Kagaku Co. Ltd., 60 g) was added to a mixture of 144 g of ethanol and 36 g of water, followed by dissolving by heating. D-mannitol (60 g) was added thereto and then suspended by stirring to obtain a coating solution.
  • Core granules (300 g) were placed in an agitation-type rotary fluidized bed granulator (NQ- 160, provided by Fuji Paudal Co., Ltd.); while the core granules were fluidized by air supplied at a temperature of 50 0 C, at an agitation rate of 120 rpm, the coating solution was applied to the surfaces of the core granules by spraying at a liquid speed of 20 g/minute. After coating, the particles were air-dried at 50°C, and subjected to sizing to obtain coated granules, using a sieve with openings of 1180 ⁇ m.
  • NQ- 160 agitation-type rotary fluidized bed granulator
  • Comparative Example 1 For comparison, coated granules containing rebamipide were obtained in the same manner as in Example 1, except that L-arginine was not used, and the dextrin amount was increased by 20 g.
  • Example 1 The coated granules (500 mg each) obtained in Example 1 and Comparative Example 1 were kept in the mouth for 60 seconds and then spat out, after which the bitterness thereof was evaluated.
  • Comparative Example 1 which do not contain L-arginine, although a bitter taste was not immediately experienced, bitterness was experienced 30 seconds afterward, and a bitter taste remained even after the granules were spat out 60 seconds after first placed in the mouth.
  • bitterness was not experienced during the 60 seconds of the test, or after the granules were spat out .
  • a mixture of 60.6 g of rebamipide, 110.7 g of lactose, 30.6 g of corn starch, 8.4 g of crystalline cellulose, 36.0 g of dextrin, 9.0 g of carboxymethyl starch sodium and 5.4 g of croscarmellose sodium was kneaded with a combining liquid of 6 g of L-arginine, 50.3 g of purified water, and 8.4 g of polysorbate 80 using a vertical granulator. The same process was repeated three times , and the resulting kneaded material was granulated using an extruding granulator equipped with a 0.6 mm diameter screen (TDG-80, provided by Fuji Paudal Co. , Ltd.
  • TDG-80 0.6 mm diameter screen
  • coated granules containing rebamipide were prepared in the same manner as in Example 2 , except that L-arginine was not added, and the dextrin amount was increased by 6 g.
  • Coated granules of Examples 3 to 7 were prepared in the same manner as in Example 2 , except that rebamipide , L-arginine (or L-arginine hydrochloride), citric acid and thaumatin were used in the amounts shown below in Table 1. Note that citric acid and L-arginine hydrochloride were added to the combining liquid in the same manner as the addition of L-arginine. Thaumatin was not added to the combining liquid, but to the rebamipide, lactose, etc.
  • the coated granules (500 mg each) obtained in Examples 2 to 7 and Comparative Example 2 were kept in the mouth for 60 seconds and then spat out, after which the bitterness thereof was evaluated.
  • Example 7 granules of Example 7 containing thaumatin in addition to L-arginine exhibited greater reduction in the bitterness of rebamipide compared to those of Examples 1 to 6.
  • Rebamipide (2.5 g) was dispersed in water (1 L) to obtain a 2.5 mg/ml suspension (Comparative Example 3).
  • 0.5 g of L-arginine or L-arginine hydrochloride was dissolved in water (1 L) , producing a 0.5 mg/ml L-arginine solution or L-arginine hydrochloride solution.
  • the rebamipide suspension (20 ml) and each L-arginine solution (1 ml) were mixed, and 5 ml of the mixture was kept in the mouth for 60 seconds and then spat out. Subsequently, the bitterness was evaluated.
  • Rebamipide (10 g) was dispersed in water (1 L) to obtain a 10 mg/ml suspension (Comparative Example 4).
  • 10 g of L-arginine was dissolved in water (1 L), producing a 10 mg/ml L-arginine solution.
  • 0.001 ml, 0.01 ml, 0.1 ml, 1 ml, 10 ml or 30 ml of an L-arginine solution was added to prepare a mixture solution containing 0.01, 0.1, 1, 10, 100 or 300 parts by weight of L-arginine per 100 parts by weight of rebamipide.
  • the resulting mixture was granulated using an extruding granulator equipped with a 0.6 mm diameter screen (TDG-80, provided by Fuji Paudal Co. , Ltd. ) , and then formed in spherical shape using aMarumerizer (QJ-400, provided by Fuji Paudal Co., Ltd.).
  • TDG-80 0.6 mm diameter screen
  • QJ-400 aMarumerizer
  • Citric and Fatty Acid Esters of Glycerol (SunSoft 621G, provided by Taiyo Kagaku Co. Ltd., 200 g) was added to a mixture of 480 g of ethanol and 120 g of water, followed by dissolving by heating.
  • D-mannitol 200 g was added thereto and then suspended by stirring to obtain a coating solution.
  • Core granules 300 g were placed in an agitation-type rotary fluidized bed granulator (NQ- 160, provided by Fuji Paudal Co. , Ltd.
  • the coating solution was applied to the surfaces of the core granules by spraying at the liquid speed of 20 g/minute. After coating, the particles were air-dried at 50° C, and subjected to sizing using a sieve with 1180 ⁇ m openings to obtain coated granules.
  • a mixture of 1010 g of rebamipide, 1745 g of lactose, 510 g of corn starch, 140 g of crystalline cellulose, 600 g of dextrin, 150 g of carboxymethyl starch sodium, 180 g of croscarmellose sodium, 5 g of thaumatin (sweetener), and 2 g of Natural Flavor (Resolver 283) was kneaded with a combining liquid of 20 g of L-arginine, 843 g of purified water, 200 g of polysorbate 80, 2O g of citric acid, 2 g of Cream Flavor (GIVO27723) and 1 g of Bitter orange Flavor using a vertical granulator.
  • the resulting mixture was granulated using an extruding granulator equipped with a 0.6 nun diameter screen (TDG-80, provided by Fuji Paudal Co. , Ltd. ) , and then formed in spherical shape using a Marumerizer (QJ-400, provided by Fuji Paudal Co. , Ltd. ) .
  • the granules thus obtained are dried, and the granules having a particle size of 0.355-1 mm are collected to give core granules .
  • Citric and Fatty Acid Esters of Glycerol (SunSoft 621G, provided by Taiyo Kagaku Co. Ltd., 200 g) was added to a mixture of 480 g of ethanol and 120 g of water, followed by dissolving by heating.
  • D-mannitol 200 g was added thereto and then suspended by stirring to obtain a coating solution.
  • Core granules 300 g were placed in an agitation-type rotary fluidized bed granulator (NQ-160, provided by Fuji Paudal Co. , Ltd.
  • the coating solution was applied to the surfaces of the core granules by spraying at the liquid speed of 20 g/minute. After coating, the particles were air-dried at 50° C , and subjected to sizing using a sieve with 1180 ⁇ m openings to obtain coated granules.
  • the resulting mixture was granulated using an extruding granulator equipped with a 0.6 mm diameter screen (TDG-80, provided by Fuji Paudal Co., Ltd.), and then formed in spherical shape using a Marumerizer (QJ-400, provided by Fuji Paudal Co. , Ltd. ) .
  • the granules thus obtained are dried, and the granules having a particle size of 0.355-1 mm are collected to give core granules .
  • Citric and Fatty Acid Esters of Glycerol (SunSoft 621G, provided by Taiyo Kagaku Co. Ltd., 360 g) was added to a mixture of 960 g of ethanol and 240 g of water, followed by dissolving by heating. Soybean lecithin (40 g) and D-mannitol (400 g) were added thereto and then suspended by stirring to obtain a coating solution. Core granules (1834 g) were placed in an agitation-type rotary fluidized bed granulator (FLO-5M, provided by Freund Industrial Co. , Ltd.
  • FLO-5M agitation-type rotary fluidized bed granulator
  • the coating solution was applied to the surfaces of the core granules by spraying at a liquid speed of 100 g/minute. After coating, the particles were air-dried at 50 0 C, and subjected to sizing using a sieve with 1180 ⁇ m openings to obtain coated granules .
  • a mixture of 1010 g of rebamipide, 1768 g of lactose, 400 g of corn starch, 180 g of crystalline cellulose, 820 g of dextrin, 120 g of carboxymethyl starch sodium, 100 g of croscarmellose sodium, 2 g of thaumatin (sweetener), and 2 g of Natural Flavor (Resolver 283 ) was kneaded with a combining liquid of 20 g of L-arginine, 843 g of purified water, 200 g of polysorbate 80, 2O g of citric acid, 2 g of Cream Flavor (GIVO27723) and 1 g of Bitter orange Flavor using a vertical granulator.
  • the resulting mixture was granulated using an extruding granulator equipped with a 0.6 mm diameter screen (TDG-80, provided by Fuji Paudal Co., Ltd.), formed in spherical shape using a Marumerizer (QJ-400, provided by Fuji Paudal Co. , Ltd. ) .
  • the granules thus obtained are dried, and the granules having a particle size of 0.355-1 mm are collected to give core granules .
  • Citric and Fatty Acid Esters of Glycerol (SunSoft 621G, provided by Taiyo Kagaku Co. Ltd., 200 g) was added to a mixture of 480 g of ethanol and 120 g of water, followed by dissolving by heating. D-raannitol (200 g) was added thereto and then suspended by stirring to obtain a coating solution.
  • Core granules 300 g were placed in an agitation- type rotary fluidized bed granulator (NQ-160, provided by Fuji Paudal Co. , Ltd.
  • the coating solution was applied to the surfaces of the core granules by spraying at the liquid speed of 20 g/minute. After coating, the particles were air-dried at 50 0 C, subjected to sizing using a sieve with 1180 ⁇ m openings, and 0.3 wt . % of magnesium stearate was added thereto, obtaining coated granules.
  • the coated granules obtained in Examples 16 to 19 can serve as excellent pharmaceutical preparations that are nearly free from bitterness, similar to the coated granules of Example 1.
  • the granules of Example 16 which contained L-arginine , citric acid and a flavoring agent, exhibited a significant reduction in the bitterness compared to the granules, which merely contained the same amount of flavoring agent , wherein the bitterness was only somewhat reduced.
  • Example 17 which further contained thaumatin in addition to L-arginine, citric acid, and a flavoring agent, exhibited a significant reduction in the bitterness compared to the granules, which merely contained the same amounts of flavoring agent and thaumatin, wherein the bitterness was only somewhat reduced.
  • the granules of Example 17 exhibited a greater reduction in the bitterness than those of Example 16.
  • Example 20 Rebamipide (2.5 g) was dispersed in water (1 L) to obtain a 2.5 mg/ml suspension.
  • 50 mg of each sweetener (sucralose, thaumatin, stevia, Acesulfame K, Aspartame, and luohan fruit extracts) was dissolved in 100 ml of water to obtain a 0.5 mg/ml aqueous solution.
  • the above-obtained rebamipide suspension (20 ml) and 0.1 ml of each sweetener solution prepared were mixed. The resulting mixture (5 ml) was kept in the mouth for 10 seconds and then spat out. Subsequently, the bitterness was evaluated.

Abstract

The present invention provides a pharmaceutical preparation wherein the expression of bitterness is reduced. The medical composition of the present invention contains rebamipide or a salt thereof and L-arginine or a salt thereof. The preferable embodiment of the medical composition of the present invention contains rebamipide or a salt thereof and L-arginine or a salt thereof along with at least one sweetener selected from the group consisting of thaumatin, stevia and luohan fruit extracts. By adding such a sweetener, bitterness of medical composition attributable to rebamipide or a salt thereof can be remarkably reduced.

Description

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DESCRIPTION MEDICAL COMPOSITION CONTAINING REBAMIPIDE
TECHNICAL FIELD The present invention relates to a medical composition containing rebamipide.
BACKGROUND ART Rebamipide or a salt thereof (hereunder, this may be simply referred to as "rebamipide") is known as a medicine for alleviating subjective and objective symptoms of gastric ulcer, gastritis and like diseases.
Rebamipide is naturally very bitter; therefore, when used in an orally administered pharmaceutical preparation, a coating is provided around the rebamipide in order to reduce the bitter taste in the mouth. The rebamipide thus takes the form of film-coated tablets, film-coated granules, etc. (Japanese Patent No. 3466921).
However, even if a coating is provided, such a tablet may be crushed when taken by a patient who is incapable of swallowing tablets . In the case of granules , an expression of bitterness is inevitable when granules remain in the mouth are crushed between the patient's teeth. In view of such circumstances, development of a preparation with further reduced expression of bitterness, even when used as a preparation with a coating, has been awaited.
Furthermore, for elderly patients who have difficulty in taking granules as well as tablets, orally disintegrating tablets that disintegrate quickly in the mouth have become popular. Such popularity requires the development of pharmaceutical preparations that can reduce bitterness without a coating.
It is also reported that rebamipide can be used to treat stomatitis (Japanese Patent No. 2839847). When used to treat stomatitis, a pharmaceutical preparation that is less of an irritant to the mucosa in the oral cavity, and is free from bitterness even when containing rebamipide in a high concentration is desired.
In order to improve the taste of pharmaceutical compositions and ease the administration thereof, corrigents, sweeteners and like additives have been widely used. However, some corrigents may reduce the stability of the pharmaceutical compositions with the passage of time. In such a case, corrigents cannot be added in an amount that would sufficiently suppress the bitterness of the preparation and facilitate its administration. Furthermore, merely increasing the amount of sweetener would not satisfactorily suppress the bitterness, and some artificial sweeteners may undesirably increase unpleasant tastes, such as bitterness, acridity, etc. Furthermore , no corrigent or sweetener has been developed that can satisfactorily suppress the intensive long-lasted bitterness of rebamipide.
DISCLOSURE OF THE INVENTION
The present invention relates to a technique to reduce the bitterness of a medical composition containing rebamipide .
MEANS FOR SOLVING THE PROBLEM
The present inventors conducted extensive research to achieve the above object, and found that bitterness of rebamipide can be reduced by adding L-arginine or a salt thereof (hereunder may be referred to as "L-arginine") to a medical composition containing rebamipide. The present inventors also found that by adding L-arginine along with an acidic substance to a medical composition containing rebamipide, irritation of the mucous membrane can be suppressed while the bitterness reduction effect is maintained.
The present inventors also found that the addition of specific sweeteners can reduce the bitterness of rebamipide . Furthermore, the present inventors found that by adding L-arginine and a sweetener, in particular thaumatin, to rebamipide, reduction of bitterness and ease of taking can be enhanced .
The present invention has been accomplished by these findings .
The present invention provides the medical compositions of Items 1 to 31 below:
Item 1. A medical composition comprising rebamipide or a salt thereof and L-arginine or a salt thereof.
Item 2. The medical composition according to Item 1, wherein the content of the L-arginine or a salt thereof is 0.001 to 300 parts by weight per 100 parts by weight of rebamipide or a salt thereof.
Item 3. The medical composition according to Item 1 or 2 , which comprises at least one sweetener selected from the group consisting of thaumatin, stevia and luohan fruit extracts.
Item 4. The medical composition according to Item 3, wherein the sweetener is thaumatin.
Item 5. The medical composition according to any one of Items 1 to 4, which further comprises an acidic substance. Item 6. The medical composition according to Item 5 , wherein the content of the acidic substance is such that the pH becomes 3 to 11 when suspended or dissolved in water.
Item 7. The medical composition according to Item 5 or 6 , wherein the acidic substance is an organic acid or an inorganic acid.
Item 8. The medical composition according to any one of Items 5 to 7 , wherein the acidic substance is at least one member selected from the group consisting of hydrochloric acid, phosphoric acid, tartaric acid, malic acid, ascorbic acid, succinic acid, citric acid, maleic acid, acetic acid, and oxalic acid.
Item 9. The medical composition according to Item 8, wherein the acidic substance is at least one member selected from the group consisting of citric acid, ascorbic acid, tartaric acid and succinic acid.
Item 10. The medical composition according to Item 9, wherein the acidic substance is citric acid. Item 11. The medical composition according to any one of Items 1 to 10 , which further comprises a flavoring agent .
Item 12. The medical composition according to any one of Items 1 to 11 , which takes the form of tablets or granules without coating, tablets or granules with coating, orally disintegrating tablet, oral liquid medicine, gargle, intraoral sprays or intraoral film agents.
Item 13. The medical composition according to Item 12, which takes the form of granules without coating or granules with coating.
Item 14. The medical composition according to Item 12, which takes the form of granules with coating.
Item 15. The medical composition according to Item 14, wherein the core particles of the granules with coating comprise rebamipide or a salt thereof, L-arginine or a salt thereof, an acidic substance, and at least one sweetener selected from the group consisting of thaumatin, stevia and luohan fruit extracts.
Item 16. The medical composition according to Item 15, which further comprises soybean lecithin in the coating.
Item 17. A medical composition comprising rebamipide or a salt thereof , and at least one sweetener selected from the group consisting of thaumatin, stevia and luohan fruit extracts. Item 18. The medical composition according to Item
17, wherein the sweetener is thaumatin.
Item 19. The medical composition according to Item 17 or 18, which further comprises an acidic substance.
Item 20. The medical composition according to Item 19, wherein the content of the acidic substance is such that the pH becomes 3 to 11 when suspended or dissolved in water.
Item 21. The medical composition according to Item 19 or 20, wherein the acidic substance is an organic or inorganic acid. Item 22. The medical composition according to any one of Items 19 to 21, wherein the acidic substance is at least one member selected from the group consisting of hydrochloric acid, phosphoric acid, tartaric acid, malic acid, ascorbic acid, succinic acid, citric acid, maleic acid, acetic acid, and oxalic acid.
Item 23. The medical composition according to Item 22, wherein the acidic substance is at least one member selected from the group consisting of citric acid, ascorbic acid, tartaric acid and succinic acid.
Item 24. The medical composition according to Item 23, wherein the acidic substance is citric acid. Item 25. The medical composition according to any one of Items 17 to 24, which further comprises an flavoring agent.
Item 26. The medical composition according to any one of Items 17 to 25, which takes the form of tablets or granules without coating, tablets or granules with coating, orally disintegrating tablet, oral liquid medicine, gargle, intraoral sprays or intraoral film agents.
Item 27. The medical composition according to Item
26, which takes the form of granules without coating or granules with coating. Item 28. The medical composition according to Item
27, which takes the form of granules with coating.
Item 29. The medical composition according to Item
28, wherein the core particles of the granules with coating comprise rebamipide or a salt thereof, an acidic substance, and at least one sweetener selected from the group consisting of thaumatin, stevia and luohan fruit extracts.
Item 30. The medical composition according to Item
29, which further comprises soybean lecithin in the coating.
Item 31. A method for reducing bitterness of rebamipide, which comprising a step of adding L-arginine or a salt thereof, citric acid and thaumatin to the rebamide- containing composition.
Medical Composition A The medical composition of the present invention contains rebamipide and L-arginine. Hereunder, this composition is referred to as Medical Composition A. The rebamipide (chemical name:
2 - ( 4 -chlorobenzoylamino) -3- [ 2 ( IH) -quinolinon-4-yl] propionic acid) is known as a medicine effective in alleviating subjective and objective symptoms of gastric ulcer, gastritis, etc. The rebamipide is odorless but has a very strong bitter taste.
Various physiologically or pharmacologically acceptable salts can be used as the pharmaceutically acceptable rebamipide salts . Specific examples thereof include salts formed with generally used bases, such as sodium hydroxide, potassium hydroxide, trometamol ( tris (hydroxymethyl ) aminomethane ) , monoethanolamine , diethanolamine , triethanolamine , diisopropanolamine, meglumine, etc. There is no limitation to the amount of the rebamipide contained in the Medical Composition A of the present invention, but it is generally about 0.01 to 99 wt.% and preferably about 0.1 to 90 wt.%.
Examples of salts of L-arginine include salts between L-arginine and an acid (such as hydrochloric acid, sulfuric acid, methanesulfonic acid, etc.).
The content of L-arginine is generally 0.001 to 300 parts by weight, preferably 0.01 to 200 parts by weight, and more preferably 0.1 to 100 parts by weight per 100 parts by weight of rebamipide . In the case of granules , it is particularly preferable that 1 to 10 parts by weight of L-arginine be added per 100 parts by weight of rebamipide. This provides a medical composition having excellent properties , such as free from smeariness in a granulation step, and thereby can be easily produced.
It is preferable that the Medical Composition A contain a sweetener. Examples of usable sweeteners include thaumatin, stevia and luohan fruit extracts. These sweeteners may be used singly or in combination. The content the sweetener is generally 0.0001 to 300 parts by weight, preferably 0.001 to 200 parts by weight, and more preferably 0.01 to 100 parts by weight per 100 parts by weight of rebamipide .
In the case of granules , it is preferable that 0.1 to 10 parts by weight of sweetener be added per 100 parts by weight of rebamipide. In particular, when a medical composition contains 0.1 to 1.5 parts by weight of thaumatin per 100 parts by weight of rebamipide, it can be easily taken, because the sweetness of thaumatin and the bitterness of rebamipide are well balanced therein.
Stevia sweeteners , which are collectively called as stevia, include, for example, stevia extracts (an extract containing stevioside at the greatest percentage among the sweetener components contained therein; an extract containing rebaudioside at the greatest percentage; etc.), stevioside, rebaudioside, dulcoside, stevia powder, glycosyl stevia, enzyme-treated stevia, etc., and these stevia sweeteners may be used singly or in combination. Among these stevioside is particularly preferable.
It is preferable that the Medical Composition A of the present invention further contain an acidic substance. By adding an acidic substance, the pH after dissolving or suspending the Medical Composition A in water can be controlled, so that irritation of the mucous membrane can be reduced.
Examples of acidic substances include various known organic acids and inorganic acids . Examples of organic acids include tartaric acid, malic acid, ascorbic acid, succinic acid, citric acid, maleic acid, acetic acid, oxalic acid, etc. Examples of inorganic acids include hydrochloric acid, phosphoric acid, etc. These acidic substances may be used singly or in combination. Among these acidic substances, citric acid, ascorbic acid, tartaric acid, and succinic acid are preferable, and citric acid is particularly preferable.
In the present invention, the acidic substance is added in such a manner that the pH, when the medical composition of the present invention is suspended or dissolved in water, generally becomes 3 to 11, preferably 4 to 10, more preferably 5 to 9, and particularly preferably 6 to 8. Specifically, generally 0.01 to 100 mol, preferably 0.1 to 50 mol, and more preferably 0.2 to 10 mol of acidic substance is added per mol of L-arginine .
It is preferable that the medical composition A further contain a flavoring agent . Examples of flavoring agents include lemons, grapefruits, oranges, pineapples, peaches, yogurt, chocolate, coffee, wine, powdered tea, gin, etc. These flavoring agents may be used singly or in combination. The content of the flavoring agent is generally 0.0001 to 300 parts by weight, preferably 0.001 to 200 parts by weight, and more preferably 0.01 to 100 parts by weight per 100 parts by weight of rebamipide . In the case of granules , content of the flavoring agent is preferably 0.1 to 10 parts by weight per 100 parts by weight of rebamipide.
The Medical Composition A of the present invention may be taken as orally administered pharmaceutical preparations, such as tablets, granules, fine particles, powdered medicines , liquid medicines , suspension pharmaceuticals, orally disintegrating tablets, intraoral film agents, intraoral sprays, gargle, etc. These tablets, granules and fine particles may be coated.
In order to prepare the oral administration preparation, various kinds of carriers can be added. Examples of usable carriers include those used in this field, such as excipients, lubricants, disintegrants , binders, surfactants, plasticizers, acidulant , diluents, etc.
Specific examples of excipients include crystalline cellulose, potato starch, dextrin, cornstarch, lactose, saccharose, mannitol, talc, calcium carbonate , etc. Specific examples of lubricants include magnesium stearate, calcium stearate, aluminum stearate, etc. Specific examples of disintegrants include sodium carboxymethyl starch, sodium carboxymethylcellulose, low substituted hydroxypropylcellulose, calcium carboxymethylcellulose, sodium crosσarmellose, hydroxypropyl starch, potato starch, polyvinyl pyrrolidone, agar, etc. Specific examples of binders include gum arable, hydroxypropylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, gelatin, etc. Specific examples of surfactants include sodium lauryl sulfate etc. Specific examples of plasticizers include Polysorbate 80, hydrogenated soya oil, hydrogenated castor oil, Japan tallow, hydrogenated beef tallow and like oils and fats; carnaubawax, beeswax and like waxes ; paraffin, ceresin, microcrystalline wax and like higher hydrocarbons; and mixtures thereof. Specific examples of acidulants include ascorbic acid, tartaric acid, malic acid, succinic acid, citric acid, maleic acid, acetic acid, oxalic acid and like acidulants. Specific examples of diluents include cetyl alcohol, stearyl alcohol and like higher alcohols; myristic acid, palmitic acid, stearic acid, behenic acid and like higher fatty acids or glycerine fatty acid esters thereof; esters between acetic acid, citric acid, succinic acid and like organic acids, and mono- or di-higher fatty acid esters.
In the preparation of the coating agent, various film coating bases used in this field may be added in such an amount that does not adversely affect the effects of the present invention. Examples of usable film coating bases include saccharose, fructose and like sugars; mannitol, sorbitol, xylitol and like sugar alcohols ; cetyl alcohol, stearyl alcohol and like higher alcohols; myristic acid, palmitic acid, stearic acid, behenic acid and like higher fatty acids or glycerin esters thereof; esters of acetic acid, citric acid, succinic acid and like organic acids with glycerin mono- or di-higher fatty acid esters; hydrogenated soya oil, hydrogenated castor oil, Japan tallow, hydrogenated beef tallow and like oils and fats; carnaubawax, beeswax and like waxes ; paraffin, ceresin, microcrystalline wax and like higher hydrocarbons; hydroxypropylmethylcellulose , ethylcellulose , hydroxymethylcellulose , hydroxypropylcellulose , hydroxypropylmethylcellulose acetate succinate, acrylic resins (methacrylic acid copolymer, acrylic acid copolymer, aminoalkylmethacrylate copolymer, etc.), shellac, polyvinyl acetate phthalate, gum arabic, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate , carboxy methyl ethyl cellulose and like polymers usable for film coating.
Commonly used additives may be added, if necessary. The amount of the coating may be suitably selected depending on the type of solid preparation. For example, in the case of granules, generally 1 to 200 wt.%, preferably 1 to 100 wt.%, and more preferably 5 to 100 wt.% per total weight of the core granules .
The oral pharmaceutical preparation of the present invention can be prepared by a generally known method. The Medical Composition A of the present invention is preferably in the form of tablets without coating, orally disintegrating tablets, oral liquid medicines, gargle, intraoral sprays or intraoral film agents, which contain rebamipide, L-arginine, and an acidic substance. The acidic substance is preferably at least one member selected from the group consisting of citric acid, tartaric acid and succinic acid.
The Medical Composition A of the present invention is also preferably in the form of tablets or granules that contain rebamipide and L-arginine, for which a coating is provided.
The Medical Composition A of the present invention is also preferably in the form of film-coated tablets or film-coated granules that contain rebamipide , L-arginine, and an acidic substance.
The medical composition A of the present invention is also preferably in the form of orally disintegrating tablets , oral liquid medicines, intraoral sprays and intraoral film agents, which contain rebamipide or a salt thereof, L-arginine or a salt thereof, an acidic substance, a sweetener, and a flavoring agent. Preferably, the sweetener is at least one member selected from the group consisting of thaumatin, stevia and luohan fruit extracts .
A particularly preferable example of the Medical Composition A is that contains rebamipide, L-arginine, an acidic substance and at least one sweetener selected from the group consisting of thaumatin, stevia and luohan fruit extracts . The Medical Composition A takes the form of granules without coating or granules with coating (particularly preferably, granules with coating) . The core particles of granules with coating contain rebamipide, L-arginine, an acidic substance, and at least one sweetener selected from the group consisting of thaumatin, stevia, and luohan fruit extracts. Such granule also contains soybean lecithin in the coating. The content of soybean lecithin in the coating is generally 0.1 to 50 wt.%, and preferably 1 to 10 wt.%.
Medical Composition B
The medical composition of the present invention comprises rebamipide or a salt thereof, and at least one sweetener selected from the group consisting of thaumatin, stevia and luohan fruit extracts (preferably, thaumatin) .
Such medical composition is hereunder referred to as Medical
Composition B.
The content of the sweetener is generally 0.0001 to 300 parts by weight, preferably 0.001 to 200 parts by weight, and more preferably 0.001 to 100 parts by weight per 100 parts by weight of rebamipide.
The components contained in the Medical Composition
B other than those mentioned in the above are the same as those contained in the Medical Composition A, and those components can take the forms the same as those in Medical Composition
A except that L-arginine is not contained.
In the Medical Composition B, the acidic substance is added in such a manner that the pH, when the medical composition B is suspended or dissolved in water, generally becomes 3 to 11, preferably 4 to 10, more preferably 5 to 9, and particularly preferably 6 to 8.
The administration amount of the oral pharmaceutical preparation of the present invention depends on usage, gender, age and other conditions of the patient , the degree of the disease, etc.; however, a rebamipide, which is the active ingredient, is generally administered in a dosage of 0.001 to 100 mg, preferably 0.001 to 50 mg, per kg of body weight per day, in such a manner that the aforementioned amount is taken once per day, or divided into several dosages during the day. The administration amount changes depending on various conditions; an administration amount less than the above-mentioned range may therefore be sufficient at times, while an administration amount exceeding the above range may also at times be necessary. The patents, patent applications and publications cited herein are incorporated by reference .
EFFECT OF THE INVENTION
The present invention provides a medical composition in which the bitterness of rebamipide or a salt thereof is reduced.
The present invention also provides a medical composition by which irritation to the mucous membrane is reduced. The medical composition of the present invention is effectively usable not only in the form of tablets, granules and like solid preparations, but also in the form of liquid agents , gargles , intraoral sprays and intraoral film agents .
Furthermore, in the case of coated tablets and granules, the bitterness reduction effect can be maintained even after the coating is broken; this provides medical compositions that can be taken more easily.
By the reduction of the bitterness of film-coated tablets and film-coated granules, which are currently taken as oral pharmaceutical preparations , the following effects can be achieved. Such preparations can be easily taken, patient compliance can be improved, and the pharmacological action inherent in the medicine can be satisfactorily expressed. The medical composition of the present invention can be taken as tablets, orally disintegrating tablets which do not require a coating, oral liquid medicines, intraoral film agents, intraoral sprays and like orally administered medicines . The present invention provides various pharmaceutical preparations that can be easily taken, improving patient compliance and widening the number of diseases the invention is applicable to.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is explained in detail below with reference to Examples and Comparative Examples .
Example 1
A mixture of 1010 g of rebamipide, 1845 g of lactose, 510 g of corn starch, 140 g of crystalline cellulose, 680 g of dextrin, 150 g of carboxymethyl starch sodium and 90 g of croscarmellose sodium was kneaded with a combining liquid of 20 g of L-arginine, 838 g of purified water, and 140 g of polysorbate 80 using a vertical granulator. The resulting mixture was granulated using an extruding granulator equipped with a 0.6 mm diameter screen (TDG-80, provided by Fuji Paudal Co., Ltd.), and then formed in spherical shape using a Marumerizer (QJ-400, provided by Fuji Paudal Co. , Ltd. ) . The granules thus obtained are dried, and the granules having a particle size of 0.355-1 mm are collected to give core granules .
Separately, Citric and Fatty Acid Esters of Glycerol (SunSoft 621G, provided by Taiyo Kagaku Co. Ltd., 60 g) was added to a mixture of 144 g of ethanol and 36 g of water, followed by dissolving by heating. D-mannitol (60 g) was added thereto and then suspended by stirring to obtain a coating solution.
Core granules (300 g) were placed in an agitation-type rotary fluidized bed granulator (NQ- 160, provided by Fuji Paudal Co., Ltd.); while the core granules were fluidized by air supplied at a temperature of 500C, at an agitation rate of 120 rpm, the coating solution was applied to the surfaces of the core granules by spraying at a liquid speed of 20 g/minute. After coating, the particles were air-dried at 50°C, and subjected to sizing to obtain coated granules, using a sieve with openings of 1180 μm.
Comparative Example 1 For comparison, coated granules containing rebamipide were obtained in the same manner as in Example 1, except that L-arginine was not used, and the dextrin amount was increased by 20 g.
Test Example 1
The coated granules (500 mg each) obtained in Example 1 and Comparative Example 1 were kept in the mouth for 60 seconds and then spat out, after which the bitterness thereof was evaluated. For the coated granules of Comparative Example 1 , which do not contain L-arginine, although a bitter taste was not immediately experienced, bitterness was experienced 30 seconds afterward, and a bitter taste remained even after the granules were spat out 60 seconds after first placed in the mouth. In contrast, for the coated granules of Example 1, which contain L-arginine, bitterness was not experienced during the 60 seconds of the test, or after the granules were spat out .
Example 2
A mixture of 60.6 g of rebamipide, 110.7 g of lactose, 30.6 g of corn starch, 8.4 g of crystalline cellulose, 36.0 g of dextrin, 9.0 g of carboxymethyl starch sodium and 5.4 g of croscarmellose sodium was kneaded with a combining liquid of 6 g of L-arginine, 50.3 g of purified water, and 8.4 g of polysorbate 80 using a vertical granulator. The same process was repeated three times , and the resulting kneaded material was granulated using an extruding granulator equipped with a 0.6 mm diameter screen (TDG-80, provided by Fuji Paudal Co. , Ltd. ) , and then formed in spherical shape using a Marumerizer (QJ-400, provided by Fuji Paudal Co., Ltd.). The granules thus obtained are dried, and the granules having a particle size of 0.355-1 nun are collected to give core granules. Coated granules were prepared in the same manner as in Example 1.
Comparative Example 2
For comparison, coated granules containing rebamipide were prepared in the same manner as in Example 2 , except that L-arginine was not added, and the dextrin amount was increased by 6 g.
Examples 3 to 7
Coated granules of Examples 3 to 7 were prepared in the same manner as in Example 2 , except that rebamipide , L-arginine (or L-arginine hydrochloride), citric acid and thaumatin were used in the amounts shown below in Table 1. Note that citric acid and L-arginine hydrochloride were added to the combining liquid in the same manner as the addition of L-arginine. Thaumatin was not added to the combining liquid, but to the rebamipide, lactose, etc. Changes in weight due to varying the amounts of L-arginine, L-arginine hydrochloride, citric acid, and thaumatin were adjusted by controlling the amount of dextrin, so that the total weight of the pharmaceutical preparations was the same in every case.
Table 1
Figure imgf000016_0001
Test Example 2
The coated granules (500 mg each) obtained in Examples 2 to 7 and Comparative Example 2 were kept in the mouth for 60 seconds and then spat out, after which the bitterness thereof was evaluated.
For the coated granules of Comparative Example 2, which do not contain L-arginine, although a bitter taste was not experienced immediately, bitterness was experienced 30 seconds afterward, and a bitter taste remained even after the granules were spat out 60 seconds after they were first placed in the mouth. In contrast , for the coated granules of Examples 2 to 7, which contain L-arginine, bitterness was not experienced during the 60 seconds of the test, or after the granules were spat out .
In particular, granules of Example 7 containing thaumatin in addition to L-arginine exhibited greater reduction in the bitterness of rebamipide compared to those of Examples 1 to 6.
Examples 8 and 9, and Comparative Example 3
Rebamipide (2.5 g) was dispersed in water (1 L) to obtain a 2.5 mg/ml suspension (Comparative Example 3). In a separate step, 0.5 g of L-arginine or L-arginine hydrochloride was dissolved in water (1 L) , producing a 0.5 mg/ml L-arginine solution or L-arginine hydrochloride solution. The rebamipide suspension (20 ml) and each L-arginine solution (1 ml) were mixed, and 5 ml of the mixture was kept in the mouth for 60 seconds and then spat out. Subsequently, the bitterness was evaluated. When a simple rebamipide suspension was evaluated, the strong bitterness particular to rebamipide was experienced; however, bitterness was nearly not experienced in Examples 8 and 9, wherein L-arginine or L-arginine hydrochloride was added. Table 2
Figure imgf000018_0001
Examples 10 to 15 and Comparative Example 4
Rebamipide (10 g) was dispersed in water (1 L) to obtain a 10 mg/ml suspension (Comparative Example 4). In a separate step, 10 g of L-arginine was dissolved in water (1 L), producing a 10 mg/ml L-arginine solution. To 10 ml of rebamipide suspension, 0.001 ml, 0.01 ml, 0.1 ml, 1 ml, 10 ml or 30 ml of an L-arginine solution was added to prepare a mixture solution containing 0.01, 0.1, 1, 10, 100 or 300 parts by weight of L-arginine per 100 parts by weight of rebamipide. The resulting solution (5 ml) was kept in the mouth for 60 seconds and then spat out. Subsequently, the bitterness of each solution was evaluated. When a simple rebamipide suspension was evaluated, the strong bitterness particular to rebamipide was experienced; however, bitterness was nearly not recognized in Examples 10 to 15, wherein L-arginine was added.
Table 3
Figure imgf000018_0002
Example 16
A mixture of 1010 g of rebamipide, 1820 g of lactose. 510 g of corn starch, 140 g of crystalline cellulose, 650 g of dextrin, 150 g of carboxymethyl starch sodium, 120 g of croscarmellose sodium, and 2 g of Natural Flavor (Resolver 283) was kneaded with a combining liquid of 20 g of L-arginine, 918 g of purified water, 140 g of polysorbate 80, 2Og of citric acid, 2 g of Cream Flavor (GIVO27723) and 1 g of Bitter orange Flavor using a vertical granulator . The resulting mixture was granulated using an extruding granulator equipped with a 0.6 mm diameter screen (TDG-80, provided by Fuji Paudal Co. , Ltd. ) , and then formed in spherical shape using aMarumerizer (QJ-400, provided by Fuji Paudal Co., Ltd.). The granules thus obtained are dried, and the granules having a particle size of 0.355-1 mm are collected to give core granules.
Separately, Citric and Fatty Acid Esters of Glycerol (SunSoft 621G, provided by Taiyo Kagaku Co. Ltd., 200 g) was added to a mixture of 480 g of ethanol and 120 g of water, followed by dissolving by heating. D-mannitol (200 g) was added thereto and then suspended by stirring to obtain a coating solution. Core granules (300 g) were placed in an agitation-type rotary fluidized bed granulator (NQ- 160, provided by Fuji Paudal Co. , Ltd. ) , while fluidizing the core granules by air supplied at a temperature of 50° C and an agitation rate of 120 rpm, the coating solution was applied to the surfaces of the core granules by spraying at the liquid speed of 20 g/minute. After coating, the particles were air-dried at 50° C, and subjected to sizing using a sieve with 1180 μm openings to obtain coated granules.
Example 17
A mixture of 1010 g of rebamipide, 1745 g of lactose, 510 g of corn starch, 140 g of crystalline cellulose, 600 g of dextrin, 150 g of carboxymethyl starch sodium, 180 g of croscarmellose sodium, 5 g of thaumatin (sweetener), and 2 g of Natural Flavor (Resolver 283) was kneaded with a combining liquid of 20 g of L-arginine, 843 g of purified water, 200 g of polysorbate 80, 2O g of citric acid, 2 g of Cream Flavor (GIVO27723) and 1 g of Bitter orange Flavor using a vertical granulator. The resulting mixture was granulated using an extruding granulator equipped with a 0.6 nun diameter screen (TDG-80, provided by Fuji Paudal Co. , Ltd. ) , and then formed in spherical shape using a Marumerizer (QJ-400, provided by Fuji Paudal Co. , Ltd. ) . The granules thus obtained are dried, and the granules having a particle size of 0.355-1 mm are collected to give core granules .
Separately, Citric and Fatty Acid Esters of Glycerol (SunSoft 621G, provided by Taiyo Kagaku Co. Ltd., 200 g) was added to a mixture of 480 g of ethanol and 120 g of water, followed by dissolving by heating. D-mannitol (200 g) was added thereto and then suspended by stirring to obtain a coating solution. Core granules (300 g) were placed in an agitation-type rotary fluidized bed granulator (NQ-160, provided by Fuji Paudal Co. , Ltd. ) , while fluidizing the core granules under the conditions of air supplying temperature of 50° C and an agitation rate of 120 rpm, the coating solution was applied to the surfaces of the core granules by spraying at the liquid speed of 20 g/minute. After coating, the particles were air-dried at 50° C , and subjected to sizing using a sieve with 1180 μm openings to obtain coated granules.
Example 18
A mixture of 1010 g of rebamipide, 1768 g of lactose, 400 g of corn starch, 180 g of crystalline cellulose, 800 g of dextrin, 120 g of carboxymethyl starch sodium, 100 g of croscarmellose sodium, 2 g of thaumatin (sweetener) and 2 g of Natural Flavor (Resolver 283) was kneaded with a combining liquid of 20 g of L-arginine, 818 g of purified water, 150 g of polysorbate 80, 1O g of citric acid, 2 g of Cream Flavor (GIVO27723) and 1 g of Bitter orange Flavor using a vertical granulator. The resulting mixture was granulated using an extruding granulator equipped with a 0.6 mm diameter screen (TDG-80, provided by Fuji Paudal Co., Ltd.), and then formed in spherical shape using a Marumerizer (QJ-400, provided by Fuji Paudal Co. , Ltd. ) . The granules thus obtained are dried, and the granules having a particle size of 0.355-1 mm are collected to give core granules .
Separately, Citric and Fatty Acid Esters of Glycerol (SunSoft 621G, provided by Taiyo Kagaku Co. Ltd., 360 g) was added to a mixture of 960 g of ethanol and 240 g of water, followed by dissolving by heating. Soybean lecithin (40 g) and D-mannitol (400 g) were added thereto and then suspended by stirring to obtain a coating solution. Core granules (1834 g) were placed in an agitation-type rotary fluidized bed granulator (FLO-5M, provided by Freund Industrial Co. , Ltd. ) , while fluidizing the core granules by air supplied at a temperature of 500C, and an agitation rate of 180 rpm, the coating solution was applied to the surfaces of the core granules by spraying at a liquid speed of 100 g/minute. After coating, the particles were air-dried at 500C, and subjected to sizing using a sieve with 1180 μm openings to obtain coated granules .
Example 19
A mixture of 1010 g of rebamipide, 1768 g of lactose, 400 g of corn starch, 180 g of crystalline cellulose, 820 g of dextrin, 120 g of carboxymethyl starch sodium, 100 g of croscarmellose sodium, 2 g of thaumatin (sweetener), and 2 g of Natural Flavor (Resolver 283 ) was kneaded with a combining liquid of 20 g of L-arginine, 843 g of purified water, 200 g of polysorbate 80, 2O g of citric acid, 2 g of Cream Flavor (GIVO27723) and 1 g of Bitter orange Flavor using a vertical granulator. The resulting mixture was granulated using an extruding granulator equipped with a 0.6 mm diameter screen (TDG-80, provided by Fuji Paudal Co., Ltd.), formed in spherical shape using a Marumerizer (QJ-400, provided by Fuji Paudal Co. , Ltd. ) . The granules thus obtained are dried, and the granules having a particle size of 0.355-1 mm are collected to give core granules .
Separately, Citric and Fatty Acid Esters of Glycerol (SunSoft 621G, provided by Taiyo Kagaku Co. Ltd., 200 g) was added to a mixture of 480 g of ethanol and 120 g of water, followed by dissolving by heating. D-raannitol (200 g) was added thereto and then suspended by stirring to obtain a coating solution. Core granules (300 g) were placed in an agitation- type rotary fluidized bed granulator (NQ-160, provided by Fuji Paudal Co. , Ltd. ) , while fluidizing the core granules under the conditions of air supplying temperature of 50° C and an agitation rate of 120 rpm, the coating solution was applied to the surfaces of the core granules by spraying at the liquid speed of 20 g/minute. After coating, the particles were air-dried at 500C, subjected to sizing using a sieve with 1180 μm openings, and 0.3 wt . % of magnesium stearate was added thereto, obtaining coated granules.
The coated granules obtained in Examples 16 to 19 can serve as excellent pharmaceutical preparations that are nearly free from bitterness, similar to the coated granules of Example 1. The granules of Example 16 , which contained L-arginine , citric acid and a flavoring agent, exhibited a significant reduction in the bitterness compared to the granules, which merely contained the same amount of flavoring agent , wherein the bitterness was only somewhat reduced. The granules of Example 17, which further contained thaumatin in addition to L-arginine, citric acid, and a flavoring agent, exhibited a significant reduction in the bitterness compared to the granules, which merely contained the same amounts of flavoring agent and thaumatin, wherein the bitterness was only somewhat reduced. The granules of Example 17 exhibited a greater reduction in the bitterness than those of Example 16.
Example 20 Rebamipide (2.5 g) was dispersed in water (1 L) to obtain a 2.5 mg/ml suspension. In a separate step, 50 mg of each sweetener (sucralose, thaumatin, stevia, Acesulfame K, Aspartame, and luohan fruit extracts) was dissolved in 100 ml of water to obtain a 0.5 mg/ml aqueous solution. The above-obtained rebamipide suspension (20 ml) and 0.1 ml of each sweetener solution prepared were mixed. The resulting mixture (5 ml) was kept in the mouth for 10 seconds and then spat out. Subsequently, the bitterness was evaluated.
The results are as below. When a simple rebamipide suspension was evaluated, the strong bitterness particular to rebamipide was experienced. Also when sucralose, Acesulfame K, or Aspartame was added, the strong bitterness particular to rebamipide was experienced. However, bitterness was reduced when thaumatin, stevia, or luohan fruit extracts was added. The bitterness was remarkably reduced when thaumatin was added.

Claims

1. A medical composition comprising (a) rebamipide or a salt thereof and (b) L-arginine or a salt thereof and/or at least one sweetener selected from the group consisting of thaumatin, stevia and luohan fruit extracts.
2. The medical composition according to claim 1, wherein the sweetener is thaumatin.
3. The medical composition according to claim 1 or
2, which further comprises an acidic substance.
4. The medical composition according to claim 3 , wherein the acidic substance is at least one member selected from the group consisting of hydrochloric acid, phosphoric acid, tartaric acid, malic acid, ascorbic acid, succinic acid, citric acid, maleic acid, acetic acid, and oxalic acid.
5. The medical composition according to claim 4 , wherein the acidic substance is citric acid.
6. The medical composition according to claim 1 , which further comprises a flavoring agent .
7. The medical composition according to claim 1 , wherein the medical composition is in the form of granules .
8. A method for reducing bitterness of rebamipide, which comprising a step of adding L-arginine or a salt thereof, citric acid and thaumatin to the rebamipide-containing composition.
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