JP3977724B2 - Pharmaceutical composition - Google Patents

Description

【００３７】
試験方法
代表的ヒスタミンＨ_２受容体拮抗剤であるファモチジン若しくはランソプラゾール、および、ウイキョウ乾燥エキス末、塩化カルニチン、ケイヒ乾燥エキス末若しくはメントール（健胃剤）の口臭抑制効果を胃痛を感じるボランティアの被験者３０名によって試験した。
被験者は、試験第一日目の昼食直後に比較例１または比較例２、実施例１〜８のいずれかの製剤を服用し、昼食３時間後に５０ｍｌの水で洗口した後、洗口直後に容量２Lのポリエチレン袋（（株）大洋社製ポリエチレン袋＜厚さ0.04m/m、巾230m/m、長さ320m/m＞）に呼気を回収した。試験第二日目も昼食直後に比較例１または比較例２、実施例１〜８のいずれかの製剤を服用し、昼食３時間後に、同様にして呼気を収集した。
回収した呼気は、袋から注射筒を用いて60mLのガスを分取し、ニオイセンサー（COSMOS社製 XP-329）を用いて呼気中のニオイレベルを測定した。第１日目と、実施例または比較例を服用した各試験日のニオイレベルの変化量の平均値を算出し、表２及び表３に示す。
【００３８】
【表２】

【００３９】
【表３】

【００４０】
試験の結果からわかるように、比較例の製剤（比較例１または２）では、食後３時間経過後の呼気のニオイレベルが高値を示すが、本発明の製剤（実施例１〜８）では、第１日目および第２日目ともにニオイレベルが低値に抑制されている。本発明の製剤では、口臭の発生が抑制されておりファモチジンまたはオメプラゾール単独服用に比較して口臭の抑制効果が高いことが認められた。
【００４１】
このような結果から、ヒスタミンＨ_２受容体拮抗剤またはプロトンポンプ阻害剤といった胃炎や胃潰瘍に有用な薬物に健胃剤をともに含有した本発明の医薬組成物によれば、ニオイレベルが有意に抑制され、口臭を強力に抑制できることが判明した。また、かかる効果は、ヒスタミンＨ_２受容体拮抗剤またはプロトンポンプ阻害剤と健胃剤とを含有する医薬組成物のみならず、これらを同時に投与、あるいは時間をおいて投与した場合にも同様である。
【００４２】
胃粘膜損傷試験
実施例及び比較例の調整と試験方法
２４時間絶食したウイスター系雄性ラット（体重１４０〜１８０ｇ）に、表４に記載した投与量となるように比較例３または４及び実施例９〜１１の製剤を強制的に経口投与した。さらに、１時間後に２００mg／５ml／kg投与量で、アスピリン溶液（０．１５N塩酸、１％カルボキシメチルセルロースナトリウム水溶液）を強制経口投与した。アスピリン経口投与３時間後に胃を摘出し、大弯に沿って縦切した後進展し、中性緩衝１％ホルマリンにて固定した。粘膜に発生した損傷部分を画像解析して面積を測定した。試験は、１群を５匹として、群毎の面積平均値を表４に示す。なお、表４に示した各薬物の投与量は、ラット体重あたりの各薬物の投与量を示し、投与液量としては５ｍｌ（０．５％メチルセルロース水溶液）/ｋｇとなるように投与し試験を行った。
【００４３】
【表４】

【００４４】
試験の結果から、シメチジン、粘膜修復剤および制酸剤の投与によってアスピリンによる胃粘膜の潰瘍面積が減少しているが、さらにケイヒ乾燥エキス末、オウレン乾燥エキス末またはｌ−メントールをともに配合した製剤では、胃粘膜潰瘍面積の減少がより顕著に認められた。ケイヒ乾燥エキス末、オウレン乾燥エキス末、ｌ−メントールには、胃粘膜障害治療効果がないか、またはあったとしても弱い効果しかないにもかかわらず、シメチジンと組み合わせることによって、顕著に胃粘膜障害治療効果が増強されていることが示された。
【００４５】
【発明の効果】
本発明では、ヒスタミンＨ_２受容体拮抗剤またはプロトンポンプ阻害剤とともに健胃剤を用いることによって、口臭を強力に抑制することができる。したがって、コンプライアンスに悪影響を与えない医薬または医薬組成物を提供することができる。また、ヒスタミンＨ_２受容体拮抗剤またはプロトンポンプ阻害剤とともに健胃剤を用いた医薬または医薬組成物は、胃粘膜障害を抑制する効果が増強され、治療効果の高い医薬または医薬組成物である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical composition using a histamine H ₂ receptor antagonist or a proton pump inhibitor. The present invention also relates to a medicine using a histamine H ₂ receptor antagonist or a proton pump inhibitor.
[0002]
[Prior art]
Histamine H ₂ receptor antagonist and proton pump inhibitor are gastric ulcer, duodenal ulcer, peptic ulcer, acute stress ulcer, hemorrhagic gastritis, reflux esophagitis, acute gastritis, chronic gastritis, gastric mucosal lesion, stress ulcer, It is a highly therapeutic drug used for the treatment of stomach pain, heartburn, stomach upset, and nausea.
[0003]
Then, in the pharmaceutical or pharmaceutical compositions using these histamine H ₂ receptor antagonists and proton pump inhibitors, a method for obtaining a more excellent therapeutic effects it has been developed. For example, in clinical settings, administration of histamine H ₂ receptor antagonists and proton pump inhibitors followed by administration of Annakasan, Hiragasakusan, and Sho-saiko-to removes Helicobacter pylori bacteria and treats it. There is a report that the effect will increase (The 47th Annual Meeting of Japanese Oriental Medicine, held in June 1996). Japanese Patent Laid-Open No. 05-246848 discloses a pharmaceutical composition containing a histamine H ₂ receptor antagonist, an antacid, and a mucosal defense factor enhancer for gastric diseases such as gastritis by synergistic action of the three. There is a description that it has an excellent effect.
[0004]
On the other hand, because histamine H ₂ receptor antagonists have a bitter taste, unsuitable preparations can affect patient compliance (drug compliance) and cause patients to fail to take, so as to obtain a certain therapeutic effect There was a problem that it would be harmful. Thus, in publications such as JP-A-62-219939, JP-A-8-99904, and JP-A-10-53538, methods for concealing the bitter taste of histamine H ₂ receptor antagonists are shown.
[0005]
As described above, with regard to a medicine or pharmaceutical composition using a histamine H ₂ receptor antagonist or a proton pump inhibitor, there are a method for obtaining a more effective therapeutic effect and a method for improving compliance by concealing bitterness. It has been reported.
[0006]
[Problems to be solved by the invention]
In patients with gastrointestinal disorders or impaired gastrointestinal function, unpleasant halitosis often occurs, but drugs or pharmaceutical compositions using histamine H ₂ receptor antagonists or proton pump inhibitors Even if it is taken, there is a problem that the generation of bad breath is not suppressed. Furthermore, when a medicine or a pharmaceutical composition using a histamine H ₂ receptor antagonist or a proton pump inhibitor is taken, there is a problem that many patients are worried about bad breath before taking. Due to the occurrence of such bad breath, when the patient's compliance is lowered, the patient shifts the dose time or does not take the correct number of times, and the adverse effect that the reliable therapeutic effect of the drug cannot be obtained also occurs.
However, there is still no report on a method for suppressing halitosis when taking a histamine H ₂ receptor antagonist or a proton pump inhibitor.
The present invention is a pharmaceutical composition that can suppress bad breath more strongly than patients who take histamine H ₂ receptor antagonists, proton pump inhibitors, or salts thereof alone, thereby improving patient compliance. The object is to provide a product or medicine. Further, an object to provide a pharmaceutical or a pharmaceutical composition having excellent therapeutic effect than the single administration of histamine H ₂ receptor antagonist or proton pump inhibitor.
[0007]
[Means for Solving the Problems]
As a result of intensive research aimed at solving the above-mentioned problems, the present inventors strongly suppressed bad breath by using a histamine H ₂ receptor antagonist or proton pump inhibitor in combination with a gastric agent, and caused gastric mucosal damage. It has been found that it can be used as a pharmaceutical composition or a medicine excellent in healing effect. The present invention has been developed based on such knowledge.
[0008]
That is, the present invention is a pharmaceutical composition listed in the following (1) to (7):
(1) a pharmaceutical composition comprising (i) a healthy gastric agent, and (ii) at least one of a histamine H ₂ receptor antagonist and a proton pump inhibitor,
(2) The pharmaceutical composition according to (1), further comprising a mucosal repair agent and an antacid
(3) The stomachic agent is aniseed fruit, aloe, musk, depressant gold, glaze, life-long herb, yellow rice, jaundice, yellow chain, processed bonito, guts, kakko, kina, homika, ginger, calumus root, psoriasis, Rice husk, coconut, cinnamon, gentian, kojin, Kobok, Kureo, cucumber, Colombo, kondurango, yam, yamana, shisoko, shrunk sand, ginger, shrimp, green skin, stone root, centaurium grass, assembly, cocoon, su Leaves, Otsuka, Daihuang, Bamboo Ginseng, Choji, Chen, Chilli, Spruce, Nigaki, Nikuzuku, Ginseng, Light-loading, Gibbon, White Birch, Hops, Homika Extract, Sleeping Leaves, Mika, Michichi, Ryobi, Ryoku, Kuji , Gobaishi, Hawthorn, Japanese bay bud, Red bud, Acacia yam, Ubai, Ketsumeishi, Genokosho, Menthol, Glutamate hydrochloride, Carnitine chloride, Bethanechol chloride and Trimethyl maleate The pharmaceutical composition according to at least one of Chin (1) or (2),
(4) (i) Aniseed fruit, aloe, musk, melancholy, glaze, life-grass, yellow rice, jaundice, yellow chain, processed bonito, gadget, currant, kina, homika, ginger, calamus root, psoriasis , Rice husk, coconut, cinnamon, gentian, kojin, kobok, wuluo, cucumber, colombo, kondurango, yam, yamana, shisoko, sand, ginger, shrimp, green skin, stone root, centaurium grass, sea bream, coral, Soha, Daigoka, Daihuang, Bamboo ginseng, Clove, Chen, Chilli, Spruce, Nigaki, Nikuzuku, Ginseng, Light load, Hibatsu, White birch, Hop, Homika extract, Sleeping leaves, Mika, Michichi, Ryobi, Ryo, Kuzin, Gobaishi, Hawthorn, Japanese bay mackerel, Red bud, Acacia yam, Ubi, Ketsumeishi, Genokosho, Menthol, Glutamate, Carnitine chloride, Bethanechol chloride and Trimepetit maleate A pharmaceutical composition comprising: (ii) at least one of a histamine H ₂ receptor antagonist and a proton pump inhibitor; and (iii) a mucosal repair agent and an antacid. object,
(5) The pharmaceutical composition according to any one of (1) to (4), which is a gastrointestinal drug,
(6) The pharmaceutical composition according to any one of (1) to (5), wherein the histamine H ₂ receptor antagonist is at least one of cimetidine, ranitidine, famotidine, roxatidine, nizatidine and a pharmaceutically acceptable salt thereof. object,
(7) The proton pump inhibitor is at least one of lansoprazole, omeprazole, pantoprazole, rabeprazole, leminoprazole, esomeprazole, and a pharmaceutically acceptable salt thereof, according to any one of (1) to (6) The pharmaceutical composition described,
(8) Mucosal repair agent is glycyrrhizic acid or a salt thereof, licorice or an extract thereof, sucrose sulfate aluminum salt (sucralfate), sodium azulenesulfonate, aldioxa, aldioxa / magnesium aluminate metasilicate, sofalcone and L-glutamine The pharmaceutical composition according to any one of (1) to (7), which is at least one of
(9) Antacid is dry aluminum hydroxide gel, magnesium aluminate silicate, hydrotalcite, magnesium hydroxide, dry aluminum hydroxide gel, gel sodium bicarbonate, magnesium carbonate, precipitated magnesium carbonate, magnesium metasilicate aluminate , A pharmaceutical composition according to any one of (1) to (8), which is at least one of dihydroxyaluminum aminoacetate and funnel extract,
Moreover, this invention is a pharmaceutical as described in (10)-(11):
(10) A pharmaceutical comprising a combination of (i) a component having a healthy stomach action and (ii) at least one of a histamine H2 receptor antagonist and a proton pump inhibitor,
(11) The medicament according to (10), further comprising a mucosal repair agent and an antacid.
[0009]
DETAILED DESCRIPTION OF THE INVENTION
Examples of the stomachic agent of the present invention include, for example, aniseed fruit, aloe, musk, depressant, glaze, life-grass, yellow rice, jaundice, yellow chain, processed potato, gadget, currant, kina, homica, ginger, columnus root, Dry rice cake, rice husk, coconut, cinnamon bark, gentian, kojin, Kobok, Kureo, pepper, Colombo, condurango, yam, yamana, shisoko, sand, ginger, shrimp, green skin, stone root, centaurium grass, assembly, Salmon, Suha, Daigoka, Daihuang, Bamboo ginseng, Clove, Chen skin, Chili, Spruce, Animal gall, Nigaki, Nikuzuku, Ginseng, Light load, Hibatsu, White birch, Hop, Homika extract, Sleeping leaves, Mika, Michi, Herbal medicines such as Ryuboku, Rakuji, Kujin, Gobaishi, Hawthorn, Japanese bay mackerel, Red bud, Asenyaku, Ubai, Ketsumeishi, Gennoshouko, etc .; Arm, parasympathetic stimulants such as tolazoline; metoclopramide, domperidone, antidopaminergic drugs such as sulpiride; trimebutine, can be exemplified menthol, glutamate and the like.
Among them, preferably aniseed fruit, aloe, musk, glaze, glaze, life-saving grass, yellow rice, jaundice, yellow chain, processed bonito, scented incense, columnus root, dry rice, chaff, coconut, cinnamon, gentian, Koujin, Kobok, Kureo, Pepper, Colombo, Conslango, Sanroku, Yamana, Shisoko, Shredded sand, Ginger, Shozuk, Blue bark, Stone root, Centaurium grass, Clam, Samurai, Suyo, Daigo incense, Daio, Bamboo ginseng , Clove, Chen, red pepper, spruce, animal gall, oyster, nutmeg, carrots, light load, baboon, white birch, hops, homica extract, sleepy leaves, mushrooms, michichi, ryu, bonito, menthol, glutamic acid, carnitine, betanecol Or trimeptine, more preferably glutamate hydrochloride, carnitine chloride, bethanechol chloride, trimeptin maleate, cinnamon, chili, carrot, wood incense, ginger, musk, Ntoru, Tadami, yellow Gon, Phellodendri Cortex, yellow with each other, aloe, ginseng, is Chen skin.
[0010]
In addition, a stomachic agent may be used individually by 1 type, and can also be used in combination of 2 or more types arbitrarily. The form and properties of the stomachic agent are not particularly limited. For example, in the case of a crude drug, a dried crude drug processed according to a commonly used method (described in an official document such as a pharmaceutical raw material standard) is used. Powdered herbal powder; Extracted ingredients in any form such as dry extract, extract powder, soft extract, flow extract, tincture; can be used in the form of essential oils, etc. It can be used in any form such as optical isomers, hydrates and the like. These can be used commercially or can be obtained by processing by a conventional method.
The amount of the stomachic agent used may be, for example, a daily dose for an adult, and in the case of a crude drug, it may be used in an amount of 0.01 to 10 g, preferably about 0.1 to 5 g as a crude drug powder. In this case, although it cannot generally be said depending on the kind of the compound, it may be used usually at a daily dose of 0.001 to 3 g, preferably about 0.1 to 2 g for an adult.
[0011]
Examples of the histamine H2 receptor antagonist of the present invention include cimetidine, famotidine, ranitidine, roxatidine, nizatidine or a pharmaceutically acceptable salt thereof (for example, ranitidine hydrochloride, roxatidine acetate, etc.). One or more types can be used. Of these, cimetidine and famotidine are preferable. The amount used can be in a range usually used for treatment, for example, 1 to 800 mg for an adult daily dose. Specifically, for cimetidine, it is preferably 10 to 800 mg, more preferably 40 to 400 mg. For famotidine, preferably 1-40 mg, more preferably 5-20 mg, for ranitidine, preferably 5-300 mg as ranitidine hydrochloride, more preferably 30-150 mg, for roxatidine, as roxatidine acetate, preferably 5-150 mg. More preferably, it is 25-75 mg.
[0012]
Examples of the proton pump inhibitor of the present invention include lansoprazole, omeprazole, pantoprazole, rabeprazole, leminoprazole, esomeprazole, and pharmaceutically acceptable salts thereof, and one or more thereof can be used. Of these, lansoprazole or omeprazole is preferable. The amount used is usually used in the range of treatment, for example, 0.01 to 100 mg per adult. Specifically, it is preferably 0.01 to 30 mg, more preferably 0.1 to 10 mg for lansoprazole, and preferably 0.01 to 20 mg, more preferably 0.1 to 5 mg for omeprazole.
[0013]
In the medicament or pharmaceutical composition of the present invention, the effect of suppressing bad breath or the effect of healing gastric mucosa is further enhanced by using a mucosal repair agent and an antacid in combination.
Examples of such mucosal repairing agents include sodium azulene sulfonate, aldioxa, magnesium aluminate aldioxa / metasilicate, glycyrrhizic acid or a salt thereof, licorice or an extract thereof, L-glutamine, copper chlorophyllin potassium, copper chlorophyllin sodium, histidine hydrochloride , Methylmethionine sulfonium chloride, red buds, Yoncho, sucrose sulfate aluminum salt (sucralfate), cetraxate hydrochloride, sofalcone, ornoprostil, sulpiride, cetraxate hydrochloride, gefarnate, teprenone, prunotol, aceglutamide aluminum, methylmethionine sulfone Examples thereof include nium chloride and sofalcone. Preferably, sodium azulene sulfonate, aldioxa, magnesium dialumina metadisilicate, L-glutamine, copper chlorophyllin potassium, copper chlorophyllin sodium, methylmethionine sulfonium chloride, licorice or its extract, sucrose sulfate aluminum salt (sucralfate), Sofalcon, cetraxate hydrochloride, more preferably glycyrrhizic acid or a salt thereof, licorice or an extract thereof, aluminum salt of sucrose sulfate ester (sucralfate), sodium azulenesulfonate, aldioxa, aldioxa magnesium aluminometasilicate, sofalcone L-glutamine. Each of these components may be used alone or in any combination of two or more.
[0014]
The amount of the mucosal repair agent used is preferably 0.1 to 50 parts by weight, more preferably 0.5 to 30 parts by weight of the mucosal repair agent with respect to 1 part by weight of the histamine H2 receptor antagonist or proton pump inhibitor. It can be used to be parts by weight. For example, as an adult daily dose, in glycyrrhizic acid or a salt thereof, licorice or an extract thereof, 10 to 600 mg, preferably 10 to 300 mg as glycyrrhizic acid, 10 to 3600 mg, preferably 300 to sucrose sulfate aluminum salt (sucralfate) ~ 1000 mg, sodium azulene sulfonate 0.1-50 mg, preferably 0.1-10 mg, aldioxa 1-400 mg, preferably 30-100 mg, aldioxa-metasilicate magnesium aluminate 10-3000 mg or 100 to 1000 mg of sofalcone can be used in an amount of 1 to 1000 mg, preferably 10 to 700 mg, and L-glutamine can be used in an amount of 10 to 4000 mg, preferably about 10 to 2000 mg.
[0015]
Examples of antacids include dry aluminum hydroxide gel, magnesium aluminate silicate, magnesium aluminate metasilicate, aluminum silicate, hydrotalcite, magnesium magnesium hydroxide, aluminum hydroxide gel, aluminum hydroxide / hydrogen carbonate Sodium coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, dihydroxyaluminum aminoacetate, dihydroxyaluminum aminoacetate, magnesium carbonate, magnesium oxide, magnesium hydroxide and Magnesium silicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, calcium lactate, calcium hydroxide, sodium bicarbonate, sodium citrate It can be exemplified sodium acetate, amino acid, polyamino methylene resins, scopolia extract, gastric mucin, cuttlefish bone, stone Ke'Akira, oysters and the like. Preferably magnesium aluminate silicate, hydrotalcite, magnesium hydroxide, dry aluminum hydroxide gel, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, magnesium metasilicate aluminate, dihydroxyaluminum aminoacetate, funnel extract, aluminum hydroxide It is a gel, an aluminum hydroxide / sodium bicarbonate coprecipitation product. In addition, each of these components may be used individually by 1 type, and can also be used in combination of 2 or more types arbitrarily.
[0016]
The amount of the antacid used can be 0.1 to 50 parts by weight, more preferably 0.5 to 20 parts by weight with respect to 1 part by weight of the histamine H2 receptor antagonist or proton pump inhibitor. . As a daily dose of the antacid, the daily maximum dose is preferably about 1 to 20 g, and the daily minimum effective amount is about 0.01 to 0.5 g.
[0017]
The medicament or pharmaceutical composition of the present invention has a comprehensive effect of suppressing halitosis and gastric mucosal damage by further using at least one of mucosal protective agents, digestive agents, adsorbents, astringents and analgesics and antispasmodics. It can be used as a useful gastrointestinal drug.
[0018]
Mucosal protective agent refers to drugs that adhere to the gastric mucosa to protect the gastric mucosa from irritation and relieve inflammation or repair tissues. Such mucosal protective agents include gum arabic, tragacanth, potato starch, cuckoo, dextrin Etc. can be illustrated. Each of these components may be used alone or in any combination of two or more.
[0019]
Examples of digestive drugs include starch digestive enzymes, protein digestive enzymes, fat digestive enzymes, fibrin digestive enzymes, ursodeoxycholic acid, oxycoranoic acid hydrochloride, cholic acid, bile powder, bile extract, dehydrocholic acid, animal gall, etc. can do. Starch digestive enzyme, protein digestive enzyme, fat digestive enzyme, or ursodeoxycholic acid is preferred. Examples of the enzyme include diastase, pancreatin, pepsin, petitarin, β-galactosidase, amylase, trypsin, papain, protease, lipase, cellulase, pancreatin, and the like, derived from animals, plants, and further from microorganisms. Can be used as appropriate. Each of these components may be used alone or in any combination of two or more. The amount used in combination is, for example, Urco, which is a non-enzymatic digestive. Desoxycholic acid can be used in the range of 0.001 to 0.6 g / day.
[0020]
An adsorbent is a drug that protects the stomach or prevents and improves stomach damage by adsorbing and removing substances that cause irritation of the gastric mucosa, such as gastric toxins, gases, bacteria, and gastric juice. Specifically, silicates such as aluminum silicate (natural / synthetic) and magnesium silicate (talc), dimethylpolysiloxane that removes gas by adsorbing gas bubbles attached to the stomach or stomach wall, acid of gastric juice Examples include anion exchange resin, kaolin, pectin, medicinal charcoal and the like that directly adsorbs and discharges. Preferred is dimethylpolysiloxane. Each of these components may be used alone or in any combination of two or more. The amount used in combination is, for example, 0.01 to 0 for dimethylpolysiloxane. It can be used in the range of 0.5 g / day.
[0021]
An astringent is a drug that acts on the gastric mucosal surface to bind and precipitate proteins to form an insoluble film, thereby forming an astringent action and preventing the spread of gastric inflammation. Basic salts of bismuth such as bismuth, bismuth carbonate, bismuth nitrate, and bismuth gallate; tannic acid, albumin tannate, and various herbal medicines containing tannic acid (Asenya, Genoko, etc.) can be mentioned. Each of these components may be used alone or in any combination of two or more.
[0022]
Analgesic and antispasmodic drugs include papaverine hydrochloride, ethyl aminobenzoate, scopolamine hydrobromide, methyl scopolamine bromide, yanko cord, licorice, magnolia, glaze, thimepidium bromide, oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, bromide Examples include methyl atropine, methyl l-hyostiamine bromide, methylbenactidium bromide, belladonna extract, funnel extract, diphenylpiperidinomethyldioxolane iodide, funnel root total alkanoid citrate and the like. Preferred are methyl scopolamine bromide, timepidium bromide, and methyl atropine bromide. Each of these components may be used alone or in any combination of two or more.
[0023]
Each component of these mucosal protective agents, digestive agents, adsorbents or analgesic / antispasmodics may be used alone or in combination of two or more. Since the effect of the present invention is enhanced, the combined use of an adsorbent or a mucosal protective agent is preferable.
[0024]
In addition to the above components, the composition of the present invention is a filler, a bulking agent, a binder, an excipient, a moistening agent, a disintegrating agent, a surface active agent, and a lubricant that are usually used in the art as other components. Moreover, diluents and excipients such as sustained-release agents can be blended. In addition, solubilizers, buffers, preservatives, solubilizers, tonicity agents, emulsifiers, suspending agents, dispersants, thickeners, gels, curing agents, absorption depending on the dosage form of the preparation Agents, adhesives, elastic agents, plasticizers, adsorbents, fragrances, colorants, taste-masking agents, antioxidants, preservatives, moisturizers, light-shielding agents, brighteners, antistatic agents, coating agents, etc. . Specifically, sucrose, calcium carbonate, lactose, corn starch, mannitol, D-sorbitol, crystalline cellulose, erythritol, sucrose, etc. as excipients; hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose, polyvinylpyrrolidone as binders , Methylcellulose, pregelatinized starch, etc .; carmellose calcium, croscarmellose sodium, carboxymethylcellulose, low-substituted hydroxypropylcellulose, crosslinked polyvinylpyrrolidone, etc. as disintegrants; magnesium stearate, calcium stearate, talc, etc. as lubricants ; As a fragrance | flavor, flavor and aromatic oils, such as 1-menthol, vanillin, lemon oil, cinnamon oil, and mint oil, can be illustrated.
[0025]
Furthermore, the composition of the present invention can be blended with other physiologically active ingredients and pharmacologically active ingredients as necessary, as long as the effects of the present invention are not hindered. Specific examples of such components include analgesics, anti-inflammatory drugs, intestinal adjusters, antidiarrheals, constipation drugs or antibiotics.
[0026]
Moreover, vitamins can be mix | blended as needed. Examples of such vitamins include vitamins C, vitamins B1, vitamins B6, vitamins B12, vitamins B2, vitamins D, vitamins E, vitamins A, such as thiamine, dicetiamine, Bisthiamine, thiamine disulfide, benfotiamine, prosultiamine, fursultiamine, bisbenchamine, chicotiamine, octothiamine, alithiamine, thiaminepropyl disulfide, thiaminetetrahydrofurfuryl disulfide, thiamine dicetyl sulfate, hydroxocobalamin hydrochloride, succinic acid d-α-tocopherol, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, bisbutiamine, bisbutiamine, thiamine monophosphate disulfide, thiamine pyrophosphate, shico Thiamine, pyridoxine, pyridoxal, mecoparamine, cyanocobalamin, hydroxocobalamin, methylcobalamin, ascorbic acid, calcium ascorbate, sodium ascorbate, retinol acetate, retinol palmitate, vitamin A oil, liver oil, strong liver oil, ergocalciferol, cholecalciferol D-α-tocopherol acetate, dl-α-tocopherol acetate, d-α-tocopherol, dl-α-tocopherol, sodium flavin adenine dinucleotide, riboflavin, sodium riboflavin phosphate, riboflavin butyrate, pyridoxine hydrochloride, pyridoxal phosphate, Biotin, nicotinic acids (nicotinic acid, nicotinic acid amide, inositol hexanicotinate, etc.), pantothenic acids (panthenol, Ntoten acid or a salt thereof, etc.). The doses of these vitamins are not particularly limited, but for example, when converted to daily doses, 25 to 5000 I.U. (as appropriate for vitamin A) for vitamin A, 0 for vitamin B1 0.1 to 300 mg (converted appropriately as thiamine nitrate, thiamine disulfide, thiamine hydrochloride or fullsultiamine depending on the molecular structure), 0.1 to 2000 μg (appropriately converted as hydroxocobalamin) for vitamin B12, and 5 to 5 for vitamin C Examples include 5000 mg (converted as ascorbic acid), 1 to 1000 mg (suitably converted as dl-α-tocopherol succinate) for vitamin E, and 1 to 500 mg for nicotinic acids.
[0027]
If necessary, aminoethylsulfonic acid, caffeine, γ-oryzanol, caffeine, anhydrous caffeine, L-cysteine, L-cysteine hydrochloride, glucurolactone, glucuronic acid amide, potassium aspartate, magnesium aspartate , Sodium chondroitin sulfate, calcium glycerophosphate, calcium gluconate, orotic acid, inorganic salts and the like can be blended.
[0028]
The medicament or pharmaceutical composition of the present invention is usually administered orally and is preferably prepared into various dosage forms that can be administered orally. Specifically, solid preparations such as tablets, chewing agents (chewable agents), pills, powders, fine granules, granules, capsules, troches, etc .; aqueous solutions, oily solutions, suspensions, emulsions, syrups, Mention may be made of liquid dosage forms such as elixirs. In addition, the tablet may have the form of multilayer tablets such as coated tablets and double tablets.
[0029]
Formulation into these dosage forms can be performed by a conventional method according to the formulation form, and preparations of various forms can be prepared ("Unit operation and machine of the formulation" Yodogawa Co., Ltd.). (Issued November 10, 1991 from the bookstore).
[0030]
The dose per administration of the pharmaceutical composition of the present invention or the administration form or method of the pharmaceutical of the present invention can be appropriately adjusted according to age, weight, sex, symptoms to be improved and the degree thereof, Usually, it is used in consideration of the dosage at which the drug used in the composition or medicament of the present invention is usually administered.
[0031]
Since the medicament or pharmaceutical composition of the present invention is excellent in improving gastrointestinal symptoms such as gastritis, gastric ulcer, and upset stomach, it can be used for any application according to such effects, but is particularly useful as a gastrointestinal drug. Useful.
[0032]
The medicament or pharmaceutical composition of the present invention is based on the finding that by using a healthy stomach agent together with a histamine H ₂ receptor antagonist or a proton pump inhibitor, bad breath is strongly suppressed and the gastric mucosa damage healing effect is enhanced. . Accordingly, in the present invention, a pharmaceutical composition comprising (a) a stomachic agent and (b) at least one of a histamine H ₂ receptor antagonist or a proton pump inhibitor, a) a stomachic agent and (b) a histamine H ₂ receptor A pharmaceutical comprising a combination of at least one of an antagonist and a proton pump inhibitor is provided.
The medicament or pharmaceutical composition of the present invention may be administered as a pharmaceutical composition containing at least one of (a) a stomachic agent and (b) a histamine H ₂ receptor antagonist or proton pump inhibitor, or in combination. As a medicament, (a) a healthy stomach and (b) at least one of histamine H ₂ receptor antagonist or proton pump inhibitor prepared as separate preparations may be administered at the same time or administered at a time. Good. The same applies when both a mucosal repair agent and an antacid are used, and (a) a stomachic agent, (b) at least one of a histamine H ₂ receptor antagonist or a proton pump inhibitor, a mucosal repair agent and an antacid A pharmaceutical composition may be used, and as a combined medicine, (a) a combination of a stomachic agent and an antacid, and (b) a combination of a mucosal repair agent, (a) and a mucosal repair agent A combination of (b) and a combination of an antacid, (a) a preparation containing a gastric agent, and (b) a combination of a mucosal repair agent and an antacid, (a) A combination of preparations such as a combination of a mucosal repair agent and an antacid preparation and a preparation containing (b) may be combined and administered at the same time or after a certain time.
[0033]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention still in detail, this invention is not limited to the said Example at all.
[0034]
<Example>
Formulation example 1 tablet (in adult daily dose of 9 tablets)
Keihi dried extract powder 435mg
Carrot dry extract powder 300mg
Cimetidine 300mg
Aldioxa 150mg
Rohto extract 5mg
Magnesium aluminate silicate 200mg
L-glutamine 405mg
L-hydroxypropylcellulose 500mg
Crystalline cellulose 215mg
Lactose 710mg
Sweetener (stevia) 20mg
Magnesium stearate 60mg
Total 3300mg
The tablet of the said prescription was manufactured according to the Japanese Pharmacopoeia preparation general rule and the term of a tablet.
Formulation example 2 tablets (9 daily doses for adults)
Carnitine chloride 300mg
Famotidine 15mg
L-glutamine 300mg
Sodium azulenesulfonate 2mg
Ursodeoxycholic acid 15mg
Lipolytic enzyme (lipase AP6) 45mg
Sodium bicarbonate 600mg
Magnesium carbonate 60mg
Dry aluminum hydroxide gel 180mg
Hydroxypropylcellulose 900mg
Stevia 10mg
Fragrance 4mg
Crystalline cellulose 979mg
Lactose 1000mg
Magnesium stearate 90mg
Total 4500 mg
The tablet of the said prescription was manufactured according to the Japanese Pharmacopoeia preparation general rule and the term of a tablet.
Formulation example 3 tablets (in adult daily dose of 9 tablets)
l-Menthol 2mg
Lemon oil 3mg
Cimetidine 300mg
Aldioxa-metasilicate magnesium aluminate 300mg
700 mg of magnesium aluminate silicate
Magnesium hydroxide 500mg
Dimethylpolysiloxane 120mg
Lactulose 660mg
β-carotene 1mg
Riboflavin 1mg
D-mannitol 581mg
Hydroxypropylcellulose 375mg
Crystalline cellulose 342mg
Aspartame 1mg
Magnesium stearate 14.5mg
Total 3900mg
The tablet of the said prescription was manufactured according to the Japanese Pharmacopoeia preparation general rule and the term of a tablet.
Formulation Example 4 Granules (3 adults in daily dose)
Ouren dry extract powder 500mg
Oat dried extract powder 500mg
l-Menthol 15mg
Cimetidine 240mg
Aldioxa 300mg
Dihydroxyaluminum acetate 780mg
Crystalline cellulose 1000mg
Lactose 1015mg
Mannitol 500mg
Hydroxypropylcellulose 150mg
Total 5000mg
Granules with the above formulation were produced according to the Japanese Pharmacopoeia General Rules for Preparations and Granules.
Formulation Example 4 Granules (3 adults in daily dose)
Carrot powder 1000mg
Licorice dry extract powder 300mg
Chimp dry extract powder 500mg
Cimetidine 300mg
Sucralfate 1500mg
Synthetic hydrotalcite 700mg
Stevia 15mg
Crystalline cellulose 900mg
Starch 302mg
Mannitol 285mg
Hydroxypropylcellulose 198mg
Total 6000mg
Granules with the above formulation were produced according to the Japanese Pharmacopoeia General Rules for Preparations and Granules.
Formulation example 5 tablets (9 daily doses for adults)
Carnitine chloride 150mg
Pheasant dried extract powder 500mg
Ouren dry extract powder 500mg
Sofalcon 150mg
Famotidine 20mg
Sodium azulenesulfonate 6mg
Precipitated calcium carbonate 300mg
Nicotinamide 5mg
Crystalline cellulose 800mg
940mg
Lactose 497mg
Hydroxypropylcellulose 120mg
Magnesium stearate 12mg
Total 4000mg
The tablet of the said prescription was manufactured according to the Japanese Pharmacopoeia preparation general rule and the term of a tablet.
Formulation Example 6 Granules (3 adults per day)
Keihi dried extract powder 500 mg
Licorice dry extract powder 490 mg
Lansoprazole 15mg
Synthetic hydrotalcite 700mg
Sucralfate 1000mg
Trimeptine maleate 300mg
Vitamin B1 25mg
Crystalline cellulose 1000mg
455mg starch
Hydroxypropylcellulose 1500mg
Magnesium stearate 15mg
Total 6000mg
Granules with the above formulation were produced according to the Japanese Pharmacopoeia General Rules for Preparations and Granules.
Formulation Example 7 Granules (3 adults per day)
Keihi dried extract powder 1000mg
Menthol 20mg
Lansoprazole 15mg
Sofalcon 150mg
Sodium bicarbonate 1800mg
Sucralfate 1000mg
Crystalline cellulose 1200mg
Lactose 635mg
Hydroxypropylcellulose 180mg
Total 6000mg
Granules with the above formulation were produced according to the Japanese Pharmacopoeia General Rules for Preparations and Granules.
Formulation Example 8 Granules (3 adult doses per day)
Aloe powder 150mg
Ogon dry extract powder 500mg
Carnitine chloride 100mg
l-Menthol 20mg
Cimetidine 300mg
Aluminum hydroxide / sodium bicarbonate coprecipitation product 500mg
Aldioxa 300mg
Licorice dry extract powder 500mg
Bismuth subcarbonate 500mg
Lactose 600mg
Crystalline cellulose 1000mg
Starch 1380mg
Hydroxypropylcellulose 150mg
Total 6000mg
Granules with the above formulation were produced according to the Japanese Pharmacopoeia General Rules for Preparations and Granules.
[0035]
<Test example>
Bad breath suppression test
Preparation of Examples and Comparative Examples Famotidine, fennel dry extract powder, carnitine chloride, cinnamon dry extract powder or menthol (healthy gastric agent), aldioxa (mucosal repair agent), synthetic hydrotalcite (antacid) Used to prepare tablets. Specifically, hydroxypropylcellulose, crystalline cellulose and lactose, magnesium stearate, and sucrose were added to the above components in the proportions shown in Table 1, respectively, and tableted according to a conventional method. Comparative Example 1 and Examples 1 to 4 tablets were obtained. Similarly, Comparative Example 2 and Examples 5 to 8 were obtained by the same formulation and the same method except that 15 mg of lanzoprazole was used instead of 6 mg of famotidine and 400 mg of crystalline cellulose was changed to 391 mg.
[0036]
[Table 1]

[0037]
Test method For volunteers who feel gastric pain due to the halitosis suppression effect of typical histamine H ₂ receptor antagonists famotidine or lansoprazole, and dried fennel extract powder, carnitine chloride, dried cinnamon extract powder or menthol (healthy gastric agent). Tested by 30 subjects.
The subject took the preparation of any one of Comparative Example 1 or Comparative Example 2 and Examples 1 to 8 immediately after lunch on the first day of the test, rinsed with 50 ml of water 3 hours after lunch, and immediately after mouthwash. The breath was collected in a 2 L polyethylene bag (polyethylene bag manufactured by Taiyo Co., Ltd. <thickness 0.04 m / m, width 230 m / m, length 320 m / m>). On the second test day, the preparation of any one of Comparative Example 1 or Comparative Example 2 and Examples 1 to 8 was taken immediately after lunch, and exhaled breath was collected in the same manner 3 hours after lunch.
For the collected exhaled breath, 60 mL of gas was collected from the bag using a syringe, and the odor level in the exhaled breath was measured using an odor sensor (COSMOS XP-329). Table 2 and Table 3 show the average values of the amount of change in the odor level on the first day and each test day taken in the examples or comparative examples.
[0038]
[Table 2]

[0039]
[Table 3]

[0040]
As can be seen from the results of the test, in the preparation of the comparative example (Comparative Example 1 or 2), the odor level of exhaled breath after 3 hours after the meal shows a high value, but in the preparation of the present invention (Examples 1 to 8), The odor level is suppressed to a low value on the first day and the second day. In the preparation of the present invention, the occurrence of halitosis was suppressed, and it was confirmed that the effect of suppressing halitosis was higher as compared to taking famotidine or omeprazole alone.
[0041]
From these results, according to the pharmaceutical composition of the present invention containing a gastric agent and a gastric agent useful for gastric inflammation and gastric ulcer such as histamine H ₂ receptor antagonist or proton pump inhibitor, the odor level is significantly suppressed, It was found that bad breath can be strongly suppressed. Moreover, this effect is the same when not only a pharmaceutical composition containing a histamine H ₂ receptor antagonist or proton pump inhibitor and a healthy stomach, but also when these are administered at the same time or after a period of time.
[0042]
Gastric mucosa damage test
Preparation and Test Methods of Examples and Comparative Examples Preparations of Comparative Example 3 or 4 and Examples 9 to 11 so as to obtain the doses shown in Table 4 to Wistar male rats (body weight 140 to 180 g) fasted for 24 hours Was forcibly administered orally. Further, after 1 hour, an aspirin solution (0.15N hydrochloric acid, 1% sodium carboxymethylcellulose aqueous solution) was forcibly orally administered at a dose of 200 mg / 5 ml / kg. Three hours after oral administration of aspirin, the stomach was excised, longitudinally cut along the large vagina and then advanced, and fixed with neutral buffered 1% formalin. The area of the damaged part of the mucous membrane was analyzed by image analysis. The test shows 5 animals per group, and the area average value for each group is shown in Table 4. The dose of each drug shown in Table 4 indicates the dose of each drug per body weight of the rat. The dose was 5 ml (0.5% methylcellulose aqueous solution) / kg. went.
[0043]
[Table 4]

[0044]
From the results of the test, the administration of cimetidine, mucosal repair agent and antacids reduced the ulcer area of the gastric mucosa caused by aspirin, but also a formulation containing keihi dry extract powder, urene dry extract powder or l-menthol together In, the reduction of gastric mucosal ulcer area was more noticeable. Despite the lack of effective treatment for gastric mucosal damage, the dry extract of Keihi, the dried aurene powder, and l-menthol have significant gastric mucosal damage when combined with cimetidine, although they have no or only weak effects. The therapeutic effect was shown to be enhanced.
[0045]
【The invention's effect】
In the present invention, bad breath can be strongly suppressed by using a gastric agent together with a histamine H ₂ receptor antagonist or a proton pump inhibitor. Therefore, it is possible to provide a pharmaceutical or a pharmaceutical composition that does not adversely affect compliance. In addition, a medicament or pharmaceutical composition using a gastric agent together with a histamine H ₂ receptor antagonist or a proton pump inhibitor is a medicament or pharmaceutical composition having an enhanced effect of suppressing gastric mucosal damage and a high therapeutic effect.

Claims (4)

(A) at least one selected from the group consisting of Keihi, Auren and menthol; and (b) at least one of cimetidine, ranitidine, famotidine, roxatidine, nizatidine and pharmaceutically acceptable salts thereof; and ( c ) mucosal repair. agents and antacids, city gastric mucosal disorder treatment agent characterized by containing (excluding therapeutic agent for gastrointestinal diseases caused by Helicobacter pylori). Mucosal repair agent is at least one of glycyrrhizic acid or a salt thereof, licorice or an extract thereof, sucrose sulfate aluminum salt (sucralfate), sodium azulene sulfonate, aldioxa, aldioxa / magnesium aluminate metasilicate, sofalcone and L-glutamine The therapeutic agent for gastric mucosa disorder according to claim 1, which is a seed. Antacid is dry aluminum hydroxide gel, magnesium aluminate silicate, hydrotalcite, magnesium hydroxide, dry aluminum hydroxide gel, gel sodium bicarbonate, magnesium carbonate, precipitated magnesium carbonate, magnesium metasilicate aluminate, dihydroxyaluminum The agent for treating gastric mucosal disorder according to claim 1 or 2, which is at least one of aminoacetate and funnel extract. (A) at least one selected from the group consisting of Keihi, Auren, and menthol; (b) at least one of cimetidine, ranitidine, famotidine, roxatidine, nizatidine, and pharmaceutically acceptable salts thereof; and ( c ) mucosal repair. An agent for treating gastric mucosal disorder in combination with an agent and an antacid (excluding a therapeutic agent for gastrointestinal diseases caused by Helicobacter pylori).