WO2000078307A1 - Preparation pharmaceutique a administration orale ayant une action therapeutique sur les troubles gastro-intestinaux, contenant de la ranitidine enrobee, du sous-citrate de bismuth et du sucralfate - Google Patents

Preparation pharmaceutique a administration orale ayant une action therapeutique sur les troubles gastro-intestinaux, contenant de la ranitidine enrobee, du sous-citrate de bismuth et du sucralfate Download PDF

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Publication number
WO2000078307A1
WO2000078307A1 PCT/KR1999/000327 KR9900327W WO0078307A1 WO 2000078307 A1 WO2000078307 A1 WO 2000078307A1 KR 9900327 W KR9900327 W KR 9900327W WO 0078307 A1 WO0078307 A1 WO 0078307A1
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Prior art keywords
ranitidine
sucralfate
coated
bismuth subcitrate
coating agent
Prior art date
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PCT/KR1999/000327
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English (en)
Inventor
Young-Hyo Yoo
Hak-Hyung Kim
Jong-Wan Lee
Joon-Woo Park
Byung-Soo Jang
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Daewoong Pharmaceutical Co., Ltd.
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Application filed by Daewoong Pharmaceutical Co., Ltd. filed Critical Daewoong Pharmaceutical Co., Ltd.
Priority to CNB998167568A priority Critical patent/CN1173698C/zh
Priority to KR10-2001-7016389A priority patent/KR100453179B1/ko
Priority to AU46551/99A priority patent/AU4655199A/en
Priority to PCT/KR1999/000327 priority patent/WO2000078307A1/fr
Publication of WO2000078307A1 publication Critical patent/WO2000078307A1/fr

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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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/29—Antimony or bismuth compounds
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings

Definitions

  • the present invention relates to a pharmaceutical preparation comprising ranitidine, bismuth subcitrate and sucralfate. More specifically, the present invention relates to a novel orally administrable pharmaceutical preparation which can obtain synergism of ranitidine, bismuth subcitrate and sucralfate by preventing reduction of therapeutic efficacy due to inhibitory action on absorption of ranitidine by sucralfate, when ranitidine, bismuth subcitrate and sucralfate are simultaneously administered per os.
  • the orally administrable pharmaceutical preparation according to the present invention increases absorption rate of ranitidine to thus exhibit remarkably improved therapeutic effect on gastric and duodenal ulcers by synergism of ranitidine, bismuth subcitrate and sucralfate.
  • Gastrointestinal disorders such as gastritis, gastric ulcer, duodenitis and duodenal ulcer are caused by various factors. Recently, it has been reported that gastrointestinal disorders are caused by imbalance of aggressive factors such as gastric acid, pepsin and Helicobacter pylori, etc. and defensive factors such as mucus secreted from mucosa, regenerative activity of tissues, improvability of blood circulation.
  • H 2 antagonists such as ranitidine, cimetidine and famotidine were developed hitherto.
  • ranitidine a compound that has a sustained therapeutic effect and thus, gastrointestinal disorders recur frequently.
  • Bismuth preparations such as bismuth subcitrate and bismuth subsalicylate were developed for treatment of gastrointestinal disorders not only by protecting gastric and duodenal ulcerative lesions by potentiating defensive factors but also by killing Helicobacter pylori [Drugs 36, 132 - 157(1988); Gut 28, 201 -205(1987); The American Journal of Gastroenterology Vol.84, No.3(1989)].
  • bismuth preparations cannot exhibit antacid effect and alleviatory effect on a pain caused by gastric acid.
  • Sucralfate is used for treatment of gastritis or gastric ulcer by inactivation of pepsin acting as an aggressive factor and by stimulation of mucus secretion, antacid action, regeneration of mucous cells and prostaglandine secretion.
  • sucralfate cannot be involved in inhibition of acid secretion.
  • a method for treatment of gastric ulcer characterized by administration of H 2 antagonists in combination with bismuth preparations is disclosed in the European Patent No. 282132 and a method characterized by administration of H 2 antagonists in combination with sucralfate is disclosed in the literature [The American Journal of Medicine, Volume 79(Suppl. 2c), August 30, 1985].
  • therapeutic effect on gastrointestinal disorders according to the above methods are merely insufficient.
  • the present inventors noticed that gastrointestinal function should be normalized on the whole by balance of aggressive factors and defensive factors, in order not only to rapidly treat gastrointestinal disorders, e. g. gastric ulcer, but also to reduce recurrence rate.
  • ranitidine when ranitidine is mixed with bismuth subcitrate, properties of ranitidine are likely to be significantly affected by bismuth subcitrate. Therefore, to separate ranitidine and bismuth subcitrate, ranitidine is manufactured into tablets according to any one of conventional methods, the manufactured tablets are film-coated with hydroxypropyl methylcellulose and glycerin to thus manufacture tablet cores. Then, the film-coated tablet cores are mixed with bismuth subcitrate and sucralfate to thus manufacture double-layer tablets comprising tablet cores.
  • ranitidine exhibits its therapeutic effect on gastrointestinal disorders by inhibitory action on secretion of gastric acid after being absorbed in the upper intestine in vivo and then migrating to the stomach along with blood circulation.
  • sucralfate is converted into viscous material in gastric juice of acidity and then, coats the walls of the stomach and thus, can protect the walls of the stomach from being attacked by various aggressive factors.
  • sucralfate exhibits high viscosity under the acidic condition, e. g. in gastric juice.
  • ranitidine and sucralfate results in adsorption of ranitidine by sucralfate because of high viscosity of sucralfate.
  • ranitidine cannot migrate to the upper small intestine any longer and absorption rate of ranitidine is reduced by 20 to 30% and consequently, its therapeutic efficacy on gastric ulcer is inevitably reduced to 55 to 65%.
  • the present inventors have performed the extensive studies to enhance therapeutic effect on gastrointestinal disorders of an orally administrable pharmaceutical preparation comprising ranitidine, bismuth subcitrate and sucralfate by increasing absorption rate of ranitidine in vivo.
  • ranitidine is film-coated, wherein the film dissolution time is longer than time required for migration of ranitidine from the stomach to the upper small intestine, it is not adsorbed by sucralfate in the stomach any longer and after migration to the small intestine, it can be absorbed therein to be highly effective for treatment of gastrointestinal disorders even in case of being orally administered by being formulated into various dosage forms such as tablets, capsules or granules, in combination with bismuth subcitrate and sucralfate, and finally, completed the present invention.
  • an object of the present invention is to provide an orally administrable pharmaceutical preparation comprising ranitidine, bismuth subcitrate and sucralfate which exhibits excellent therapeutic effect on gastrointestinal disorders by preventing adsorption of ranitidine by sucralfate and by increasing absorption rate of ranitidine.
  • ranitidine when ranitidine is orally administered in combination with bismuth subcitrate and sucralfate, it is not eluted to be adsorbed by sucralfate of high viscosity in the stomach but is eluted and disintegrated after migration to the upper small intestine and thereby it can be absorbed at a high rate in vivo to thus enhance therapeutic efficacy of gastric ulcer.
  • the present invention provides an orally administrable pharmaceutical preparation comprising ranitidine, bismuth subcitrate and sucralfate, which makes it possible that ranitidine migrates to the upper small intestine and is absorbed therein to display inhibitory effect on secretion of gastric juice, while bismuth subcitrate and sucralfate are disintegrated in the stomach immediately after being administered and exhibit rapidly their therapeutic effects on gastrointestinal disorders.
  • ranitidine is separated from bismuth subcitrate and sucralfate by being coated with a coating agent, in order not to be denatured by bismuth subcitrate, not to be adsorbed by sucralfate and to be absorbed at a high rate in the small intestine. More specifically, ranitidine is coated with a coating agent and subsequently, the coated ranitidine is mixed with bismuth subcitrate and sucralfate to being pharmaceutically manufactured into an orally administrable formulation containing ranitidine, bismuth subcitrate and sucralfate. After the preparation of the present invention is administered, bismuth subcitrate and sucralfate are immediately eluted and then, ranitidine is exposed to gastric juice in the stomach.
  • ranitidine is eluted and disintegrated in the stomach before it migrates to the small intestine, it is adsorbed by sucralfate of high viscosity. Therefore, in order to be efficiently absorbed in vivo, it is important not to be eluted and to successfully migrate to the small intestine.
  • ranitidine when ranitidine is administered to the empty stomach, it migrates to the upper small intestine 20 to 30 minutes after entry into the stomach and it completes passage through the upper small intestine, 70 to 90 minutes after being administered.
  • ranitidine is coated to have a film dissolution time of 20 to 90 minutes, more preferably, 30 to 70 minutes, in gastric juice of acidity, in order not to be adsorbed by sucralfate in the stomach and to be absorbed after migration to the small intestine.
  • the film dissolution time was measured by placement of the film coated ranitidine in a beaker in which 0.07M of HC1 was contained at a temperature of 37°C .
  • the film dissolution time was evaluated by measuring a period of time after which ranitidine was visually inspected for the first time along with dissolution of the film.
  • the pharmaceutical preparation according to the present invention is characterized in that ranitidine is coated with a coating agent to have a film dissolution time ranging from 20 to 90 minutes as evaluated in the above-described test, which can prevent ranitidine from being denatured by bismuth subcitrate and being adsorbed by sucralfate in the stomach to thus increase absorption rate of ranitidine.
  • ranitidine is coated with a coating agent according to any one of conventional methods which are known in the art, in a conventional coating machine, for example, Manesty Accela cota, Driam coater or Hi-coater.
  • the coated ranitidine may be dried by being allowed to stand in the coating machine or by being transferred to a dry oven or a high-temperature drier.
  • a coating agent which is used for coating ranitidine must have a film dissolution time of 20 minutes or longer in gastric juice of acidity, i. e. in 0.07M of HC1, or must be dissolved in the small intestine of alkalinity or neutrality without being dissolved under the acidic condition.
  • coating agent examples include enteric-coating agents such as hydroxypropyl methylcellulose phthalate, Eudragit L. S. alone or in combination with another cellulose base polymer which may be used in both of water-soluble and water-insoluble solvent systems(e. g. hydroxypropoxy and methyl ether based on cellulose substrate such as Sepifilm 002), alkyl cellulose which may be used in water-soluble solvent systems(e. g. methylcellulose, hydroxypropyl methylcellulose), or polymeric material which can form a film such as Eudragit E.
  • enteric-coating agents such as hydroxypropyl methylcellulose phthalate, Eudragit L. S. alone or in combination with another cellulose base polymer which may be used in both of water-soluble and water-insoluble solvent systems(e. g. hydroxypropoxy and methyl ether based on cellulose substrate such as Sepifilm 002), alkyl cellulose which may be used in water-soluble solvent systems(e. g. methylcellulose, hydroxy
  • the coating agent may contain excipients selected from the group plasticizers, e. g. propylene glycol, Myvacet, glycerol, sorbitol, glycerol triacetate, diethyl phthalate or triethyl citrate; preservatives, e. g. methyl or propyl hydroxybenzoate; and colorant, e. g. titanium dioxide containing crimson lakes or ferric oxide.
  • plasticizers e. g. propylene glycol, Myvacet, glycerol, sorbitol, glycerol triacetate, diethyl phthalate or triethyl citrate
  • preservatives e. g. methyl or propyl hydroxybenzoate
  • colorant e. g. titanium dioxide containing crimson lakes or ferric oxide.
  • the coating agent may be preferably used in an amount of 0.1 to 10.0% by weight based on the weight of ranitidine. If less than 0.1% by weight, the film is dissolved in gastric juice and then, ranitidine is eluted before migration to the small intestine and is adsorbed by sucralfate. If more than 10.0% by weight, the film dissolution is delayed and ranitidine pass through the upper small intestine without being eluted to be absorbed in the small intestine.
  • two methods are provided for manufacture of orally administrable dosage forms by coating ranitidine with a coating agent.
  • ranitidine is manufactured into granules according to any one of conventional methods and then, the granules are coated with a coating agent to obtain film-coated granules. Thereafter, the film-coated granules are mixed with bismuth subcitrate and sucralfate, in combination with one or more pharmaceutically acceptable carriers or excipients to obtain granules, tablets or capsules comprising the film-coated granules of ranitidine.
  • tablet cores containing ranitidine are manufactured according to any one of conventional methods and then, the tablet cores are coated with a coating agent to obtain film-coated tablet cores containing ranitidine. Thereafter, the film-coated tablet cores are mixed with bismuth subcitrate and sucralfate in combination with one or more pharmaceutically acceptable carriers or excipients to obtain double-layer tablets comprising tablet cores.
  • Granules, tablets, capsules and double-layer tablets comprising tablet cores may be manufactured according to any one of conventional methods known in the art, and may comprise one or more pharmaceutically acceptable carriers or excipients, for example, binders, e. g. pregelatinized corn starch, poly vinyl pyrrolidone or hydroxypropyl methylcellulose such as HPMC 5 or 6; fillers, e. g. starch, lactose, microcrystalline cellulose or calcium phosphate; disintegrators, e. g. potato starch, sodium starch glycolate, skim soybean extracts, cross-linked polyvinyl pyrrolidone or cross-linked carboxymethylcellulose; lubricant or glidant, e. g. hydrogenated vegetable oil, talc or silica, or humectant, e. g. sodium lauryl sulfate.
  • binders e. g. pregelatinized corn starch, poly vinyl pyrrolidone or hydroxyprop
  • the orally administrable preparation of the present invention may comprise 1 to 2 parts by weight of ranitidine, 2 to 4 parts by weight of bismuth subcitrate and 6 to 12 parts by weight of sucralfate based on the total weight of preparation, preferably, 50 to 300 mg of ranitidine, 100 to 400 mg of bismuth subcitrate and 300 to 1200 mg of sucralfate, and more preferably, 50 — 150 mg of ranitidine, 100 to 200 mg of bismuth subcitrate and 300 to 600 mg of sucralfate.
  • the preparation of the present invention may be preferably administered once or twice a day, with a unit dose of 50 to 150 mg as ranitidine. However, the unit dose may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the preparation of the present invention.
  • the present inventors identified that the orally administrable preparation can completely resolve the problems that absorption rate of ranitidine is reduced by sucralfate, to thus enhance the absorption rate of ranitidine and to exhibit excellent therapeutic effect on gastric disorders by synergism of ranitidine, bismuth subcitrate and sucralfate
  • the granules manufactured in 1) were film coated with the coating composition according to a conventional method to manufacture film-coated granules of ranitidine.
  • a mixture of 7.3 mg of hydroxypropyl methylcellulose phthalate, 1.8 mg of purified shellac and 0.9 mg of Myvacet was added to a solution of methylene chloride and isopropanol in distilled water to prepare an enteric coating composition.
  • the granules manufactured in 1) were enteric coated with the coating composition according to a conventional method to prepare enteric-coated granules of ranitidine.
  • a mixture of 300 mg of sucralfate, 100 mg of bismuth subcitrate, 2.83 mg of microcrystalline cellulose and 14 mg of hydroxypropyl cellulose was added to distilled water and the whole mixture was granulated in a high-velocity mixer and the granulated mixture was dried to manufacture granules comprising sucralfate and bismuth subcitrate.
  • the granules manufactured in B. were mixed with 104.17 mg of the film-coated or enteric-coated ranitidine granules(75 mg as ranitidine) manufactured in 1) to obtain granules comprising coated granules of ranitidine.
  • Example 2
  • 600 mg of tablets were manufactured according to a conventional method using a mixture of 104.17 mg of the film-coated granules of ranitidine(75 mg as ranitidine) manufactured in example 1.
  • A 300 mg of sucralfate, 100 mg of bismuth subcitrate, 53.83 mg of microcrystalline cellulose, 30 mg of lactose, 10 mg of carboxymethylcellulose and 2 mg of magnesium stearate.
  • ranitidine hydrochloride 75 mg as ranitidine
  • 6 mg of microcrystalline cellulose and 1 mg of hydroxypropyl cellulose were mixed and the mixture was added to ethanol solution.
  • the whole mixture was kneaded and granulated according to a conventional method.
  • the granulated mixture was dried and sieved.
  • the granules were mixed with 8 mg of carboxymethylcellulose and 2 mg of magnesium stearate and the whole mixture was compressed into tablet cores of ranitidine.
  • a mixture of 3 mg of hydroxypropyl methylcellulose, 1 mg of ethyl cellulose, 0.8 mg of titanium dioxide, 0.4 mg of talc and 0.2 mg of polyethylene glycol was added to ethanol solution to prepare a film coating composition.
  • a mixture of 7.2 mg of hydroxypropyl methylcellulose phthalate and 0.8 mg of Myvacet was added to a solution of acetone and ethanol to prepare an enteric coating composition.
  • the tablet cores of ranitidine manufactured in 1) were coated with the coating composition according to a conventional method to manufacture enteric-coated tablet cores of ranitidine.
  • sucralfate 100 mg of bismuth subcitrate, 86.46 mg of microcrystalline cellulose and 20 mg of hydroxypropyl cellulose was added to ethanol solution.
  • the whole mixture was kneaded and then, the kneaded mixture was granulated and dried according to a conventional method to manufacture granules of sucralfate and bismuth subcitrate.
  • the granules of bismuth subcitrate and sucralfate manufactured in B. were mixed with 20 mg of calcium carboxymethylcellulose and 4 mg of magnesium stearate.
  • the thus obtained mixture was manufactured into double-layer tablets comprising tablet cores according to a conventional method, in combination with 106.4 mg of the film- or enteric-coated tablet cores of ranitidine hydrochloride(75 mg as ranitidine).
  • a mixture of 6.5 mg of hydroxypropyl methylcellulose, 1.7 mg of titanium dioxide, 0.9 mg of talc and 0.34 mg of polyethylene glycol was added to ethanol solution to prepare a film coating composition.
  • the double-layer tablets manufactured in C. were film coated with the film coating composition to obtain film-coated double-layer tablets.
  • Double-layer tablets comprising tablet cores of ranitidine were manufactured using a mixture of 84 mg of ranitidine hydrochloride(75 mg as ranitidine), 300 mg of sucralfate, 100 mg of bismuth subcitrate, 3.5 mg of microcrystalline cellulose, 14.0 mg of hydroxypropyl methylcellulose, 17 mg of carboxymethylcellulose, 11 mg of magnesium stearate, 14. 5 mg of hydroxypropyl methylcellulose, 5.1 mg of glycerin and 0.9 mg of titanium dioxide, according to the method disclosed in preparation 4 of the Korean Patent Publication No. 97-6083.
  • Film-dissolution times of the double-layer tablets manufactured in example 4 and the comparative example were measured as follows. 0.07 M of hydrochloric acid solution at 37 °C was contained in a beaker and thereto were added the double-layer tablets manufactured in example 4 and the comparative example, respectively. Thereafter, the film-dissolution times was evaluated by measuring a period of time after which the film was dissolved and ranitidine was visually inspected for the first time, respectively. The results are shown in the following table 1.
  • film-dissolution times of the double-layer tablets manufactured in example 4 were longer than 30 minutes, while the films of the double-layer tablets prepared in the comparative example were rapidly dissolved and their film-dissolution times were shorter than 8 minutes.
  • Test Example 2 Measurement of absorption rate of ranitidine in case of being orally administered in vivo
  • the double-layer tablets according to the present invention exhibited significantly increased AUC and maximum blood concenrration(Cmax) in comparison with those according to comparative example. Therefore, ranitidine is expected to be efficiently absorbed in case of administration of the preparation according to the present invention.
  • the granules manufactured in example 1 were administered per os. for six weeks to the volunteers of an age of 20 to 50 suffering from gastric ulcer, the diameter of which ranged from 10 to 25 mm. Complete treatment of gastric ulcer was determined by endoscopy. The results are shown in the following table 3. Table 3. Therapeutic effect on gastric ulcer in the human body.
  • the double-layer tablets and granules of the present invention exhibited remarkably improved therapeutic effect on gastric ulcer in comparison with the double-layer tablets of the comparative example.
  • the orally administrable pharmaceutical preparation of the present invention which comprises ranitidine, bismuth subcitrate and sucralfate, wherein the ranitidine is coated with a coating agent to have a film-dissolution time ranging from 20 to 90 minutes, exhibit excellent therapeutic effect on gastrointestinal disorders by completely resolving the problem of the prior art that ranitidine cannot be efficiently absorbed in vivo by adsorption by sucralfate in the stomach. Consequently, according to the present invention, unexpectedly remarkable therapeutic effect on gastric ulcer can be obtained by synergism of ranitidine, bismuth subcitrate and sucralfate.

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Abstract

La présente invention concerne une préparation pharmaceutique à administration orale ayant une action thérapeutique sur les troubles gastro-intestinaux, contenant comme principes actifs de la ranitidine, du sous-citrate de bismuth et du sucralfate; la ranitidine étant enrobée avec un agent d'enrobage lui conférant un temps de dissolution de film compris entre 20 et 90 minutes.
PCT/KR1999/000327 1999-06-21 1999-06-21 Preparation pharmaceutique a administration orale ayant une action therapeutique sur les troubles gastro-intestinaux, contenant de la ranitidine enrobee, du sous-citrate de bismuth et du sucralfate WO2000078307A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CNB998167568A CN1173698C (zh) 1999-06-21 1999-06-21 包含包衣的雷尼替丁、碱式柠檬酸铋和硫糖铝的对胃肠障碍具有治疗作用的可口服给药的药物制剂
KR10-2001-7016389A KR100453179B1 (ko) 1999-06-21 1999-06-21 피복된 라니티딘, 비스마스 서브시트레이트 및수크랄페이트를 함유하는 경구용 위장질환 치료용 약제조성물
AU46551/99A AU4655199A (en) 1999-06-21 1999-06-21 Orally administrable pharmaceutical preparation having therapeutic effect on gastrointestinal disorders comprising coated ranitidine, bismuth subcitrate and sucralfate
PCT/KR1999/000327 WO2000078307A1 (fr) 1999-06-21 1999-06-21 Preparation pharmaceutique a administration orale ayant une action therapeutique sur les troubles gastro-intestinaux, contenant de la ranitidine enrobee, du sous-citrate de bismuth et du sucralfate

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PCT/KR1999/000327 WO2000078307A1 (fr) 1999-06-21 1999-06-21 Preparation pharmaceutique a administration orale ayant une action therapeutique sur les troubles gastro-intestinaux, contenant de la ranitidine enrobee, du sous-citrate de bismuth et du sucralfate

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WO2000078307A1 true WO2000078307A1 (fr) 2000-12-28

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WO2006103702A2 (fr) * 2005-04-01 2006-10-05 Mccullough Ricky W Procede pour la fabrication de compositions a base de polymeres d'adherence biologique notamment pour le revetement de l'epithelium des muqueuses et epidermique
WO2016122226A2 (fr) 2015-01-30 2016-08-04 Daewoong Pharmaceutical Co., Ltd. Composition pharmaceutique pour le traitement de maladies gastro-intestinales

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CN101507717B (zh) * 2009-03-13 2013-01-23 沈阳药科大学 一种治疗消化性溃疡的复方片剂及其制备方法
CN101607086B (zh) * 2009-07-21 2011-11-02 山西安特生物制药股份有限公司 一种复方铋剂组合物及其制备方法
KR101801064B1 (ko) 2015-07-20 2017-11-27 안국약품 주식회사 위장질환 치료용 삼중층 정제
KR101794529B1 (ko) * 2016-06-14 2017-11-07 주식회사 인트로바이오파마 위장질환 치료용 필름코팅정제, 및 이의 제조방법
KR20230156474A (ko) 2022-05-06 2023-11-14 에니솔루션 주식회사 위장질환 치료용 복합정제

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JPH10109942A (ja) * 1996-08-13 1998-04-28 Takeda Chem Ind Ltd 医 薬

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006103702A2 (fr) * 2005-04-01 2006-10-05 Mccullough Ricky W Procede pour la fabrication de compositions a base de polymeres d'adherence biologique notamment pour le revetement de l'epithelium des muqueuses et epidermique
WO2006103702A3 (fr) * 2005-04-01 2006-12-21 Ricky W Mccullough Procede pour la fabrication de compositions a base de polymeres d'adherence biologique notamment pour le revetement de l'epithelium des muqueuses et epidermique
WO2016122226A2 (fr) 2015-01-30 2016-08-04 Daewoong Pharmaceutical Co., Ltd. Composition pharmaceutique pour le traitement de maladies gastro-intestinales
CN107205947A (zh) * 2015-01-30 2017-09-26 株式会社大熊制药 用于治疗胃肠道疾病的药物组合物
JP2018503672A (ja) * 2015-01-30 2018-02-08 デウォン ファーマシューティカル カンパニー リミテッド 胃腸疾患治療用医薬組成物
EP3250199A4 (fr) * 2015-01-30 2018-08-08 Daewoong Pharmaceutical Co., Ltd. Composition pharmaceutique pour le traitement de maladies gastro-intestinales

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CN1354660A (zh) 2002-06-19
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CN1173698C (zh) 2004-11-03
AU4655199A (en) 2001-01-09

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