WO2016122226A2 - A pharmaceutical composition for treating gastrointestinal diseases - Google Patents
A pharmaceutical composition for treating gastrointestinal diseases Download PDFInfo
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- WO2016122226A2 WO2016122226A2 PCT/KR2016/000935 KR2016000935W WO2016122226A2 WO 2016122226 A2 WO2016122226 A2 WO 2016122226A2 KR 2016000935 W KR2016000935 W KR 2016000935W WO 2016122226 A2 WO2016122226 A2 WO 2016122226A2
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- pharmaceutical composition
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- sucralfate
- bismuth subcitrate
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- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
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- 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
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- 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
- A61K31/7024—Esters of saccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/245—Bismuth; Compounds thereof
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- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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 pharmaceutical composition for treating gastrointestinal diseases comprising ranitidine, sucralfate and bismuth subcitrate as active ingredients.
- Ranitidine is a drug of suppressing gastric acid production through H2 receptor blocking and is being used to treat stomach ulcers or reflux esophagitis.
- the fact that, when ranitidine is administered together with bismuth subcitrate and sucralfate as a combination therapy, it shows an excellent therapeutic effect for stomach ulcers and duodenal ulcer has been known (Korean Laid-open Patent No. 1997-006083, Patent Literature 1). Therefore, a combination drug comprising these three drugs as active ingredients is currently commercially available.
- ranitidine has strong hygroscopicity, causes a moisture absorption while being stored, and causes a change in a weight and a property of a tablet (PDA J. Pharm. Sci. Tech. 2009 May-Jun:63(3):223-33). Therefore, it has a problem in that a disintegration time of a tablet is changed.
- ranitidine when ranitidine is mixed with bismuth subcitrate, there is a problem in that a physical property of ranitidine is changed due to bismuth subcitrate.
- Patent Literature 1 discloses a method in which ranitidine is prepared as a core tablet, and bismuth subcitrate and sucralfate are mixed to prepare a tablet-within-a-tablet containing the core tablet.
- Patent Literature 2 discloses a method in which a problem in that, when ranitidine is released in a stomach, ranitidine is adsorbed to sucralfate and an absorption rate of ranitidine decreases was identified, accordingly a core tablet containing ranitidine is coated with a film-forming composition and then mixed with bismuth subcitrate and sucralfate to prepare a tablet-within-a-tablet.
- a combination drug that can address the following problems: 1) a problem of hygroscopicity of ranitidine itself, 2) a problem of a decrease in stability of ranitidine according to mixing with bismuth subcitrate, and 3) a problem of a decrease in a drug absorption rate due to mixing of three drugs when a combination drug of ranitidine, bismuth subcitrate and sucralfate is prepared. Further, it is necessary to prepare a combination drug than have simple preparation process, is more comfortable for a patient to swallow, and have excellent bioavailability.
- Patent Literature 1 Korean Laid-open Patent No.1997-006083
- Patent Literature 2 Korea Patent No. 10-0453179
- Non-Patent Literature 1 PDA J. Pharm. Sci. Tech. 2009 May-Jun:63(3):223-33
- the present invention provides a combination drug capable of addressing problems with regard to formulation stability and bioavailability in a combination drug of ranitidine, bismuth subcitrate and sucralfate, and that has a simple preparation process and more comfortable for a patient to swallow.
- a grinder or a mesh for each type was used to classify sucralfate and bismuth subcitrate for each particle size, a particle size was measured, sucralfate and bismuth subcitrate classified for each size were used and mixed with ranitidine, and then a moisture content, formulation stability and bioavailability of ranitidine were observed. As a result, it was confirmed that a moisture content of ranitidine was suppressed in a specific particle size range of sucralfate and bismuth subcitrate, formulation stability was maintained, and drug bioavailability was excellent. Then, the size was selected as an optimum particle size.
- the present invention provides a pharmaceutical composition for treating gastrointestinal diseases comprising ranitidine, sucralfate and bismuth subcitrate as active ingredients, and satisfies at least one of the following conditions:
- sucralfate has an average particle size of 1 to 25 ⁇ m
- bismuth subcitrate has an average particle size of 5 to 90 ⁇ m.
- the sucralfate may have an average particle size of 1 to 25 ⁇ m, for example, 1 to 20 ⁇ m, 2 to 25 ⁇ m, 2 to 20 ⁇ m, 2 to 15 ⁇ m, 3 to 15 ⁇ m, 2 to 10 ⁇ m, 3 to 10 ⁇ m, 3 to 8 ⁇ m, 4 to 10 ⁇ m, or 4 to 8 ⁇ m.
- the bismuth subcitrate may have an average particle size of 5 to 90 ⁇ m, for example, 5 to 80 ⁇ m, 5 to 75 ⁇ m, 5 to 70 ⁇ m, 10 to 75 ⁇ m, 10 to 60 ⁇ m, 10 to 50 ⁇ m, 15 to 75 ⁇ m, 20 to 75 ⁇ m, 25 to 70 ⁇ m, 25 to 65 ⁇ m, 25 to 60 ⁇ m, 25 to 55 ⁇ m, or 25 to 50 ⁇ m.
- the sucralfate may have an average particle size of 2 to 25 ⁇ m, or 2 to 10 ⁇ m.
- the bismuth subcitrate may have an average particle size of 5 to 75 ⁇ m, 25 to 70 ⁇ m, or 25 to 50 ⁇ m.
- the sucralfate may have an average particle size of 1 to 25 ⁇ m
- the bismuth subcitrate may have an average particle size of 5 to 90 ⁇ m.
- sucralfate may have an average particle size of 2 to 25 ⁇ m
- bismuth subcitrate may have an average particle size of 5 to 75 ⁇ m.
- the sucralfate may have an average particle size of 2 to 10 ⁇ m
- the bismuth subcitrate may have an average particle size of 25 to 70 ⁇ m.
- sucralfate and bismuth subcitrate having an average particle size within the above-exemplified range are combined and used, it is possible to obtain a pharmaceutical composition that is an object of the present invention.
- the average particle size is an average of a volume or a mass, and refers to a volume weighted Mean D[4,3] value with respect to a weight of a distribution.
- a general mill capable of micronizing particles such as a Z-mill, a hammer mill, a ball mill, a fluid energy mill or the like may be used for grinding.
- a sieve method that is performed using a sieve or a size classification method such as air current classification is used, it is possible to subdivide a particle size of a drug.
- a method of regulating a desired particle size is well-known in the related art. For example, the following document: [Pharmaceutical dosage forms: volume 2, 2nd edition, Ed.: H.A.Lieberman, L.Lachman, J.B.Schwartz (Chapter 3: SIZE REDUCTION)] is referenced to.
- d(10) represents a diameter of a particle at a point at which particle sizes of a drug accumulate in ascending order and the result reaches 10%.
- d(50) represents a diameter of a particle at a point at which particle sizes of a drug accumulate in ascending order and the result reaches 50%.
- d(90) represents a diameter of a particle at a point at which particle sizes of a drug accumulate in ascending order and the result reaches 90%.
- d(X) is alternatively represented as d(0.X), and d(X) and d(0.X) are interchangeable.
- d(50) is represented as d(0.5)
- d(10) and d(90) are represented as d(0.1) and d(0.9), respectively.
- a number, a volume, or a weight that is used as a reference when the particle size distribution d(X) represents a percent with respect to total accumulated particles is changed according to a method that is used to measure a particle size distribution.
- the method of measuring the particle size distribution and a type of % related thereto are known in the related art.
- an X value of d(X) represents a percent calculated according to a volume average.
- the particle size distribution measurement result obtained by a specific method may have a correlation with results obtained from other techniques based on experiences through general experiments.
- a volume average particle size is provided to correspond to a volume of a particle, which corresponds to a weight average particle size when a density is constant.
- a commercially available device using a laser diffraction and scattering method based on a Mie theory may be used.
- a commercially available device such as a Mastersizer laser diffraction device of Malvern Instruments may be used for measurement. This device is used to obtain a particle diameter distribution such that, when a helium-neon laser beam is emitted toward or a blue light emitting diode emits light toward particles, scattering is caused, a light scattering pattern is shown in a detector, and this light scattering pattern is analyzed according to the Mie theory.
- Any of dry and wet methods may be used as the measurement method, but results measured by the wet method are shown in the following examples.
- the pharmaceutical composition of the present invention may have a particle size distribution of sucralfate that additionally satisfies at least one of the following conditions.
- d(10) is 1 to 10 ⁇ m
- d(50) is 3 to 25 ⁇ m
- d(90) is 5 to 50 ⁇ m.
- the pharmaceutical composition of the present invention may have a particle size distribution of bismuth subcitrate that additionally satisfies at least one of the following conditions.
- d(50) is 20 to 70 ⁇ m
- d(90) is 40 to 130 ⁇ m.
- the pharmaceutical composition of the present invention may have a particle size distribution of sucralfate that additionally satisfies at least one of the following conditions:
- d(10) is 1 to 10 ⁇ m
- d(50) is 3 to 25 ⁇ m
- d(90) is 5 to 50 ⁇ m
- a particle size distribution of bismuth subcitrate may satisfy at least one of the following conditions:
- d(50) is 20 to 70 ⁇ m
- d(90) is 40 to 130 ⁇ m.
- a particle size of ranitidine included in the pharmaceutical composition of the present invention is not particularly limited.
- the present invention also provides a pharmaceutical composition in which sucralfate and bismuth subcitrate whose average particle size or particle size distribution are within the above range, and sucralfate has a dissolution rate whose level is equivalent to a dissolution rate of sucralfate of Albis TM Tablet.
- sucralfate and bismuth subcitrate whose average particle size or particle size distribution are within the above range
- sucralfate has a dissolution rate whose level is equivalent to a dissolution rate of sucralfate of Albis TM Tablet.
- the guidelines for drug equivalence test control may be used to determine whether the dissolution rate shows an equivalent level.
- the present invention also provides a pharmaceutical composition in which sucralfate and bismuth subcitrate whose average particle sizes or particle size distributions are within the above range, and ranitidine and bismuth subcitrate show an area under the concentration-time curve (AUC) and a maximum observed plasma concentration (C max ) of a bioequivalence level, compared to Albis TM Tablet having the same active ingredient dose.
- drug equivalence criteria may be used to determine whether the area under the concentration-time curve (AUC) and the maximum observed plasma concentration (C max ) show a bioequivalence level.
- AUC area under the concentration-time curve
- C max maximum observed plasma concentration
- contents of ranitidine, sucralfate and bismuth subcitrate which are active ingredients of the pharmaceutical composition of the present invention, may be included at a composition ratio of 1 to 2 parts by weight of ranitidine, 6 to 12 parts by weight of sucralfate, and 2 to 4 parts by weight of bismuth subcitrate to be pharmacologically effectively functioned.
- the pharmaceutical composition of the present invention is preferably prepared to comprise ranitidine at 50 to 300 mg, sucralfate at 240 to 1200 mg, and bismuth subcitrate at 80 to 400 mg, and particularly preferably prepared to include ranitidine at 50 to 150 mg, sucralfate at 240 to 600 mg, and bismuth subcitrate at 80 to 200 mg.
- the pharmaceutical composition of the present invention comprises at least one excipient other than the active ingredients.
- a diluent increases a volume of a solid pharmaceutical composition, and enables for a patient and a caregiver to handle more easily a pharmaceutical dosage form including the composition.
- Exemplary diluents for the solid composition include microcrystalline cellulose (for example, Avicel ® ), microfine cellulose, lactose, a starch, a pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrate, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, a magnesium oxide, maltodextrin, mannitol a polymethacrylate (for example, Eudragit ® ), calcium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
- microcrystalline cellulose for example, Avicel ®
- microfine cellulose for example, lactose, a starch, a pregelatinized starch
- the solid pharmaceutical composition compressed in a dosage form such as a tablet may comprise an excipient that helps the active ingredient to be bound to another excipient after compression.
- Binders for the solid pharmaceutical composition include acacia, alginic acid, a carbomer (for example, a carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxy ethylcellulose, hydroxypropyl cellulose (for example, Klucel ® ), hydroxypropylmethylcellulose (for example, Methocel ® ), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, a polymethacrylate, povidone (for example, Kollidon ® and Plasdone ® ), a pregelatinized starch, sodium alginate and a starch.
- a carbomer for example, a carbopol
- sodium carboxymethylcellulose dextrin
- ethylcellulose gelatin
- the disintegrant includes hydroxypropylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium (for example, Ac-Di-Sol ® , Primellose ® ), microcrystalline cellulose, methylcellulose, powdered cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone (for example, Kollidon ® and Polyplasdone ® ), guar gum, magnesium aluminum silicate, polacrilin potassium, a pregelatinized starch, alginic acid, sodium alginate, sodium starch glycolate (for example, Explotab ® ) and a starch.
- hydroxypropylcellulose carboxymethylcellulose calcium, carboxymethylcellulose sodium (for example, Ac-Di-Sol ® , Primellose ® ), microcrystalline cellulose, methylcellulose, powdered cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone (for example, Kollidon ® and Polyplasdone ® ), guar gum,
- a powder composition When a powder composition is compressed to prepare a dosage form such as a tablet, the composition receives a pressure from a punch and a dye. Some excipients and active ingredients tend to adhere to a surface of the punch and the dye, which may cause pitting and other surface irregularity in products. In order to decrease adhesiveness and easily extract a product material from the dye, a lubricant may be added to the composition.
- the lubricant includes stearate salts such as magnesium stearate, calcium stearate, aluminum stearate and zinc stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, a polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, talc and the like.
- stearate salts such as magnesium stearate, calcium stearate, aluminum stearate and zinc stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, a polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, talc and the like.
- storage and chelate formulations such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid may be added at a safe intake level.
- the pharmaceutical composition of the present invention is not limited thereto, but may be formulated as a tablet.
- the pharmaceutical composition of the present invention may be formulated as a matrix tablet.
- the pharmaceutical composition of the present invention is not formulated as a tablet-within-a-tablet containing a core tablet, but is formulated as a matrix tablet after particle sizes of sucralfate and bismuth subcitrate are controlled. Nevertheless, it was confirmed that all problems of a combination formulation in the related art were solved.
- a tablet comprising the pharmaceutical composition according to the present invention may be additionally coated with a coating agent.
- An embodiment of the present invention provides a tablet in which an uncoated tablet comprising ranitidine, sucralfate, and bismuth subcitrate as active ingredients is coated with a polyvinyl alcohol.
- Granules are prepared at a mixing ratio of 150:600:200 of ranitidine, sucralfate and bismuth.
- a binder hydroxypropylmethylcellulose, hydroxypropylcellulose, a polyvinylpyrrolidone and the like may be used as other binders.
- drying is preferably performed at a temperature of 30 to 60 °C such that a moisture content of a granule composition becomes 11% or less with respect to a total weight, and drying is most preferably performed at a temperature of 50 °C.
- the present invention provides a method of treating gastrointestinal diseases comprising administering the pharmaceutical composition comprising ranitidine, sucralfate and bismuth subcitrate having the above-exemplified particle size range as active ingredients to a subject in need thereof, and a use of the composition comprising ranitidine, sucralfate and bismuth subcitrate as active ingredients to prepare a drug for treating gastrointestinal diseases.
- gastrointestinal diseases include all symptoms or diseases such as inflammation and ulcer that occur in a digestive organ.
- gastrointestinal diseases include stomach ulcers, gastritis, duodenal ulcer, Zollinger-Ellison syndrome, reflux esophagitis, medication before anesthesia (prevention Mendelson's syndrome), post-op ulcer, and gastroduodenal ulcer due to nonsteroidal anti-inflammatory drugs (NSAIDs), but the present invention is not limited thereto.
- NSAIDs nonsteroidal anti-inflammatory drugs
- the term "subject" refers to a warm-blooded animal such as a mammal suffering from specific diseases, disorders or diseases, and includes, for example, a human, an orangutan, a chimpanzee, a mouse, a rat, a dog, a cow, a chicken, a pig, a goat, a sheep and the like, but the present invention is not limited thereto.
- treatment includes alleviating symptoms, temporarily or permanently removing causes of symptoms, prevention or slowdown of occurrence of symptoms and progress of diseases, disorders or illness, but the present invention is not limited thereto.
- an effective dose of the active ingredient of the pharmaceutical composition of the present invention refers to an amount that is necessary to treat diseases. Therefore, the effective dose may be regulated according to various factors such as type of disease, severity of disease, type and contents of an active ingredient and other components contained in the composition, types of dosage forms, a patient's age, weight, general health condition, and gender, diet, an administration time, an administration route, a releasing rate of the composition, a treatment period, and a drug used at the same time.
- the pharmaceutical composition of the present invention may be administered once to three times a day, and a dose of 50 to 150 mg based on ranitidine may be administered once, but the present invention is not limited thereto.
- a combination drug that can address problems of hygroscopicity of ranitidine and formulation stability and has a simple preparation process and excellent bioavailability, by controlling particle sizes of sucralfate and bismuth subcitrate when the combination drug of ranitidine, sucralfate and bismuth subcitrate is prepared.
- FIGS. 1 and 2 show change of average concentration of bismuth subcitrate in plasma of subjects to which tablets of Preparation Examples 12, 15 and 16 and Preparation Examples 14 and 17 are administered.
- FIG. 2 shows the enlarged FIG. 1.
- FIGS. 3 to 5 show change of average concentration of ranitidine in plasma of subjects to which tablets of Preparation Examples 12, 15 and 16 are administered.
- the raw material particle size was measured using a particle size measurement device (Malvern Mastersizer 2000/Hydro S) according to a wet method under the following conditions.
- Sucralfate and bismuth subcitrate were micronized using the Z-mill and the grinder or using a mesh in order to regulate particle sizes.
- sucralfate and bismuth subcitrate were classified as sucralfates 1 to 6 and bismuth subcitrates 1 to 5, and described in the following Tables 2 and 3.
- a formulation comprising ranitidine, sucralfate and bismuth subcitrate having different raw material particle size combinations was prepared to select a particle size of a drug that can ensure formulation stability, and an appropriate dissolution rate and bioavailability of the drug.
- Composition (wt%) of tablet comprising ranitidine, sucralfate and bismuth subcitrate Classification Content Ranitidine 12.2 Sucralfate 49.0 Bismuth subcitrate 16.3 Microcrystalline cellulose 13.0 Hydroxypropylcellulose 2.0 Croscarmellose sodium 5.0 Magnesium stearate 2.5 Total 100.0
- dry granules or wet granules according to a general method were prepared using purified water (or a mixed solvent of purified water and ethanol), dried at 50 °C, and then established as an 18 mesh. Then, the prepared granules were tableted and coated to prepare a matrix tablet. Coating was performed with 3% PVA. Finally, a yellowish green rectangular film-coated tablet was obtained.
- the tablets of Preparation Examples 1 to 6 were used to perform the comparison dissolution test of sucralfate. Since sucralfate is not absorbed in vivo, the bioequivalence test was not performed, but a comparison dissolution result was alternatively used.
- Albis TM Tablet commercially available from Daewoong pharmaceutical Co., Ltd.
- the comparison dissolution test was performed according to Article 3, Section 1, No 1 (the guidelines for drug equivalence test control). A dissolution solution having a pH of 1.2 was used. According to the Korean Pharmacopeia Guideline of dissolution testing (the second method (paddle method)), an HPLC method was performed at a dissolution solution temperature of 37 ⁇ 0.5 °C and 50 rpm for 2 hours.
- sucralfates 4 to 6 of Table 2 were preferably used as sucralfate. Therefore, a particle size of sucralfate was fixed to a particle size of "sucralfate 6" and then a particle size of bismuth subcitrate was regulated to evaluate stability of a tablet according to the particle size of bismuth.
- ranitidine, sucralfate and bismuth subcitrate were prepared to dry granules or wet granules according to a general method using purified water (or a mixed solvent of purified water and ethanol), dried at 50 °C and then established as an 18 mesh. Then, the prepared granules were tableted and prepared as a matrix tablet, and room temperature stability was evaluated.
- PVA was selected as the coating agent, and the uncoated tablets of Preparation Examples 7, 8, 10, and 11 were coated with 3 wt% PVA to prepare coated tablets of Preparation Examples 14, 15, 16, and 17. Then, these coated tablets were used to perform the following experimental examples.
- the coated tablets of Preparation Examples 12, 14, 15, 16 and 17 were used to perform a moisture content test as follows. The test was performed at room temperature for 6 months. In order to measure a moisture content, a Karl Fisher method among general test methods according to the Korean Pharmacopeia Guideline was used as a moisture measurement method. Using the fact that water is quantitatively reacted with iodine and sulfur dioxide in the presence of low level alcohol such as methanol and an organic base such as pyridine, methanol for moisture measurement was used as a reagent used for a moisture measurement method. A sample was obtained by grinding a tablet and about 200 mg thereof was used for the test.
- Moisture content test results of coated tablets Test item Classification Criteria Initial Room temperature stability 1 month 3 months 6 months Moisture content Preparation Example 12 11% or less 9.16% 9.11% 9.23% 9.30% Preparation Example 14 9.17% 10.05% 10.92% - Preparation Example 15 10.22% 9.80% 9.97% 10.11% Preparation Example 16 8.49% 8.88% 8.67% 8.90% Preparation Example 17 9.35% 10.01% 10.75% -
- tablets of Preparation Examples 12, 15 and 16 were appropriate for moisture content criteria.
- the tablets of Preparation Examples 14 and 17 had an inappropriate property in the room temperature stability test for 6 months, and thus an additional moisture test was not performed. Based on such results, it was confirmed that a moisture content of ranitidine was suppressed due to particle sizes of sucralfate and bismuth subcitrate, and a more excellent stability of a product through PVA coating can be confirmed.
- the coated tablets of Preparation Examples 12, 14, 15, 16 and 17 were used to perform a PK test on healthy subjects. With respect to log-transformed values of two comparison evaluation items of AUC and C max , analysis of variance was performed with bismuth subcitrate and ranitidine.
- Albis TM Tablet (commercially available from Daewoong pharmaceutical Co., Ltd.) was used as the reference drug.
- FIGS. 1 and 2 are comprehensive graphs that statistically show bioavailability parameters of the area under the concentration-time curve (AUC) and the maximum observed plasma concentration (C max ) of bismuth subcitrate obtained from blood drug concentration data of subjects to which the tablets of Preparation Example 12, 14, 15, 16 and 17 were administered.
- FIGS. 3 to 5 are graphs that statistically show bioavailability parameters of the area under the concentration-time curve (AUC) and the maximum observed plasma concentration (C max ) of ranitidine obtained from blood drug concentration data of subjects to which the tablets of Preparation Examples 12, 15 and 16 were administered.
- PK test results of the tablet of Preparation Example 12 were compared with PK test results of the reference drug.
- AUC was 0.8749 to 1.1967
- C max was 0.8681 to 1.12342. Therefore, it was confirmed that PK was equivalent.
- ranitidine AUC was 0.9282 to 1.1213, C max was 0.9282 to 1.1539, and thus it was also equivalent.
- the tablets of Preparation Examples 12, 15 and 16 suppressed a moisture content of ranitidine by appropriately regulating particle sizes of sucralfate and bismuth subcitrate and can be used as a combination drug of suppressing a change in a physical property due to drug mixing, and providing excellent bioavailability.
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Abstract
Description
Particle size distribution | Ranitidine | Sucralfate | Bismuth subcitrate |
d(10) | 2.59 ㎛ | 21.172 ㎛ | 18.565 ㎛ |
d(50) | 8.55 ㎛ | 75.135 ㎛ | 72.380 ㎛ |
d(90) | 20.74 ㎛ | 176.62 ㎛ | 195.559 ㎛ |
Average | 10.54 ㎛ | 89.154 ㎛ | 95.563 ㎛ |
Particle size distribution | Sucralfate 1 (before micronization) |
|
|
Sucralfate 4 |
|
Sucralfate 6 |
d(10) | 21.172 ㎛ | 12.355 ㎛ | 10.302 ㎛ | 6.052 ㎛ | 3.269 ㎛ | 1.727 ㎛ |
d(50) | 5.135 ㎛ | 32.169 ㎛ | 29.961 ㎛ | 20.339 ㎛ | 9.275 ㎛ | 3.901 ㎛ |
d(90) | 176.62 ㎛ | 63.957 ㎛ | 54.248 ㎛ | 39.574 ㎛ | 19.441 ㎛ | 8.116 ㎛ |
Average | 89.154 ㎛ | 35.395 ㎛ | 29.122 ㎛ | 23.657 ㎛ | 12.664 ㎛ | 4.517 ㎛ |
Particle size distribution | Bismuth subcitrate 1 (before micronization) | Bismuth subcitrate 2 |
|
Bismuth subcitrate 4 | Bismuth subcitrate 5 |
d(10) | 18.565 ㎛ | 14.533 ㎛ | 12.269 ㎛ | 11.582 ㎛ | 0.786 ㎛ |
d(50) | 72.380 ㎛ | 67.703 ㎛ | 39.756 ㎛ | 26.387 ㎛ | 4.264 ㎛ |
d(90) | 195.559 ㎛ | 122.137 ㎛ | 77.674 ㎛ | 48.833 ㎛ | 9.547 ㎛ |
Average | 95.563 ㎛ | 68.068 ㎛ | 42.698 ㎛ | 28.455 ㎛ | 4.824 ㎛ |
Classification | Content |
Ranitidine | 12.2 |
Sucralfate | 49.0 |
Bismuth subcitrate | 16.3 |
Microcrystalline cellulose | 13.0 |
Hydroxypropylcellulose | 2.0 |
Croscarmellose sodium | 5.0 |
Magnesium stearate | 2.5 |
Total | 100.0 |
Classification | Ranitidine | Sucralfate | Bismuth subcitrate | |
Preparation Example 1 | | sucralfate | 1 | |
Preparation Example 2 | |
|||
Preparation Example 3 | |
|||
Preparation Example 4 | sucralfate 4 | |||
Preparation Example 5 | |
|||
Preparation Example 6 | |
Classification/time(min) | Dissolution rate (%) | |||||||
5 | 10 | 15 | 30 | 45 | 60 | 90 | 120 | |
Reference drug | 3.4±2.1 | 31.2±4.2 | 45.2±3.8 | 64.2±3.2 | 72.3±3.0 | 79.6±2.4 | 86.2±2.1 | 91.2±1.0 |
Preparation Example 1 | 0.8±0.1 | 5.4±1.1 | 11.3±1.2 | 30.1±1.8 | 43.1±1.2 | 55.7±0.8 | 62.4±0.6 | 68.4±0.4 |
Preparation Example 2 | 1.1±0.2 | 12.1±1.0 | 25.3±0.6 | 42.6±1.9 | 55.2±1.5 | 66.5±0.9 | 72.4±1.7 | 76.1±1.2 |
Preparation Example 3 | 1.5±1.2 | 13.9±0.6 | 28.3±1.1 | 47.2±1.6 | 59.4±1.0 | 70.2±0.6 | 74.9±1.2 | 79.7±0.8 |
Preparation Example 4 | 2.0±1.4 | 21.2±0.9 | 35.4±0.5 | 53.7±1.6 | 67.5±1.1 | 76.0±1.0 | 81.4±1.5 | 85.6±0.7 |
Preparation Example 5 | 2.6±0.9 | 26.4±0.8 | 42.5±0.7 | 57.0±1.1 | 70.3±1.0 | 80.1±1.2 | 85.4±1.8 | 90.0±0.9 |
Preparation Example 6 | 2.1±1.0 | 33.4±0.8 | 48.2±1.1 | 63.4±1.2 | 75.2±0.8 | 83.2±0.1 | 88.3±1.1 | 92.4±0.7 |
Classification | Ranitidine | Sucralfate | Bismuth subcitrate |
Preparation Example 7 | Non-micronized ranitidine of Table 1 | |
|
Preparation Example 8 | |
||
Preparation Example 9 | |
||
Preparation Example 10 | bismuth subcitrate 4 | ||
Preparation Example 11 | |
Test item | Classsification | Criteria | Initial | |
||
1 |
3 |
6 months | ||||
Property | Preparation Example 7 | rectangular uncoated tablet | appropriate | appropriate | appropriate | inappropriate |
Preparation Example 8 | appropriate | appropriate | appropriate | appropriate | ||
Preparation Example 9 | appropriate | appropriate | appropriate | appropriate | ||
Preparation Example 10 | appropriate | appropriate | appropriate | appropriate | ||
Preparation Example 11 | appropriate | appropriate | appropriate | inappropriate | ||
Moisture content | Preparation Example 7 | 11% or less | 9.11% | 11.44% | 14.22% | - |
Preparation Example 8 | 9.31% | 9.92% | 10.47% | 10.90% | ||
Preparation Example 9 | 8.91% | 9.32% | 10.07% | 10.84% | ||
Preparation Example 10 | 9.12% | 9.72% | 10.26% | 10.74% | ||
Preparation Example 11 | 8.55% | 10.90% | 13.22% | - |
Test item | Classification | Criteria | Initial | |
||
1 |
3 |
6 months | ||||
Property | Preparation Example 12 | rectangular film-coated tablet | appropriate | appropriate | appropriate | appropriate |
Preparation Example 13 | appropriate | appropriate | appropriate | appropriate | ||
Moisture content | Preparation Example 12 | 11% or less | 9.30% | 9.45% | 9.44% | 9.51% |
Preparation Example 13 | 9.44% | 11.19% | 14.14% | 16.92% |
Test item | Classification | Criteria | Initial | 1 month | 3 months | 6 months | ||
accelerated | room temperature | accelerated | room temperature | accelerated | ||||
Property | Preparation Example 12 | yellowish green film-coated tablet | appropriate | appropriate | appropriate | appropriate | appropriate | appropriate |
Preparation Example 14 | appropriate | appropriate | appropriate | inappropriate | inappropriate | inappropriate | ||
Preparation Example 15 | appropriate | appropriate | appropriate | appropriate | appropriate | appropriate | ||
Preparation Example 16 | appropriate | appropriate | appropriate | appropriate | appropriate | appropriate | ||
Preparation Example 17 | appropriate | appropriate | appropriate | appropriate | inappropriate | inappropriate | ||
Ranitidine | Preparation Example 12 | 90.0 to 110.0% | 100.20% | 100.47% | 100.54% | 100.06% | 100.72% | 99.50% |
Preparation Example 14 | 100.80% | 99.45% | 99.70% | - | - | - | ||
Preparation Example 15 | 100.47% | 100.20% | 100.26% | 100.34% | 99.80% | 99.94% | ||
Preparation Example 16 | 99.28% | 100.41% | 99.20% | 99.45% | 99.52% | 99.64% | ||
Preparation Example 17 | 99.10% | 99.81% | 98.50% | 99.48% | - | - | ||
Sucralfate | Preparation Example 12 | 90.0 to 110.0% | 101.40% | 101.22% | 101.52% | 101.70% | 101.20% | 100.19% |
Preparation Example 14 | 100.10% | 101.59% | 101.82% | - | - | - | ||
Preparation Example 15 | 99.87% | 99.94% | 100.10% | 99.93% | 100.31% | 99.91% | ||
Preparation Example 16 | 102.33% | 101.50% | 101.76% | 101.80% | 101.24% | 101.92% | ||
Preparation Example 17 | 100.22% | 100.86% | 100.30% | 100.90% | - | - | ||
Bismuth | Preparation Example 12 | 90.0 to 110.0% | 99.90% | 98.50% | 99.93% | 99.56% | 99.13% | 99.72% |
Preparation Example 14 | 99.10% | 97.84% | 99.77% | - | - | - | ||
Preparation Example 15 | 101.38% | 100.99% | 100.84% | 100.68% | 100.44% | 100.38% | ||
Preparation Example 16 | 100.80% | 100.37% | 100.58% | 99.80% | 99.76% | 99.84% | ||
Preparation Example 17 | 100.20% | 98.85% | 98.86% | 99.33% | - | - | ||
Disintegration test | Preparation Example 12 | Within 30 minutes | 9 minutes | 9 minutes | 10 minutes | 9 minutes | 9 minutes | 9 minutes |
Preparation Example 14 | 10 minutes | 10 minutes | 10 minutes | - | - | - | ||
Preparation Example 15 | 9 minutes | 9 minutes | 10 minutes | 9 minutes | 10 minutes | 9 minutes | ||
Preparation Example 16 | 9 minutes | 9 minutes | 9 minutes | 10 minutes | 9 minutes | 9 minutes | ||
Preparation Example 17 | 8 minutes | 8 minutes | 8 minutes | 9 minutes | - | - |
Test item | Classification | Criteria | Initial | |
||
1 |
3 |
6 months | ||||
Moisture content | Preparation Example 12 | 11% or less | 9.16% | 9.11% | 9.23% | 9.30% |
Preparation Example 14 | 9.17% | 10.05% | 10.92% | - | ||
Preparation Example 15 | 10.22% | 9.80% | 9.97% | 10.11% | ||
Preparation Example 16 | 8.49% | 8.88% | 8.67% | 8.90% | ||
Preparation Example 17 | 9.35% | 10.01% | 10.75% | - |
Claims (19)
- A pharmaceutical composition for treating gastrointestinal diseases comprising ranitidine, sucralfate and bismuth subcitrate as active ingredients, and satisfying at least one of the following conditions:(a) the sucralfate has an average particle size of 1 to 25 ㎛,(b) the bismuth subcitrate has an average particle size of 5 to 90 ㎛.
- The pharmaceutical composition according to claim 1,wherein the sucralfate has an average particle size of 2 to 25 ㎛.
- The pharmaceutical composition according to claim 1,wherein the sucralfate has an average particle size of 2 to 10 ㎛.
- The pharmaceutical composition according to claim 1,wherein the bismuth subcitrate has an average particle size of 5 to 75 ㎛.
- The pharmaceutical composition according to claim 1,wherein the bismuth subcitrate has an average particle size of 25 to 70 ㎛.
- The pharmaceutical composition according to claim 1,wherein the bismuth subcitrate has an average particle size of 25 to 50 ㎛.
- The pharmaceutical composition according to claim 1,wherein the sucralfate has an average particle size of 1 to 25 ㎛, and the bismuth subcitrate has an average particle size of 5 to 90 ㎛.
- The pharmaceutical composition according to claim 1,wherein the sucralfate has an average particle size of 2 to 25 ㎛, and the bismuth subcitrate has an average particle size of 5 to 75 ㎛.
- The pharmaceutical composition according to claim 1,wherein the sucralfate has an average particle size of 2 to 10 ㎛, and the bismuth subcitrate has an average particle size of 25 to 70 ㎛.
- The pharmaceutical composition according to claim 1,wherein the sucralfate has a particle size distribution that satisfies at least one of the following conditions:1) d(10) is 1 to 10 ㎛,2) d(50) is 3 to 25 ㎛,3) d(90) is 5 to 50 ㎛.
- The pharmaceutical composition according to claim 1,wherein the bismuth subcitrate has a particle size distribution that satisfies at least one of the following conditions:1) d(10) is 5 to 17 ㎛,2) d(50) is 20 to 70 ㎛,3) d(90) is 40 to 130 ㎛.
- The pharmaceutical composition according to claim 1,wherein the sucralfate has a particle size distribution that satisfies at least one of the following conditions,1) d(10) is 1 to 10 ㎛,2) d(50) is 3 to 25 ㎛,3) d(90) is 5 to 50 ㎛, andwherein the bismuth subcitrate has a particle size distribution that satisfies at least one of the following condition:1) d(10) is 5 to 17 ㎛,2) d(50) is 20 to 70 ㎛,3) d(90) is 40 to 130 ㎛.
- The pharmaceutical composition according to claim 1,wherein the sucralfate has a dissolution rate whose level is equivalent to a dissolution rate of sucralfate of AlbisTM Tablet.
- The pharmaceutical composition according to claim 1,wherein the ranitidine and the bismuth subcitrate in the pharmaceutical composition show an area under the concentration-time curve (AUC) and a maximum observed plasma concentration (Cmax) of a bioequivalence level compared to AlbisTM Tablet having the same active ingredient dose.
- The pharmaceutical composition according to any of claims 1 to 14,wherein the pharmaceutical composition comprises ranitidine at 50 to 300 mg, sucralfate at 240 to 1200 mg and bismuth subcitrate at 80 to 400 mg.
- The pharmaceutical composition according to any of claims 1 to 14,wherein the pharmaceutical composition is formulated in the form of a tablet.
- The pharmaceutical composition according to any of claims 1 to 14,wherein the pharmaceutical composition is formulated in the form of a matrix tablet.
- The pharmaceutical composition according to claim 17,wherein the tablet is coated with a coating agent.
- The pharmaceutical composition according to claim 18,wherein the coating agent is a polyvinyl alcohol.
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
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MYPI2017702737A MY195824A (en) | 2015-01-30 | 2016-01-28 | A Pharmaceutical Composition for Treating Gastrointestinal Diseases |
EA201791458A EA032385B9 (en) | 2015-01-30 | 2016-01-28 | Pharmaceutical composition for treating gastrointestinal diseases |
UAA201707833A UA116517C2 (en) | 2015-01-30 | 2016-01-28 | A pharmaceutical composition for treating gastrointestinal diseases |
EP16743704.5A EP3250199A4 (en) | 2015-01-30 | 2016-01-28 | A pharmaceutical composition for treating gastrointestinal diseases |
MX2017007567A MX2017007567A (en) | 2015-01-30 | 2016-01-28 | A pharmaceutical composition for treating gastrointestinal diseases. |
JP2017540683A JP6419347B2 (en) | 2015-01-30 | 2016-01-28 | Pharmaceutical composition for treatment of gastrointestinal diseases |
CN201680007680.7A CN107205947B (en) | 2015-01-30 | 2016-01-28 | Pharmaceutical composition for treating gastrointestinal diseases |
BR112017013857-3A BR112017013857B1 (en) | 2015-01-30 | 2016-01-28 | PHARMACEUTICAL COMPOSITION TO TREAT GASTROINTESTINAL DISEASES |
CONC2017/0006222A CO2017006222A2 (en) | 2015-01-30 | 2017-06-23 | Pharmaceutical composition for the treatment of gastrointestinal diseases |
PH12017550051A PH12017550051A1 (en) | 2015-01-30 | 2017-07-25 | A pharmaceutical composition for treating gastrointestinal diseases |
SA517382016A SA517382016B1 (en) | 2015-01-30 | 2017-07-29 | A Pharmaceutical Composition for Treating Gastrointestinal Diseases |
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KR10-2015-0015339 | 2015-01-30 | ||
KR20150015339 | 2015-01-30 | ||
KR10-2015-0147513 | 2015-10-22 | ||
KR1020150147513A KR101583452B1 (en) | 2015-01-30 | 2015-10-22 | A pharmaceutical composition for treating gastrointestinal diseases |
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WO2016122226A2 true WO2016122226A2 (en) | 2016-08-04 |
WO2016122226A3 WO2016122226A3 (en) | 2016-09-15 |
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PCT/KR2016/000935 WO2016122226A2 (en) | 2015-01-30 | 2016-01-28 | A pharmaceutical composition for treating gastrointestinal diseases |
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EP (1) | EP3250199A4 (en) |
JP (1) | JP6419347B2 (en) |
KR (2) | KR101583452B1 (en) |
CN (1) | CN107205947B (en) |
AR (1) | AR105413A1 (en) |
CL (1) | CL2017001680A1 (en) |
CO (1) | CO2017006222A2 (en) |
EA (1) | EA032385B9 (en) |
EC (1) | ECSP17038599A (en) |
GE (1) | GEP20196941B (en) |
MA (1) | MA41432A (en) |
MX (1) | MX2017007567A (en) |
MY (1) | MY195824A (en) |
PE (1) | PE20171340A1 (en) |
PH (1) | PH12017550051A1 (en) |
SA (1) | SA517382016B1 (en) |
TW (1) | TWI635859B (en) |
UA (1) | UA116517C2 (en) |
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KR101988479B1 (en) | 2017-10-11 | 2019-09-24 | (주)휴럼 | Litsenolide used as an active ingredient for gastrointestinal disease, and A composition comprising the same as an active ingredient |
JP2021518422A (en) * | 2018-04-13 | 2021-08-02 | サムヤン バイオファーマシューティカルズ コーポレイションSamyang Biopharmaceuticals Corporation | Pharmaceutical composition containing lenalidomide |
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KR970006083A (en) | 1995-07-06 | 1997-02-19 | 한승준 | Installation structure of wire fixing device of automobile cowl |
WO2000078307A1 (en) | 1999-06-21 | 2000-12-28 | Daewoong Pharmaceutical Co., Ltd. | Orally administrable pharmaceutical preparation having therapeutic effect on gastrointestinal disorders comprising coated ranitidine, bismuth subcitrate and sucralfate |
KR20140072673A (en) | 2012-12-05 | 2014-06-13 | (주)한국파비스제약 | Oral tablet for treatment of gastrointestinal disease |
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ATE81011T1 (en) * | 1987-03-09 | 1992-10-15 | Procter & Gamble | COMPOSITIONS AND THEIR USE IN THE TREATMENT OF GASTROINTESTINAL DISORDERS. |
US4990610A (en) * | 1988-08-25 | 1991-02-05 | Applied Analytical Industries, Inc. | Method for preparing high potency sucralfate |
EP0403048A3 (en) * | 1989-06-14 | 1991-01-30 | Warner-Lambert Company | Medicated compositions containing sucralfate and processes for their production |
KR970006083B1 (en) * | 1992-01-22 | 1997-04-23 | 주식회사 대웅제약 | A pharmaceutical composition for treating gastrointestinal disorders |
BR9507533A (en) * | 1994-04-26 | 1997-09-02 | Chugai Pharmaceutical Co Ltd | Fused granulated sucralfate preparations and a process for their production |
JPH0879097A (en) * | 1994-09-01 | 1996-03-22 | Matsushita Electric Ind Co Ltd | Portable radio equipment |
WO1999010000A1 (en) * | 1997-08-25 | 1999-03-04 | The Procter & Gamble Company | Combined preparations for treating upper gastrointestinal tract distress |
JP2006076956A (en) * | 2004-09-10 | 2006-03-23 | Taiyo Yakuhin Kogyo Kk | Compounding agent for treating/preventing gastritis |
WO2010001930A1 (en) * | 2008-07-01 | 2010-01-07 | ライオン株式会社 | Solid preparation for internal application |
KR20110105223A (en) * | 2010-03-18 | 2011-09-26 | 일양약품주식회사 | Oral pharmaceutical composition for preventing or treating a gastroenteric disease comprising ilaprazole and a mixture of sucralfate and bismuth agents |
-
2015
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- 2016-01-28 CN CN201680007680.7A patent/CN107205947B/en active Active
- 2016-01-28 WO PCT/KR2016/000935 patent/WO2016122226A2/en active Application Filing
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- 2016-01-28 EP EP16743704.5A patent/EP3250199A4/en not_active Withdrawn
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- 2017-07-25 PH PH12017550051A patent/PH12017550051A1/en unknown
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KR970006083A (en) | 1995-07-06 | 1997-02-19 | 한승준 | Installation structure of wire fixing device of automobile cowl |
WO2000078307A1 (en) | 1999-06-21 | 2000-12-28 | Daewoong Pharmaceutical Co., Ltd. | Orally administrable pharmaceutical preparation having therapeutic effect on gastrointestinal disorders comprising coated ranitidine, bismuth subcitrate and sucralfate |
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Publication number | Publication date |
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UA116517C2 (en) | 2018-03-26 |
WO2016122226A3 (en) | 2016-09-15 |
PH12017550051A1 (en) | 2018-01-29 |
PE20171340A1 (en) | 2017-09-13 |
CN107205947A (en) | 2017-09-26 |
MY195824A (en) | 2023-02-22 |
CN107205947B (en) | 2020-05-22 |
EA032385B9 (en) | 2019-07-31 |
BR112017013857A2 (en) | 2018-02-27 |
EP3250199A2 (en) | 2017-12-06 |
ECSP17038599A (en) | 2017-09-29 |
CL2017001680A1 (en) | 2018-01-12 |
EP3250199A4 (en) | 2018-08-08 |
TWI635859B (en) | 2018-09-21 |
KR101583452B1 (en) | 2016-01-11 |
EA032385B1 (en) | 2019-05-31 |
CO2017006222A2 (en) | 2017-09-20 |
AR105413A1 (en) | 2017-10-04 |
GEP20196941B (en) | 2019-01-10 |
KR20160094268A (en) | 2016-08-09 |
SA517382016B1 (en) | 2021-03-18 |
KR101583452B9 (en) | 2022-05-02 |
TW201639559A (en) | 2016-11-16 |
MX2017007567A (en) | 2017-10-19 |
JP2018503672A (en) | 2018-02-08 |
JP6419347B2 (en) | 2018-11-07 |
EA201791458A1 (en) | 2017-11-30 |
MA41432A (en) | 2017-12-05 |
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