WO1997034601A1 - Compositions medicamenteuses a solubilite amelioree - Google Patents
Compositions medicamenteuses a solubilite amelioree Download PDFInfo
- Publication number
- WO1997034601A1 WO1997034601A1 PCT/JP1997/000853 JP9700853W WO9734601A1 WO 1997034601 A1 WO1997034601 A1 WO 1997034601A1 JP 9700853 W JP9700853 W JP 9700853W WO 9734601 A1 WO9734601 A1 WO 9734601A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- present
- drug
- pyridylmethyl
- hydroxy
- dimethyl
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 50
- 239000003814 drug Substances 0.000 title claims abstract description 28
- 229940079593 drug Drugs 0.000 title claims abstract description 28
- 239000000126 substance Substances 0.000 claims abstract description 35
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 238000007906 compression Methods 0.000 claims abstract description 4
- 230000006835 compression Effects 0.000 claims abstract description 4
- 229920003169 water-soluble polymer Polymers 0.000 claims description 16
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 14
- 229920001577 copolymer Polymers 0.000 claims description 13
- 229920000642 polymer Polymers 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 5
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 4
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 4
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 4
- 238000000465 moulding Methods 0.000 claims description 4
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 claims description 3
- 238000001125 extrusion Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 2
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 claims 2
- 239000008186 active pharmaceutical agent Substances 0.000 claims 1
- 229940088679 drug related substance Drugs 0.000 claims 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims 1
- IONAQTGMWFXHIX-UHFFFAOYSA-N E3040 Chemical compound CC1=C(O)C(C)=C2SC(NC)=NC2=C1CC1=CC=CN=C1 IONAQTGMWFXHIX-UHFFFAOYSA-N 0.000 abstract description 4
- 238000013019 agitation Methods 0.000 abstract description 2
- 239000006185 dispersion Substances 0.000 abstract description 2
- 238000007493 shaping process Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 238000000034 method Methods 0.000 description 12
- -1 methyl butyl Chemical group 0.000 description 11
- 238000010828 elution Methods 0.000 description 9
- 239000008187 granular material Substances 0.000 description 9
- 238000002156 mixing Methods 0.000 description 9
- 239000000843 powder Substances 0.000 description 8
- 239000007962 solid dispersion Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000010586 diagram Methods 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000008247 solid mixture Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- RRICOAOKWWUFOX-UHFFFAOYSA-N 2-(pyridin-3-ylmethyl)-1,3-benzothiazole Chemical compound N=1C2=CC=CC=C2SC=1CC1=CC=CN=C1 RRICOAOKWWUFOX-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 229920003152 Eudragit® RS polymer Polymers 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- VKEQBMCRQDSRET-UHFFFAOYSA-N Methylone Chemical compound CNC(C)C(=O)C1=CC=C2OCOC2=C1 VKEQBMCRQDSRET-UHFFFAOYSA-N 0.000 description 1
- 229920001007 Nylon 4 Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- FSXVSUSRJXIJHB-UHFFFAOYSA-M ethyl prop-2-enoate;methyl 2-methylprop-2-enoate;trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium;chloride Chemical compound [Cl-].CCOC(=O)C=C.COC(=O)C(C)=C.CC(=C)C(=O)OCC[N+](C)(C)C FSXVSUSRJXIJHB-UHFFFAOYSA-M 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- OOYGSFOGFJDDHP-KMCOLRRFSA-N kanamycin A sulfate Chemical group OS(O)(=O)=O.O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N OOYGSFOGFJDDHP-KMCOLRRFSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000005871 repellent Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
Definitions
- the present invention relates to a pharmaceutical composition containing 6-hydroxy-5,7-dimethyl-2-methylamino-4- (3-pyridylmethyl) benzothiazole, which has improved solubility and which can be controlled in release.
- 6-Hydroxy-1,5,7-dimethyl-12-methylamino 4- (3-pyridylmethyl) benzothiazole (hereinafter sometimes referred to as the compound of the present invention) is a drug for treating ulcerative colitis and Crohn's disease It is a compound under development.
- the compounds according to the invention have a very low solubility, especially in the alkaline region.
- fine powdering of the drug fine powdering of the drug, formation of solvates, increase of surface area by solid surface adsorption, polymorphism, mixing and grinding with excipients, solid dispersion, etc.
- water-repellent salts such as metal salts of fatty acids and acrylic acid-based polymers And those utilizing the interaction between Eudragit RS (trade name) and organic acids.
- 6-hydroxy-5,7-dimethyl-2-methylamino-4- (3-pyridyl T-methyl) benzothiazol does not substantially dissolve in neutral to alkaline water depending on the usual formulation, so its absorption rate when administered to a living body may be low and its fluctuation may be large.
- the method based on pulverization has a limited effect, and the use of surfactants has problems in terms of safety.
- the present invention comprises dissolving or dispersing 6-hydroxy-1,5,7-dimethyl-12-methylamino-4- (3-1-pyridylmethyl) benzothiazole and a polymer substance in a solvent, and then distilling off the solvent. It is a pharmaceutical composition. Further, it is a pharmaceutical composition obtained by molding 6-hydroxy-5,7-dimethyl-12-methylamino-14- (3-pyridylmethyl) benzothiazole and a polymer substance by a stirring compression type extrusion granulator. .
- the present invention is a drug composition obtained by further adding a water-soluble polymer substance to the above-mentioned drug composition.
- 6-Hydroxy-1,5,7-dimethyl-1-methylamino-4- (3-pyridylmethyl) benzothiazole has the following structural formula:
- the high molecular substance in the present invention means a high molecular substance dissolved or dispersed in water, and specifically, hydroxypropyl methylcellulose phthalate, hydroxypropynolemethinolecinolate, and canoleboxymethinoletinolate.
- ethyl acrylate means a copolymer, and preferred examples thereof include hydroxypropylmethylcellulose phthalate and canoleboxymethylethylcellulose.
- Preferred as the water-soluble polymer substance to be further added to the drug composition are hydroxypropyl senorelose, hydroxyl butylmethylcellulose, carboxymethinolethynolacese / rerose, methizoresenorelose, and polyvinyl acetate.
- the solvent in the present invention means a solvent capable of dissolving or dispersing 6-hydroxy-1,5,7-dimethyl-12-methylamino41- (3-pyridylmethyl) benzothiazole and a polymer substance, for example, water
- a solvent capable of dissolving or dispersing 6-hydroxy-1,5,7-dimethyl-12-methylamino41- (3-pyridylmethyl) benzothiazole and a polymer substance, for example, water
- examples include ethanol, methanol, dichloromethane, and chloroform.
- these solvents can be used in combination.
- the mixing ratio of the water-Z ethanol mixed solvent is usually 1 to 90% of water, and the ethanol is 99 to: L0 ⁇ 1 ⁇ 2. More preferably, it is 1 to 30% of water and 99 to 70% of ethanol.
- the mixing ratio in which the compound according to the present invention and the high molecular substance are both dissolved can be appropriately selected.
- the compound of the present invention and the water-soluble polymer substance
- the agitation compression type extrusion granulator in the present invention refers to a screen or a nozzle while stirring and mixing the compound of the present invention and a water-soluble polymer substance with a screw or the like installed in the granulator.
- a machine that extrudes under pressure and performs granulation molding Some preferred examples include a twin-screw extruder. During granulation and molding, the temperature is usually raised to 30 to 180 ° C.
- the compound of the present invention may be a solid dispersion.
- the solid dispersion refers to a state in which the compound according to the present invention is dispersed in a polymer material that is a medium, and means that the compound is in a molecular state or an amorphous state. When it is not a body, that is, for example, even if it is dispersed in a crystalline state, the effects of the present invention can be obtained.
- a drug composition formed by adding a powder of a water-soluble polymer to the above-mentioned drug composition, or a water-soluble polymer dissolved in a solvent is used.
- the above-mentioned drug composition can be made into a drug composition which is formed into granules.
- the release of 6-hydroxy-1,5,7-dimethyl-2-methylamino-4- (3-pyridylmethyl) benzothiazole is freely controlled by the type and amount of water-soluble polymer added, and the absorption improvement effect does not decrease. As a result, the drug can be delivered to the target site in a required amount for a required time, and an excellent drug effect can be obtained.
- the mixing ratio of (3-pyridylmethyl) benzothiazole and the polymer substance is 6-hydroxy-5,7-dimethyl-2-methylamino-1- (3-pyridylmethyl) benzothiazole per 1 part by weight of polymer
- the substance is at least 1 part by weight, preferably at least 4 parts by weight.
- the upper limit of the mixing ratio of the polymer substance is usually 20 parts by weight or less.
- the production method of the composition according to the present invention is obtained, for example, by dissolving the compound according to the present invention and hydroxypropylmethylcellulose phthalate in a mixed solvent of 85% ethanol / water and evaporating the solvent to dryness. Can be.
- the obtained composition can be pulverized and sieved, and if necessary, mixed with other substances to prepare granules, tablets and the like.
- a compound according to the present invention and a hydroxypropylcellulose acetate lid The composition according to the present invention can be obtained by mixing the rates and granulating with a biaxial extruder. In this case, the mixture is 40-120.
- composition C can be heated and plasticizers such as Jardin wax, sugar ester, and stearic acid can be added.
- plasticizers such as Green wax, sugar ester, and stearic acid
- the obtained composition can be pulverized and sieved, and if necessary, mixed with other substances to prepare a preparation such as a granule or a tablet.
- the ratio of the case where the water-soluble polymer substance is further added to the 6-hydroxy-1,5,7-dimethyl-2-methylamino-4- (3-pyridylmethyl) benzothiazol-containing drug composition in the present invention is as follows.
- the water-soluble polymer is used in an amount of 0.01 to 10 parts by weight, preferably 0.02 to 5 parts by weight, more preferably 0.05 to 0.5 part by weight, based on 1 part by weight of the drug composition. 5 parts by weight. It is appropriately selected depending on the purpose of the release control.
- a water-soluble polymer substance is added to the above-mentioned drug composition and then mixed and tableted, or the composition is formed into granules by using a water-soluble polymer substance dissolved in a solvent. It can be manufactured by doing. In the case of tablets and granules, formulation aids such as commonly used disintegrants and lubricants can be used. Action:
- 6-hydroxy-1,5,7-dimethyl-12-methylamino-14- (3-pyridylmethyl) benzothiazole is not decomposed, its crystal structure is changed, and the original crystal form is exhibited.
- the solubility is transiently higher than the solubility.
- the compound according to the present invention is absorbed from the digestive tract, and the effect can be more reliably exhibited.
- v type of water soluble polymer and the amount by 6-arsenide Dorokishi one 5, 7-dimethyl one 2 - Mechiruamino one 4 one (3-pyridylmethyl) release of benzothiazole Ichiru is freely controlled, and improved absorption The effect does not decrease. This makes it possible to deliver a required amount of a drug to a target site for a required time, thereby achieving an excellent drug effect.
- FIG. 1 is a diagram showing the elution of the compound according to the present invention when various polymer substances are blended.
- FIG. 2 is a diagram showing elution when a substance according to the present invention is mixed with carboxymethylethylcellulose at various ratios and produced by a biaxial extruder.
- FIG. 3 is a graph showing changes in the blood glucose level of the substance of the present invention when the substance of the present invention and carboxymethylethyl cellulose mixture are produced by a biaxial extruder and administered to a beagle dog. is there.
- FIG. 4 is a diagram showing the elution of the compound according to the present invention from tablets obtained by tableting after adding various types of polymer substances to powder.
- FIG. 5 is a diagram showing the dissolution of the compound according to the present invention from tablets obtained by tableting after adding powder of hydroxymethyl pill methyl cellulose.
- FIG. 6 is a diagram showing the dissolution of the compound according to the present invention from a tablet obtained by tableting after adding powder of carboxymethylethylcellulose.
- FIG. 7 is a diagram showing the elution of the compound according to the present invention from granules produced by dissolving methacrylic acid / methyl acrylate / copolymer in ethanol.
- a mixture of 100 g of hydroxypropynolemethinolecellulose phthalate and 200 g of 6-hydroxy-5,7-dimethyl-2-methylamino-141- (3-pyridylmethyl) benzothiazole is mixed with 200 g to form a biaxial type.
- Ekusutoru one da one sieved and crushed 3 the composition prepared a composition according to the present invention warmed to 8 0 C in Jietsu Bok mill, A powder was produced.
- Example 2 To 10 g of the composition obtained in Example 1, 2.5 g of powder of carboxymethylethylcellulose, hydroxypropylmethylcellulose, polybutylpyrrolidone, methylcellulose or hydroxy-5-hydroxypropylcellulose was added. A post-lubricating agent was added, and the mixture was compressed at a pressure of 600 kg to produce a tablet having a diameter of 9 mm and a tablet of 300 mg.
- Hydroxypropyl methylcellulose was added to 10 g of the composition obtained in Example 2 after adding 5%, 12.5% or 25% powder, and the mixture was compressed at a pressure of 800 kg to give a tablet having a diameter of 9 mm and 1 tablet. 30 Omg tablets were produced.
- compositions according to the present invention exhibited higher solubility and a higher dissolution rate than the control.
- - 1 to 1 part by weight of the compound of the present invention was mixed with 3 to 10 parts by weight of carboxymethylethylcellulose to obtain a biaxial type.
- the composition according to the present invention manufactured by an extruder the results of measuring the elution (37 ° C, 900 mi, paddle method, 100 rpm) of the compound of the present invention in two solutions of S station, and Figure 2 shows.
- FIG. 4 shows the results obtained by measuring the elution of the compound with the paddle method at 100 rpm.
- the solid dispersion according to the present invention was used. It is clear that the solid composition according to the present invention can control the release in one Japanese Pharmacopoeia by the added water-soluble polymer substance while maintaining the solubility in the two Japanese Pharmacopoeia.
- FIG. 5 shows the results of the measurement using the paddle method at 100 rpm.
- the solid composition according to the present invention was released in 1st JP by the added hydroxypropylmethyl cellulose while maintaining the solubility in 2nd PS. It is clear that the control of is possible.
- FIG. 7 shows the results of measuring the elution of the compound by the paddle method at 100 rpm.
- the solid dispersion according to the present invention was used. It is clear that the solid composition according to the present invention can control the release in one Japanese Pharmacopoeia by the addition amount of methacrylic acid / methyl acrylate / copolymer while maintaining the solubility in two Japanese Pharmacopoeia. is there.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Compositions médicamenteuses à solubilité améliorée, et compositions médicamenteuses à solubilité améliorée et à dissolution contrôlée. L'invention concerne une composition médicamenteuse préparée par dissolution ou dispersion de 6-hydroxy-5,7-diméthyl-2-méthylamino-4-(3-pyridylméthyl)benzothiazole et d'une substance polymère dans un solvant, puis par distillation de la solution ou de la dispersion obtenue, de façon à éliminer le solvant; une autre composition médicamenteuse préparée par formage simultané du 6-hydroxy-5,7-diméthyl-2-méthylamino-4-(3-pyridylméthyl)benzothiazole et d'une substance polymère au moyen d'un granulateur d'extrusion de type à agitation et compression; ainsi que d'autres compositions médicamenteuses préparées par adjonction de substances polymères hydrosolubles à ces compositions.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6098696 | 1996-03-18 | ||
| JP8/60986 | 1996-03-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997034601A1 true WO1997034601A1 (fr) | 1997-09-25 |
Family
ID=13158277
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1997/000853 WO1997034601A1 (fr) | 1996-03-18 | 1997-03-18 | Compositions medicamenteuses a solubilite amelioree |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1997034601A1 (fr) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008114859A1 (fr) * | 2007-03-22 | 2008-09-25 | Astellas Pharma Inc. | Composition pharmaceutique contenant un dérivé de pyrazole |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5446837A (en) * | 1977-09-19 | 1979-04-13 | Kanebo Ltd | Easily absorbable nifedipin composition, its preparation, and anti-stenocardia containing the same |
| JPS58183615A (ja) * | 1982-04-19 | 1983-10-26 | エラン・コ−ポレ−シヨン・リミテツド | 高度溶解性医薬及びその製造法 |
| JPS6038322A (ja) * | 1983-08-11 | 1985-02-27 | Fujisawa Pharmaceut Co Ltd | ジヒドロピリジンａ物質含有易溶性固形製剤 |
| JPH0249720A (ja) * | 1988-05-18 | 1990-02-20 | Mitsubishi Kasei Corp | 難溶性薬剤組成物 |
| JPH05139973A (ja) * | 1991-11-20 | 1993-06-08 | Shin Etsu Chem Co Ltd | ニフエジピン含有固形製剤の製造方法 |
| JPH05178855A (ja) * | 1991-04-04 | 1993-07-20 | Eisai Co Ltd | ベンゾチアゾール誘導体 |
-
1997
- 1997-03-18 WO PCT/JP1997/000853 patent/WO1997034601A1/fr active Application Filing
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5446837A (en) * | 1977-09-19 | 1979-04-13 | Kanebo Ltd | Easily absorbable nifedipin composition, its preparation, and anti-stenocardia containing the same |
| JPS58183615A (ja) * | 1982-04-19 | 1983-10-26 | エラン・コ−ポレ−シヨン・リミテツド | 高度溶解性医薬及びその製造法 |
| JPS6038322A (ja) * | 1983-08-11 | 1985-02-27 | Fujisawa Pharmaceut Co Ltd | ジヒドロピリジンａ物質含有易溶性固形製剤 |
| JPH0249720A (ja) * | 1988-05-18 | 1990-02-20 | Mitsubishi Kasei Corp | 難溶性薬剤組成物 |
| JPH05178855A (ja) * | 1991-04-04 | 1993-07-20 | Eisai Co Ltd | ベンゾチアゾール誘導体 |
| JPH05139973A (ja) * | 1991-11-20 | 1993-06-08 | Shin Etsu Chem Co Ltd | ニフエジピン含有固形製剤の製造方法 |
Non-Patent Citations (2)
| Title |
|---|
| BASIC COURSE ON MEDICINE DEVELOPMENT X, (18), "Pharmaceutical Engineering (in Japanese)", (CHIJIN SHOKAN), March 1971, p. 119-127. * |
| RECENT PREPARATIVE TECHNIQUE OF DRUGS AND ITS APPLICATION I TECHNIQUE OF DRUGS AND ITS APPLICATION I (IYAKU JOURNAL-SHA), September 1983, HIROSHI FUJIWARA, "Continuation of Wet Granulation (in Japanese)", p. 47-50. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008114859A1 (fr) * | 2007-03-22 | 2008-09-25 | Astellas Pharma Inc. | Composition pharmaceutique contenant un dérivé de pyrazole |
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