JP5390014B2 - 抗凝固剤の溶出改善方法 - Google Patents
抗凝固剤の溶出改善方法 Download PDFInfo
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- JP5390014B2 JP5390014B2 JP2012505679A JP2012505679A JP5390014B2 JP 5390014 B2 JP5390014 B2 JP 5390014B2 JP 2012505679 A JP2012505679 A JP 2012505679A JP 2012505679 A JP2012505679 A JP 2012505679A JP 5390014 B2 JP5390014 B2 JP 5390014B2
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- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000007765 cera alba Substances 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940119744 dextran 40 Drugs 0.000 description 1
- PGZIKUPSQINGKT-UHFFFAOYSA-N dialuminum;dioxido(oxo)silane Chemical compound [Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O PGZIKUPSQINGKT-UHFFFAOYSA-N 0.000 description 1
- XLIDPNGFCHXNGX-UHFFFAOYSA-N dialuminum;oxygen(2-);silicon(4+) Chemical compound [O-2].[O-2].[O-2].[O-2].[O-2].[Al+3].[Al+3].[Si+4] XLIDPNGFCHXNGX-UHFFFAOYSA-N 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- CRVGKGJPQYZRPT-UHFFFAOYSA-N diethylamino acetate Chemical compound CCN(CC)OC(C)=O CRVGKGJPQYZRPT-UHFFFAOYSA-N 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- 229960000622 edoxaban Drugs 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 238000009775 high-speed stirring Methods 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound 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 description 1
- 229940031702 hydroxypropyl methylcellulose 2208 Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003130 hypromellose 2208 Polymers 0.000 description 1
- 229940031707 hypromellose 2208 Drugs 0.000 description 1
- 229920003125 hypromellose 2910 Polymers 0.000 description 1
- 229940031672 hypromellose 2910 Drugs 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 201000010849 intracranial embolism Diseases 0.000 description 1
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 1
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000001055 magnesium Nutrition 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical class [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 235000016337 monopotassium tartrate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- CLWLSXFPGZCOBC-UHFFFAOYSA-N phenylmethanesulfonic acid;hydrate Chemical compound O.OS(=O)(=O)CC1=CC=CC=C1 CLWLSXFPGZCOBC-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- ZFACJPAPCXRZMQ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O.OC(=O)C1=CC=CC=C1C(O)=O ZFACJPAPCXRZMQ-UHFFFAOYSA-N 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- KYKNRZGSIGMXFH-ZVGUSBNCSA-M potassium bitartrate Chemical compound [K+].OC(=O)[C@H](O)[C@@H](O)C([O-])=O KYKNRZGSIGMXFH-ZVGUSBNCSA-M 0.000 description 1
- 229940086065 potassium hydrogentartrate Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 description 1
- 239000000770 propane-1,2-diol alginate Substances 0.000 description 1
- 230000007575 pulmonary infarction Effects 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000019830 sodium polyphosphate Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 1
- 229960005196 titanium dioxide Drugs 0.000 description 1
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000010497 wheat germ oil Substances 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 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
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
[1](A)化合物I、その薬学的に許容される塩またはそれらの溶媒和物、
(B)糖アルコール類および水膨潤性添加剤からなる群から選択される1以上の賦形剤、
(C)崩壊剤、および
(D)結合剤を、
造粒中の造粒物の最大水分値を10%以下に維持する条件下で造粒する工程を包含する、化合物I、その薬学的に許容される塩またはそれらの溶媒和物を含有する造粒物の製造方法;
[2]造粒中の造粒物の最大水分値が8%以下である、[1]に記載の方法;
[3]賦形剤として、少なくとも1以上の糖アルコール類および少なくとも1以上の水膨潤性添加剤を用いる、[1]または[2]に記載の方法;
[4]糖アルコール類が、マンニトール、キシリトールまたはエリスリトールである、[1]〜[3]のいずれか1項に記載の方法;
[5]糖アルコール類がマンニトールである、[1]〜[4]のいずれか1に記載の方法;
[6]水膨潤性添加剤が、部分アルファー化デンプンまたは結晶セルロースである、[1]〜[5]のいずれか1に記載の方法;
[7]水膨潤性添加剤が、部分アルファー化デンプンである、[1]〜[6]のいずれか1に記載の方法;
[8]糖アルコール類がマンニトールであり、水膨潤性添加剤が部分アルファー化デンプンである、[5]または[7]のいずれか1に記載の方法;
[9]崩壊剤が、クロスポビドンまたはカルボキシメチルスターチナトリウムである、[1]〜[8]のいずれか1に記載の方法;
[10]崩壊剤が、クロスポビドンである、[1]〜[9]のいずれか1に記載の方法;
[11]結合剤が、ヒドロキシプロピルセルロースである、[1]〜[10]のいずれか1に記載の方法;
[12]造粒が、流動層造粒である、[1]〜[11]のいずれか1に記載の方法;
[13](A)の成分が、下記の式(Ia)
[14][1]〜[13]のいずれか1に記載の方法で得られる造粒物;
[15](A)化合物I、その薬学的に許容される塩またはそれらの溶媒和物、
(B)糖アルコール類および水膨潤性添加剤からなる群から選択される1以上の賦形剤、
(C)崩壊剤、および
(D)結合剤を、
造粒中の造粒物の最大水分値を10%以下に維持する条件下で造粒する工程、
を包含する、化合物I、その薬学的に許容される塩またはそれらの溶媒和物を含有する医薬組成物の製造方法;
[16]造粒中の造粒物の最大水分値が8%以下である、[15]に記載の方法;
[17]賦形剤としてが、糖アルコール類および水膨潤性添加剤を用いる、[15]または[16]に記載の方法;
[18]糖アルコール類が、マンニトール、キシリトールまたはエリスリトールである、[15]〜[17]のいずれか1に記載の方法;
[19]糖アルコール類がマンニトールである、[15]〜[18]のいずれか1に記載の方法;
[20]水膨潤性添加剤が、部分アルファー化デンプンまたは結晶セルロースである、[15]〜[19]のいずれか1に記載の方法;
[21]水膨潤性添加剤が、部分アルファー化デンプンである、[15]〜[20]のいずれか1に記載の方法;
[22]糖アルコール類がマンニトールであり、水膨潤性添加剤が部分アルファー化デンプンである、[19]または[21]のいずれか1に記載の方法;
[23]崩壊剤が、クロスポビドンまたはカルボキシメチルスターチナトリウムである、[15]〜[22]のいずれか1に記載の方法;
[24]崩壊剤が、クロスポビドンである、[15]〜[23]のいずれか1に記載の方法;
[25]結合剤が、ヒドロキシプロピルセルロースである、[15]〜[24]のいずれか1に記載の方法;
[26]造粒が、流動層造粒である、[15]〜[25]のいずれか1項に記載の方法;
[27](A)の成分が化合物Iaである、[15]〜[26]のいずれか1に記載の方法;
[28]得られた造粒物を乾燥させる工程を含む、[15]〜[27]のいずれか1に記載の方法;
[29]得られた造粒物を打錠する工程を含む、[15]〜[28]のいずれかに1に記載の方法;
[30]造粒工程の後にコーティング工程を含む、[15]〜[29]のいずれか1に記載の方法;
[31]コーティング剤が、セルロース誘導体およびポリビニル化合物からなる群から選択される1種以上のコーティング剤である、[15]〜[30]のいずれか1に記載の方法;
[32]コーティング剤が、ヒプロメロース、エチルセルロースおよびポリビニルアルコールからなる群から選択される1種以上のコーティング剤である、[15]〜[31]のいずれか1に記載の方法;
[33][15]〜[32]のいずれか1に記載の方法で得られる医薬組成物;
[34]パドル法毎分50回転で溶出試験を行なうとき、pH6.8の溶出試験液中における式(I)で表わされる化合物の平均溶出率が、溶出試験開始後30分で60%以上、かつ溶出試験開始後60分で70%以上であることを特徴とする[33]に記載の医薬組成物;
[35]パドル法毎分50回転で溶出試験を行なうとき、pH6.8の溶出試験液中における式(I)で表わされる化合物の平均溶出率が、溶出試験開始後30分で70%以上、かつ溶出試験開始後60分で80%以上であることを特徴とする[33]または[34]に記載の医薬組成物、
に関する。
N1−(5−クロロピリジン−2−イル)−N2−((1S,2R,4S)−4−[(ジメチルアミノ)カルボニル]−2−{[(5−メチル−4,5,6,7−テトラヒドロチアゾロ[5,4−c]ピリジン−2−イル)カルボニル]アミノ}シクロヘキシル)エタンジアミド;
N1−(5−クロロピリジン−2−イル)−N2−((1S,2R,4S)−4−[(ジメチルアミノ)カルボニル]−2−{[(5−メチル−4,5,6,7−テトラヒドロチアゾロ[5,4−c]ピリジン−2−イル)カルボニル]アミノ}シクロヘキシル)エタンジアミド 塩酸塩;
N1−(5−クロロピリジン−2−イル)−N2−((1S,2R,4S)−4−[(ジメチルアミノ)カルボニル]−2−{[(5−メチル−4,5,6,7−テトラヒドロチアゾロ[5,4−c]ピリジン−2−イル)カルボニル]アミノ}シクロヘキシル)エタンジアミド p−トルエンスルホン酸塩;および
下記の式(Ia)
(造粒)
表1に記載の条件下、1010gの化合物Ia、2480gの篩過したマンニトール(マンニットP、東和化成工業製)、1050gの部分アルファー化デンプン(PCS PC−10、旭化成ケミカルズ社製)、および267.5gのクロスポビドン(Polyplasdone INF−10、ISP社製)を、7w/v%のヒドロキシプロピルセルロース(HPC−L、日本曹達社製)水溶液2179mLを用い流動層造粒した。流動層造粒には、Fluidized−bed granulator(FLO−5、フロイント産業株式会社製)を用いた。
次に、上述したように造粒した造粒物を、それぞれ、乾燥後の造粒物の水分値が4.0%以上(表2のA−1、B−1)、2.0%以上4.0%未満(表2のA−2、B−2)または2.0%未満(表2のA−3、B−3)になるように、乾燥させた。
上述したように造粒し、乾燥させた各造粒物198.4gずつを1.6gのステアリン酸マグネシウム(HyQual Code 5712、タイコヘルスケア社製)と混合し、これらを単発打錠機で打錠(8.5mmφ、7R、錠厚4.2mm、200mg/錠)することにより、製錠を行なった。続いてこれらの各錠剤をパンコーティング機(ハイコーターミニ、フロイント社製)にてヒプロメロースを主成分としたコーティング剤(OPADRY(登録商標)03F42132)を12w/v%の懸濁液としてそれぞれコート量が10mgとなるようフィルムコーティングした。1錠当たりの各成分の量を以下の表3に示す。
造粒条件および乾燥条件を変化させたときの、各顆粒および各錠剤の物性を表4に示す。
造粒中の造粒物の最大水分値を変化させたときの、pH 6.8リン酸塩緩衝液における各錠剤からの化合物Iの溶出性を試験した。
20.2kgの化合物Ia、49.6kgの篩過したマンニトール(PEARITOL 50C、Roquette製)、21kgの部分アルファー化デンプン(PCS PC−10、旭化成ケミカルズ社製)、および5.35kgのクロスポビドン(Polyplasdone INF−10、ISP社製)を、7w/w%のヒドロキシプロピルセルロース(HPC−L、日本曹達社製)水溶液43.57kgを用い、流動層造粒した。流動層造粒には、WSG−120 ((株)パウレック社製)を用いた。吸気温度、スプレー液速およびスプレーエア流量は、それぞれ、造粒中の造粒物の最大水分値(%)が10%以下となるように、90℃、700g/分、750NL/分に設定した。
Claims (31)
- (A)下記の式(I)
で表される、N1−(5−クロロピリジン−2−イル)−N2−((1S,2R,4S)−4−[(ジメチルアミノ)カルボニル]−2−{[(5−メチル−4,5,6,7−テトラヒドロチアゾロ[5,4−c]ピリジン−2−イル)カルボニル]アミノ}シクロヘキシル)エタンジアミド、その薬学的に許容される塩またはそれらの溶媒和物、
(B)糖アルコール類および水膨潤性添加剤からなる群から選択される1以上の賦形剤、
(C)崩壊剤、および
(D)結合剤を、
造粒中の造粒物の最大水分値を10%以下に維持する条件下で造粒する工程
を包含する、式(I)で表される化合物、その薬学的に許容される塩またはそれらの溶媒和物を含有する造粒物の製造方法。 - 造粒中の造粒物の最大水分値が8%以下である、請求項1に記載の方法。
- 賦形剤として、少なくとも1以上の糖アルコール類および少なくとも1以上の水膨潤性添加剤を用いる、請求項1または2に記載の方法。
- 糖アルコール類が、マンニトール、キシリトールまたはエリスリトールである、請求項1〜3のいずれか1項に記載の方法。
- 糖アルコール類がマンニトールである、請求項1〜4のいずれか1項に記載の方法。
- 水膨潤性添加剤が、部分アルファー化デンプンまたは結晶セルロースである、請求項1〜5のいずれか1項に記載の方法。
- 水膨潤性添加剤が、部分アルファー化デンプンである、請求項1〜6のいずれか1項に記載の方法。
- 糖アルコール類がマンニトールであり、水膨潤性添加剤が部分アルファー化デンプンである、請求項5または7のいずれか1項に記載の方法。
- 崩壊剤が、クロスポビドンまたはカルボキシメチルスターチナトリウムである、請求項1〜8のいずれか1項に記載の方法。
- 崩壊剤が、クロスポビドンである、請求項1〜9のいずれか1項に記載の方法。
- 結合剤が、ヒドロキシプロピルセルロースである、請求項1〜10のいずれか1項に記載の方法。
- 造粒が、流動層造粒である、請求項1〜11のいずれか1項に記載の方法。
- (A)の成分が、下記の式(Ia)
で表されるN1−(5−クロロピリジン−2−イル)−N2−((1S,2R,4S)−4−[(ジメチルアミノ)カルボニル]−2−{[(5−メチル−4,5,6,7−テトラヒドロチアゾロ[5,4−c]ピリジン−2−イル)カルボニル]アミノ}シクロヘキシル)エタンジアミド p−トルエンスルホン酸塩 1水和物である、請求項1〜12のいずれか1項に記載の方法。 - (A)下記の式(I)
で表される、N1−(5−クロロピリジン−2−イル)−N2−((1S,2R,4S)−4−[(ジメチルアミノ)カルボニル]−2−{[(5−メチル−4,5,6,7−テトラヒドロチアゾロ[5,4−c]ピリジン−2−イル)カルボニル]アミノ}シクロヘキシル)エタンジアミド、その薬学的に許容される塩またはそれらの溶媒和物、
(B)糖アルコール類および水膨潤性添加剤からなる群から選択される1以上の賦形剤、
(C)崩壊剤、および
(D)結合剤を、
造粒中の造粒物の最大水分値を10%以下に維持する条件下で造粒する工程、
を包含する、式(I)で表される化合物、その薬学的に許容される塩またはそれらの溶媒和物を含有する医薬組成物の製造方法。 - 造粒中の造粒物の最大水分値が8%以下である、請求項14に記載の方法。
- 賦形剤として、糖アルコール類および水膨潤性添加剤を用いる、請求項14または15に記載の方法。
- 糖アルコール類が、マンニトール、キシリトールまたはエリスリトールである、請求項14〜16のいずれか1項に記載の方法。
- 糖アルコール類がマンニトールである、請求項14〜17のいずれか1項に記載の方法。
- 水膨潤性添加剤が、部分アルファー化デンプンまたは結晶セルロースである、請求項14〜18のいずれか1項に記載の方法。
- 水膨潤性添加剤が、部分アルファー化デンプンである、請求項14〜19のいずれか1項に記載の方法。
- 糖アルコール類がマンニトールであり、水膨潤性添加剤が部分アルファー化デンプンである、請求項18または20のいずれか1項に記載の方法。
- 崩壊剤が、クロスポビドンまたはカルボキシメチルスターチナトリウムである、請求項14〜21のいずれか1項に記載の方法。
- 崩壊剤が、クロスポビドンである、請求項14〜22のいずれか1項に記載の方法。
- 結合剤が、ヒドロキシプロピルセルロースである、請求項14〜23のいずれか1項に記載の方法。
- 造粒が、流動層造粒である、請求項14〜24のいずれか1項に記載の方法。
- (A)の成分が、下記の式(Ia)
で表されるN1−(5−クロロピリジン−2−イル)−N2−((1S,2R,4S)−4−[(ジメチルアミノ)カルボニル]−2−{[(5−メチル−4,5,6,7−テトラヒドロチアゾロ[5,4−c]ピリジン−2−イル)カルボニル]アミノ}シクロヘキシル)エタンジアミド p−トルエンスルホン酸塩 1水和物である、請求項14〜25のいずれか1項に記載の方法。 - 得られた造粒物を乾燥させる工程を含む、請求項14〜26のいずれか1項に記載の方法。
- 得られた造粒物を打錠する工程を含む、請求項14〜27のいずれか1項に記載の方法。
- 造粒工程の後にコーティング工程を含む、請求項14〜28のいずれか1項に記載の方法。
- コーティング剤が、セルロース誘導体およびポリビニル化合物からなる群から選択される1種以上のコーティング剤である、請求項29に記載の方法。
- コーティング剤が、ヒプロメロース、エチルセルロースおよびポリビニルアルコールからなる群から選択される1種以上のコーティング剤である、請求項29に記載の方法。
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EP2540317A4 (en) | 2010-02-22 | 2014-04-16 | Daiichi Sankyo Co Ltd | SOLID PREPARATION WITH DELAYED RELEASE FOR ORAL ADMINISTRATION |
ES2706880T3 (es) | 2010-02-22 | 2019-04-01 | Daiichi Sankyo Co Ltd | Preparación sólida de liberación sostenida para uso oral |
WO2011115067A1 (ja) | 2010-03-19 | 2011-09-22 | 第一三共株式会社 | 抗凝固剤の溶出改善方法 |
CN102058889A (zh) | 2010-11-05 | 2011-05-18 | 王定豪 | 包含抗凝血类药物的分散片及其应用 |
WO2013022059A1 (ja) | 2011-08-10 | 2013-02-14 | 第一三共株式会社 | ジアミン誘導体含有医薬組成物 |
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CA2793525C (en) | 2014-05-06 |
US9918975B2 (en) | 2018-03-20 |
US20130022683A1 (en) | 2013-01-24 |
CN102791271A (zh) | 2012-11-21 |
TW201139452A (en) | 2011-11-16 |
KR101792299B1 (ko) | 2017-10-31 |
BR112012023654B1 (pt) | 2022-04-12 |
JPWO2011115067A1 (ja) | 2013-06-27 |
CA2793525A1 (en) | 2011-09-22 |
EP2548556B1 (en) | 2016-08-10 |
EP2548556A4 (en) | 2014-07-16 |
CN102791271B (zh) | 2014-05-14 |
KR20130016224A (ko) | 2013-02-14 |
IL221946A (en) | 2017-03-30 |
ES2601884T3 (es) | 2017-02-16 |
HUE031059T2 (en) | 2017-06-28 |
EP2548556A1 (en) | 2013-01-23 |
BR112012023654A2 (pt) | 2020-11-24 |
TWI496787B (zh) | 2015-08-21 |
WO2011115067A1 (ja) | 2011-09-22 |
HK1180252A1 (zh) | 2013-10-18 |
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