JP5507447B2 - 微粒子中にソマトスタチン誘導体を含む持続放出組成物 - Google Patents
微粒子中にソマトスタチン誘導体を含む持続放出組成物 Download PDFInfo
- Publication number
- JP5507447B2 JP5507447B2 JP2010508860A JP2010508860A JP5507447B2 JP 5507447 B2 JP5507447 B2 JP 5507447B2 JP 2010508860 A JP2010508860 A JP 2010508860A JP 2010508860 A JP2010508860 A JP 2010508860A JP 5507447 B2 JP5507447 B2 JP 5507447B2
- Authority
- JP
- Japan
- Prior art keywords
- polymer
- glycolide
- microparticles
- weight
- pharmaceutical composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000011859 microparticle Substances 0.000 title claims description 70
- 239000000203 mixture Substances 0.000 title claims description 27
- 238000013268 sustained release Methods 0.000 title claims description 10
- 239000012730 sustained-release form Substances 0.000 title claims description 10
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical class C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 title description 4
- 229920000642 polymer Polymers 0.000 claims description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- 239000008194 pharmaceutical composition Substances 0.000 claims description 30
- 239000004480 active ingredient Substances 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000011159 matrix material Substances 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 15
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 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 claims description 10
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 10
- 229920002959 polymer blend Polymers 0.000 claims description 9
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 239000010419 fine particle Substances 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- 239000002562 thickening agent Substances 0.000 claims description 8
- 239000008103 glucose Substances 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 239000000080 wetting agent Substances 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 239000007951 isotonicity adjuster Substances 0.000 claims description 4
- 235000021317 phosphate Nutrition 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 239000012929 tonicity agent Substances 0.000 claims description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 239000008121 dextrose Substances 0.000 claims description 3
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 3
- 229920001993 poloxamer 188 Polymers 0.000 claims description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- 150000001447 alkali salts Chemical class 0.000 claims description 2
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- HSXBEUMRBMAVDP-QKXVGOHISA-N [(3s,6s,9s,12r,15s,18s,20r)-9-(4-aminobutyl)-3-benzyl-12-(1h-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-15-phenyl-6-[(4-phenylmethoxyphenyl)methyl]-1,4,7,10,13,16-hexazabicyclo[16.3.0]henicosan-20-yl] n-(2-aminoethyl)carbamate;4-[(3-carboxy-2-hydroxynaphtha Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1.C([C@H]1C(=O)N2C[C@@H](C[C@H]2C(=O)N[C@H](C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@H](C(N[C@@H](CC=2C=CC(OCC=3C=CC=CC=3)=CC=2)C(=O)N1)=O)CCCCN)C=1C=CC=CC=1)OC(=O)NCCN)C1=CC=CC=C1 HSXBEUMRBMAVDP-QKXVGOHISA-N 0.000 claims 3
- 229960002570 pasireotide pamoate Drugs 0.000 claims 3
- 239000006185 dispersion Substances 0.000 claims 1
- 239000000314 lubricant Substances 0.000 claims 1
- 229940126062 Compound A Drugs 0.000 description 51
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 51
- 239000002609 medium Substances 0.000 description 26
- 239000000243 solution Substances 0.000 description 20
- 241000283973 Oryctolagus cuniculus Species 0.000 description 16
- 239000003814 drug Substances 0.000 description 14
- 230000036470 plasma concentration Effects 0.000 description 14
- 238000011282 treatment Methods 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 12
- 229920000728 polyester Polymers 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- 229920002988 biodegradable polymer Polymers 0.000 description 10
- 239000004621 biodegradable polymer Substances 0.000 description 10
- 239000002245 particle Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 230000002744 anti-aggregatory effect Effects 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 8
- 150000003839 salts Chemical group 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 235000019322 gelatine Nutrition 0.000 description 6
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 6
- 108010010803 Gelatin Proteins 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 150000003077 polyols Chemical group 0.000 description 5
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 238000007922 dissolution test Methods 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010000599 Acromegaly Diseases 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 3
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 3
- 208000001344 Macular Edema Diseases 0.000 description 3
- 208000008589 Obesity Diseases 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 208000002458 carcinoid tumor Diseases 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 241000251468 Actinopterygii Species 0.000 description 2
- 208000023328 Basedow disease Diseases 0.000 description 2
- 208000014311 Cushing syndrome Diseases 0.000 description 2
- 206010058202 Cystoid macular oedema Diseases 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- 208000015023 Graves' disease Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 208000010067 Pituitary ACTH Hypersecretion Diseases 0.000 description 2
- 208000020627 Pituitary-dependent Cushing syndrome Diseases 0.000 description 2
- 206010038934 Retinopathy proliferative Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 201000010206 cystoid macular edema Diseases 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 208000030533 eye disease Diseases 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229920002689 polyvinyl acetate Polymers 0.000 description 2
- 239000011118 polyvinyl acetate Substances 0.000 description 2
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 208000019553 vascular disease Diseases 0.000 description 2
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 1
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 241000700112 Chinchilla Species 0.000 description 1
- 208000000668 Chronic Pancreatitis Diseases 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010012688 Diabetic retinal oedema Diseases 0.000 description 1
- 208000008279 Dumping Syndrome Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 208000000624 Esophageal and Gastric Varices Diseases 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 206010018404 Glucagonoma Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 206010062904 Hormone-refractory prostate cancer Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 229920002858 MOWIOL ® 4-88 Polymers 0.000 description 1
- 206010025415 Macular oedema Diseases 0.000 description 1
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 206010033647 Pancreatitis acute Diseases 0.000 description 1
- 206010033649 Pancreatitis chronic Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 208000032395 Post gastric surgery syndrome Diseases 0.000 description 1
- 229920003078 Povidone K 12 Polymers 0.000 description 1
- 229920003079 Povidone K 17 Polymers 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 108050001286 Somatostatin Receptor Proteins 0.000 description 1
- 102000011096 Somatostatin receptor Human genes 0.000 description 1
- 208000009311 VIPoma Diseases 0.000 description 1
- 206010056091 Varices oesophageal Diseases 0.000 description 1
- 208000024248 Vascular System injury Diseases 0.000 description 1
- 208000012339 Vascular injury Diseases 0.000 description 1
- 206010053648 Vascular occlusion Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- 206010064930 age-related macular degeneration Diseases 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 201000011190 diabetic macular edema Diseases 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- KDQPSPMLNJTZAL-UHFFFAOYSA-L disodium hydrogenphosphate dihydrate Chemical compound O.O.[Na+].[Na+].OP([O-])([O-])=O KDQPSPMLNJTZAL-UHFFFAOYSA-L 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 208000024170 esophageal varices Diseases 0.000 description 1
- 201000010120 esophageal varix Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 208000030304 gastrointestinal bleeding Diseases 0.000 description 1
- 239000003629 gastrointestinal hormone Substances 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 206010022498 insulinoma Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 208000003243 intestinal obstruction Diseases 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 238000013532 laser treatment Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 201000010230 macular retinal edema Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 201000011116 pancreatic cholera Diseases 0.000 description 1
- 208000021255 pancreatic insulinoma Diseases 0.000 description 1
- 108700017947 pasireotide Proteins 0.000 description 1
- VMZMNAABQBOLAK-DBILLSOUSA-N pasireotide Chemical compound C([C@H]1C(=O)N2C[C@@H](C[C@H]2C(=O)N[C@H](C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@H](C(N[C@@H](CC=2C=CC(OCC=3C=CC=CC=3)=CC=2)C(=O)N1)=O)CCCCN)C=1C=CC=CC=1)OC(=O)NCCN)C1=CC=CC=C1 VMZMNAABQBOLAK-DBILLSOUSA-N 0.000 description 1
- 229960005415 pasireotide Drugs 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 208000028591 pheochromocytoma Diseases 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
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 208000030761 polycystic kidney disease Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 208000021331 vascular occlusion disease Diseases 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/31—Somatostatins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
-
- 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
-
- 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
- A61P1/12—Antidiarrhoeals
-
- 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
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
- A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
-
- 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
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Immunology (AREA)
- Heart & Thoracic Surgery (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Neurosurgery (AREA)
- Oncology (AREA)
- Ophthalmology & Optometry (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Medicinal Preparation (AREA)
Description
一つの態様において、本発明は、1種以上の生物分解性ポリマーおよび活性成分としての化合物Aパモ酸塩を含むポリマーマトリックスを含む微粒子を含む持続放出用医薬組成物であって、ウサギにおいて4mg/kgの投与後最初の24時間以内の活性成分の最大血漿濃度(バースト)が15ng/ml、好ましくは12ng/mlまたは10ng/ml以下である医薬組成物を提供する。
好ましくは、微粒子の製造に使用する本発明の化合物は、非結晶粉末の形である。
典型的に、粒径が小さいほど、バーストおよび最初の拡散相中、例えば最初の20日間の放出が少ない。好ましくは、微粒子の製造に使用する本発明の化合物の粒子は、約0.1〜約15ミクロン、好ましくは約5ミクロン未満、さらに好ましくは約3ミクロン未満のサイズを有する。
このポリマーマトリックスは、全てのまたは実質的に全ての活性剤の放出後1〜6ヶ月以内に投与部位から運ばれるのに十分に分解するように設計する。
本ポリマーマトリックスは、微粒子の約40〜99重量%の総量で存在し得る。
(i)
(ia)ポリマーを14.24%〜17.45%、好ましくは15.0%〜16.5%、さらに好ましくは約15.9%(重量/重量)の濃度で塩化メチレンに溶解し、
そして所望により
− 多孔性作用剤(porosity-influencing agent)を工程(ia)で得た溶液に溶解/分散させるか、または
− 工程(ia)で得た溶液に塩基性塩を添加し、
− 工程(ia)により得た溶液に界面活性剤を添加し;
(ib)本発明の化合物を工程(ia)で得たポリマー溶液に懸濁させるか、または
本発明の化合物を工程(ia)で使用した溶媒と混和性の溶媒に溶解し、該溶液とポリマー溶液を混合するか、または
本発明の化合物をポリマー溶液に直接溶解させるか、または
水溶性塩の形の本発明の化合物を水相に溶解し、該水溶液とポリマー溶液(ia)を乳化させる
ことを含む、内部有機層の製造;
(ii)
(iia)pHを7−7.5に調節するための緩衝液、例えば酢酸またはリン酸緩衝液、例えばNa2HPO4およびKH2PO4を製造し、そして
(iib)工程(iia)で得られた溶液に安定剤を添加する
ことを含む、外部水相の製造;
(iii)内部有機相と外部水相の、例えば特定の高剪断力を有するデバイス、例えばタービンまたは静的ミキサーを用いた、または超音波の適用によるまたは超音波均質化による混合によるエマルジョンの形成;および
(iv)微粒子の溶媒蒸発または溶媒抽出による硬化、微粒子の、例えば水での洗浄、微粒子の回収および乾燥、例えば凍結乾燥または真空下の乾燥
を含む方法を適用する。
a)好ましくは約10,000〜約150,000Da、例えば約30,000Daの重量平均分子量を有する、ポリビニルアルコール(PVA)。本ポリビニルアルコールが、20℃で4%水溶液で測定して、またはDIN 53015により、約3〜約9mPa sの動的粘性を有する低粘性を有するのが好都合である。本ポリビニルアルコールはポリビニル酢酸の加水分解により得られ得るのが適切である。好ましくは、ポリビニル酢酸の含量は、ポリビニルアルコールの約10〜約90%である。加水分解の程度が約85〜約89%であるのが好都合である。典型的に、残りのアセチル含量は約10〜12%である。好ましい銘柄は、Clariant AG Switzerlandから入手可能なMowiol(登録商標) 4-88、8-88および18-88を含む。
好ましくは本ポリビニルアルコールは、外部水相の容積に対して約0.1〜約5重量%、例えば約0.5重量%の量で存在する;
好ましくは、HECおよび/またはHPCは、外部水相の容積の約0.01〜約5重量%、例えば約0.5重量%の総量で存在する;
好ましくは、本ゼラチンは、外部水相の容積の約0.01〜約5重量%、例えば約0.5重量%の量で存在する。
− 直鎖状ポリラクチド−コ−グリコリドポリマーと分枝鎖状ポリラクチド−コ−グリコリドポリマーの混合物を塩化メチレンに溶解し、
− このポリマー溶液を活性成分化合物Aパモ酸塩に添加し、
− リン酸塩類とポリビニルアルコールの水溶液を製造し、
− ポリマー/活性成分溶液とポリビニルアルコール/リン酸溶液を混合し、
− 塩化メチレンを蒸発させ、得られた微粒子を濾取する、
工程を含み、ここで、塩化メチレン中のポリマー混合物の重量は14.2〜17.5重量%である。
好ましくは、抗凝集剤は、微粒子の約0.1〜約10重量%、例えば約4重量%の量で存在する。
投与前に、本微粒子を注射に適切な媒体に懸濁させる。
増粘剤、例えばCMC−Naは、媒体(容積で)の約0.1〜約2%、例えば約0.7%または約1.75%の量で、例えば媒体中約1〜約30mg/ml、例えば約7mg/mlまたは約17.5mg/mlの濃度で存在してよい。
a)過剰のGH分泌および/または過剰のIGF−1を含むまたはそれに関連する病因を有する障害の予防または処置、例えば末端肥大症の処置ならびにI型またはII型真性糖尿病、特にその合併症、例えば血管障害、糖尿病性増殖性網膜症、糖尿病性黄斑浮腫、腎症、ニューロパシーおよび暁現象、およびインスリンまたはグルカゴン放出に関連する他の代謝障害、例えば肥満、例えば病的肥満または視床下部性または高インスリン性肥満の処置、
b)腸管皮膚および膵液(pancreaticocutaneous)瘻、過敏性腸症候群、炎症性疾患、例えばグレーブス病、炎症性腸疾患、乾癬またはリウマチ性関節炎、多嚢胞性腎臓疾患、ダンピング症候群、水様性下痢症候群、AIDS関連下痢、化学療法剤誘発下痢、急性または慢性膵炎および消化器ホルモン分泌性腫瘍(例えばGEP腫瘍、例えばビポーマ、グルカゴノーマ、インスリノーマ、カルチノイド等)、リンパ球悪性腫瘍、例えばリンパ腫または白血病、肝細胞癌腫ならびに消化器出血、例えば食道静脈瘤出血の処置、
c)炎症性眼疾患、黄斑浮腫、例えば嚢胞様黄斑浮腫、特発性嚢胞様黄斑浮腫、滲出性加齢黄斑変性症、脈絡膜新生血管関連障害および増殖性網膜症を含む、上記で示した血管形成、炎症性障害の予防または処置、
d)例えば臓器の移植、例えば心臓、肺、複合心臓−肺、肝臓、腎臓または膵臓移植における、移植片血管疾患、例えば同種または異種移植片脈管障害、例えば、移植片血管アテローム性動脈硬化症の予防または治療(combating)、または静脈移植片狭窄、例えばカテーテル化法または血管を掻き取る方法、例えば経皮経管的血管形成術、レーザー処置または血管内膜または内皮の完全性を破壊する他の侵襲製方法による、血管傷害後の再狭窄および/または血管閉塞の予防または処置、
e)ソマトスタチン受容体発現または蓄積腫瘍、例えば下垂体腫瘍、例えばクッシング病または症候群、胃腸膵臓、カルチノイド、中枢神経系、乳房、前立腺(進行性ホルモン難治性前立腺癌を含む)、卵巣または大腸腫瘍、小細胞肺癌、悪性腸閉塞、パラ神経膠腫、腎臓癌、皮膚癌、神経芽腫、褐色細胞腫、髄様甲状腺癌腫、骨髄腫、リンパ腫、ホジキンおよび非ホジキンリンパ腫、骨腫瘍およびその転移、ならびに自己免疫性または炎症性障害、例えばリウマチ性関節炎、グレーブス病または他の炎症性眼疾患の処置
に有用である。
本発明の微粒子および組成物の性質は、標準動物試験または臨床試験で試験し得る。
本発明の微粒子および組成物は十分許容性である。
本発明の組成物の適当な投与量は、当然、例えば処置する状態(例えば疾患タイプまたは耐性の性質)、使用する薬剤、望む効果および投与方式によって変わる。
次の実施例は、何等限定せずに本発明を説明するために提供する:
ポリマーを表1に示す一定量の塩化メチレンに溶解する。次いで、ポリマー溶液を化合物Aパモ酸塩に添加する。得られた懸濁液をUltra-Turraxで1分間処理する。
2lの水を90℃に加熱する。加温中、表1に示す量の2種のリン酸塩を交互に添加する。90℃で、表1に示す量のPVA 18-88を添加する。次いで得られた溶液を20℃に冷却し、水で必要量まで増やす。
ポリマー/薬剤懸濁液およびPVA/リン酸溶液を、3300upmの混合速度で90ml/分および1800ml/分の一定ポンプ比で混合し、塩化メチレンを、300分間に渡り2℃/20分で加熱する温度プログラムを使用して真空下で蒸発させる。続いて、微粒子を濾取し、水(WBU)で洗浄し、減圧下(0.1mbar)、室温で乾燥させる。
乾燥させた微粒子をバイアルに入れ、排気し、最終滅菌する。最終滅菌は、27.7〜34.1kGyの放射線量を適用するガンマ照射により行う。
表2に示す量のCMC−Na、マンニトールおよびPluronic F68を、約90℃の温度の約15mlの熱脱イオン化水に、マグネティック・スラーラーでの激しい撹拌下に溶解させる。得られた透明溶液を20℃に冷却し、脱イオン水で20.0mlに増やす。
ウサギ1kgあたり4mgの化合物Aに対応する量の実施例1および参考例の微粒子を、1mlの媒体組成物Dに懸濁させる。懸濁液を約30秒間振盪することにより均一化し、試験開始前に約3kgの重さのウサギ(雄チンチラ系雑種ウサギ、約7ヶ月齢)の左腓腹筋に、19G針を使用して注射する。
血液サンプル(約1ml)を55日間にわたり採取する。化合物Aの血漿濃度をELISA法を使用して測定する。投与後の化合物Aの平均濃度を表3に示す。平均AUC(0−55日)が、実施例1については287ng/ml dおよび参考例については227ng/ml dであることが判明する。
溶解試験を、37℃、80min-1(n=3)に設定したシェーカー浴で24時間行った。サンプルを、4x4cmのポリエステル袋に計り入れ、密封した。サンプル袋を50ml Schottビンに入れ、50mlの予熱した(37℃)媒体を添加した。
媒体を、例えば2.98gのリン酸水素二ナトリウム二水和物、8.0gの塩化ナトリウム、0.19gのリン酸二水素カリウム、0.01gの塩化ベンズアルコニウムおよび0.2gのtween 80を1000mlの水に溶解し、リン酸85%でpHを7.4に調節することにより製造した。
24時間後、媒体を吸引した。データは、個々の袋中のサンプル重量に対して標準化した。バーストは、アッセイ前測定値に対する放出薬剤のパーセントである薬剤含量%として測定でき、すなわち100mgの微粒子(MP)が25mgの化合物Aを含み、0.25mgの化合物Aが24時間後に放出されたら、これは、バーストが1%であることを意味する。
Claims (15)
- パシレオチドパモ酸塩をポリマー溶液に懸濁することにより生成される、直鎖状および分枝鎖状ポリラクチド−コ−グリコリドポリマーおよび活性成分としてのパシレオチドパモ酸塩を含むポリマーマトリックスを含む微粒子を含む持続放出用医薬組成物であって、該ポリマー溶液が塩化メチレンならびに該直鎖状および分枝鎖状ポリラクチド−コ−グリコリドポリマーのポリマー混合物を含み、塩化メチレン中のポリマー混合物の濃度が14.24%〜17.45%(ポリマー溶液重量あたりのポリマー重量)である、医薬組成物。
- ポリマーマトリックスが47,000〜63,000Daの重量平均分子量を有する直鎖状および分枝鎖状ポリラクチド−コ−グリコリドポリマーを含む、請求項1に記載の医薬組成物。
- 直鎖状ポリラクチド−コ−グリコリド対分枝鎖状ポリラクチド−コ−グリコリドの比が60:40〜40:60である、請求項1または2に記載の医薬組成物。
- 塩化メチレン中のポリマー混合物の濃度が15.9%(ポリマー溶液重量あたりのポリマー重量)である、請求項1〜3のいずれか一項に記載の医薬組成物。
- さらに界面活性剤、多孔性作用剤および/または塩基性塩を含む、請求項1〜4のいずれか一項に記載の医薬組成物。
- 請求項1〜5のいずれか一項に記載の医薬組成物および水ベースの媒体を含む、キット。
- 水ベースの媒体が潤剤、等張化剤および増粘剤を含む、請求項6に記載のキット。
- 湿潤剤がポロキサマーおよび/またはポリオキシエチレン−ソルビタン−脂肪酸エステルから選択される、請求項7に記載のキット。
- 等張化剤がマンニトール、塩化ナトリウム、グルコース、デキストロース、スクロースおよびグリセリンから選択される、請求項7に記載のキット。
- 増粘剤がカルボキシメチルセルロースナトリウム(CMC−Na)、ソルビトール、ポリビニルピロリドンおよびモノステアリン酸アルミニウムから選択される、請求項7に記載のキット。
- 水ベースの媒体がカルボキシメチルセルロースナトリウム、マンニトールおよびPluronic F68を含む、バイアルにおいて使用するための請求項6〜10のいずれか一項に記載のキット。
- 微粒子の製造方法であって、
− 直鎖状ポリラクチド−コ−グリコリドポリマーおよび分枝鎖状ポリラクチド−コ−グリコリドポリマーの混合物を塩化メチレンに溶解してポリマー溶液を得ること、
− このポリマー溶液を活性成分パシレオチドパモ酸塩に添加すること、
− リン酸塩類およびポリビニルアルコールの水性分散を製造すること、
− ポリマー/活性成分溶液とポリビニルアルコール/リン酸溶液を混合すること、
− 塩化メチレンを蒸発させ、得られた微粒子を濾取すること、
を含み、ここで、塩化メチレン中のポリマー混合物濃度が14.2〜17.5%(ポリマー溶液重量あたりのポリマー重量)である、方法。 - 塩化メチレン中のポリマー混合物の濃度が15.9%(ポリマー溶液重量あたりのポリマー重量)である、請求項12に記載の方法。
- 直鎖状および分枝鎖状ポリラクチド−コ−グリコリドポリマーが47,000〜63,000Daの重量平均分子量を有する、請求項12または13に記載の方法。
- 直鎖状ポリラクチド−コ−グリコリド対分枝鎖状ポリラクチド−コ−グリコリドの比が60:40〜40:60である、請求項12〜14のいずれか一項に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07108796 | 2007-05-24 | ||
EP07108796.9 | 2007-05-24 | ||
PCT/EP2008/056347 WO2008142153A1 (en) | 2007-05-24 | 2008-05-23 | An extended-release composition comprising a somatostatin derivative in microparticles |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2010527971A JP2010527971A (ja) | 2010-08-19 |
JP5507447B2 true JP5507447B2 (ja) | 2014-05-28 |
Family
ID=38222465
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010508860A Active JP5507447B2 (ja) | 2007-05-24 | 2008-05-23 | 微粒子中にソマトスタチン誘導体を含む持続放出組成物 |
Country Status (42)
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR057181A1 (es) * | 2005-11-30 | 2007-11-21 | Astra Ab | Nueva forma de dosificacion de combinacion |
US20120156304A1 (en) * | 2010-12-15 | 2012-06-21 | Thomas Tice | Branched polyol polyesters, blends, and pharmaceutical formulations comprising same |
HUE032310T2 (hu) | 2011-04-25 | 2017-09-28 | Shandong luye pharmaceutical co ltd | Nyújtott risperidon-leadású mikrogömb kompozíció |
TWI562991B (en) * | 2012-04-23 | 2016-12-21 | Otsuka Pharma Co Ltd | Dihydrate of benzothiophene compound or of a salt thereof, and process for producing the same |
US11672843B2 (en) * | 2012-05-25 | 2023-06-13 | Camurus Ab | Somatostatin receptor agonist formulations |
US10821200B2 (en) * | 2016-12-05 | 2020-11-03 | Hyalo Technologies, LLC | Method of sterilization of microparticles |
EP3339372A1 (en) * | 2016-12-22 | 2018-06-27 | Solvay SA | Glycolic acid polymer composition |
CN110870853B (zh) * | 2018-08-29 | 2020-12-11 | 深圳翰宇药业股份有限公司 | 缓释帕瑞肽微球及其制备方法 |
JP2022510454A (ja) * | 2018-12-04 | 2022-01-26 | バンダ・ファーマシューティカルズ・インコーポレイテッド | イロペリドンの持効性投与 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
CH656884A5 (de) | 1983-08-26 | 1986-07-31 | Sandoz Ag | Polyolester, deren herstellung und verwendung. |
US5538739A (en) | 1989-07-07 | 1996-07-23 | Sandoz Ltd. | Sustained release formulations of water soluble peptides |
CA2316052C (en) * | 1989-07-07 | 2008-09-02 | David Bodmer | Sustained release formulations of water soluble peptides |
PH30995A (en) | 1989-07-07 | 1997-12-23 | Novartis Inc | Sustained release formulations of water soluble peptides. |
FI106926B (fi) * | 1989-07-07 | 2001-05-15 | Novartis Ag | Menetelmä pitkäaikaisesti vapautuvan koostumuksen muodostamiseksi |
IE960308A1 (en) * | 1996-04-23 | 1997-11-05 | Kinerton Ltd | Sustained release ionic conjugate |
AU5678398A (en) * | 1997-01-29 | 1998-08-18 | Takeda Chemical Industries Ltd. | Sustained-release microspheres, their production and use |
EP1240896A3 (en) | 1998-07-23 | 2003-03-26 | Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. | Encapsulation of water soluble peptides |
GB0018891D0 (en) | 2000-08-01 | 2000-09-20 | Novartis Ag | Organic compounds |
GB0326602D0 (en) * | 2003-11-14 | 2003-12-17 | Novartis Ag | Organic compounds |
MY158342A (en) * | 2003-11-14 | 2016-09-30 | Novartis Ag | Pharmaceutical composition |
KR20060118504A (ko) * | 2003-11-25 | 2006-11-23 | 노파르티스 아게 | 소마토스타틴 유사체 치료법의 효능에 대한 바이오마커 |
-
2008
- 2008-05-22 PE PE2008000880A patent/PE20090387A1/es not_active Application Discontinuation
- 2008-05-22 AR ARP080102168A patent/AR066677A1/es not_active Application Discontinuation
- 2008-05-23 ME MEP-2009-331A patent/ME00955B/me unknown
- 2008-05-23 PA PA20088781501A patent/PA8781501A1/es unknown
- 2008-05-23 SI SI200832103T patent/SI2164473T1/sl unknown
- 2008-05-23 DK DK08759948.6T patent/DK2164473T3/da active
- 2008-05-23 HU HUE08759948A patent/HUE046490T2/hu unknown
- 2008-05-23 CL CL2008001509A patent/CL2008001509A1/es unknown
- 2008-05-23 US US12/600,740 patent/US20100178344A1/en not_active Abandoned
- 2008-05-23 GE GEAP200811569A patent/GEP20125582B/en unknown
- 2008-05-23 BR BRPI0811904-0A2A patent/BRPI0811904A2/pt not_active IP Right Cessation
- 2008-05-23 PL PL08759948T patent/PL2164473T3/pl unknown
- 2008-05-23 JP JP2010508860A patent/JP5507447B2/ja active Active
- 2008-05-23 KR KR1020157032784A patent/KR101930588B1/ko active IP Right Grant
- 2008-05-23 ES ES08759948T patent/ES2761227T3/es active Active
- 2008-05-23 CN CN200880016626.4A patent/CN101677965B/zh active Active
- 2008-05-23 EP EP19196299.2A patent/EP3666263A1/en not_active Withdrawn
- 2008-05-23 TW TW097119228A patent/TWI412373B/zh not_active IP Right Cessation
- 2008-05-23 UA UAA200912088A patent/UA97396C2/ru unknown
- 2008-05-23 EP EP08759948.6A patent/EP2164473B1/en active Active
- 2008-05-23 CA CA2683935A patent/CA2683935C/en active Active
- 2008-05-23 MX MX2009012536A patent/MX2009012536A/es active IP Right Grant
- 2008-05-23 AU AU2008252931A patent/AU2008252931B2/en active Active
- 2008-05-23 UY UY31103A patent/UY31103A1/es not_active Application Discontinuation
- 2008-05-23 EA EA200901523A patent/EA018203B1/ru not_active IP Right Cessation
- 2008-05-23 WO PCT/EP2008/056347 patent/WO2008142153A1/en active Application Filing
- 2008-05-23 KR KR1020097026865A patent/KR20100017904A/ko active Application Filing
- 2008-05-23 NZ NZ580589A patent/NZ580589A/en not_active IP Right Cessation
- 2008-05-23 PT PT87599486T patent/PT2164473T/pt unknown
- 2008-05-23 MY MYPI20094854A patent/MY148915A/en unknown
-
2009
- 2009-10-14 ZA ZA200907168A patent/ZA200907168B/xx unknown
- 2009-10-15 IL IL201571A patent/IL201571B/en active IP Right Grant
- 2009-10-23 CR CR11078A patent/CR11078A/es unknown
- 2009-10-29 TN TNP2009000447A patent/TN2009000447A1/fr unknown
- 2009-11-20 CU CU2009000200A patent/CU24028B1/es active IP Right Grant
- 2009-11-20 GT GT200900302A patent/GT200900302A/es unknown
- 2009-11-20 NI NI200900207A patent/NI200900207A/es unknown
- 2009-11-20 DO DO2009000262A patent/DOP2009000262A/es unknown
- 2009-11-23 HN HN2009003296A patent/HN2009003296A/es unknown
- 2009-11-24 SV SV2009003421A patent/SV2009003421A/es unknown
- 2009-12-11 EC EC2009009793A patent/ECSP099793A/es unknown
- 2009-12-14 MA MA32419A patent/MA31445B1/fr unknown
- 2009-12-22 CO CO09146673A patent/CO6241097A2/es active IP Right Grant
- 2009-12-23 SM SM200900099T patent/SMP200900099B/it unknown
-
2013
- 2013-01-17 US US13/743,385 patent/US9351923B2/en active Active
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5507447B2 (ja) | 微粒子中にソマトスタチン誘導体を含む持続放出組成物 | |
JP2015129145A (ja) | 医薬組成物 | |
RU2404749C2 (ru) | Микрочастицы, содержащие аналоги соматостатина | |
WO2011112576A1 (en) | Microspheres for sustained release of octreotide acetate | |
JP5721635B2 (ja) | 一定して高い曝露レベルを有するオクトレオチドのデポー製剤 | |
JP2015107985A (ja) | オクトレオチドおよび3種の線状ポリラクチド−コ−グリコリドポリマーを含む徐放性製剤 | |
AU2007263004A1 (en) | Sustained release formulations of aromatase inhibitors | |
WO2019079095A2 (en) | COMPOSITION AND PROCESS FOR PRODUCTION OF PROLONGED RELEASE PREPARATION OF RISPERIDONE |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20110517 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130205 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130502 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20130813 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20131213 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20140213 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20140311 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20140319 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5507447 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |