JP2536876B2 - Dissolvable powder formulation of cyclosporine - Google Patents
Dissolvable powder formulation of cyclosporineInfo
- Publication number
- JP2536876B2 JP2536876B2 JP62193129A JP19312987A JP2536876B2 JP 2536876 B2 JP2536876 B2 JP 2536876B2 JP 62193129 A JP62193129 A JP 62193129A JP 19312987 A JP19312987 A JP 19312987A JP 2536876 B2 JP2536876 B2 JP 2536876B2
- Authority
- JP
- Japan
- Prior art keywords
- organic solvent
- soluble
- pharmaceutically acceptable
- solid
- cyclosporins
- 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.)
- Expired - Lifetime
Links
- 229930182912 cyclosporin Natural products 0.000 title claims description 22
- 108010036949 Cyclosporine Proteins 0.000 title claims description 20
- 229960001265 ciclosporin Drugs 0.000 title claims description 20
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 title claims description 18
- 239000000203 mixture Substances 0.000 title claims description 16
- 239000000843 powder Substances 0.000 title claims description 16
- 238000009472 formulation Methods 0.000 title claims description 12
- 238000002360 preparation method Methods 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 20
- 239000000126 substance Substances 0.000 claims description 19
- 239000003960 organic solvent Substances 0.000 claims description 14
- 239000004094 surface-active agent Substances 0.000 claims description 14
- 108010036941 Cyclosporins Proteins 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 239000011872 intimate mixture Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000010298 pulverizing process Methods 0.000 claims description 2
- 239000008180 pharmaceutical surfactant Substances 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 229930105110 Cyclosporin A Natural products 0.000 description 13
- -1 cyclosporine compound Chemical class 0.000 description 9
- 239000008187 granular material Substances 0.000 description 8
- 239000002702 enteric coating Substances 0.000 description 5
- 238000009505 enteric coating Methods 0.000 description 5
- 210000002751 lymph Anatomy 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 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 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- GEUKOOCPPICVTB-SMOCYEBVSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s)-33-[(1r,2r)-1-hydroxy-2-methylhexyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21,30-tri(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32- Chemical compound CCCC[C@@H](C)[C@@H](O)C1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H](C(C)C)NC1=O GEUKOOCPPICVTB-SMOCYEBVSA-N 0.000 description 1
- JTOKYIBTLUQVQV-QRVTZXGZSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-[(1r)-1-hydroxyethyl]-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontan Chemical compound C\C=C\C[C@@H](C)[C@@H](O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H]([C@@H](C)O)NC1=O JTOKYIBTLUQVQV-QRVTZXGZSA-N 0.000 description 1
- UCOQITKXMNKTKF-MXGZYYNMSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28,30-decamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23 Chemical compound C\C=C\C[C@@H](C)[C@@H](O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H](C)NC1=O UCOQITKXMNKTKF-MXGZYYNMSA-N 0.000 description 1
- ZNVBEWJRWHNZMK-SYOLRUPNSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21,30-tri(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,2 Chemical compound C\C=C\C[C@@H](C)[C@@H](O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H](C(C)C)NC1=O ZNVBEWJRWHNZMK-SYOLRUPNSA-N 0.000 description 1
- ZMKGDQSIRSGUDJ-VSROPUKISA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-30-propyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,1 Chemical compound CCC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O ZMKGDQSIRSGUDJ-VSROPUKISA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- JTOKYIBTLUQVQV-UHFFFAOYSA-N Cyclosporin C Natural products CC=CCC(C)C(O)C1N(C)C(=O)C(C(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(C)NC(=O)C(C)NC(=O)C(CC(C)C)N(C)C(=O)C(C(C)C)NC(=O)C(CC(C)C)N(C)C(=O)CN(C)C(=O)C(C(C)O)NC1=O JTOKYIBTLUQVQV-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102100028675 DNA polymerase subunit gamma-2, mitochondrial Human genes 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 229920003139 Eudragit® L 100 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
- 101000837415 Homo sapiens DNA polymerase subunit gamma-2, mitochondrial Proteins 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- ZMKGDQSIRSGUDJ-UHFFFAOYSA-N NVa2 cyclosporine Natural products CCCC1NC(=O)C(C(O)C(C)CC=CC)N(C)C(=O)C(C(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(C)NC(=O)C(C)NC(=O)C(CC(C)C)N(C)C(=O)C(C(C)C)NC(=O)C(CC(C)C)N(C)C(=O)CN(C)C1=O ZMKGDQSIRSGUDJ-UHFFFAOYSA-N 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 241001149960 Tolypocladium inflatum Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 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
- 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 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000007931 coated granule Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 108010019248 cyclosporin C Proteins 0.000 description 1
- 108010019594 cyclosporin D Proteins 0.000 description 1
- 108010019249 cyclosporin G Proteins 0.000 description 1
- 108010040786 dihydrocyclosporin C Proteins 0.000 description 1
- 108010040781 dihydrocyclosporin D Proteins 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl 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
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
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- 235000008390 olive oil Nutrition 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- 230000005945 translocation Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
【発明の詳細な説明】 ［産業上の利用分野］ この発明は、油性製剤の形で供給されていたシクロス
ポリン類を、粉末状製剤の形で供給することを可能にす
るものである。DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention enables cyclosporins that have been supplied in the form of an oily preparation to be supplied in the form of a powdered preparation.
［従来の技術］ シクロスポリン類は、トリポクラジウム・インフラツ
ム（Tolypocladium inflatum）等の菌が生産する一群の
代謝物質である。そのうちシクロスポリンＡは、免疫抑
制剤として実用化されている。しかし、シクロスポリン
類は、水に不溶性であるため、通常用いられている製剤
の形で供給することができず、オリーブ油を基剤とする
油性製剤の形で供給されていた。しかし、油性製剤は、
保管、運搬、使用上著しく不便であるため、これらの欠
点を除いた製剤の開発が望まれていた。[Prior Art] Cyclosporins are a group of metabolites produced by bacteria such as Tolypocladium inflatum. Of these, cyclosporin A has been put to practical use as an immunosuppressant. However, since cyclosporins are insoluble in water, they cannot be supplied in the form of a commonly used formulation, and they have been supplied in the form of an oil-based formulation based on olive oil. However, the oil-based formulation
Since it is extremely inconvenient to store, transport, and use, it has been desired to develop a formulation that eliminates these drawbacks.
［発明の記載］ この発明者は、シクロスポリン類の粉末化製剤を目的
として鋭意研究の結果、有機溶媒に可溶性の界面活性剤
と有機溶媒に可溶性の固体を用いればシクロスポリンを
粉末化することができ、しかも得られた粉末化製剤は生
物学的利用能等の点でも使用に適するものであることを
見出し、この発明を完成したのである。[Description of the Invention] The present inventor has conducted extensive research as a powdered preparation of cyclosporins, and as a result, a cyclosporin can be powdered by using a surfactant soluble in an organic solvent and a solid soluble in the organic solvent. Moreover, they have found that the obtained powdered preparation is suitable for use in terms of bioavailability, and completed the present invention.
すなわち、この発明は、シクロスポリン類の少なくと
も１種と、医薬的に許容される有機溶媒可溶性界面活性
剤と、医薬的に許容される常温で固体の有機溶媒可溶性
物質との緊密混合物の粉末からなる、シクロスポリンの
溶解性粉末状製剤を提供するものである。That is, the present invention comprises a powder of an intimate mixture of at least one of cyclosporins, a pharmaceutically acceptable organic solvent-soluble surfactant, and a pharmaceutically acceptable organic solvent-soluble substance which is solid at room temperature. , A soluble powdered formulation of cyclosporine.
上記の製剤は、 （イ）有機溶媒に、シクロスポリン類の少なくとも１種
と、医薬的に許容される有機溶媒可溶性界面活性剤と、
医薬的に許容される常温で固体の有機溶媒可溶性物質と
を溶解し、ついで溶媒を蒸発させ、残留する固体を粉末
化すること、または （ロ）医薬的に許容される常温で固体の有機溶媒可溶性
物質を加熱溶融し、これにシクロスポリン類の少なくと
も１種と、医薬的に許容される有機溶媒可溶性界面活性
剤とを溶解し、冷却して固化させた後粉末化することに
より製造される。The above-mentioned preparation comprises (a) an organic solvent, at least one cyclosporine compound, and a pharmaceutically acceptable organic solvent-soluble surfactant.
A pharmaceutically acceptable organic solvent that is solid at room temperature and a soluble substance are dissolved, and then the solvent is evaporated to powder the remaining solid, or (b) a pharmaceutically acceptable organic solvent that is solid at room temperature. It is produced by heating and melting a soluble substance, dissolving at least one of cyclosporins and a pharmaceutically acceptable organic solvent-soluble surfactant, cooling and solidifying, and then pulverizing.
［定義］ この発明において、シクロスポリン類の語は、シクロ
スポリンＡ、シクロスポリンＢ、シクロスポリンＣ、ジ
ヒドロシクロスポリンＣ、シクロスポリンＤ、ジヒドロ
シクロスポリンＤ、シクロスポリンＧ、イソシクロスポ
リンＧ等、およびこれらの環状ポリペプチドを構成する
アミノ酸のいくつかをアミノ酸で置換し、除去し、また
は修飾したものを包含する。これらは、例えば特公昭56
−15235号、特開昭52−59180号、特開昭53−139789号、
特開昭55−55150号、特開昭61−43120号等に記載されて
いる。なお、上に示したのは例示であって完全なリスト
ではない。好ましいシクロスポリン類はシクロスポリン
Ａである。[Definition] In the present invention, the term cyclosporin constitutes cyclosporin A, cyclosporin B, cyclosporin C, dihydrocyclosporin C, cyclosporin D, dihydrocyclosporin D, cyclosporin G, isocyclosporin G, etc., and cyclic polypeptides thereof. It includes those in which some of the amino acids are replaced with amino acids, removed, or modified. These are, for example, Japanese Patent Publication Sho 56
-15235, JP-A-52-59180, JP-A-53-139789,
It is described in JP-A-55-55150, JP-A-61-43120 and the like. It should be noted that what is shown above is an example and not a complete list. A preferred cyclosporin is cyclosporin A.
有機溶媒可溶性の語は、その語の付された物質が有機
溶媒、好ましくは極性をもつ有機溶媒、さらに好ましく
は親水性有機溶媒、例えばメタノール、エタノール、ア
セトン、テトラヒドロフラン、ジオキサン、エトキシエ
タノール、ジメチルホルムアミド、エーテル、クロロホ
ルム等に溶解し得ることを意味する。The term organic solvent-soluble means that the substance to which the term is attached is an organic solvent, preferably a polar organic solvent, more preferably a hydrophilic organic solvent such as methanol, ethanol, acetone, tetrahydrofuran, dioxane, ethoxyethanol, dimethylformamide. It means that it can be dissolved in ether, chloroform or the like.
有機溶媒可溶性界面活性剤としては、イオン性（陰イ
オン性、陽イオン性、両性）界面活性剤（例えばアルキ
ルスルホネート、塩化ベンザルコニウム等）および非イ
オン性界面活性剤（例えば脂肪酸ソルビタンエステル、
ポリオキシエチレンアルキルエーテル、ポリオキシエチ
レンソルビタン脂肪酸エステル、ポリオキシエチレン硬
化ひまし油、脂肪酸アルカノールアミド等）が含まれ
る。非イオン性界面活性剤が好ましい。Organic solvent-soluble surfactants include ionic (anionic, cationic, amphoteric) surfactants (eg, alkyl sulfonate, benzalkonium chloride, etc.) and nonionic surfactants (eg, fatty acid sorbitan ester,
Polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, fatty acid alkanolamide, etc.) are included. Nonionic surfactants are preferred.
常温で固体の有機溶媒可溶性物質としては、有機溶媒
に可溶の製剤用賦形剤物質、例えば糖類（グルコース、
ソルビトール、麦芽糖等）、酸類（酒石酸、マロン酸、
マレイ酸、りんご酸、くえん酸、けいひ酸等）、中性物
質（尿素等）、重合体（分子量1000〜10000、好ましく
は2000〜8000のポリエチレングリコール、ポリビニルピ
ロリドン等）および腸溶性基剤（セルロースアセテート
フタレート、ヒドロキシプロピルメチルセルロースアセ
テートサクシネート、メタクリル酸エチルコポリマー
等）が含まれる。As an organic solvent-soluble substance that is solid at room temperature, a pharmaceutical excipient substance that is soluble in an organic solvent, for example, a saccharide (glucose,
Sorbitol, maltose, etc.), acids (tartaric acid, malonic acid,
Maleic acid, malic acid, citric acid, cinnamic acid, etc.), neutral substances (urea, etc.), polymers (polyethylene glycol, polyvinylpyrrolidone, etc., having a molecular weight of 10,000 to 10,000, preferably 2000 to 8,000) and enteric bases ( Cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, ethyl methacrylate copolymer, etc.) are included.
緊密混合物とは、２種以上の物質が例えば固溶体のよ
うに微細に混合分散したものであって、例えば肉眼的に
構成成分を識別し得ない混合物を意味する。The intimate mixture means a mixture in which two or more kinds of substances are finely mixed and dispersed, for example, as a solid solution, and the constituent components cannot be visually identified, for example.
［製造法］ 上記（イ）の方法によりこの発明の製剤を製造するに
は、まず、前述したような有機溶媒の１種または混合物
にシクロスポリン類の少なくとも１種を溶解し、さらに
医薬的に許容される有機溶媒可溶性界面活性剤と医薬的
に許容される常温で固体の有機溶媒可溶性物質とを溶解
する。溶解は攪拌下に行なうのが好ましく、また加温に
より促進することができる。ついで、得られた均質な溶
液から溶媒を蒸発させる。蒸発に際しては適宜減圧す
る。最後に、得られた固体を粉砕する。[Production Method] To produce the preparation of the present invention by the method (a) above, first, at least one cyclosporine compound is dissolved in one or a mixture of the above-mentioned organic solvents, and further pharmaceutically acceptable. The organic solvent-soluble surfactant and the pharmaceutically acceptable solid substance soluble in an organic solvent at room temperature are dissolved. The dissolution is preferably performed under stirring, and can be accelerated by heating. The solvent is then evaporated from the resulting homogeneous solution. When evaporating, the pressure is appropriately reduced. Finally, the solid obtained is ground.
上記（ロ）の方法によりこの発明の製剤を製造するに
は、まず医薬的に許容される常温で固体の有機溶媒可溶
性物質を加熱して溶融する。ついで、溶融物にシクロス
ポリン類の少なくとも１種および医薬的に許容される有
機溶媒可溶性界面活性剤を加えて、これらを溶解させ
る。放冷または強制冷却により冷却して溶融物を固化さ
せ、得られた固体を粉砕する。この方法は、医薬的に許
容される常温で固体の物質として重合体を用いる場合に
適用するのが好ましい。In order to produce the preparation of the present invention by the above method (b), first, a solid organic solvent-soluble substance is heated and melted at a pharmaceutically acceptable room temperature. Then, at least one of cyclosporins and a pharmaceutically acceptable organic solvent-soluble surfactant are added to the melt to dissolve them. The melt is solidified by cooling by standing cooling or forced cooling, and the solid obtained is ground. This method is preferably applied when the polymer is used as a pharmaceutically acceptable solid substance at room temperature.
なお、上記の各方法において、医薬的に許容される常
温で固体の物質として腸溶性基剤以外の物質を使用した
場合には、得られた粉末を顆粒化して腸溶被覆を施すこ
とが望ましい。粉末の顆粒化は常法にしたがって行なう
ことができる。例えば、粉末に少量の水、メタノール、
アセトン等の溶媒を加え、適当な孔径の網目を通して顆
粒化し、乾燥する。このとき、炭酸水素ナトリウムのよ
うな炭酸塩を混合すると、発泡性顆粒を作ることができ
る。発泡性顆粒は、例えば速放性を示す点が利点を有す
る。腸溶性被覆は、常法にしたがって、例えば腸溶性被
覆剤の有機溶媒（例えば含水アセトン）溶液を顆粒に噴
霧した後、乾燥することによって施すことができる。腸
溶性被覆剤としては、セルロースアセテートフタレー
ト、ヒドロキシプロピルメチルセルロース、フタレー
ト、カルボキシメチルエチルセルロース、メタクリル酸
メタクリルメチルコポリマー、HP55等が用いられる。In each of the above methods, when a substance other than an enteric base is used as a pharmaceutically acceptable solid substance at room temperature, it is desirable to granulate the obtained powder and apply an enteric coating. . Granulation of the powder can be performed according to a conventional method. For example, powder with a little water, methanol,
A solvent such as acetone is added, and the mixture is granulated through a mesh having an appropriate pore size and dried. At this time, effervescent granules can be prepared by mixing a carbonate such as sodium hydrogen carbonate. Effervescent granules have the advantage, for example, of exhibiting rapid release. The enteric coating can be carried out by a conventional method, for example, by spraying an organic solvent (for example, water-containing acetone) solution of the enteric coating agent on the granules and then drying. As the enteric coating agent, cellulose acetate phthalate, hydroxypropyl methyl cellulose, phthalate, carboxymethyl ethyl cellulose, methacryl methyl methacrylate copolymer, HP55 and the like are used.
そのほか、この発明の製剤には、色素、着香剤、安定
剤等の常用添加剤を加えることができる。In addition, conventional additives such as dyes, flavoring agents and stabilizers can be added to the preparation of the present invention.
また、上記のようにして製造した粉末または顆粒はカ
プセルまたは小袋に充填することができる。Further, the powder or granules produced as described above can be filled into capsules or sachets.
［実施例］ 以下、実施例によりこの発明をさらに詳細に説明す
る。[Examples] Hereinafter, the present invention will be described in more detail with reference to Examples.
実施例１〜13 シクロスポリンA100mgにメタノール10mlおよびアセト
ン0.5mlを加えて完全に溶解させる。これに、ポリオキ
シエチレン硬化ひまし油［HCO−60、界面活性剤（可溶
化剤）］の第１表に示す量を加え、マグネチックスター
ラー上で攪拌して溶かす。このとき、50℃程度に加温す
ると溶解が早くなる。最後に、第１表に示す固体物質を
加え、完全に溶解させる。溶液を乳鉢に移し、乾燥気流
下、約30℃で乳棒で攪拌しながら溶媒を留去する。デシ
ケータ内に減圧下で２〜５時間放置して完全に乾燥し、
乳棒で粉砕して粉末を得る。Examples 1 to 13 To 100 mg of cyclosporin A, 10 ml of methanol and 0.5 ml of acetone are added and completely dissolved. To this, the amount of polyoxyethylene hydrogenated castor oil [HCO-60, surfactant (solubilizing agent)] shown in Table 1 was added, and the mixture was stirred on a magnetic stirrer to dissolve. At this time, if it is heated to about 50 ° C, dissolution will be accelerated. Finally, the solid substances shown in Table 1 are added and completely dissolved. The solution is transferred to a mortar, and the solvent is distilled off while stirring with a pestle at about 30 ° C. in a dry air stream. Leave in a desiccator under reduced pressure for 2-5 hours to completely dry,
Grind with a pestle to obtain a powder.
実施例14 ポリエチレングリコール（4000）13.5×103mgを70℃
に加熱して溶融させ、これにシクロスポリンA100mgおよ
び界面活性剤（HCO−60）1500mgを加えて溶かし、充分
混合後冷却する。得られた固体を粉砕する。 Example 14 Polyethylene glycol (4000) 13.5 × 10 3 mg at 70 ° C.
It is heated to melt to add 100 mg of cyclosporin A and 1500 mg of a surfactant (HCO-60) to dissolve it, and after sufficiently mixing, cool. The solid obtained is ground.
実施例15 上記実施例１〜13で得られた粉末に少量の水：メタノ
ール（50:50）混合液を加えて混練する。これを、30メ
ッシュ（500μｍ）または18メッシュ（850μｍ）のスレ
ンテス製鋼に通して顆粒を得る。腸溶性被覆剤（HP−55
またはオイドラギットＬ−100）のアセトン（微量の水
を含む）溶液を回転ドラム内で顆粒に噴霧する。噴霧は
３〜６回（例えば５回）反復してピンホールを防ぐ。こ
れを乾燥して腸溶性顆粒を得る。Example 15 A small amount of water: methanol (50:50) mixed solution is added to the powders obtained in Examples 1 to 13 and kneaded. This is passed through 30 mesh (500 μm) or 18 mesh (850 μm) Slentes steel to obtain granules. Enteric coating (HP-55
Alternatively, a solution of Eudragit L-100) in acetone (comprising traces of water) is sprayed onto the granules in a rotating drum. The spraying is repeated 3-6 times (eg 5 times) to prevent pinholes. This is dried to obtain enteric coated granules.
実施例16 上記実施例１〜13で得られた粉末に、10分の１量（重
量比）の炭酸水素ナトリウムを加え、少量のメタノール
を加えて混練する。以下、実施例15と同様に処理して、
発泡性腸溶顆粒を得る。Example 16 To the powders obtained in Examples 1 to 13 described above, 1/10 amount (weight ratio) of sodium hydrogen carbonate was added, and a small amount of methanol was added and kneaded. Hereinafter, the same process as in Example 15 was performed,
Effervescent enteric granules are obtained.
試験例１ 体重400〜500gの雄性ウイスター系ラットに、実施例
１〜14で得た製剤および対照製剤（サンドイミユン、シ
クロスポリンＡの油性製剤）をシクロスポリンＡが7mg/
kgとなるように投与する。投与は、実施例１〜13の製剤
および対照製剤は十二指腸内へ、実施例14の製剤は胃内
へ行なう。投与に際しては、粉末製剤を内径0.4mm、外
径0.6mmのテフロン製管（長さ10cm）内に入れ、十二指
腸壁または胃壁に設けた5mmの切開部を通して投与部位
に挿入する。外径0.35mmのスレンレス棒で管の内容物を
投与部位へ押し出した後、0.5mlの生理食塩水で２回管
内を洗い込む。Test Example 1 Male Wistar rats weighing 400 to 500 g were treated with the preparations obtained in Examples 1 to 14 and the control preparations (sandimimiyun, an oily preparation of cyclosporin A) containing 7 mg / cyclosporin A.
Dosage to be kg. Administration is carried out intraduodenally for the formulations of Examples 1 to 13 and the control formulation, and intragastrically for the formulation of Example 14. At the time of administration, the powder preparation is placed in a Teflon tube (10 cm in length) having an inner diameter of 0.4 mm and an outer diameter of 0.6 mm, and inserted into the administration site through a 5 mm incision formed in the duodenal wall or the stomach wall. After pushing the contents of the tube to the administration site with a stainless steel rod having an outer diameter of 0.35 mm, wash the inside of the tube twice with 0.5 ml of physiological saline.
投与後６時間にわたり、頸動脈および胸管リンパ管か
ら血液およびリンパ液を採取し、血漿中濃度およびリン
パ液中濃度を測定する。結果は、第１〜10図に示す通り
である。また、リンパ液における６時間後の回収率を計
算し、第２表に示す結果を得た。Blood and lymph are collected from the carotid artery and thoracic duct lymph vessels for 6 hours after administration, and plasma and lymph concentrations are measured. The results are as shown in FIGS. Further, the recovery rate after 6 hours in lymph was calculated, and the results shown in Table 2 were obtained.
上記の結果から、この発明の製剤が血漿中濃度および
リンパ液移行性において充分使用に耐えるものであるこ
とがわかった。また、リンパ液移行性においては対照製
剤よりすぐれた結果を示すものが多く、このことは、シ
クロスポリンＡの薬理作用がヘルパーＴ細胞の特異的抑
制にあることから考えると大きな利点をもたらすもので
ある。 From the above results, it was found that the preparation of the present invention is well tolerated in terms of plasma concentration and lymphatic fluid transferability. In addition, many of them show superior results to lymphoid translocation than the control preparation, which brings a great advantage considering that the pharmacological action of cyclosporin A lies in the specific suppression of helper T cells.
第１図〜第10図は試験例１の結果を示し、そのうち第１
図は実施例１および２の製剤、第２図は実施例３〜６の
製剤、第３図は実施例７および14の製剤、第４図は実施
例８および９の製剤、第５図は実施例11〜13の製剤、第
６図は対照製剤を用いたときの血漿中シクロスポリンＡ
濃度を示す。また、第７図は実施例１、２、７、14の製
剤および対照製剤、第８図は実施例３〜６の製剤、第９
図は実施例８および９の製剤、第10図は実施例10〜13の
製剤を用いたときのリンパ液中シクロスポリンＡ濃度を
示す。1 to 10 show the results of Test Example 1, of which the first
The figures show the preparations of Examples 1 and 2, FIG. 2 shows the preparations of Examples 3 to 6, FIG. 3 shows the preparations of Examples 7 and 14, FIG. 4 shows the preparations of Examples 8 and 9, and FIG. Preparations of Examples 11 to 13, FIG. 6 shows cyclosporin A in plasma when a control preparation was used.
Indicates the concentration. Further, FIG. 7 shows the preparations of Examples 1, 2, 7, and 14 and the control preparation, and FIG. 8 shows the preparations of Examples 3 to 6, 9
The figure shows the concentrations of cyclosporin A in the lymph when the formulations of Examples 8 and 9 and FIG. 10 are used.
Claims (3)
薬的に許容される有機溶媒可溶性界面活性剤と、医薬的
に許容される常温で固体の有機溶媒可溶性物質との緊密
混合物の粉末からなる、シクロスポリンの溶解性粉末状
製剤。1. A powder of an intimate mixture of at least one of cyclosporins, a pharmaceutically acceptable organic solvent-soluble surfactant and a pharmaceutically acceptable organic solvent-soluble substance which is solid at room temperature. A soluble powder formulation of cyclosporine.
も１種と、医薬的に許容される有機溶媒可溶性界面活性
剤と、医薬的に許容される常温で固体の有機溶媒可溶性
物質とを溶解し、ついで溶媒を蒸発させ、残留する固体
を粉末化することからなる、シクロスポリン類の少なく
とも１種と、医薬的に許容される有機溶媒可溶性界面活
性剤と、医薬的に許容される常温で固体の有機溶媒可溶
性物質との緊密混合物の粉末からなる、シクロスポリン
の溶解性粉末状製剤の製法。2. At least one of cyclosporins, a pharmaceutically acceptable organic solvent-soluble surfactant, and a pharmaceutically acceptable organic solvent-soluble substance which is solid at room temperature are dissolved in an organic solvent, Then, the solvent is evaporated, and the remaining solid is pulverized, and at least one of cyclosporins, a pharmaceutically acceptable organic solvent-soluble surfactant, and a pharmaceutically acceptable organic solid at room temperature. A process for preparing a soluble powder formulation of cyclosporine, which consists of a powder in an intimate mixture with a solvent-soluble substance.
可溶性物質を加熱溶融し、これにシクロスポリン類の少
なくとも１種と、医薬的に許容される有機溶媒可溶性界
面活性剤とを溶解し、冷却して固化させた後粉末化する
ことからなる、シクロスポリン類の少なくとも１種と、
医薬的に許容される有機溶媒可溶性界面活性剤と、医薬
的に許容される常温で固体の有機溶媒可溶性物質との緊
密混合物の粉末からなる、シクロスポリンの溶解性粉末
状製剤の製法。3. A pharmaceutically acceptable solid substance soluble in an organic solvent at room temperature is heated and melted, and at least one of cyclosporins and a pharmaceutically acceptable surfactant soluble in an organic solvent are dissolved therein. At least one of cyclosporins, which comprises cooling and solidifying and then pulverizing,
A process for producing a soluble powdery preparation of cyclosporine, which comprises a powder of an intimate mixture of a pharmaceutically acceptable organic solvent-soluble surfactant and a pharmaceutically acceptable organic solvent-soluble substance which is solid at room temperature.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62193129A JP2536876B2 (en) | 1987-07-31 | 1987-07-31 | Dissolvable powder formulation of cyclosporine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62193129A JP2536876B2 (en) | 1987-07-31 | 1987-07-31 | Dissolvable powder formulation of cyclosporine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6438029A JPS6438029A (en) | 1989-02-08 |
| JP2536876B2 true JP2536876B2 (en) | 1996-09-25 |
Family
ID=16302750
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62193129A Expired - Lifetime JP2536876B2 (en) | 1987-07-31 | 1987-07-31 | Dissolvable powder formulation of cyclosporine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2536876B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005289825A (en) * | 2004-03-31 | 2005-10-20 | Meruku Hoei Kk | Cyclosporin preparation |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5756450A (en) * | 1987-09-15 | 1998-05-26 | Novartis Corporation | Water soluble monoesters as solubilisers for pharmacologically active compounds and pharmaceutical excipients and novel cyclosporin galenic forms |
| CH679277A5 (en) * | 1989-02-09 | 1992-01-31 | Sandoz Ag | |
| KR0146671B1 (en) * | 1994-02-25 | 1998-08-17 | 김충환 | Cyclosporin-containing powder composition |
| FR2722984B1 (en) * | 1994-07-26 | 1996-10-18 | Effik Lab | PROCESS FOR THE PREPARATION OF DRY PHARMACEUTICAL FORMS AND THE PHARMACEUTICAL COMPOSITIONS THUS PRODUCED |
| US5679566A (en) * | 1995-01-20 | 1997-10-21 | University Of Massachusetts Medical Center | Yeast NMD2 gene |
| JP4821042B2 (en) * | 2000-10-31 | 2011-11-24 | ソニー株式会社 | Data conversion apparatus, storage apparatus, protocol conversion apparatus, device control apparatus, recording / reproducing system, and recording / reproducing method |
| DE102007009243A1 (en) * | 2007-02-22 | 2008-09-18 | Evonik Röhm Gmbh | Pellets with a drug matrix and a polymer coating, and a method for producing the pellets |
| JP6242655B2 (en) * | 2013-10-29 | 2017-12-06 | リンテック株式会社 | Release method of functional substance, kit for releasing functional substance, and release composition |
| CN116879437B (en) * | 2023-07-11 | 2026-04-03 | 苏州欧康维视生物科技有限公司 | A method for detecting the in vitro release of ophthalmic implants |
| CN119367291B (en) * | 2024-10-31 | 2025-11-18 | 国家纳米科学中心 | A nanomicelle ophthalmic formulation, its preparation method and application |
-
1987
- 1987-07-31 JP JP62193129A patent/JP2536876B2/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005289825A (en) * | 2004-03-31 | 2005-10-20 | Meruku Hoei Kk | Cyclosporin preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6438029A (en) | 1989-02-08 |
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