JPS6213049B2 - - Google Patents
Info
- Publication number
- JPS6213049B2 JPS6213049B2 JP2445381A JP2445381A JPS6213049B2 JP S6213049 B2 JPS6213049 B2 JP S6213049B2 JP 2445381 A JP2445381 A JP 2445381A JP 2445381 A JP2445381 A JP 2445381A JP S6213049 B2 JPS6213049 B2 JP S6213049B2
- Authority
- JP
- Japan
- Prior art keywords
- ethyl cellulose
- polyvinyl acetate
- wall
- microcapsules
- solvent
- 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
Links
- 239000003094 microcapsule Substances 0.000 claims description 62
- 239000001856 Ethyl cellulose Substances 0.000 claims description 52
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 52
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 52
- 229920001249 ethyl cellulose Polymers 0.000 claims description 52
- 239000011118 polyvinyl acetate Substances 0.000 claims description 39
- 229920002689 polyvinyl acetate Polymers 0.000 claims description 39
- 239000011162 core material Substances 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 30
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 238000010438 heat treatment Methods 0.000 claims description 11
- 238000005191 phase separation Methods 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 239000012528 membrane Substances 0.000 claims description 8
- 230000002744 anti-aggregatory effect Effects 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 4
- 238000006116 polymerization reaction Methods 0.000 claims description 4
- 239000000411 inducer Substances 0.000 claims description 3
- 239000004094 surface-active agent Substances 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 13
- 239000002775 capsule Substances 0.000 description 12
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 10
- 239000006185 dispersion Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- UHSXRTHJCJGEKG-UQKRIMTDSA-N (1s)-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinolin-2-ium-6,7-diol;chloride Chemical compound Cl.COC1=C(OC)C(OC)=CC(C[C@H]2C3=CC(O)=C(O)C=C3CCN2)=C1 UHSXRTHJCJGEKG-UQKRIMTDSA-N 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 108010024636 Glutathione Proteins 0.000 description 6
- 229960003180 glutathione Drugs 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- -1 so for example Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 4
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 4
- 235000011130 ammonium sulphate Nutrition 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- HUTIVPWAVQGKQA-UHFFFAOYSA-N calcium;octadecyl 2-hydroxypropanoate Chemical compound [Ca].CCCCCCCCCCCCCCCCCCOC(=O)C(C)O HUTIVPWAVQGKQA-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- 239000004698 Polyethylene Substances 0.000 description 2
- 229920002367 Polyisobutene Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- FSRLGULMGJGKGI-BTJKTKAUSA-N Trimebutine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=CC=1C(CC)(N(C)C)COC(=O)C1=CC(OC)=C(OC)C(OC)=C1 FSRLGULMGJGKGI-BTJKTKAUSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 239000003006 anti-agglomeration agent Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000004205 dimethyl polysiloxane Substances 0.000 description 2
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229920002050 silicone resin Polymers 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000000273 veterinary drug Substances 0.000 description 2
- GXFZCDMWGMFGFL-KKXMJGKMSA-N (+)-Tubocurarine chloride hydrochloride Chemical compound [Cl-].[Cl-].C([C@H]1[N+](C)(C)CCC=2C=C(C(=C(OC3=CC=C(C=C3)C[C@H]3C=4C=C(C(=CC=4CC[NH+]3C)OC)O3)C=21)O)OC)C1=CC=C(O)C3=C1 GXFZCDMWGMFGFL-KKXMJGKMSA-N 0.000 description 1
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- QZNNVYOVQUKYSC-JEDNCBNOSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid;hydron;chloride Chemical compound Cl.OC(=O)[C@@H](N)CC1=CN=CN1 QZNNVYOVQUKYSC-JEDNCBNOSA-N 0.000 description 1
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 description 1
- JXXCENBLGFBQJM-UHFFFAOYSA-N (3-carboxy-2-hydroxypropyl)-trimethylazanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC(O)CC(O)=O JXXCENBLGFBQJM-UHFFFAOYSA-N 0.000 description 1
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 description 1
- XULIXFLCVXWHRF-UHFFFAOYSA-N 1,2,2,6,6-pentamethylpiperidine Chemical compound CN1C(C)(C)CCCC1(C)C XULIXFLCVXWHRF-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- CZWJCQXZZJHHRH-YCRXJPFRSA-N 2-[(1r,2r,3s,4r,5r,6s)-3-(diaminomethylideneamino)-4-[(2r,3r,4r,5s)-3-[(2s,3s,4s,5r,6s)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy-4-hydroxy-4-(hydroxymethyl)-5-methyloxolan-2-yl]oxy-2,5,6-trihydroxycyclohexyl]guanidine;sulfuric acid Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](CO)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](CO)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O CZWJCQXZZJHHRH-YCRXJPFRSA-N 0.000 description 1
- FEDJGPQLLNQAIY-UHFFFAOYSA-N 2-[(6-oxo-1h-pyridazin-3-yl)oxy]acetic acid Chemical compound OC(=O)COC=1C=CC(=O)NN=1 FEDJGPQLLNQAIY-UHFFFAOYSA-N 0.000 description 1
- SPCKHVPPRJWQRZ-UHFFFAOYSA-N 2-benzhydryloxy-n,n-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 SPCKHVPPRJWQRZ-UHFFFAOYSA-N 0.000 description 1
- QEPPAOXKZOTMPM-UHFFFAOYSA-N 3-(2-chloro-5-oxo-10-phenothiazinyl)-N,N-dimethyl-1-propanamine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3S(=O)C2=C1 QEPPAOXKZOTMPM-UHFFFAOYSA-N 0.000 description 1
- RYWSYCQQUDFMAU-UHFFFAOYSA-N Acetomenaphthone Chemical compound C1=CC=C2C(OC(=O)C)=CC(C)=C(OC(C)=O)C2=C1 RYWSYCQQUDFMAU-UHFFFAOYSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- RZZPDXZPRHQOCG-OJAKKHQRSA-M CDP-choline(1-) Chemical compound O[C@@H]1[C@H](O)[C@@H](COP([O-])(=O)OP([O-])(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 RZZPDXZPRHQOCG-OJAKKHQRSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- RGHNJXZEOKUKBD-QTBDOELSSA-N L-gulonic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O RGHNJXZEOKUKBD-QTBDOELSSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- VRAHPESAMYMDQI-UHFFFAOYSA-N Nicomol Chemical compound C1CCC(COC(=O)C=2C=NC=CC=2)(COC(=O)C=2C=NC=CC=2)C(O)C1(COC(=O)C=1C=NC=CC=1)COC(=O)C1=CC=CN=C1 VRAHPESAMYMDQI-UHFFFAOYSA-N 0.000 description 1
- 229930195708 Penicillin V Natural products 0.000 description 1
- AJOQSQHYDOFIOX-UHFFFAOYSA-N Pheneturide Chemical compound NC(=O)NC(=O)C(CC)C1=CC=CC=C1 AJOQSQHYDOFIOX-UHFFFAOYSA-N 0.000 description 1
- 239000005062 Polybutadiene Substances 0.000 description 1
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 1
- YDBYJHTYSHBBAU-YFKPBYRVSA-N S-methyl-L-methioninate Chemical compound C[S+](C)CC[C@H](N)C([O-])=O YDBYJHTYSHBBAU-YFKPBYRVSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- UHWVSEOVJBQKBE-UHFFFAOYSA-N Trimetazidine Chemical compound COC1=C(OC)C(OC)=CC=C1CN1CCNCC1 UHWVSEOVJBQKBE-UHFFFAOYSA-N 0.000 description 1
- HOBWAPHTEJGALG-JKCMADFCSA-N [(1r,5s)-8-methyl-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate;sulfate Chemical compound [O-]S([O-])(=O)=O.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1 HOBWAPHTEJGALG-JKCMADFCSA-N 0.000 description 1
- RVCSYOQWLPPAOA-CVPHZBIISA-M [(5s)-spiro[8-azoniabicyclo[3.2.1]octane-8,1'-azolidin-1-ium]-3-yl] 2-hydroxy-2,2-diphenylacetate;chloride Chemical compound [Cl-].[N+]12([C@H]3CCC2CC(C3)OC(=O)C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCC1 RVCSYOQWLPPAOA-CVPHZBIISA-M 0.000 description 1
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- 229960000571 acetazolamide Drugs 0.000 description 1
- 229960001466 acetohexamide Drugs 0.000 description 1
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 description 1
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- 230000008023 solidification Effects 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960000654 sulfafurazole Drugs 0.000 description 1
- QPPBRPIAZZHUNT-UHFFFAOYSA-N sulfamerazine Chemical compound CC1=CC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 QPPBRPIAZZHUNT-UHFFFAOYSA-N 0.000 description 1
- 229960002597 sulfamerazine Drugs 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 description 1
- 229960005105 terbutaline sulfate Drugs 0.000 description 1
- KFVSLSTULZVNPG-UHFFFAOYSA-N terbutaline sulfate Chemical compound [O-]S([O-])(=O)=O.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1 KFVSLSTULZVNPG-UHFFFAOYSA-N 0.000 description 1
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 229960000344 thiamine hydrochloride Drugs 0.000 description 1
- 235000019190 thiamine hydrochloride Nutrition 0.000 description 1
- 239000011747 thiamine hydrochloride Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229960005345 trimebutine Drugs 0.000 description 1
- 229960001177 trimetazidine Drugs 0.000 description 1
- 229960001530 trospium chloride Drugs 0.000 description 1
- 229960002655 tubocurarine chloride Drugs 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/20—After-treatment of capsule walls, e.g. hardening
- B01J13/22—Coating
Description
本発明はポリ酢酸ビニルとエチルセルロースの
二重壁膜からなる新規マイクロカプセルとその製
法に関する。
壁膜剤としてポリ酢酸ビニルを用い有機溶媒系
の相分離を利用してポリ酢酸ビニル壁膜を有する
マイクロカプセルの製造法はすでに知られている
(特公昭37−7730号、特公昭43−28699号)。しか
しながら、これらのポリ酢酸ビニル壁膜を有する
マイクロカプセルはポリ酢酸ビニル特有の粘着性
もしくは接着性を保持しているため、例えば製造
中一度生成したマイクロカプセルも加熱乾燥を行
なうとマイクロカプセルが互いに融合してかたま
る難点を有し、又、これを避けるため低温で乾燥
を行なうとマイクロカプセル中に多量の溶媒が残
留することとなる。あるいはかかるマイクロカプ
セルは室温で保存してもマイクロカプセルが互い
に融合して流動性を失ない、遂には大きな団塊を
形成し実用に供し得なくなる。
しかるに本発明者らはポリ酢酸ビニル壁膜を有
するマイクロカプセルの改良を目的として種々研
究を続けた結果、凝集防止剤としてエチルセルロ
ースを用いてポリ酢酸ビニル壁膜を形成させつい
で該ポリ酢酸ビニル壁膜上にさらにエチルセルロ
ースの壁膜を形成させれば、得られた二重壁膜を
有するマイクロカプセルは保存中もカプセルが互
いに融合せず、また流動性を失なわない等の優れ
た特性を有することを見出した。
かかる知見に基づく本発明は芯物質、ポリ酢酸
ビニルおよびエチルセルロースを構成成分とする
マイクロカプセルであつて、該カプセルの壁膜が
(ア) 芯物質をとり囲む前記ポリ酢酸ビニルよりな
る壁膜と
(イ) 該壁膜をとり囲む前記エチルセルロースより
なる壁膜と
の二重に構成されてなるマイクロカプセルおよび
その製法である。
本発明において用いられる芯物質としては医薬
化合物、動物薬、農薬、化粧品、食品等をいずれ
も用いることができ、これらは固体であつてもゲ
ル状物質であつてもよい。さらには泥状物質であ
つても使用することができる。これらの物質を芯
物質として用いるに際しその粒径には特に制限は
ないが一般的には概ね約20〜1000μ、とりわけ約
70〜500μの粒度のものを用いるのが好ましい。
本発明においてマイクロカプセル壁内層を形成
するポリ酢酸ビニルとしては重合度約20〜1000の
ものを用いるのが好ましく、とりわけ重合度約40
〜400のものが好ましい。ポリ酢酸ビニルの使用
量は芯物質に対し約0.05〜5倍量、とりわけ約
0.1〜1倍量が適当である。このポリ酢酸ビニル
の壁膜をとり囲んでカプセル壁外層を形成するエ
チルセルロースとしてはエトキシ含有率が約46.5
〜55%であつて粘度(本発明においてエチルセル
ロースの粘度はトルエン・エタノール(4:1)
混液にエチルセルロースを5%濃度となるよう溶
解し、該溶液の25℃における粘度として表わ
す。)約3〜500cPのものを用いるのが好まし
い。エチルセルロースの使用量は芯物質に対し約
0.05〜5倍量であるのが適当である。
上記本発明のマイクロカプセルは
(ア) 壁膜剤たるポリ酢酸ビニル、凝集防止剤たる
エチルセルロースを含有する溶液に芯物質を分
散せしめた後、該ポリ酢酸ビニルの相分離によ
つて芯物質上に壁膜を形成せしめ、
(イ) 該溶液から溶媒を留去し、ついでこの残液に
壁膜剤たるエチルセルロースと非溶媒を加えて
溶解し、
(ウ) 該エチルセルロースの相分離によつて芯物質
上のポリ酢酸ビニル壁膜上にさらにエチルセル
ロースの壁膜を形成せしめることにより製する
ことができる。
以下詳細に説明する。
(ア) まず、本発明におけるポリ酢酸ビニル及び凝
集防止剤たるエチルセルロース含有溶液は溶媒
にポリ酢酸ビニルおよびエチルセルロースを任
意の順序で加え、溶解させることにより調製す
ることができる。また凝集防止剤たるエチルセ
ルロースとしては、壁膜剤として用いるエチル
セルロースと同様のエトキシ含有率および粘度
を有するものをいずれも用いることができる。
さらに本発明のマイクロカプセルの調製に際
し、溶媒としては、前記芯物質を溶解せず、壁
膜剤たる前記ポリ酢酸ビニルおよび凝集防止剤
たるエチルセルロースを溶解し、かつ沸点が約
81℃以下である溶媒であればいずれも用いるこ
とができる。かかる溶媒としては例えばクロロ
ホルム、酢酸メチル、酢酸エチル、アセトン、
メチルエチルケトン、メタノール、ベンゼンが
あげられ、さらにはメチルアセトン〔酢酸メチ
ル、アセトン、メタノールを主として含有し、
木材の乾留によつて得られる。沸点50〜67℃〕
の如き混合溶媒であつても、又、これら溶媒に
前記条件を満たす範囲内でシクロヘキサンを混
合した混液であつても用いることができる。ポ
リ酢酸ビニルは溶液中の濃度が約0.1〜20W/
W%となるよう用いるのが好ましく、またエチ
ルセルロースの溶液中濃度は約0.1〜20W/W
%とするのが好ましい。ついでこの溶媒に前記
した如き芯物質を加えかくはんすることにより
芯物質分散液が得られる。
かくして得られた分散液に非溶媒を徐々に滴
下すれば相分離によつて芯物質上にポリ酢酸ビ
ニルが沈着しポリ酢酸ビニル壁膜が形成され
る。この相分離を生じさせるための非溶媒とし
ては上記溶媒と任意の割合で混和し、芯物質お
よびポリ酢酸ビニルを溶解せず、かつ前記溶媒
と任意の比率で混和するものであればいずれも
用いることができ、かかる条件を満たすものと
しては例えばシクロヘキサンがあげられる。非
溶媒は溶媒に対し約2〜5倍量使用するのが好
ましい。非溶媒の滴下が一定量以上になると、
相分離したポリ酢酸ビニルが芯物質上に沈着し
てゲル化し、さらに非溶媒の滴下を続けること
により壁膜が固化し安定化する。かくして生成
したポリ酢酸ビニル壁膜を有するマイクロカプ
セルは該壁膜がゲル化から固化に至る段階で液
中のエチルセルロースをカプセル壁膜表面に吸
着する。生成したマイクロカプセルはこのエチ
ルセルロースの吸着層によりカプセル相互の凝
集が効果的に阻止される。
(イ) ついで生成したポリ酢酸ビニルマイクロカプ
セルを含有する分散液からの溶媒の留去は加熱
下に行なうのが好ましく、非溶媒と溶媒との沸
点の差あるいは両者の共沸を利用して溶媒を系
外へ留去する。溶媒の留去は溶媒の種類によつ
ても若干差があるが、溶媒の残存量が非溶媒の
0.1倍量以下となるまで行なうのが好ましい。
ついで溶媒留去後の残液にエチルセルロースお
よび非溶媒を任意の順序で加えて溶解させる。
エチルセルロースは非溶媒を加えた後の溶液中
の濃度が約0.5〜10W/W%、とりわけ約1〜
5W/W%となるよう用いるのが好ましい。
又、用いるエチルセルロース量を増減すること
により得られるマイクロカプセル壁膜の厚さを
変化させることができ、芯物質の放出を制御し
得る。又、非溶媒は留去した溶媒量に対し0.1
〜4倍量、とりわけ同量用いるのが好ましい。
上記エチルセルロースは加熱して溶解させるの
が好ましく、例えば約67〜80℃、とりわけ約70
〜78℃でかく拌することによりエチルセルロー
スは容易に溶解する。又、本発明のマイクロカ
プセルの調製に際しそは壁膜剤たるエチルセル
ロースと共に、壁膜形成助剤、相分離誘起剤、
又は界面活性剤を適宜用いることができる。こ
の場合壁膜形成助剤としては例えばジメチルポ
リシロキサン、メチルフエニルポリシロキサン
および二酸化ケイ素を1〜20%配合したジメチ
ルポリシロキサン、相分離誘起剤としては例え
ばポリエチレン、ブチルゴム、ポリイソブチレ
ン、ポリブタジエン、界面活性剤としては例え
ばソルビタン脂肪酸エステル、グリセリン脂肪
酸エステル、大豆リン脂質、ステアリル乳酸カ
ルシウム等を用いることができる。これらの添
加はエチルセルロースを溶解させる際に共に加
えればよく、添加量は溶液中の濃度が壁膜形成
助剤は約0.01〜20%、相分離誘起剤は約0.2〜
10%、界面活性剤は約0.001〜10%となるよう
用いるのが好ましい。
(ウ) 上記(イ)で得られた分散液からのエチルセルロ
ースの相分離は例えば上記分散液を毎分約0.05
〜4℃の速度で冷却することにより実施するの
が好ましい。更に冷却を続けることによつてポ
リ酢酸ビニル上に沈着したエチルセルロースが
固化され安定化する。この場合、冷却は約40℃
以下に至るまで行なうのが適当である。
かくして生成したマイクロカプセルの分離は通
常の分離方法によつて実施できる。例えばデカン
テーシヨン、ろ過、遠心分離等が採用でき、これ
らいずれの方法によつてもカプセルが互に付着し
たり凝集したりすることは殆んどない。
ついで得られたマイクロカプセルを例えばシク
ロヘキサン、n−ヘキサン、石油エーテル等で洗
浄し常法により乾燥することによつて保存・流動
性にすぐれたマイクロカプセルを得ることができ
る。当該マイクロカプセルの乾燥は約40〜170℃
の範囲で一般的に実施できるが、とりわけ約60〜
120℃で加熱乾燥するのが好ましい。即ち約60〜
120℃で加熱乾燥すればマイクロカプセル壁膜内
層を構成するポリ酢酸ビニルが流動変形を生じカ
プセル壁膜がより緻密になるというとりわけ好ま
しい効果が得られる。
なお上記本発明のマイクロカプセルは医薬品に
限らず動物薬、農薬、化粧品、食品、印刷用イン
キなど種々の物質に広く適用できる。本発明のマ
イクロカプセル及びその製法を適用し得る医薬品
を具体的に列挙すれば、例えばアスコルビン酸、
塩酸チアミン、塩酸ピリドキシン、パントテン酸
カルシウム、メチルメチオニン・スルホニウム・
クロリドのようなビタミン類;アスパラギン酸カ
リウム、アスパラギン酸マグネシウム、グルタチ
オン、グルタミン酸ナトリウムの如きアミノ酸又
はペプチド;スルフアミン、スルフアジアジン、
スルフアメラジン、スルフイソキサゾール、パラ
アミノサリチル酸カルシウム、イソニアジドグル
クロン酸ナトリウムの如き化学療法剤;フエノキ
シメチルペニシリン、プロピシリンカリウム、ス
ルベニシリンナトリウム、硫酸ジヒドロストレプ
トマイシン、硫酸フラジオマイシン、塩酸テトラ
サイクリン、コハク酸クロラムフエニコールナト
リウムの如き抗生物質;塩酸トリメトキノール、
硫酸サルブタモール、硫酸テルブタリン、塩酸ク
ロルプレナリンの如き呼吸促進・鎮咳去たん剤、
シタラビン、メソトレキセート、塩酸ブレオマイ
シン、フルオロウラシルの如き抗悪性腫瘍剤、臭
化チメピジウム(化学名;1,1−ジメチル−5
−メトキシ−3−(ジチエン−2−イル−メチレ
ン)ピペリジウムブロミド)、塩化トロスピウム
(化学名;8−ベンジロイル−オキシ−6.10−エ
タノ−5−アゾナスピロ〔4.5〕デカンクロリ
ド)の如き自律神経用薬剤;炭酸リチウム、シチ
コリン、γ−アミノ酪酸、ホパンテン酸カルシウ
ム(化学名;D−(+)−4−(2.4−ジヒドロキシ
−3.3−ジメチルブチラミン)酪酸カルシウム.
1/2水和物)、クロルプロマジンスルフオキサイ
ド、ペラジン、チオピロペラジンの如き精神神経
用薬剤;塩酸プロカイン、塩酸リドカイン、塩酸
タナカイン(化学名;2−メチル−2−n−プロ
ピルアミノプロピオン−0−トルイジン塩酸
塩)、塩化ツボクラリンの如き局所麻酔剤・筋弛
緩剤;ケイ酸マグネシウム、沈降炭酸カルシウ
ム、メトクロプラミド、タンニン酸ベルベリン、
塩酸ヒスチジン、マレイン酸トリメブチン(化学
名;1−(3,4,5−トリメトキシベンゾイル
オキシ)−2−ジメチルアミノ−2−フエニルブ
タンマレイン酸塩)、DL−塩化カルニチンの如き
消化器官用薬剤;タンニン酸ジフエンヒドラミ
ン、塩酸プロメタジン、ホモクロルシクリジンの
如き抗ヒスタミン剤;硫酸アトロピン、チオ硫酸
ナトリウム、炭酸水素ナトリウム、カルシウムソ
ジウムエデテート、D−ペニシラミンの如き中毒
治療剤;アモバルビタールナトリウム、シクロバ
ルビタールカルシウム、フエノバルビタールナト
リウム、ペントバルビタールカルシウムの如き催
眠鎮静剤;エチルフエナセミド、アセタゾラミド
の如き抗てんかん剤;イミプラミン、アスピリン
アルミニウムの如き解熱鎮痛消炎剤;ジゴキシ
ン、テオサリシン(テオブロミンカルシウムとサ
リチル酸カルシウムの等モルからなる複塩または
錯塩)、アミノフイリン、塩酸ブプラノロールの
如き強心剤・不整脈治療剤;ペントリウム、ペン
ピジン、硫酸ベタニジン(N−ベンジル−N′,
N″−ジメチルグアニジン硫酸塩)、メチルドー
パ、酒石酸カリウムナトリウム、塩化カリウムの
如き降圧利尿剤;イトラミントシレート、トリメ
タジジン二塩基酸塩、塩酸ジルチアゼム(化学
名;d−3−アセトキシ−シス−2,3−ジヒド
ロ−5−〔2−(ジメチルアミノ)エチル〕−2−
(p−メトキシフエニル)−1,5−ベンゾチアゼ
ピン−4(5H)−オン・塩酸塩)、シンナリジン
の如き血管拡張剤、ニコモール、デキストロチロ
キシン、アルミニウムニコチネートの如き動脈硬
化治療剤;塩化カルシウム、リン酸水素カルシウ
ム、グロン酸第一鉄、デキストラン鉄、ビスヒド
ロキシクマリンのような滋養強壮変質剤・抗凝血
剤;アセトメナフトン、グルコン酸カルシウム、
カルバゾクロムスルホン酸ナトリウムの如き止血
剤;オロチン酸、プロトポルフイリンナトリウム
の如き肝臓用薬剤;アセトヘキサミド、グリピザ
イド、塩酸フエンフオルミンの如き糖尿病治療
剤;リン酸コデイン、酒石酸レボルフアノールの
ような麻薬およびアデノシン、アロプリノール、
イノシンなどをあげることができる。
上記方法により得られた本発明のマイクロカプ
セルは(1)壁膜外層がエチルセルロースであるため
室温で保存してもマイクロカプセルが相互に凝集
することがなく自由流動性に富む;(2)二重壁膜を
形成しているため芯物質の保護にすぐれ、放出制
御が容易となる、等の優れた特徴を有する。また
これに加えて加熱乾燥を経たマイクロカプセルは
カプセル壁膜内層を形成するポリ酢酸ビニルが流
動変形を起こし外層のエチルセルロース壁膜の細
孔や亀裂部分を閉塞・修復するのでカプセル壁膜
がさらに緻密で強じんなものとなり、そのため(3)
芯物質の保護にすぐれ、かつさらに溶出制御が容
易となると共に、(4)従来のマイクロカプセルに比
べてもより一層カプセル壁膜を薄くすることがで
き、結果としてマイクロカプセル中の芯物質含量
を増加させ得るのでコストダウンをはかることも
できる。等のすぐれた効果を有する。
以下、本発明を実験例、実施例によりさらに詳
細に説明する。
実験例 1
臭化チメピジウム含有マイクロカプセルを調製
しマイクロカプセルの収率、カプセル中の臭化チ
メピジウム含量、服用時の苦味感および崩壊試験
第1液における臭化チメピジウムの溶出率を経時
的に測定し本発明の効果を比較した。
実験方法
(1) 芯物質
粒径74〜149μの臭化チメピジウムを芯物質
として用いた。
(2) マイクロカプセルの調製
(本発明のマイクロカプセル)
ポリ酢酸ビニルとエチルセルロース(凝集防
止止剤;エトキシ含有率48.5%粘度45cP)15g
をアセトン500mlに溶解し、ついでこの溶液に
芯物質150gを分散させる。ついでこの分散液
を約400r.p.mでかく拌しながら3000mlのシク
ロヘキサンを徐々に加える。生成したマイクロ
カプセル分散液を加熱して共沸点52〜58℃の共
沸混合物約700mlを留去した後シクロヘキサン
700ml、ステアリル乳酸カルシウム(化学名;
カルシウムステアリル−2−ラクチレート)15
g、第四版食品添加物公定書の基準に適合した
シリコーン樹脂90gおよびエチルセルロースを
加え78℃で加熱溶解する。生成したマイクロカ
プセルを分散しn−ヘキサンで洗浄した後105
℃にて加熱乾燥する。得られたマイクロカプセ
ルを目開き350μのJIS標準ふるいで篩過し標準
ふるいを通過せるものを集めることにより第九
改正日本薬局方の散剤基準に適合した臭化チメ
ピジウム含有マイクロカプセルを得る。
(対照群マイクロカプセル)
上記と同様にエチルセルロース(凝集防止
剤、上記と同じもの)15gをアセトン500mlに
溶解し、芯物質150gを分散させる。ついでこ
の分散液に3000mlのシクロヘキサンを加えた
後、52〜58℃の共沸混合物約700mlを留去す
る。残液にシクロヘキサン700ml、ステアリル
乳酸カルシウム15gシリコーン樹脂90gおよび
エチルセルロースを加え76℃で加熱溶解する。
以下上記と同様に実施することにより対照マイ
クロカプセル(iii)および(iv)を得る。
(3) 結果
結果は下記第1表に示す通りである。尚、臭
化チメピジウムの溶出率の比較は後記第1図で
示した
The present invention relates to a new microcapsule consisting of a double-walled membrane of polyvinyl acetate and ethylcellulose, and a method for producing the same. A method for producing microcapsules having a polyvinyl acetate wall using polyvinyl acetate as a wall agent and utilizing organic solvent-based phase separation is already known (Japanese Patent Publication No. 7730/1973, Japanese Patent Publication No. 7730/1983, Japanese Patent Publication No. 28699/1989). issue). However, these microcapsules with polyvinyl acetate wall membranes retain the stickiness or adhesion characteristic of polyvinyl acetate, so for example, microcapsules that have been formed during manufacturing can fuse with each other when heated and dried. In addition, if drying is carried out at a low temperature to avoid this problem, a large amount of solvent will remain in the microcapsules. Alternatively, even if such microcapsules are stored at room temperature, the microcapsules fuse with each other and do not lose their fluidity, eventually forming large lumps and becoming unusable for practical use. However, as a result of various studies aimed at improving microcapsules having a polyvinyl acetate wall, the inventors of the present invention formed a polyvinyl acetate wall using ethyl cellulose as an anti-aggregation agent. If an ethyl cellulose wall film is further formed on top of the microcapsules, the resulting double-walled microcapsules have excellent properties such as the capsules do not fuse with each other and do not lose fluidity even during storage. I found out. Based on this knowledge, the present invention provides a microcapsule comprising a core material, polyvinyl acetate, and ethyl cellulose as constituent components, wherein the wall film of the capsule comprises (a) a wall film made of the polyvinyl acetate surrounding the core material; b) A microcapsule having a double structure with a wall membrane made of ethylcellulose surrounding the wall membrane, and a method for producing the same. As the core substance used in the present invention, any of pharmaceutical compounds, veterinary drugs, agricultural chemicals, cosmetics, foods, etc. can be used, and these may be solid or gel-like substances. Furthermore, even muddy substances can be used. When using these materials as core materials, there is no particular restriction on the particle size, but generally it is about 20 to 1000μ, especially about
Preferably, particles with a particle size of 70 to 500 microns are used. In the present invention, polyvinyl acetate forming the inner layer of the microcapsule wall preferably has a polymerization degree of about 20 to 1000, particularly about 40 to 1000.
~400 is preferred. The amount of polyvinyl acetate used is approximately 0.05 to 5 times the amount of the core material, especially approximately
0.1 to 1 times the amount is appropriate. The ethyl cellulose that surrounds this polyvinyl acetate wall to form the outer layer of the capsule wall has an ethoxy content of approximately 46.5
~55% and viscosity (in the present invention, the viscosity of ethylcellulose is toluene/ethanol (4:1)
Ethyl cellulose was dissolved in the mixed solution to a concentration of 5%, and the viscosity of the solution was expressed as the viscosity at 25°C. ) It is preferable to use one with a value of about 3 to 500 cP. The amount of ethyl cellulose used is approximately
A suitable amount is 0.05 to 5 times. The above microcapsules of the present invention are produced by (a) dispersing a core material in a solution containing polyvinyl acetate as a wall agent and ethyl cellulose as an anti-aggregation agent, and then dispersing the core material onto the core material by phase separation of the polyvinyl acetate. Forming a wall film, (a) distilling off the solvent from the solution, then adding and dissolving ethyl cellulose as a wall film agent and a non-solvent to the remaining liquid, and (c) forming a core material by phase separation of the ethyl cellulose. It can be manufactured by further forming an ethyl cellulose wall on the polyvinyl acetate wall. This will be explained in detail below. (A) First, a solution containing polyvinyl acetate and ethyl cellulose as an anti-aggregation agent in the present invention can be prepared by adding polyvinyl acetate and ethyl cellulose to a solvent in any order and dissolving them. Moreover, as the ethyl cellulose which is an anti-aggregation agent, any material having the same ethoxy content and viscosity as the ethyl cellulose used as a wall film agent can be used.
Furthermore, when preparing the microcapsules of the present invention, the solvent should not dissolve the core material, but dissolve the polyvinyl acetate as the wall agent and the ethyl cellulose as the agglomeration inhibitor, and have a boiling point of about
Any solvent can be used as long as it has a temperature of 81°C or less. Such solvents include, for example, chloroform, methyl acetate, ethyl acetate, acetone,
Examples include methyl ethyl ketone, methanol, and benzene, and methyl acetone [mainly containing methyl acetate, acetone, and methanol;
Obtained by carbonization of wood. Boiling point 50-67℃〕
It is possible to use a mixed solvent such as, or a mixture of these solvents and cyclohexane within a range that satisfies the above conditions. The concentration of polyvinyl acetate in solution is approximately 0.1 to 20W/
It is preferable to use the ethyl cellulose so that the concentration is approximately 0.1 to 20 W/W.
% is preferable. Next, a core material dispersion liquid is obtained by adding the above-mentioned core material to this solvent and stirring. When a non-solvent is gradually added dropwise to the dispersion thus obtained, polyvinyl acetate is deposited on the core material through phase separation to form a polyvinyl acetate wall film. As the non-solvent for causing this phase separation, any non-solvent can be used as long as it is miscible with the above solvent in any proportion, does not dissolve the core material and polyvinyl acetate, and is miscible with the above solvent in any proportion. An example of a material that satisfies this condition is cyclohexane. It is preferable to use the nonsolvent in an amount of about 2 to 5 times the amount of the solvent. When the amount of non-solvent dripped exceeds a certain amount,
The phase-separated polyvinyl acetate is deposited on the core material and becomes a gel, and by continuing to drop the non-solvent, the wall film is solidified and stabilized. The thus produced microcapsules having a polyvinyl acetate wall adsorb ethyl cellulose in the liquid onto the surface of the capsule wall during the stage from gelation to solidification. The produced microcapsules are effectively prevented from aggregating with each other by this ethylcellulose adsorption layer. (b) The solvent is preferably distilled off from the resulting dispersion containing polyvinyl acetate microcapsules under heating. is distilled out of the system. There are slight differences in the amount of solvent distilled off depending on the type of solvent, but the amount of remaining solvent is
It is preferable to continue until the amount becomes 0.1 times or less.
Then, ethyl cellulose and a non-solvent are added in any order to the residual solution after the solvent is distilled off to dissolve them.
Ethyl cellulose has a concentration in the solution after adding a non-solvent of about 0.5 to 10 W/W%, especially about 1 to 1.
It is preferable to use it so that it becomes 5W/W%.
Furthermore, by increasing or decreasing the amount of ethyl cellulose used, the thickness of the resulting microcapsule wall membrane can be changed, and the release of the core substance can be controlled. In addition, the amount of non-solvent is 0.1 based on the amount of solvent distilled off.
It is preferable to use ~4 times the amount, especially the same amount.
The above ethylcellulose is preferably dissolved by heating, for example about 67 to 80°C, especially about 70°C.
Ethylcellulose is easily dissolved by stirring at ~78°C. In addition, in preparing the microcapsules of the present invention, in addition to ethyl cellulose as a wall film agent, a wall film forming aid, a phase separation inducing agent,
Alternatively, a surfactant can be used as appropriate. In this case, examples of wall film forming aids include dimethylpolysiloxane, methylphenylpolysiloxane, and dimethylpolysiloxane containing 1 to 20% silicon dioxide, and examples of phase separation inducers include polyethylene, butyl rubber, polyisobutylene, polybutadiene, and interfaces. As the activator, for example, sorbitan fatty acid ester, glycerin fatty acid ester, soybean phospholipid, calcium stearyl lactate, etc. can be used. These additions can be added together when dissolving ethyl cellulose, and the concentration in the solution is approximately 0.01 to 20% for the wall film forming aid and approximately 0.2 to 20% for the phase separation inducer.
10%, and the surfactant is preferably used in an amount of about 0.001 to 10%. (c) The phase separation of ethylcellulose from the dispersion obtained in (a) above can be performed, for example, at a rate of about 0.05 per minute.
Preferably, it is carried out by cooling at a rate of ~4°C. By further cooling, the ethyl cellulose deposited on the polyvinyl acetate is solidified and stabilized. In this case, cooling is approximately 40℃
It is appropriate to do the following. The microcapsules thus produced can be separated by a conventional separation method. For example, decantation, filtration, centrifugation, etc. can be employed, and any of these methods will hardly cause the capsules to stick to each other or aggregate. By washing the obtained microcapsules with, for example, cyclohexane, n-hexane, petroleum ether, etc. and drying them by a conventional method, microcapsules with excellent storage and fluidity can be obtained. The microcapsules are dried at approximately 40 to 170℃.
It can generally be carried out in the range of , but especially about 60 to
It is preferable to heat and dry at 120°C. That is about 60~
Drying by heating at 120° C. produces a particularly favorable effect in that the polyvinyl acetate constituting the inner layer of the microcapsule wall undergoes flow deformation and the capsule wall becomes more dense. The microcapsules of the present invention can be widely applied not only to pharmaceuticals but also to various substances such as veterinary drugs, agricultural chemicals, cosmetics, foods, and printing inks. Specifically, pharmaceuticals to which the microcapsules and manufacturing method of the present invention can be applied include ascorbic acid,
Thiamine hydrochloride, pyridoxine hydrochloride, calcium pantothenate, methylmethionine/sulfonium/
Vitamins such as chloride; amino acids or peptides such as potassium aspartate, magnesium aspartate, glutathione, monosodium glutamate; sulfamine, sulfadiazine,
Chemotherapeutic agents such as sulfamerazine, sulfisoxazole, calcium para-aminosalicylate, sodium isoniazido glucuronate; phenoxymethylpenicillin, propicillin potassium, sulbenicillin sodium, dihydrostreptomycin sulfate, fradiomycin sulfate, tetracycline hydrochloride, succinic acid Antibiotics such as chloramphenicol sodium; trimethoquinol hydrochloride;
Respiratory promoting/antitussive expectorants such as salbutamol sulfate, terbutaline sulfate, and chlorprenaline hydrochloride;
Antineoplastic agents such as cytarabine, methotrexate, bleomycin hydrochloride, fluorouracil, thimepidium bromide (chemical name: 1,1-dimethyl-5
-methoxy-3-(dithien-2-yl-methylene)piperidium bromide), trospium chloride (chemical name: 8-benzyloyl-oxy-6.10-ethano-5-azonaspiro[4.5]decane chloride) Lithium carbonate, citicoline, γ-aminobutyric acid, calcium hopantenate (chemical name: D-(+)-4-(2,4-dihydroxy-3.3-dimethylbutyramine) calcium butyrate.
Neuropsychiatric drugs such as chlorpromazine sulfoxide, perazine, thiopyroperazine; procaine hydrochloride, lidocaine hydrochloride, tanacaine hydrochloride (chemical name: 2-methyl-2-n-propylaminopropion-0-toluidine) hydrochloride), local anesthetics/muscle relaxants such as tubocurarine chloride; magnesium silicate, precipitated calcium carbonate, metoclopramide, berberine tannate,
Gastrointestinal agents such as histidine hydrochloride, trimebutine maleate (chemical name: 1-(3,4,5-trimethoxybenzoyloxy)-2-dimethylamino-2-phenylbutane maleate), and DL-carnitine chloride ; antihistamines such as diphenhydramine tannate, promethazine hydrochloride, homochlorcyclidine; poisoning agents such as atropine sulfate, sodium thiosulfate, sodium bicarbonate, calcium sodium edetate, D-penicillamine; sodium amobarbital, cyclo Hypnotic and sedative agents such as barbital calcium, phenobarbital sodium, and pentobarbital calcium; antiepileptic agents such as ethylphenacemide and acetazolamide; antipyretic analgesic antiinflammatory agents such as imipramine, aspirin aluminum; digoxin, theosalicin (theobromine calcium and calcium salicylate); equimolar double salts or complex salts), aminophylline, cardiotonic agents and antiarrhythmia agents such as bupranolol hydrochloride; pentrium, pempidine, betanidine sulfate (N-benzyl-N',
Antihypertensive diuretics such as N''-dimethylguanidine sulfate), methyldopa, potassium sodium tartrate, potassium chloride; itramint sylate, trimetazidine dibasic acid salt, diltiazem hydrochloride (chemical name: d-3-acetoxy-cis-2, 3-dihydro-5-[2-(dimethylamino)ethyl]-2-
(p-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one hydrochloride), vasodilators such as cinnarizine, therapeutic agents for arteriosclerosis such as nicomol, dextrothyroxine, aluminum nicotinate; Nutrients and anticoagulants such as calcium chloride, calcium hydrogen phosphate, ferrous gulonate, iron dextran, bishydroxycoumarin; acetomenaphtone, calcium gluconate,
Hemostatic agents such as carbazocrom sodium sulfonate; liver agents such as orotic acid, protoporphyrin sodium; antidiabetic agents such as acetohexamide, glipizide, fenformine hydrochloride; narcotics and adenosine such as codeine phosphate, levorphanol tartrate. , allopurinol,
Inosine etc. can be given. The microcapsules of the present invention obtained by the above method have (1) the outer wall layer made of ethyl cellulose, so the microcapsules do not aggregate with each other even when stored at room temperature, and are highly free-flowing; (2) double-walled. Since it forms a wall film, it has excellent characteristics such as excellent protection of the core substance and easy release control. In addition, in microcapsules that have undergone heating and drying, the polyvinyl acetate that forms the inner layer of the capsule wall undergoes fluid deformation and closes and repairs the pores and cracks in the outer ethyl cellulose wall, making the capsule wall even more dense. It becomes strong and therefore (3)
In addition to providing excellent protection of the core substance and facilitating elution control, (4) the capsule wall membrane can be made even thinner than conventional microcapsules, and as a result, the core substance content in the microcapsules can be reduced. Since it can be increased, it is also possible to reduce costs. It has excellent effects such as Hereinafter, the present invention will be explained in more detail using experimental examples and examples. Experimental Example 1 Microcapsules containing thimepidium bromide were prepared, and the yield of the microcapsules, the content of thimepidium bromide in the capsules, the bitter taste upon ingestion, and the elution rate of thimepidium bromide in the first solution of disintegration test were measured over time. The effects of the present invention were compared. Experimental method (1) Core material Thimepidium bromide with a particle size of 74 to 149μ was used as the core material. (2) Preparation of microcapsules (microcapsules of the present invention) Polyvinyl acetate and ethyl cellulose (anti-aggregation agent; ethoxy content 48.5% viscosity 45cP) 15g
is dissolved in 500 ml of acetone, and then 150 g of core material is dispersed in this solution. Next, 3000 ml of cyclohexane is gradually added to this dispersion while stirring at about 400 rpm. After heating the resulting microcapsule dispersion and distilling off about 700 ml of the azeotropic mixture with an azeotropic point of 52 to 58°C, cyclohexane was added.
700ml, calcium stearyl lactate (chemical name;
Calcium stearyl-2-lactylate) 15
g, 90 g of silicone resin that complies with the standards of the 4th Edition Food Additives Official Standards, and ethyl cellulose are added and dissolved by heating at 78°C. After dispersing the generated microcapsules and washing with n-hexane, 105
Heat and dry at ℃. The obtained microcapsules are sieved through a JIS standard sieve with an opening of 350 μm, and those that can pass through the standard sieve are collected to obtain thimepidium bromide-containing microcapsules that meet the powder standards of the Ninth Edition Japanese Pharmacopoeia. (Control group microcapsules) In the same manner as above, 15 g of ethyl cellulose (anti-agglomeration agent, same as above) is dissolved in 500 ml of acetone, and 150 g of the core material is dispersed. Next, 3000 ml of cyclohexane is added to this dispersion, and about 700 ml of the azeotrope at 52-58°C is distilled off. Add 700 ml of cyclohexane, 15 g of calcium stearyl lactate, 90 g of silicone resin, and ethyl cellulose to the remaining liquid and dissolve by heating at 76°C.
Control microcapsules (iii) and (iv) are obtained by carrying out the same procedure as described above. (3) Results The results are shown in Table 1 below. A comparison of the elution rates of thimepidium bromide is shown in Figure 1 below.
【表】【table】
【表】
実験例 2
塩酸トリメトキノール含有マイクロカプセルを
調製し、散剤基準に適合したマイクロカプセルの
収率、カプセル中の塩酸トリメトキノール含量、
崩壊試験第1液中における塩酸トリメトキノール
の50%溶出率ならびに経時的な溶出率を測定し、
カプセルを乾燥する際の加熱効果を比較した。
(1) 芯物質
粒径105〜210μの塩酸トリメトキノールを芯
物質として用いた。
(2) マイクロカプセルの調製
重合度40のポリ酢酸ビニル30gとエチルセル
ロース(凝集防止剤;エトキシ含有率48.5%、
粘度100cP)15gをアセトン500mlに溶解し、
ついで、この溶液にシクロヘキサン500mlを加
え、さらに芯物質300gを分散させた後約400r.
p.m.でかくはんしながら2500mlのシクロヘキ
サンを滴下する。ついで、生成したマイクロカ
プセルの分散液を加熱して共沸点51゜〜54℃の
共沸混合物700mlを留去する。この残分散液
に、シクロヘキサン700ml、分子量1200000のポ
リイソブチレン90gおよびエチルセルロース
(エトキシ含有率48.5%、粘度100cP)30gを加
えて78℃にて加熱溶解する。ついでこの溶液を
室温まで徐々に冷却する。生成したマイクロカ
プセルを分取しn−ヘキサンで洗浄したのち、
下記第2表に示す温度で送風乾燥し、目開き
350μのJIS標準ふるいを通過するものを集める
ことにより第九改正日本薬局方の散剤基準に適
合した塩酸トリメトキノール含有マイクロカプ
セルを得る。
(3) 結果
下記第2表に示す通りである。尚、塩酸トリ
メトキノールの溶出率の経時的変化は後記第2
図で示した。[Table] Experimental example 2 Trimethoquinol hydrochloride-containing microcapsules were prepared, and the yield of microcapsules that met powder standards, the content of trimethoquinol hydrochloride in the capsules,
Disintegration test Measure the 50% dissolution rate of trimethoquinol hydrochloride in the first solution and the dissolution rate over time,
We compared the heating effects when drying capsules. (1) Core material Trimethoquinol hydrochloride with a particle size of 105 to 210 μm was used as the core material. (2) Preparation of microcapsules 30 g of polyvinyl acetate with a degree of polymerization of 40 and ethyl cellulose (anti-agglomeration agent; ethoxy content 48.5%,
Dissolve 15g (viscosity 100cP) in 500ml acetone,
Next, 500 ml of cyclohexane was added to this solution, and 300 g of core material was further dispersed, and then heated for about 400 r.
Add 2500 ml of cyclohexane dropwise while stirring at pm. Then, the resulting dispersion of microcapsules is heated to distill off 700 ml of an azeotropic mixture having an azeotropic point of 51° to 54°C. To this residual dispersion, 700 ml of cyclohexane, 90 g of polyisobutylene with a molecular weight of 1,200,000, and 30 g of ethyl cellulose (ethoxy content 48.5%, viscosity 100 cP) are added and dissolved by heating at 78°C. The solution is then gradually cooled to room temperature. After separating the generated microcapsules and washing them with n-hexane,
Dry with air at the temperature shown in Table 2 below and open the mesh.
Microcapsules containing trimethoquinol hydrochloride that meet the powder standards of the Ninth Edition Japanese Pharmacopoeia are obtained by collecting those that pass through a 350μ JIS standard sieve. (3) Results The results are shown in Table 2 below. The change in elution rate of trimethoquinol hydrochloride over time is described in Section 2 below.
Illustrated in the diagram.
【表】
実施例 1
重合度60のポリ酢酸ビニル90gおよびエチルセ
ルロース(エトキシ含有率;48.0%、粘度45cP)
15gをアセトン500mlに溶解させる。ついでこの
溶液にシクロヘキサン500mlを加え、さらに粒径
74〜149μのグルタチオン300gを分散させた後約
400r.p.m.でかく拌しながら2500mlのシクロヘキ
サンを徐々に加える。生成したマイクロカプセル
分散液を加熱して共沸点52〜58℃の共沸混合物
700mlを留去した後、残液にシクロヘキサン700
ml、分子量7000のポリエチレン90gおよびエチル
セルロース(エトキシ含有率48.5%、粘度
100cP)45gを78℃で加熱溶解し徐々に室温まで
冷却する。生成したマイクロカプセルを分取しn
−ヘキサンで洗浄した後90℃にて乾燥する。かく
して得られたマイクロカプセルを目開き350μの
JIS標準ふるいで篩過することにより第九改正日
本薬局方の散剤基準に適合したグルタチオン含有
マイクロカプセル437gを得る。
本品はグルタチオンを66.9%含有する。又、本
品を第九改正日本薬局方の崩壊試験第1液に投入
し、37℃において本品から含有されるグルタチオ
ンの50%が溶出するまでの時間を測定したところ
180分であつた。
実施例 2
実施例1のアセトンおよびグルタチオンに代え
てメタノール800mlおよび粒径210〜350μの硫酸
アンモニウム100gを用い、実施例1において共
沸点52〜58℃の共沸混合物の留去に代えて共沸点
53〜56℃の共沸混合物1500mlを留去する以外は実
施例1と同様に処理することにより粒径210〜420
μ硫酸アンモニウム含有マイクロカプセル431g
を得る。
本品は硫酸アンモニウムを40.5%含有する。
又、本品を25℃の水に投入し本品から含有硫酸ア
ンモニウムの50%が溶出するまでの時間を測定し
たところ34.5日であつた。[Table] Example 1 90 g of polyvinyl acetate with a degree of polymerization of 60 and ethyl cellulose (ethoxy content: 48.0%, viscosity 45 cP)
Dissolve 15g in 500ml of acetone. Next, add 500ml of cyclohexane to this solution and further adjust the particle size.
After dispersing 300g of 74-149μ glutathione, approx.
Gradually add 2500 ml of cyclohexane while stirring at 400 rpm. The resulting microcapsule dispersion is heated to form an azeotropic mixture with an azeotropic point of 52 to 58°C.
After distilling off 700ml, add 700ml of cyclohexane to the remaining liquid.
ml, 90 g of polyethylene with a molecular weight of 7000 and ethyl cellulose (ethoxy content 48.5%, viscosity
100cP) 45g is heated and dissolved at 78℃ and gradually cooled to room temperature. Separate the generated microcapsules
- Dry at 90°C after washing with hexane. The thus obtained microcapsules were sized with an opening of 350μ.
By sieving through a JIS standard sieve, 437 g of glutathione-containing microcapsules that meet the powder standards of the Ninth Edition Japanese Pharmacopoeia are obtained. This product contains 66.9% glutathione. In addition, this product was put into the disintegration test liquid 1 of the Ninth Edition Japanese Pharmacopoeia, and the time until 50% of the glutathione contained in this product was eluted at 37°C was measured.
It took 180 minutes. Example 2 800 ml of methanol and 100 g of ammonium sulfate with a particle size of 210 to 350 μ were used in place of acetone and glutathione in Example 1, and the azeotrope was removed in place of distillation of the azeotropic mixture with an azeotropic point of 52 to 58°C in Example 1.
A particle size of 210 to 420 was obtained by the same treatment as in Example 1 except that 1500 ml of the azeotrope at 53 to 56°C was distilled off.
431g microcapsules containing μ ammonium sulfate
get. This product contains 40.5% ammonium sulfate.
Furthermore, when this product was placed in water at 25°C, the time required for 50% of the ammonium sulfate contained in the product to be eluted from the product was measured, and it was 34.5 days.
第1図は実験例1(i)〜(iv)の臭化チメピジウム含
有マイクロカプセルを第九改正日本薬局方崩壊試
験第1液に投入した場合の37℃におけるマイクロ
カプセルからの臭化チメピジウム溶出率を表わ
し、第2図は実験例2(i)および(ii)の塩酸トリメト
キノール含有マイクロカプセルを崩壊試験第1液
に投入した場合の溶出率をそれぞれ示す。
Figure 1 shows the dissolution rate of thimepidium bromide from the microcapsules at 37°C when the microcapsules containing thimepidium bromide of Experimental Examples 1 (i) to (iv) were added to the first solution of the Ninth Revised Japanese Pharmacopoeia disintegration test. Figure 2 shows the dissolution rates when the microcapsules containing trimethoquinol hydrochloride of Experimental Examples 2 (i) and (ii) were added to the first disintegration test liquid.
Claims (1)
スを構成成分とするマイクロカプセルであつて、
(ア)芯物質をとり囲む当該ポリ酢酸ビニル壁膜と(イ)
該壁膜をとり囲むエチルセルロース壁膜との二重
の壁膜で構成されてなるマイクロカプセル。 2 ポリ酢酸ビニルが重合度20〜1000のポリ酢酸
ビニルであり、エチルセルロースがエトキシ含有
率44〜55%、粘度3〜500cPのエチルセルロース
である特許請求の範囲第1項記載のマイクロカプ
セル。 3 (ア) 壁膜剤たるポリ酢酸ビニル、凝集防止剤
たるエチルセルロースを含有する溶液に芯物質
を分散せしめた後、該ポリ酢酸ビニルの相分離
によつて芯物質上に壁膜を形成せしめ (イ) 該溶液から溶媒を留去し、この残液に壁膜剤
たるエチルセルロースと非溶媒を加えて溶解
し、ついで (ウ) 該エチルセルロースの相分離によつてポリ酢
酸ビニル壁膜上にさらにエチルセルロースの壁
膜を形成せしめることを特徴とするマイクロカ
プセルの製法。 4 壁膜剤たるエチルセルロースを溶解するに際
し留去した溶媒量に対し0.1倍量以上の非溶媒を
加え、ついでこれを加熱してエチルセルロースを
溶解させた後、該溶液を冷却してポリ酢酸ビニル
上にエチルセルロース壁膜を形成せしめ、更に得
られたマイクロカプセルを加熱乾燥する特許請求
の範囲第3項記載の製法。 5 50℃〜160℃で加熱乾燥する特許請求の範囲
第4項記載の製法。 6 非溶媒がシクロヘキサンである特許請求の範
囲第3項、第4項又は第5項記載の製法。 7 壁膜剤たるエチルセルロースを含有する溶液
に壁膜形成助剤、相分離誘起剤又は界面活性剤を
共存させる特許請求の範囲第3項、第4項、第5
項又は第6項記載の製法。[Scope of Claims] 1. A microcapsule comprising a core material, polyvinyl acetate and ethyl cellulose,
(a) The polyvinyl acetate wall film surrounding the core material and (b)
A microcapsule composed of a double-walled membrane with an ethyl cellulose wall surrounding the wall. 2. The microcapsule according to claim 1, wherein the polyvinyl acetate is polyvinyl acetate with a degree of polymerization of 20 to 1000, and the ethyl cellulose is ethyl cellulose with an ethoxy content of 44 to 55% and a viscosity of 3 to 500 cP. 3 (a) After dispersing the core material in a solution containing polyvinyl acetate as a wall film agent and ethyl cellulose as an anti-aggregation agent, a wall film is formed on the core material by phase separation of the polyvinyl acetate ( b) The solvent is distilled off from the solution, ethyl cellulose as a wall film agent and a non-solvent are added and dissolved in the remaining liquid, and then (c) the ethyl cellulose is phase separated to form further ethyl cellulose on the polyvinyl acetate wall film. A method for producing microcapsules characterized by forming a wall membrane of. 4 Add a non-solvent in an amount of 0.1 times or more to the amount of solvent distilled off when dissolving ethyl cellulose as a wall agent, then heat this to dissolve the ethyl cellulose, cool the solution and apply it on polyvinyl acetate. 4. The method according to claim 3, wherein the microcapsules are formed with an ethyl cellulose wall, and the resulting microcapsules are dried by heating. 5. The manufacturing method according to claim 4, which comprises heating and drying at 50°C to 160°C. 6. The production method according to claim 3, 4, or 5, wherein the nonsolvent is cyclohexane. 7 Claims 3, 4, and 5 in which a wall film forming aid, a phase separation inducer, or a surfactant is made to coexist in a solution containing ethyl cellulose, which is a wall film agent.
The manufacturing method described in Section 6 or Section 6.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2445381A JPS57140641A (en) | 1981-02-20 | 1981-02-20 | Microcapsule and preparation thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2445381A JPS57140641A (en) | 1981-02-20 | 1981-02-20 | Microcapsule and preparation thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS57140641A JPS57140641A (en) | 1982-08-31 |
JPS6213049B2 true JPS6213049B2 (en) | 1987-03-24 |
Family
ID=12138572
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2445381A Granted JPS57140641A (en) | 1981-02-20 | 1981-02-20 | Microcapsule and preparation thereof |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS57140641A (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2698561B1 (en) * | 1992-11-27 | 1995-02-17 | Flamel Tech Sa | Microcapsules containing at least one active principle, application of these microcapsules in systems for instantaneous release of active principles, and coating process useful for preparing said microcapsules. |
EP1118382B1 (en) * | 2000-01-13 | 2003-04-02 | Kureha Kagaku Kogyo Kabushiki Kaisha | Microcapsule and process for production thereof |
US6833191B2 (en) * | 2001-11-20 | 2004-12-21 | Encap Technologies, Llc | Microencapsulated particles and process for manufacturing same |
BR112013026802A2 (en) * | 2011-04-21 | 2016-09-20 | Intercontinental Great Brands Llc | improved peroxide stability in oral treatment compositions |
CN111408325B (en) * | 2019-01-07 | 2022-03-15 | 长春理工大学 | Preparation method of magnetic microcapsule |
-
1981
- 1981-02-20 JP JP2445381A patent/JPS57140641A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS57140641A (en) | 1982-08-31 |
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