JPS637091B2 - - Google Patents
Info
- Publication number
- JPS637091B2 JPS637091B2 JP8102582A JP8102582A JPS637091B2 JP S637091 B2 JPS637091 B2 JP S637091B2 JP 8102582 A JP8102582 A JP 8102582A JP 8102582 A JP8102582 A JP 8102582A JP S637091 B2 JPS637091 B2 JP S637091B2
- Authority
- JP
- Japan
- Prior art keywords
- microcapsules
- organic solvent
- phase separation
- ethylcellulose
- core material
- 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 68
- 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 40
- 239000001856 Ethyl cellulose Substances 0.000 claims description 40
- 229920001249 ethyl cellulose Polymers 0.000 claims description 40
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 40
- 239000011162 core material Substances 0.000 claims description 32
- 239000003960 organic solvent Substances 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 19
- 238000005191 phase separation Methods 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 14
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 10
- -1 alkyl lactic acid ester Chemical class 0.000 claims description 9
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 230000001939 inductive effect Effects 0.000 claims description 6
- SVONRAPFKPVNKG-UHFFFAOYSA-N 2-ethoxyethyl acetate Chemical compound CCOCCOC(C)=O SVONRAPFKPVNKG-UHFFFAOYSA-N 0.000 claims description 4
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 4
- 239000000194 fatty acid Substances 0.000 claims description 4
- 229930195729 fatty acid Natural products 0.000 claims description 4
- 150000004665 fatty acids Chemical class 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 3
- 230000004931 aggregating effect Effects 0.000 claims description 3
- 125000005907 alkyl ester group Chemical group 0.000 claims description 3
- POAOYUHQDCAZBD-UHFFFAOYSA-N 2-butoxyethanol Chemical compound CCCCOCCO POAOYUHQDCAZBD-UHFFFAOYSA-N 0.000 claims description 2
- 229940093475 2-ethoxyethanol Drugs 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 150000005215 alkyl ethers Chemical class 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000002245 particle Substances 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- 230000002744 anti-aggregatory effect Effects 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 230000002776 aggregation Effects 0.000 description 9
- 239000006185 dispersion Substances 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 229920002367 Polyisobutene Polymers 0.000 description 8
- 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 8
- 229940079593 drug Drugs 0.000 description 8
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 8
- 229960005345 trimebutine Drugs 0.000 description 8
- 238000004220 aggregation Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 238000005054 agglomeration Methods 0.000 description 4
- 229920005549 butyl rubber Polymers 0.000 description 4
- 239000004503 fine granule Substances 0.000 description 4
- 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 4
- 230000007246 mechanism Effects 0.000 description 4
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 239000005062 Polybutadiene Substances 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000004205 dimethyl polysiloxane Substances 0.000 description 3
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000000411 inducer Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 3
- 229920002857 polybutadiene Polymers 0.000 description 3
- 229920000573 polyethylene Polymers 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229930003268 Vitamin C Natural products 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Chemical compound CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011812 mixed powder Substances 0.000 description 2
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229920002050 silicone resin Polymers 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 235000019154 vitamin C Nutrition 0.000 description 2
- 239000011718 vitamin C Substances 0.000 description 2
- NMRPBPVERJPACX-UHFFFAOYSA-N (3S)-octan-3-ol Natural products CCCCCC(O)CC NMRPBPVERJPACX-UHFFFAOYSA-N 0.000 description 1
- ZNQOETZUGRUONW-UHFFFAOYSA-N 1-(2-butoxyethoxy)ethanol Chemical compound CCCCOCCOC(C)O ZNQOETZUGRUONW-UHFFFAOYSA-N 0.000 description 1
- WOFPPJOZXUTRAU-UHFFFAOYSA-N 2-Ethyl-1-hexanol Natural products CCCCC(O)CCC WOFPPJOZXUTRAU-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- KYEJCTUGRVHOBN-UHFFFAOYSA-N 2-[2-(dimethylamino)-2-phenylbutyl]-3,4,5-trimethoxybenzoic acid Chemical compound C=1C=CC=CC=1C(CC)(N(C)C)CC1=C(C(O)=O)C=C(OC)C(OC)=C1OC KYEJCTUGRVHOBN-UHFFFAOYSA-N 0.000 description 1
- NVXANRCSLBRSJA-UHFFFAOYSA-N 2-butoxyethanol;2-(2-methoxyethoxy)ethanol Chemical compound CCCCOCCO.COCCOCCO NVXANRCSLBRSJA-UHFFFAOYSA-N 0.000 description 1
- TZYRSLHNPKPEFV-UHFFFAOYSA-N 2-ethyl-1-butanol Chemical compound CCC(CC)CO TZYRSLHNPKPEFV-UHFFFAOYSA-N 0.000 description 1
- YIWUKEYIRIRTPP-UHFFFAOYSA-N 2-ethylhexan-1-ol Chemical compound CCCCC(CC)CO YIWUKEYIRIRTPP-UHFFFAOYSA-N 0.000 description 1
- WBPAQKQBUKYCJS-UHFFFAOYSA-N 2-methylpropyl 2-hydroxypropanoate Chemical compound CC(C)COC(=O)C(C)O WBPAQKQBUKYCJS-UHFFFAOYSA-N 0.000 description 1
- KVZLHPXEUGJPAH-UHFFFAOYSA-N 2-oxidanylpropanoic acid Chemical compound CC(O)C(O)=O.CC(O)C(O)=O KVZLHPXEUGJPAH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- LPEKGGXMPWTOCB-UHFFFAOYSA-N 8beta-(2,3-epoxy-2-methylbutyryloxy)-14-acetoxytithifolin Natural products COC(=O)C(C)O LPEKGGXMPWTOCB-UHFFFAOYSA-N 0.000 description 1
- MRABAEUHTLLEML-UHFFFAOYSA-N Butyl lactate Chemical compound CCCCOC(=O)C(C)O MRABAEUHTLLEML-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 210000000467 autonomic pathway Anatomy 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- NJSUFZNXBBXAAC-UHFFFAOYSA-N ethanol;toluene Chemical compound CCO.CC1=CC=CC=C1 NJSUFZNXBBXAAC-UHFFFAOYSA-N 0.000 description 1
- 229940116333 ethyl lactate Drugs 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 229940066493 expectorants Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000004083 gastrointestinal agent Substances 0.000 description 1
- 229940125695 gastrointestinal agent Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000007602 hot air drying Methods 0.000 description 1
- 239000005554 hypnotics and sedatives Substances 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000976 ink Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229940035429 isobutyl alcohol Drugs 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940057867 methyl lactate Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 229940017144 n-butyl lactate Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- GXOHBWLPQHTYPF-UHFFFAOYSA-N pentyl 2-hydroxypropanoate Chemical compound CCCCCOC(=O)C(C)O GXOHBWLPQHTYPF-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- ROFVJSWBDQUQGW-UHFFFAOYSA-N piperidin-1-ium;bromide Chemical compound Br.C1CCNCC1 ROFVJSWBDQUQGW-UHFFFAOYSA-N 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000003169 respiratory stimulant agent Substances 0.000 description 1
- 229940066293 respiratory stimulants Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 1
- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 238000009736 wetting Methods 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
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/08—Simple coacervation, i.e. addition of highly hydrophilic material
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Preparation (AREA)
- Manufacturing Of Micro-Capsules (AREA)
Description
本発明は非凝集性マイクロカプセルの製法に関
する。従来、エチルセルロースの相分離を利用し
てマイクロカプセルを製造する方法としては、例
えばブチルゴム、ポリブタジエン、ポリエチレ
ン、ポリイソブチレン等の炭化水素系高分子物質
を相分離誘起剤として使用する方法(特公昭42−
528号、同44−11399号および同50−30136号)が
知られている。この方法によれば、あらかじめ上
記相分離誘起剤を溶解した熱シクロヘキサン溶液
にエチルセルロースの如き壁膜形成剤を溶解し、
これに芯物質を均一に分散させ、ついで冷却して
コアセルベーシヨンを誘起させることにより該壁
膜形成剤をカプセル壁膜とするマイクロカプセル
を製することができる。しかしながらブチルゴ
ム、ポリブタジエン、ポリイソブチレン等の炭化
水素系高分子物質を相分離誘起剤として使用する
場合、マイクロカプセルが生成する過程でマイク
ロカプセル同士が多数付着して凝集塊を作り充分
流動性に富んだ単核状のマイクロカプセルが得ら
れなかつたり、あるいは製造装置に付着してマイ
クロカプセルの収量が低下する等の難点がある。
上記の現象は特に比較的低分子量の炭化水素系高
分子物質を相分離誘起剤として使用する場合に著
しいことが知られている。このようなマイクロカ
プセル同士の凝集や製造装置への付着を防ぐ方法
として、高分子量の炭化水素系高分子物質と低分
子量の炭化水素系高分子物質の併用あるいは界面
活性剤や保護コロイドの使用が通常行なわれてい
る。しかしながら、上記方法においては、凝集防
止作用の強弱の調節がきわめて難かしく凝集防止
作用が強すぎる場合には芯物質が壁膜で十分被覆
されなかつたり、また被覆されたとしても緻密で
均一な壁膜を有するマイクロカプセルが得難い。
一方凝集防止作用が弱い場合には流動性に富んだ
単核状の、かつ損傷の少ない壁膜でスムースに被
覆されたマイクロカプセルが得難い。このため壁
膜の製膜性や芯物質の放出性も著しい制約を受け
るという難点もある。
本発明者らは上記の如き難点のないマイクロカ
プセルの製造法について種々研究を重ねた結果、
エチルセルロースの相分離によつて芯物質上にエ
チルセルロース壁膜を形成させてマイクロカプセ
ルを製法するに際し、凝集防止剤としてある種の
有機溶媒を使用することによつて緻密な壁膜を有
しかつ凝集のない流動性に富んだマイクロカプセ
ルを製造しうることを見い出し本発明を完成する
に至つた。すなわち、本発明方法は、エチルセル
ロース含有シクロヘキサン溶液に芯物質を分散さ
せたのち、エチルセルロースの相分離により芯物
質上にエチルセルロース壁膜を形成させてエチル
セルロースマイクロカプセルを製造する方法にお
いて、エチルセルロースの相分離を溶解パラメー
タの水素結合成分δhが3.5〜11.0〔(cal/cm2)1/2〕
で
ありかつシクロヘキサンに溶解ないし部分溶解す
る有機溶媒の存在下に実施することを特徴とする
非凝集性マイクロカプセルの製法である。
本発明方法に用いられる有機溶媒の凝集防止機
構と従来用いられてきた凝集防止剤の凝集防止機
構とは下記の点で全く異質である。すなわち、従
来用いられてきた凝集防止剤の凝集防止機構はマ
イクロカプセル壁膜上に高分子物質のような保護
コロイドあるいは界面活性剤が吸着して凝集防止
作用を発揮するものであるのに対し、本発明に係
る有機溶媒の凝集防止機構は、有機溶媒分子が水
素結合の如き相互作用によりマイクロカプセル壁
膜上に集まつてクラスターを形成してカプセル相
互間の付着・凝集を防止するものである。
本発明において凝集防止剤として用いられる有
機溶媒は、下式
δh=(Eh/V)1/2
(但し、Ehは水素結合エネルギーを表わし、V
はモル体積を表わす。)
で求められる溶解パラメータの水素結合成分δh
〔Ind.Eng.Chem.、Prod.Res.Dev.、8、2
(1969)〕が概ね3.5〜11.0(cal/cm2)1/2、とりわけ
3.8〜9.5(cal/cm2)1/2であり、かつシクロヘキサン
に溶解もしくは部分溶解する有機溶媒が用いられ
る。かかる有機溶媒としては、例えばメタノー
ル、エタノール、1−プロパノール、2−プロパ
ノール、1−ブタノール、イソブチルアルコー
ル、2−ブタノール、2−メチル−2−プロパノ
ール、1−ペンタノール、3−メチル−1−ブタ
ノール、2−ペンタノール、3−ペンタノール、
2−メチル−2−ブタノール、1−ヘキサノー
ル、2−エチル−1−ブタノール、4−メチル−
2−ペンタノール、2−エチル−1−ヘキサノー
ル、シクロヘキサノール、の如き炭素数1〜8の
鎖状あるいは環状アルカノール;乳酸メチル、乳
酸エチル、乳酸n−ブチル、乳酸イソブチル、乳
酸n−アミル、乳酸イソアミルの如き乳酸低級ア
ルキルエステル;2−メトキシエタノール、2−
エトキシエタノール、2−ブトキシエタノールの
如き低級アルコキシ置換低級アルカノール;2−
(2−メトキシエトキシ)エタノール、2−(2−
ブトキシエトキシ)エタノールの如き低級アルコ
キシ低級アルコキシ置換低級アルカノール;酢酸
2−エトキシエチルエステルの如き酢酸低級アル
コキシ置換低級アルキルエステル;ギ酸、酢酸、
プロピオン酸、酪酸、イソ酪酸の如き低級脂肪
酸;テトラヒドロフラン;ジエチレングリコール
ジメチルエーテルの如きジエチレングリコールジ
低級アルキルエーテル;トリメチルホスフエー
ト、トリエチルホスフエートの如きトリ低級アル
キルホスフエート;ジアセトンアルコールの如き
低級アルカノイル置換低級アルカノールが挙げら
れる。これらのうち、特に好ましい有機溶媒とし
ては、エタノール、1−プロパノール、2−エト
キシエタノール、2−ブトキシエタノール、酢酸
2−エトキシエチルエステル、酢酸、テトラヒド
ロフラン等を挙げることができる。これら有機溶
媒の使用量は壁膜形成剤であるエチルセルロース
の使用量によつて若干影響を受けるが通常エチル
セルロース含有シクロヘキサン溶液に対して上記
有機溶媒を約0.05〜20V/V%濃度、とりわけ0.5
〜10V/V%濃度となるように使用するのが好ま
しい。
本発明において芯物質をとり囲んでマイクロカ
プセル壁膜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%であり、粘度〔ト
ルエン−エタノール(4:1)混液にエチルセル
ロースを5%濃度となるように溶解。該溶液の25
℃における粘度〕が約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
質に対して約0.05〜5倍量用いるのが適当であ
り、シクロヘキサンに対しては通常0.5〜10W/
W%、とりわけ約1〜5W/W%使用するのが好
ましい。
更に本発明のマイクロカプセル化法の適用でき
る芯物質としては、一般的にはシクロヘキサン、
あるいは凝集防止剤である有機溶媒およびエチル
セルロースを含有するシクロヘキサン溶液に溶解
しないものであればいずれの物質でもよく、これ
らは固体、液体、スラリーあるいはゲル状のいず
れであつてもよい。またこれらの芯物質を用いる
に際しその粒径には特に制限はないが、概ね約5
〜1000μm、とりわけ約50〜500μmの粒径のもの
を用いるのが好ましい。
本発明において、エチルセルロースマイクロカ
プセルを製造するにあたつては、まずシクロヘキ
サンに凝集防止剤である有機溶媒、壁膜形成剤で
あるエチルセルロースおよび芯物質を加え、この
混合物を80℃に加熱攪拌して芯物質の分散液を調
製し、この分散液を攪拌しながら適宜冷却すれ
ば、該芯物質粒子上にエチルセルロースの壁膜が
形成されてエチルセルロースマイクロカプセルが
生成する。分散液の冷却は毎分約0.05〜4℃、と
りわけ0.5〜2℃の速度で行なうのが好ましい。
かくしてまずエチルセルロースの相分離が起こり
エチルセルロースが分離し始め、更に冷却を続け
ることによりエチルセルロース壁膜ができ、更に
固化し安定な壁膜が形成する。そして更に室温ま
で冷却することにより壁膜からシクロヘキサンの
放出が起つて壁膜が完成され、安定なエチルセル
ロースマイクロカプセルが生成する。尚、安定な
マイクロカプセルが生成した時点で必要に応じて
シクロヘキサン、石油エーテル、n−ヘキサンな
どのような非溶媒を加えれば上記で生成したマイ
クロカプセルはさらに安定化する。
このように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、例えばデカンテーシヨン、
ロ過、遠心分離等により実施できる。得られたマ
イクロカプセルは、ついで必要に応じてシクロヘ
キサン、石油エーテル、n−ヘキサン等で洗浄
し、熱風乾燥、伝熱加熱乾燥等の常法により乾燥
することができる。かくして凝集の少ない、流動
性に富んだマイクロカプセルを得ることができ
る。
また、本発明方法においては、芯物質分散液か
らのエチルセルロースの相分離は、相分離誘起剤
あるいは壁膜形成助剤の存在下においても実施で
き、相分離現象としてはコアセルベーシヨンある
いはフロキユレーシヨンのいずれの相分離現象を
利用しても実施することができる。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、ポリブタジエン等を用いること
ができる。また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
キサン等を用いることができる。これら相分離誘
起剤あるいは壁膜形成助剤は、シクロヘキサンに
凝集防止剤である有機溶媒、エチルセルロース、
芯物質を加える際に同時に加えればよく、その添
加量はエチルセルロース含有溶液に対し相分離誘
起剤は約0.1〜10W/V%、壁膜形成助剤は0.01
〜10W/V%であるのが好ましい。
上記の如き本発明方法によれば、相分離により
芯物質上に沈着したコアセルベートあるいはゲル
からなるカプセル壁膜中のエチルセルロース分子
にシクロヘキサン中の有機溶媒分子が主として水
素結合のような相互作用によつて集まり、壁膜上
に有機溶媒分子のクラスターを形成し、このクラ
スターがマイクロカプセル相互の付着・凝集に対
する障壁となるため、カプセル壁膜の形成ならび
に固化・安定化がスムースに進行する。また該有
機溶媒クラスターの可塑化作用により、相分離し
たエチルセルロースの粘弾性と粘着性が適度なも
のとなり、芯物質粒子上へのエチルセルロースの
沈着性並びに“ぬれ”が著しく向上し、その結果
緻密なる壁膜を有しかつ凝集のない、流動性に富
んだマイクロカプセルを製造することができる。
更に有機溶媒を凝集防止剤として用いる本発明方
法によれば、マイクロカプセル製造過程において
生成したマイクロカプセルの製造装置への付着が
ほとんど起らない。従つて本発明方法はマイクロ
カプセルの工業的製法として非常に有利な方法で
ある。
上記本発明のマイクロカプセル化法は医薬、動
物薬、農薬、化粧品、食品、印刷用インキ等種々
の物質に広く適用することが出来る。特に医薬品
の場合は、その安定化、効力の持続化、あるいは
味、臭、刺激等を緩和し的確な改善効果を得るこ
とができる。本発明のマイクロカプセル化法を適
用し得る医薬品を列挙すれば、例えばビタミン
類、アミノ酸、ペプチド、化学療法剤、抗生物
質、呼吸促進剤、鎮咳去たん剤、抗悪性腫瘍剤、
自律神経用薬剤、精神神経用薬剤、局所麻酔剤、
筋弛緩剤、消化器官用薬剤、抗ヒスタミン剤、中
毒治療剤、催眠鎮静剤、抗てんかん剤、解熱鎮痛
消炎剤、強心剤、不整脈治療剤、降圧利尿剤、血
管拡張剤、抗脂血剤、滋養強壮変質剤、抗凝血
剤、肝臓用薬剤、血糖降下剤、血圧降下剤などを
広くあげることができる。
以下実験例および実施例をあげて本発明を説明
する。
尚、本明細書においては、「低級アルキル」、
「低級アルコキシ」、「低級アルカノール」および
「低級脂肪酸」はそれぞれ炭素数1〜5のアルキ
ル、炭素数1〜5のアルコキシ、炭素数1〜3の
アルカノールおよび炭素数1〜5の脂肪酸を意味
する。
実験例 1
1−メチル−5−メトキシ−3−(ジチエン−
2−イルメチレン)ピペリジニウム・臭化水素酸
塩(以下主薬〔〕と称する)含有マイクロカプ
セルを下記方法により調製し、第十改正日本薬局
方の細粒剤基準(以後単に細粒剤基準と略称す
る)に適合したマイクロカプセルの収量、マイク
ロカプセル中の主薬含量および37℃の0.2%塩化
ナトリウム水溶液中においてマイクロカプセルか
ら主薬が50%溶出するまでの時間(50%溶出時
間)を測定した。結果は第1表に示す通りであ
る。
(マイクロカプセルの調製)
(1) 芯物質の調製
主薬〔〕11.8部、乳糖82.8部、白色デキス
トリン5.4部の混合粉末に40V/V%エタノー
ル水溶液7部を加え、常法により練合して造粒
した後、乾燥して粒径105〜350μmの粒子に整
粒し、芯物質として用いた。
(2) マイクロカプセルの調製
シクロヘキサン1000mlに、第1表に示す量の
2−エトキシエチルアセテート、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
(25℃における粘度が100〜1100cStであるジメ
チルポリシロキサンに対して二酸化ケイ素を3
〜15%配合したもの)30g、エチルセルロース
(エトキシ含量:48.2%、粘度:101cP)28gお
よび(1)で得た芯物質212gを加え80℃に加熱攪
拌して芯物質の分散液を調製し、この分散液を
400rpmで攪拌しながら室温まで冷却した。か
くして生成したマイクロカプセルを常法により
分離し、n−ヘキサンで洗浄したのち乾燥し
た。得られたマイクロカプセルのうち目開き
500μmのJIS標準ふるいを通過し、目開き105μ
mのJIS標準ふるい上に残留するものを集める
ことにより、細粒剤基準に適合した主薬〔〕
含有マイクロカプセルを得た。
The present invention relates to a method for producing non-agglomerated microcapsules. Conventionally, as a method for manufacturing microcapsules using phase separation of ethyl cellulose, for example, a method using a hydrocarbon-based polymer material such as butyl rubber, polybutadiene, polyethylene, polyisobutylene as a phase separation inducing agent (Japanese Patent Publication No. 1973-
No. 528, No. 44-11399 and No. 50-30136) are known. According to this method, a wall film forming agent such as ethyl cellulose is dissolved in a hot cyclohexane solution in which the phase separation inducing agent is dissolved in advance,
By uniformly dispersing the core substance therein and then cooling it to induce coacelvation, microcapsules having the wall film-forming agent as the capsule wall film can be produced. However, when hydrocarbon-based polymers such as butyl rubber, polybutadiene, and polyisobutylene are used as a phase separation inducer, many microcapsules adhere to each other during the microcapsule generation process, forming aggregates that are sufficiently fluid. There are disadvantages such as not being able to obtain mononuclear microcapsules, or adhesion to manufacturing equipment, which reduces the yield of microcapsules.
It is known that the above phenomenon is particularly remarkable when a relatively low molecular weight hydrocarbon polymer substance is used as a phase separation inducing agent. As a method to prevent such microcapsules from aggregating with each other and adhering to manufacturing equipment, it is possible to use a combination of high molecular weight hydrocarbon polymer substances and low molecular weight hydrocarbon polymer substances, or use surfactants and protective colloids. Usually done. However, in the above method, it is extremely difficult to adjust the strength of the anti-agglomeration effect, and if the anti-agglomeration effect is too strong, the core material may not be sufficiently covered with the wall film, or even if it is coated, a dense and uniform wall may not be formed. Microcapsules with membranes are difficult to obtain.
On the other hand, if the aggregation prevention effect is weak, it is difficult to obtain highly fluid, mononuclear microcapsules that are smoothly coated with a wall film with little damage. For this reason, there is also the drawback that the film-forming properties of the wall membrane and the release properties of the core substance are severely restricted. The present inventors have conducted various studies on a method for manufacturing microcapsules that does not have the above-mentioned difficulties, and have found that
When manufacturing microcapsules by forming an ethyl cellulose wall film on a core material through phase separation of ethyl cellulose, a certain type of organic solvent is used as an anti-aggregation agent to form a dense wall film and agglomerate. The present inventors have discovered that it is possible to produce microcapsules with excellent fluidity and are free from silica, leading to the completion of the present invention. That is, the method of the present invention involves dispersing a core material in a cyclohexane solution containing ethyl cellulose, and then forming an ethyl cellulose wall film on the core material through phase separation of ethyl cellulose to produce ethyl cellulose microcapsules. Hydrogen bond component δh of solubility parameter is 3.5 to 11.0 [(cal/cm 2 ) 1/2 ]
This is a method for producing non-aggregating microcapsules, which is characterized in that it is carried out in the presence of an organic solvent that dissolves or partially dissolves in cyclohexane. The agglomeration prevention mechanism of the organic solvent used in the method of the present invention and the aggregation prevention mechanism of the conventionally used aggregation inhibitor are completely different in the following points. In other words, the anti-aggregation mechanism of conventionally used anti-aggregation agents is that a protective colloid such as a polymeric substance or a surfactant is adsorbed onto the microcapsule wall to exert an anti-aggregation effect. The organic solvent aggregation prevention mechanism according to the present invention is that organic solvent molecules gather on the microcapsule wall film through interactions such as hydrogen bonds to form clusters, thereby preventing adhesion and aggregation between capsules. . The organic solvent used as an anti-aggregation agent in the present invention has the following formula δh=(Eh/V) 1/2 (where Eh represents hydrogen bond energy and V
represents molar volume. ) The hydrogen bond component δh of the solubility parameter is
[Ind.Eng.Chem., Prod.Res.Dev., 8 , 2
(1969)] is approximately 3.5 to 11.0 (cal/cm 2 ) 1/2 , especially
3.8 to 9.5 (cal/cm 2 ) 1/2 , and an organic solvent that dissolves or partially dissolves in cyclohexane is used. Examples of such organic solvents include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutyl alcohol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 3-methyl-1-butanol. , 2-pentanol, 3-pentanol,
2-methyl-2-butanol, 1-hexanol, 2-ethyl-1-butanol, 4-methyl-
Chain or cyclic alkanols having 1 to 8 carbon atoms such as 2-pentanol, 2-ethyl-1-hexanol, cyclohexanol; methyl lactate, ethyl lactate, n-butyl lactate, isobutyl lactate, n-amyl lactate, lactic acid Lactic acid lower alkyl esters such as isoamyl; 2-methoxyethanol, 2-
Lower alkoxy-substituted lower alkanols such as ethoxyethanol, 2-butoxyethanol; 2-
(2-methoxyethoxy)ethanol, 2-(2-
lower alkoxy-substituted lower alkanols such as (butoxyethoxy) ethanol; lower alkoxy-substituted lower alkyl esters of acetic acid such as 2-ethoxyethyl acetate; formic acid, acetic acid,
lower fatty acids such as propionic acid, butyric acid, and isobutyric acid; tetrahydrofuran; diethylene glycol dilower alkyl ethers such as diethylene glycol dimethyl ether; trilower alkyl phosphates such as trimethyl phosphate and triethyl phosphate; lower alkanoyl-substituted lower alkanols such as diacetone alcohol. Can be mentioned. Among these, particularly preferred organic solvents include ethanol, 1-propanol, 2-ethoxyethanol, 2-butoxyethanol, acetic acid 2-ethoxyethyl ester, acetic acid, and tetrahydrofuran. The amount of these organic solvents used is slightly influenced by the amount of ethyl cellulose used as a wall film forming agent, but usually the above organic solvents are added at a concentration of about 0.05 to 20 V/V%, especially 0.5
It is preferable to use it at a concentration of ~10 V/V%. In the present invention, the ethoxy cellulose that surrounds the core substance and forms the microcapsule wall has an ethoxy content of about 46.5 to 55%, and has a viscosity [5% concentration of ethyl cellulose in a toluene-ethanol (4:1) mixture]. Soluble. 25 of the solution
It is preferable to use one having a viscosity of about 3 to 500 cP. It is appropriate to use ethyl cellulose in an amount of about 0.05 to 5 times the core material, and for cyclohexane it is usually 0.5 to 10 W/
It is preferred to use W%, especially about 1 to 5 W/W%. Furthermore, the core material to which the microencapsulation method of the present invention can be applied is generally cyclohexane,
Alternatively, any substance may be used as long as it does not dissolve in the cyclohexane solution containing the organic solvent and ethyl cellulose which are anti-aggregation agents, and these may be in the form of solid, liquid, slurry or gel. In addition, there is no particular restriction on the particle size when using these core materials, but the particle size is approximately 5.
Preference is given to using particle sizes of ~1000 .mu.m, especially about 50-500 .mu.m. In the present invention, when producing ethyl cellulose microcapsules, first, an organic solvent as an anti-aggregation agent, ethyl cellulose as a wall film forming agent, and a core material are added to cyclohexane, and the mixture is heated to 80°C and stirred. When a dispersion of the core material is prepared and the dispersion is appropriately cooled while stirring, a wall film of ethylcellulose is formed on the core material particles to produce ethylcellulose microcapsules. Preferably, the dispersion is cooled at a rate of about 0.05 DEG to 4 DEG C., particularly 0.5 DEG to 2 DEG C., per minute.
In this way, phase separation of ethyl cellulose first occurs and ethyl cellulose begins to separate, and by further cooling, an ethyl cellulose wall film is formed, which is further solidified to form a stable wall film. Further cooling to room temperature causes the release of cyclohexane from the wall film, completing the wall film and producing stable ethyl cellulose microcapsules. The microcapsules produced above can be further stabilized by adding a non-solvent such as cyclohexane, petroleum ether, n-hexane, etc., if necessary, when stable microcapsules are produced. The microcapsules produced in this way can be separated using conventional separation methods such as decantation,
This can be carried out by filtration, centrifugation, etc. The obtained microcapsules can then be washed with cyclohexane, petroleum ether, n-hexane, etc., if necessary, and dried by a conventional method such as hot air drying or heat transfer drying. In this way, microcapsules with low aggregation and high fluidity can be obtained. Furthermore, in the method of the present invention, the phase separation of ethyl cellulose from the core material dispersion can be carried out in the presence of a phase separation inducing agent or a wall film forming aid, and the phase separation phenomenon is caused by coacelvation or flocculence. It can be carried out using any phase separation phenomenon of ration. As the phase separation inducing agent, for example, polyethylene, butyl rubber, polyisobutylene, polybutadiene, etc. can be used. Further, as the wall film forming aid, for example, dimethylpolysiloxane, methylphenylpolysiloxane, etc. can be used. These phase separation inducers or wall film forming aids include cyclohexane, an organic solvent that is an anti-aggregation agent, ethyl cellulose,
It can be added at the same time as adding the core material, and the amount added is approximately 0.1 to 10 W/V% for the phase separation inducer and 0.01% for the wall film forming aid relative to the ethyl cellulose-containing solution.
It is preferable that it is 10 W/V%. According to the method of the present invention as described above, the organic solvent molecules in cyclohexane interact mainly with the ethyl cellulose molecules in the capsule wall film made of coacervate or gel deposited on the core material through interactions such as hydrogen bonds. They gather to form a cluster of organic solvent molecules on the wall membrane, and this cluster acts as a barrier to mutual adhesion and aggregation of microcapsules, so that the formation, solidification, and stabilization of the capsule wall membrane proceed smoothly. In addition, due to the plasticizing effect of the organic solvent cluster, the viscoelasticity and adhesiveness of the phase-separated ethylcellulose become appropriate, and the deposition and "wetting" of ethylcellulose on the core material particles are significantly improved, resulting in a dense layer. It is possible to produce highly fluid microcapsules that have wall membranes and are free from agglomeration.
Furthermore, according to the method of the present invention using an organic solvent as an anti-aggregation agent, the microcapsules produced during the microcapsule manufacturing process hardly adhere to the manufacturing equipment. Therefore, the method of the present invention is a very advantageous method for industrially producing microcapsules. The above microencapsulation method of the present invention can be widely applied to various substances such as pharmaceuticals, veterinary drugs, agricultural chemicals, cosmetics, foods, and printing inks. Particularly in the case of pharmaceuticals, it is possible to obtain accurate improvement effects by stabilizing them, prolonging their efficacy, or alleviating taste, odor, irritation, etc. Pharmaceutical products to which the microencapsulation method of the present invention can be applied include, for example, vitamins, amino acids, peptides, chemotherapeutic agents, antibiotics, respiratory stimulants, antitussive expectorants, antineoplastic agents,
Autonomic nerve agents, psychiatric nerve agents, local anesthetics,
Muscle relaxant, gastrointestinal agent, antihistamine, poison treatment agent, hypnotic sedative, antiepileptic agent, antipyretic, analgesic, antiinflammatory agent, cardiotonic agent, antiarrhythmia agent, antihypertensive diuretic, vasodilator, antilipidemic agent, nourishing tonic and altering agent. A wide range of drugs can be listed, including anticoagulants, liver drugs, hypoglycemic agents, and antihypertensive agents. The present invention will be explained below with reference to experimental examples and examples. In addition, in this specification, "lower alkyl",
"Lower alkoxy", "lower alkanol" and "lower fatty acid" mean alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanol having 1 to 3 carbon atoms, and fatty acid having 1 to 5 carbon atoms, respectively. . Experimental example 1 1-methyl-5-methoxy-3-(dithiene-
Microcapsules containing 2-ylmethylene) piperidinium hydrobromide (hereinafter referred to as the active ingredient) were prepared by the following method, and were prepared according to the fine granule standards of the 10th edition of the Japanese Pharmacopoeia (hereinafter simply referred to as fine granule standards). ), the content of the active ingredient in the microcapsules, and the time required for 50% of the active ingredient to elute from the microcapsules (50% elution time) in a 0.2% sodium chloride aqueous solution at 37°C were measured. The results are shown in Table 1. (Preparation of microcapsules) (1) Preparation of core substance Add 7 parts of a 40V/V% ethanol aqueous solution to a mixed powder of 11.8 parts of the main drug, 82.8 parts of lactose, and 5.4 parts of white dextrin, and knead using a conventional method. After granulating, it was dried and sized into particles with a particle size of 105 to 350 μm, and used as a core material. (2) Preparation of microcapsules Add 2-ethoxyethyl acetate in the amount shown in Table 1 to 1000 ml of cyclohexane, and add a silicone resin that meets the standards of the Japanese Food Additives Standard, 4th edition (viscosity at 25°C is 100 to 1100 cSt). 3 silicon dioxide to dimethylpolysiloxane
Add 30g of ethyl cellulose (ethyl cellulose (ethoxy content: 48.2%, viscosity: 101cP)), 212g of the core material obtained in (1) and heat to 80°C and stir to prepare a core material dispersion. This dispersion
The mixture was cooled to room temperature while stirring at 400 rpm. The microcapsules thus produced were separated by a conventional method, washed with n-hexane, and then dried. The opening of the obtained microcapsules
Passes through a 500μm JIS standard sieve with an opening of 105μ
By collecting the residue on a JIS standard sieve, the active ingredient complies with fine granule standards.
Containing microcapsules were obtained.
【表】
第1表から、本発明方法により細粒剤基準に適
合したマイクロカプセルを収量よく得ることがで
きることがわかる。
実験例 2
実験例1と同じ主薬〔〕含有マイクロカプセ
ルを凝集防止剤である種々の有機溶媒の存在下で
調製し、マイクロカプセルの収量ならびにマイク
ロカプセル中の主薬の含量を測定した。
結果は下記第2表に示す通りである。
(マイクロカプセルの調製)
(1) 芯物質の調整
主薬〔〕5部、乳糖87部、白色デキストリ
ン8部の混合粉末に45V/V%エタノール水溶
液10部を加え、常法により練合して造粒した
後、乾燥して粒径105〜350μmの粒子に整粒
し、芯物質として用いた。
(2) マイクロカプセルの調整
シクロヘキサン800mlに、第2表に示す有機
溶媒24ml、シリコーン樹脂(実験例1で使用し
たものと同じ)24g、エチルセルロース(エト
キシ含量:47.8%、粘度:80cp)22.4gおよび
(1)で得た芯物質112gを加え80℃に加熱攪拌し
て芯物質の分散液を調製し、この分散液を
300rpmでかくはんしながら室温まで冷却し、
n−ヘキサン500mlを加えた。かくして生成し
たマイクロカプセルを常法により分離し、n−
ヘキサンで洗浄したのち乾燥する。以後実験例
1と同様に処理することにより細粒剤基準に適
合した主薬〔〕含有マイクロカプセルを得
た。Table 1 shows that microcapsules meeting the standards for fine granules can be obtained in good yield by the method of the present invention. Experimental Example 2 Microcapsules containing the same main drug as in Experimental Example 1 were prepared in the presence of various organic solvents as anti-aggregation agents, and the yield of the microcapsules and the content of the main drug in the microcapsules were measured. The results are shown in Table 2 below. (Preparation of microcapsules) (1) Adjustment of core substance Add 10 parts of a 45V/V% ethanol aqueous solution to a mixed powder of 5 parts of the main drug, 87 parts of lactose, and 8 parts of white dextrin, and knead using a conventional method. After granulating, it was dried and sized into particles with a particle size of 105 to 350 μm, and used as a core material. (2) Preparation of microcapsules 800 ml of cyclohexane, 24 ml of the organic solvent shown in Table 2, 24 g of silicone resin (same as that used in Experimental Example 1), 22.4 g of ethyl cellulose (ethoxy content: 47.8%, viscosity: 80 cp), and
Add 112g of the core material obtained in (1) and heat and stir at 80℃ to prepare a core material dispersion.
Cool to room temperature while stirring at 300 rpm.
500 ml of n-hexane was added. The microcapsules thus produced are separated by a conventional method, and n-
Wash with hexane and dry. Thereafter, microcapsules containing the main drug that met the standards for fine granules were obtained by processing in the same manner as in Experimental Example 1.
【表】【table】
【表】【table】
【表】
実験例 3
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)ピペリジニウム・臭化水素酸塩)含有マイ
クロカプセルを種々の有機溶媒の存在下で調製し
た。得られたマイクロカプセルの粒度分布、細粒
剤基準に適合したマイクロカプセルの収率及び次
式で算出される仕込量に対するマイクロカプセル
の収率を下記第3〜6表に示す。
仕込量に対するマイクロカプセルの収率(%)
=〔マイクロカプセルの収量/仕込エチルセ
ルロース量+仕込芯物質量〕x100
なお、第3〜4表は本願発明方法による実験結
果を示し、第5〜6表は比較例として、水素結合
成分が本願発明方法の範囲外である有機溶媒を用
いた場合の実験結果を示す。
(マイクロカプセルの調製)
(1) 芯物質の調整
主薬として、臭化チメピジウムを用いる以外
は実験例2−(1)と同様に造粒して、粒径105〜
350μmの粒子を製し、芯物質として用いた。
(2) マイクロカプセルの調製
シクロヘキサン80mlに、下記第3〜6表に示
す有機溶媒2.4ml、ポリイソブチレン(分子量
9000)2.4g、エチルセルロース(エトキシ含
量:47.8%、粘度:80cp)2.24g及び(1)で得た
芯物質11.2gを実験例1−(2)と同様に処理し
て、臭化チメピジウム含有マイクロカプセルを
得た。
(結果)
本願発明方法(第3〜4表)によれば、細粒剤
基準に適合したマイクロカプセルの収率は約81%
以上であるのに対し、比較例(第5〜6表)での
それは約14〜33%であつた。[Table] Experimental Example 3 Microcapsules containing thimepidium bromide (chemical name: 1,1-dimethyl-5-methoxy-3-(dithien-2-ylmethylene) piperidinium hydrobromide) were incubated in the presence of various organic solvents. Prepared below. Tables 3 to 6 below show the particle size distribution of the obtained microcapsules, the yield of microcapsules meeting the fine granule standards, and the yield of microcapsules with respect to the charge amount calculated by the following formula. Yield of microcapsules (%) with respect to the amount charged = [yield of microcapsules/amount of ethyl cellulose charged + amount of core material charged]x100 Tables 3 and 4 show the experimental results according to the method of the present invention, and Tables 5 and 6 shows, as a comparative example, experimental results when using an organic solvent whose hydrogen bond component is outside the range of the method of the present invention. (Preparation of microcapsules) (1) Adjustment of core substance Particles were granulated in the same manner as in Experimental Example 2-(1) except that thimepidium bromide was used as the main drug.
Particles of 350 μm were prepared and used as core material. (2) Preparation of microcapsules To 80 ml of cyclohexane, 2.4 ml of the organic solvent shown in Tables 3 to 6 below, polyisobutylene (molecular weight
9000), 2.24 g of ethyl cellulose (ethoxy content: 47.8%, viscosity: 80 cp), and 11.2 g of the core material obtained in (1) were treated in the same manner as in Experimental Example 1-(2) to obtain thimepidium bromide-containing microorganisms. Got the capsule. (Results) According to the method of the present invention (Tables 3 and 4), the yield of microcapsules that meet the standards for fine granules is approximately 81%.
In contrast, it was about 14 to 33% in the comparative examples (Tables 5 and 6).
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】
実施例 1
シクロヘキサン800mlに、酢酸24ml、エチルセ
ルロース(エトキシ含量:47.8%、粘度:80cP)
20g、ポリイソブチレン(スタウデインガー
(Staudinger)の粘度平均分子量が9000のもの)
18.7gおよび粒径105〜177μmのマレイン酸トリ
メブチン(化学名:2−ジメチルアミノ−2−フ
エニルブチル−3・4・5−トリメトキシベンゾ
エートヒドロジエンマレエート)100gを加え80
℃に加熱攪拌して芯物質の分散液を調製し、この
分散液を350rpmで攪拌しながら室温まで冷却し、
n−ヘキサン500mlを加えた。かくして生成した
マイクロカプセルを常法により分離し、n−ヘキ
サンで洗浄した後乾燥した。得られたマイクロカ
プセルを目開き350μmのJIS標準ふるいで処理す
ることにより第十改正日本薬局方の散剤基準(以
後単に散剤基準と略称する)に適合したマレイン
酸トリメブチン含有マイクロカプセル114gを得
た。
実施例 2
実施例1においてポリイソブチレンに代えて、
ポリエチレン(粘度平均分子量;7000)18.7gを
用い、以下実施例1と同様に処理することによ
り、散剤基準に適合したマレイン酸トリメブチン
含有マイクロカプセル118gを得た。
実施例 3
実施例1においてポリイソブチレンに代えて、
ブチルゴム〔ムーニ粘度:67(ML−8/100℃)〕
18.7gを用い、以下実施例1と同様に処理するこ
とにより、散剤基準に適合したマレイン酸トリメ
ブチン含有マイクロカプセル118gを得た。
実施例 4
実施例1においてポリイソブチレンに代えて、
ジメチルポリシロキサン(25℃における粘度:
500000cSt)24gを用い、以下実施例1と同様に
処理することにより、散剤基準に適合したマレイ
ン酸トリメブチン含有マイクロカプセル114gを
得た。
実施例 5
実施例1において酢酸に代えて、エタノール16
mlを用い、以下実施例1と同様に処理することに
より、散剤基準に適合したマレイン酸含有マイク
ロカプセル115gを得た。
実施例 6
実施例1においてマレイン酸トリメブチンに代
えて、粒径105〜177μmのビタミンC100gを用
い、以下実施例1と同様に処理することにより、
散剤基準に適合したビタミンC含有マイクロカプ
セル116gを得た。
実施例 7
実施例1において酢酸とマレイン酸トリメブチ
ンに代えて、メタノール16mlと粒径105〜177μm
のグルタチオン100gとを用い、以下実施例1と
同様に処理することにより、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112gを得た。
実施例 8
実施例1においてエトキシ含量47.8%、粘度
80cPのエチルセルロースに代えて、エトキシ含
量49.0%、粘度45cPのエチルセルロース20gを用
い、以下実施例1と同様に処理することにより、
散剤基準に適合したマレイン酸トリメブチン含有
マイクロカプセル115gを得た。[Table] Example 1 800 ml of cyclohexane, 24 ml of acetic acid, ethyl cellulose (ethoxy content: 47.8%, viscosity: 80 cP)
20g polyisobutylene (Staudinger viscosity average molecular weight 9000)
Add 18.7 g and 100 g of trimebutine maleate (chemical name: 2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxybenzoate hydrodiene maleate) with a particle size of 105 to 177 μm to 80 g.
A dispersion of the core substance was prepared by heating and stirring at ℃, and this dispersion was cooled to room temperature while stirring at 350 rpm.
500 ml of n-hexane was added. The microcapsules thus produced were separated by a conventional method, washed with n-hexane, and then dried. The obtained microcapsules were processed through a JIS standard sieve with an opening of 350 μm to obtain 114 g of trimebutine maleate-containing microcapsules that met the powder standards of the 10th edition of the Japanese Pharmacopoeia (hereinafter simply referred to as powder standards). Example 2 In place of polyisobutylene in Example 1,
By using 18.7 g of polyethylene (viscosity average molecular weight: 7000) and treating in the same manner as in Example 1, 118 g of trimebutine maleate-containing microcapsules meeting powder standards were obtained. Example 3 In place of polyisobutylene in Example 1,
Butyl rubber [Mouni viscosity: 67 (ML-8/100℃)]
By using 18.7 g and treating in the same manner as in Example 1, 118 g of trimebutine maleate-containing microcapsules meeting the powder standards were obtained. Example 4 In place of polyisobutylene in Example 1,
Dimethylpolysiloxane (viscosity at 25℃:
500,000 cSt) was treated in the same manner as in Example 1 to obtain 114 g of trimebutine maleate-containing microcapsules that met powder standards. Example 5 In Example 1, ethanol 16 was used instead of acetic acid.
ml and was treated in the same manner as in Example 1 to obtain 115 g of maleic acid-containing microcapsules that met powder standards. Example 6 In place of trimebutine maleate in Example 1, 100 g of vitamin C with a particle size of 105 to 177 μm was used, and the following treatment was carried out in the same manner as in Example 1.
116 g of vitamin C-containing microcapsules meeting powder standards were obtained. Example 7 In Example 1, instead of acetic acid and trimebutine maleate, 16 ml of methanol and a particle size of 105 to 177 μm were used.
By using 100 g of glutathione and treating in the same manner as in Example 1, 112 g of glutathione-containing microcapsules meeting powder standards were obtained. Example 8 In Example 1, the ethoxy content was 47.8% and the viscosity was
In place of 80 cP ethyl cellulose, 20 g of ethyl cellulose with an ethoxy content of 49.0% and a viscosity of 45 cP was used, and the following treatment was carried out in the same manner as in Example 1.
115 g of trimebutine maleate-containing microcapsules meeting powder standards were obtained.
Claims (1)
芯物質を分散させたのち、エチルセルロースの相
分離により芯物質上にエチルセルロース壁膜を形
成させてエチルセルロースマイクロカプセルを製
造する方法において、エチルセルロースの相分離
を溶解パラメータの水素結合成分δhが3.5〜11.0
〔(cal/cm2)1/2〕でありかつシクロヘキサンに溶解
ないし部分溶解する有機溶媒の存在下に実施する
ことを特徴とする非凝集性マイクロカプセルの製
法。 2 有機溶媒が炭素数1〜8の鎖状あるいは環状
アルカノール、乳酸低級アルキルエステル、低級
アルコキシ置換低級アルカノール、低級アルコキ
シ低級アルコキシ置換低級アルカノール、酢酸低
級アルコキシ置換低級アルキルエステル、低級脂
肪酸、テトラヒドロフラン、ジエチレングリコー
ルジ低級アルキルエーテル、トリ低級アルキルホ
スフエートまたは低級アルカノイル置換低級アル
カノールである特許請求の範囲第1項記載の製
法。 3 有機溶媒がエタノール、1−プロパノール、
2−エトキシエタノール、2−ブトキシエタノー
ル、酢酸2−エトキシエチルエステル、酢酸また
はテトラヒドロフランである特許請求の範囲第1
項記載の製法。 4 エチルセルロースの相分離を有機溶媒と共に
相分離誘起剤の存在下に実施する特許請求の範囲
第1項、第2項または第3項記載の製法。 5 エチルセルロースの相分離を有機溶媒と共に
壁膜形成助剤の存在下に実施する特許請求の範囲
第1項、第2項または第3項記載の製法。[Scope of Claims] 1. A method for manufacturing ethylcellulose microcapsules by dispersing a core material in a cyclohexane solution containing ethylcellulose and then forming an ethylcellulose wall film on the core material by phase separation of the ethylcellulose. Hydrogen bond component δh of solubility parameter is 3.5 to 11.0
[(cal/cm 2 ) 1/2 ] A method for producing non-aggregating microcapsules, which is carried out in the presence of an organic solvent that dissolves or partially dissolves in cyclohexane. 2 The organic solvent is a linear or cyclic alkanol having 1 to 8 carbon atoms, lower alkyl lactic acid ester, lower alkoxy-substituted lower alkanol, lower alkoxy-substituted lower alkanol, lower alkoxy-substituted acetic acid lower alkyl ester, lower fatty acid, tetrahydrofuran, diethylene glycol di The method according to claim 1, which is a lower alkyl ether, a tri-lower alkyl phosphate, or a lower alkanoyl-substituted lower alkanol. 3 The organic solvent is ethanol, 1-propanol,
Claim 1: 2-ethoxyethanol, 2-butoxyethanol, acetic acid 2-ethoxyethyl ester, acetic acid or tetrahydrofuran
Manufacturing method described in section. 4. The manufacturing method according to claim 1, 2 or 3, wherein the phase separation of ethylcellulose is carried out in the presence of an organic solvent and a phase separation inducing agent. 5. The manufacturing method according to claim 1, 2 or 3, wherein the phase separation of ethyl cellulose is carried out together with an organic solvent in the presence of a wall film forming aid.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP8102582A JPS58196842A (en) | 1982-05-13 | 1982-05-13 | Preparation of non-coagulable microcapsule |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP8102582A JPS58196842A (en) | 1982-05-13 | 1982-05-13 | Preparation of non-coagulable microcapsule |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS58196842A JPS58196842A (en) | 1983-11-16 |
JPS637091B2 true JPS637091B2 (en) | 1988-02-15 |
Family
ID=13734932
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP8102582A Granted JPS58196842A (en) | 1982-05-13 | 1982-05-13 | Preparation of non-coagulable microcapsule |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS58196842A (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUP0000116A3 (en) * | 1996-10-01 | 2000-08-28 | Stanford Res Inst Int | Taste-masked microcapsule compositions and methods of manufacture |
JP4683687B2 (en) * | 1999-03-12 | 2011-05-18 | 株式会社サクラクレパス | Powdered microcapsule and manufacturing method thereof |
-
1982
- 1982-05-13 JP JP8102582A patent/JPS58196842A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS58196842A (en) | 1983-11-16 |
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