WO1994009898A1 - Verfahren zur herstellung von mikrokapseln - Google Patents
Verfahren zur herstellung von mikrokapseln Download PDFInfo
- Publication number
- WO1994009898A1 WO1994009898A1 PCT/CH1993/000246 CH9300246W WO9409898A1 WO 1994009898 A1 WO1994009898 A1 WO 1994009898A1 CH 9300246 W CH9300246 W CH 9300246W WO 9409898 A1 WO9409898 A1 WO 9409898A1
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- WO
- WIPO (PCT)
- Prior art keywords
- microcapsules
- biodegradable
- solution
- active ingredient
- dissolved
- Prior art date
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- 239000003094 microcapsule Substances 0.000 title claims abstract description 55
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 31
- 229920000642 polymer Polymers 0.000 claims abstract description 27
- 229920002988 biodegradable polymer Polymers 0.000 claims abstract description 15
- 239000004621 biodegradable polymer Substances 0.000 claims abstract description 15
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 12
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 12
- 108090000790 Enzymes Proteins 0.000 claims abstract description 11
- 102000004190 Enzymes Human genes 0.000 claims abstract description 11
- 150000002148 esters Chemical class 0.000 claims abstract description 11
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 8
- 239000000725 suspension Substances 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 7
- 239000004480 active ingredient Substances 0.000 claims description 36
- 239000006185 dispersion Substances 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 229960005486 vaccine Drugs 0.000 claims description 11
- 238000002604 ultrasonography Methods 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 8
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000000758 substrate Substances 0.000 claims description 5
- 239000012736 aqueous medium Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000243 solution Substances 0.000 abstract description 43
- 239000013543 active substance Substances 0.000 abstract description 20
- 229940088598 enzyme Drugs 0.000 abstract description 9
- 239000000203 mixture Substances 0.000 abstract description 9
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 8
- 239000007864 aqueous solution Substances 0.000 abstract description 7
- 238000005507 spraying Methods 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 229940079919 digestives enzyme preparation Drugs 0.000 abstract description 2
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 abstract 1
- 239000004533 oil dispersion Substances 0.000 abstract 1
- 239000007921 spray Substances 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 12
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 12
- 238000001694 spray drying Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000843 powder Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229930182843 D-Lactic acid Natural products 0.000 description 5
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 description 5
- 238000011068 loading method Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000012798 spherical particle Substances 0.000 description 5
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 4
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 4
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- -1 isopropyl ester Chemical class 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000012620 biological material Substances 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 238000005354 coacervation Methods 0.000 description 2
- 238000004581 coalescence Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229960005309 estradiol Drugs 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 238000009434 installation Methods 0.000 description 2
- 239000011859 microparticle Substances 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 1
- 235000011330 Armoracia rusticana Nutrition 0.000 description 1
- 240000003291 Armoracia rusticana Species 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 101710117490 Circumsporozoite protein Proteins 0.000 description 1
- 229920001634 Copolyester Polymers 0.000 description 1
- 108020005199 Dehydrogenases Proteins 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 1
- 241000224017 Plasmodium berghei Species 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 108010055044 Tetanus Toxin Proteins 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 229920000229 biodegradable polyester Polymers 0.000 description 1
- 239000004622 biodegradable polyester Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940003372 compro Drugs 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 229960002986 dinoprostone Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 229940065514 poly(lactide) Drugs 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- WIKYUJGCLQQFNW-UHFFFAOYSA-N prochlorperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 WIKYUJGCLQQFNW-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229940126577 synthetic vaccine Drugs 0.000 description 1
- 229940118376 tetanus toxin Drugs 0.000 description 1
- 229960000814 tetanus toxoid Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- 231100000925 very toxic Toxicity 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
-
- 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
- B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
- B01J13/043—Drying and spraying
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
-
- 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
- B01J13/12—Making microcapsules or microballoons by phase separation removing solvent from the wall-forming material solution
Definitions
- microcapsule encompasses both actual microcapsules and microspheres and microparticles according to the following definitions:
- microcapsules describes spherical particles in the grain size range from 1 to 1000 ⁇ , composed of an inner core which contains the active ingredient in liquid or solid form, and the capsule wall made of polymer.
- microspheres or microparticles describe spherical and non-spherical particles in the grain size range from 1 to 1000 ⁇ m, built up from a polymer matrix in which the active substance is embedded as a so-called solid solution or suspension.
- Biologically highly active and sensitive active substances such as certain medicinal substances, peptides, proteins, enzymes and vaccines are preferably used parenterally as a solution for injection.
- many of these agents have a short biological half-life or are not very active when applied in solution (vaccines).
- a continuous or pulse-like supply of active substance (long-term release) is an indispensable prerequisite for successful therapeutic or preventive treatment.
- Such an active substance supply which lasts over a longer period of time can be achieved by incorporating the active substance into a biodegradable release system, for example. Release systems of this type can be produced in the form of microcapsules or implant rods. Biodegradable microcapsules have proven particularly successful in the past, since these particles can be administered parenterally easily with conventional injection needles.
- DH Lewis Controlled release of bioactive agents from lactide / glycolide polymers, in: Biodegradable polymers as drug delivery Systems, M. Chasin, and R. Langer (Eds.), M. Dekker, New York, 1990, pp. 1-41).
- microcapsules are produced by coacervation, which are particularly contaminated with such organic solvents.
- other organic solvents are used for the actual phase separation, for curing and for washing the microcapsules.
- the microcapsules produced in this way are relatively large and easily agglomerate during the production process, which makes the removal of residual solvents even more difficult.
- Spray drying is a well-known, simple and fast method for producing biodegradable microcapsules.
- it is repeatedly pointed out the difficulty of producing spherical and non-porous particles with the biodegradable polymers of lactic and glycolic acid.
- poly (d, 1-lactic acid) dissolved in methylene chloride, very irregularly shaped microcapsules with an irregular surface and a high proportion of fiber-like material are obtained (R. Bodmeier et al., J. Pharm. Pharmacol. 40, 754-757 ( 1988)).
- PS-EP AI 315,875 it is known that the copolymers of lactic and glycolic acid (PLGA) cannot be processed into microcapsules by means of spray drying.
- microencapsulated protein is released within 1-3 days; this is generally attributed to a high proportion of insufficiently encapsulated active substance and high microcapsule porosity (HT Wang et al., Biomaterials, 11, 679-685 (1990)).
- water-miscible solvents such as acetone, tetrahydrofuran, dioxane, acetonitrile and others cannot be used, since it is precisely because of this miscibility that precipitation or aggregation of the active ingredient and / or polymer occurs.
- the object of the invention is achieved in that the biodegradable polymer is dissolved in a biodegradable and toxicologically acceptable solvent, and the active ingredients, respectively.
- the biologically active substances such as drugs, peptides, proteins, enzymes and vaccines are introduced into them, and microcapsules are produced by spray drying.
- steps 1-8 show the flowchart for a method for producing microcapsules, which is described below by steps 1-8:
- the starting point of the process is all biodegradable polymers insofar as they are soluble in the solvents according to the invention, such as mono- and copolyesters of lactic, glycolic and ß-hydroxybutyric acid, as well as of ⁇ -valerolactone and ⁇ -caprolactone.
- Polylactic and polyglycolic acid are also referred to as poly (lactide) and poly (glycolide).
- the biodegradable polymer, or a mixture of biodegradable polymers is dissolved in the solvents according to the invention, a polymer solution (first solution) being formed.
- These solvents include the group of simple esters, composed of a Cj-C 3 alcohol and a Cj-C 3 monocarboxylic acid, and mixtures of these simple esters with a Cj-C 3 alcohol.
- These biodegradable solvents include, for example, ethyl formate, propyl ester, butyl ester, ethyl acetate, propyl ester, isopropyl ester, ethyl propionate, ethyl butyrate and ethyl valerate, and mixtures of these esters with ethanol, propanol, isopropanol and others.
- solvents or solvent mixtures have, for example for the biodegradable polyester compounds from glycolic, lactic, ⁇ -hydroxybutyric acid, ⁇ -valerolactone and from ⁇ -caprolactone, a surprisingly high solvency. They are able to dissolve both homo- and copolymers of these hydroxycarboxylic acids in a wide variety of molar ratios, such as 50:50, 65:35, 75:25 or 85:15 and in a wide range of molecular weights (2000 - 150000).
- the polymers can be brought into solution individually or as a mixture, and the solvents according to the invention individually or as solvent mixture consisting of different esters or of esters and alcohols can be used.
- the active substance to be encapsulated is introduced into the biodegradable polymer in three ways, depending on its solubility, in accordance with steps 3, 5 and 6.
- the following are defined as active substances, which have a biological effect in living organisms, where this can be, for example, pharmacological, immunological or enzymatic.
- the active ingredient to be encapsulated is generally in solid form (powder), but can also be in liquid form and processed as a liquid.
- Active ingredients that can be dissolved in the biodegradable solvents according to the invention consisting of esters, Cj-Cj alcohols and any ester-alcohol mixtures thereof, are dissolved directly therein, resulting in an organic active ingredient solution (second solution).
- This active ingredient solution represents the preferred process step, since it can be produced with minimal effort and is thermodynamically stable.
- the polymer solution (first solution) and the organic active ingredient solution (second solution) are then combined and mixed, whereby the substrate 'solution' is obtained.
- the solvents described here are characterized by a high solvency for a large number of low-molecular-weight active substances, such as certain medicinal substances and peptides. This advantageous property of these solvents also makes it possible to bring the active ingredient and the biodegradable polymer into solution at the same time by using the same solvent or a combination of biodegradable solvents.
- step 8. 5 Suspend
- Active substances which cannot be dissolved sufficiently in water or in the solvents according to the invention are suspended mechanically or by means of ultrasound in the polymer solution which contains the biodegradable polymer in the biodegradable solvents, as a result of which the substrate 'suspension' is obtained.
- the active ingredient is preferably presented in micronized form. Particles smaller than 10 ⁇ m are generally sought for the active ingredient. The process continues with step 8.
- Active substances which are readily soluble in water such as certain medicinal substances, peptides, proteins, enzymes, or vaccines, which cannot be dissolved in the solvents according to the invention, are advantageously dissolved in the smallest possible volume of an aqueous medium, resulting in an aqueous active substance solution.
- the aqueous medium can contain additives such as, for example, buffer salts, surfactants, stabilizers and preservatives.
- the aqueous active ingredient solution obtained after step 6 is subsequently finely dispersed in the polymer solution which contains the biodegradable polymer in the solvents according to the invention, as a result of which the substrate 'W / O dispersion' is obtained.
- Aqueous active ingredient solutions with a volume fraction of 50% and with little energy expenditure can be incorporated into the polymer solution nanodisperse.
- the dispersion can be carried out by simple shaking, but better by means of a mechanical dispersing device or ultrasound.
- the preferred dispersion method is ultrasonication with 50-400 W for 10-300 s or longer if necessary.
- microcapsules produced by spray drying generally have a diameter of 1-50 ⁇ m, but a maximum of 100 ⁇ m, and can therefore easily pass through an injection needle.
- the degree of loading of the microcapsules (active ingredient content) is between 0 and 50%, but preferably between 0 and 20%.
- microcapsules produced in this way are expediently processed - and adapted to the end use - whereby, for example, a washing process, fractionation into different grain sizes, final drying under high vacuum, sterilization by means of ⁇ -radiation or any other processes can follow.
- the method described here with steps 1-8 enables high incorporation efficiency and a homogeneous active ingredient-in-polymer distribution for active ingredients with different solubility because of the high solvency of the solvents according to the invention for many active ingredients and because of the easy dispersibility of aqueous active ingredient solutions - characteristics.
- the active ingredient is made from the microcapsules depending on the polymer used, the degree of loading and any additives (release regulators) released over a period of 1 day to 1 year.
- the biodegradable solvents according to the invention make it possible to produce microcapsules by spray drying, also using poly (d, 1-lactic acid) or poly (milk-co-glycolic acid).
- the products obtained show a regular spherical particle morphology and a smooth non-porous surface. Particle sticking, agglomerations or deformations are hardly observed.
- the solvents according to the invention also have the extraordinary advantage that they are toxicologically harmless. Just like the polymers on which the microcapsules are based, the solvents according to the invention build up in the organism into smaller, non-toxic, and in some cases. physiological components. This breakdown occurs essentially by hydrolysis, but can also take place enzymatically, for example by esterases or dehydrogenases. In contrast to the solvents according to the invention, the otherwise commonly used solvents are converted into toxic metabolites in the organism. In addition to the well-founded suspicion of a carcinogenic potential and various toxic effects, methylene chloride in the organism produces, for example, the respiratory poison carbon monoxide.
- Example 1 describes the preparation of microcapsules containing a protein: 0.09 g bovine serum albumin (Fluka, CH-Buchs) were dissolved in 2.16 g water. The aqueous solution was dispersed in a solution of 3.0 g of poly (d, 1-lactic acid) (Reso er R202, Boehringer Ingelheim) in 57.0 g of isopropyl acetate with the aid of an ultrasound generator. The dispersion was carried out under ice cooling in an ultrasound processor (Vibracell, VC375, Sonics and Materials, Danbury, CT) with an energy of 260 W for 2 x 30 s.
- an ultrasound processor Vibracell, VC375, Sonics and Materials, Danbury, CT
- the dispersion is in a laboratory spray dryer (Mini Spray Dryer, Büchi 190, Büchi Laboratorien, CH-Flawil) sprayed under the following conditions: inlet temperature: 55 ° C, spray flow: 400 scale parts, aspirator: 15 scale parts, spray speed: 2.4 ml / min.
- a laboratory spray dryer Mini Spray Dryer, Büchi 190, Büchi Laboratorien, CH-Flawil
- microcapsules are produced as a white, free-flowing powder. Yield: 1.8 g (58% of theory), active ingredient content: 2.9% (100% of theory).
- Example 2 describes the preparation of microcapsules containing a protein: 0.09 g of bovine serum albumin was dissolved in 2.16 g of water. The aqueous solution was dispersed in a solution of 3.0 g of poly (d, 1-lactic acid) (Resomer R202, Boehringer Ingelheim) in 57.0 g of ethyl acetate using an ultrasound generator (260 W for 30 s). Dispersion and spray drying were carried out under identical conditions as in Example 1. Yield: 1.6 g (52% of theory), active ingredient content: 2.9% (100% of theory).
- Example 3 describes the preparation of microcapsules containing a vaccine: 0.100 g of lyophilized tetanus toxoid was dissolved in 2.0 ml of water. The aqueous solution was dispersed in a solution of 5.0 g of poly (d, 1-lactic acid-co-glycolic acid) (resomer RG502, Boehringer Ingelheim) in 100.0 g of ethyl formate using an ultrasound generator. The dispersion was carried out under ice cooling with an ultrasound energy of 210 W for 2 x 30 s. The dispersion was sprayed in a laboratory spray dryer under the following conditions: inlet temperature: 55 ° C., spray flow: 500 scale parts, aspirator: 17.5 scale parts, spray speed: 2.4 ml / min.
- microcapsules were obtained as a white, free-flowing powder. Yield: 0.7 g (40% of theory), protein content: 1.82%, corresponding to 93% of the theoretically determined active substance content.
- Example 4 describes the production of microcapsules containing an enzyme: 15 mg peroxidase from horseradish with an activity of 75.8 U / mg (Fluka, CH-Buchs) are in 0.6 ml Water dissolved.
- the aqueous solution is dispersed by means of ultrasound of 375 W for 30 s with ice cooling in a solution of 1.5 g of poly (d, 1-lactic acid) (Resomer R202, Boehringer Ingelheim) in 30.0 g of ethyl formate.
- the dispersion is sprayed with a laboratory spray dryer under the following conditions: inlet temperature: 47 ° C., spray flow: 450 scale parts, aspirator: 17 scale parts, spray speed: 1.6 ml / min.
- microcapsules are produced as a white, free-flowing powder. Yield: 0.92 g (61% of theory), enzyme activity: 0.177 U / mg microcapsules, corresponding to 23.4% of the theoretically determined activity.
- Example 5 describes the production of microcapsules containing a medicament: 30 mg prostaglandin E2 (Fluka, CH-Buchs) and 6.0 g poly (d, 1-lactic acid-co-glycolic acid) (Resomer RG502, Boehringer Ingelheim) were separated into 60 g each of ethyl formate dissolved. The combined solutions were sprayed under the following conditions: inlet temperature: 45 ° C., spray flow: 420 scale parts, aspirator: 15 scale parts, spray speed: 2.4 ml / min.
- microcapsules are produced as a white, free-flowing powder. Yield: 4.2 g (70% of theory), degree of loading: 4.99 ⁇ g / mg microcapsules (100% of theory).
- Example 6 describes the preparation of microcapsules containing a hormone: 25 g of 17- ⁇ -estradiol are dissolved in a mixture of 125 ml of anhydrous water and 312.5 ml of ethyl acetate. 100 g of Resomer RG 503 (Boehringer Ingelheim) are dissolved in 812.5 ml of ethyl formate. Before spraying, both solutions are combined with stirring and formation of a stable suspension.
- the suspension is sprayed under the following conditions in a mobile minor spray dryer (from NIRO AS, Copenhagen): inlet temperature: 67 ° C., spray speed: 0.9 l / h.
- a mobile minor spray dryer from NIRO AS, Copenhagen
- microcapsules are obtained as a white powder containing discrete, spherical particles. Yield: 80 g (80% of theory); Degree of loading: 70.2 ⁇ g / mg microcapsules (85.1% of theory).
- Example 7 describes the preparation of microcapsules containing a hormone: 10 g of 17 ⁇ -estradiol are dissolved in a mixture of 100 ml of anhydrous ethanol and 250 ml of ethyl acetate. 90 g of Resomer RG 752 (Boehringer Ingelheim) are dissolved in 650 ml of ethyl formate. The two solutions are combined with stirring and sprayed under the following conditions in a mobile minor spray dryer (from NIRO AS, Copenhagen): inlet temperature: 70 ° C., spray speed: 0.9 l / h.
- a mobile minor spray dryer from NIRO AS, Copenhagen
- microcapsules are obtained as a white powder containing discrete, spherical particles. Yield: 100 g (85% of theory); Degree of loading: 89.6 ⁇ g / mg microcapsules (89.6% of theory).
- Example 8 describes the production of microcapsules containing a synthetic vaccine: 0.02 g of a synthetic protein consisting of the peptide sequence 947-967 of the tetanus toxin and a B cell epitope of the repetitive region of the circumsporozoite protein from Plasmodium berghei dissolved in 1.0 ml of water.
- the aqueous solution was dispersed in a solution of 2.0 g of poly (d, 1-lactic acid-co-glycolic acid) (Resomer RG 752, Boehringer Ingelheim) in 40.0 g of ethyl formate using an ultrasound generator.
- the dispersion took place under ice cooling with an ultrasonic energy of 210 W for 2 x 30 s.
- the dispersion was sprayed in a laboratory spray dryer under the following conditions:
- Inlet temperature 50 ° C
- spray flow 450 divisions
- aspirator 14 divisions
- spray speed 2.6 ml / min.
- microcapsules are produced as a white, free-flowing powder. Yield: 1.12 g (56% of theory); Protein content: 0.66%, corresponding to 0.6% of the theoretically determined active substance content.
- biodegradable solution Means are proposed, so that the microcapsules thus produced are free of residual toxic solvents.
- the microcapsules are obtained by spraying a solution, suspension or dispersion of active ingredients and polymers. Both water-soluble and water-insoluble substances are suitable as active substances to be embedded. Water-soluble active ingredients such as peptides, proteins, vaccines are preferably dispersed as an aqueous solution in the polymer solution. A method is hereby available which is used in the manufacture of pharmaceutical, vaccine and enzyme preparations.
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002126685A CA2126685C (en) | 1992-10-26 | 1993-10-18 | Process for the production of microcapsules |
DK93922486T DK0625069T3 (da) | 1992-10-26 | 1993-10-18 | Fremgangsmåde til fremstilling af mikrokapsler |
JP51051894A JP3523254B2 (ja) | 1992-10-26 | 1993-10-18 | マイクロカプセルの製造方法 |
KR1019940702042A KR100225983B1 (ko) | 1992-10-26 | 1993-10-18 | 마이크로캡슐의 제조 방법 |
HU9401329A HU221308B1 (en) | 1992-10-26 | 1993-10-18 | Process for producing microcapsules |
EP93922486A EP0625069B1 (de) | 1992-10-26 | 1993-10-18 | Verfahren zur herstellung von mikrokapseln |
DE59309257T DE59309257D1 (de) | 1992-10-26 | 1993-10-18 | Verfahren zur herstellung von mikrokapseln |
FI943067A FI943067A (fi) | 1992-10-26 | 1994-06-23 | Mikrokapselien valmistusmenetelmä |
GR990400601T GR3029504T3 (en) | 1992-10-26 | 1999-02-26 | Method of manufacturing microcapsules. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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CH3319/92-3 | 1992-10-26 | ||
CH331992 | 1992-10-26 |
Publications (1)
Publication Number | Publication Date |
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WO1994009898A1 true WO1994009898A1 (de) | 1994-05-11 |
Family
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Application Number | Title | Priority Date | Filing Date |
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PCT/CH1993/000246 WO1994009898A1 (de) | 1992-10-26 | 1993-10-18 | Verfahren zur herstellung von mikrokapseln |
Country Status (14)
Country | Link |
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US (1) | US5648096A (de) |
EP (1) | EP0625069B1 (de) |
JP (1) | JP3523254B2 (de) |
KR (1) | KR100225983B1 (de) |
CN (1) | CN1058864C (de) |
AT (1) | ATE175132T1 (de) |
CA (1) | CA2126685C (de) |
DE (1) | DE59309257D1 (de) |
DK (1) | DK0625069T3 (de) |
ES (1) | ES2127835T3 (de) |
FI (1) | FI943067A (de) |
GR (1) | GR3029504T3 (de) |
HU (1) | HU221308B1 (de) |
WO (1) | WO1994009898A1 (de) |
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EP0315875A1 (de) * | 1987-11-11 | 1989-05-17 | Hoechst Aktiengesellschaft | Verfahren zur Herstellung von bioabbaubaren Mikrokapseln wasserlöslicher Peptide und Proteine sowie nach diesem Verfahren erhaltene Mikrokapseln |
EP0330180A1 (de) * | 1988-02-24 | 1989-08-30 | Biomaterials Universe, Inc. | Physiologisch aktive Substanzen enthaltende Mikrosphären des Polymilchsäuretyps sowie Verfahren zu deren Herstellung |
EP0505966A1 (de) * | 1991-03-25 | 1992-09-30 | Hoechst Aktiengesellschaft | Langwirkende bioabbaubare Mikropartikel und ein Verfahren zur Herstellung |
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US4637905A (en) * | 1982-03-04 | 1987-01-20 | Batelle Development Corporation | Process of preparing microcapsules of lactides or lactide copolymers with glycolides and/or ε-caprolactones |
IE58110B1 (en) * | 1984-10-30 | 1993-07-14 | Elan Corp Plc | Controlled release powder and process for its preparation |
ES2051968T3 (es) * | 1988-12-22 | 1994-07-01 | American Cyanamid Co | Metodo para el tratamiento de enfermedad periodontal mediante la liberacion continua de un agente terapeutico a la bolsa periodontal; composicion de materia del mismo y aparato para su administracion. |
IL92344A0 (en) * | 1989-01-04 | 1990-07-26 | Gist Brocades Nv | Microencapsulation of bioactive substances in biocompatible polymers,microcapsules obtained and pharmaceutical preparation comprising said microcapsules |
JPH04247987A (ja) * | 1991-01-18 | 1992-09-03 | Fuji Photo Film Co Ltd | 感熱記録材料 |
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1993
- 1993-10-18 WO PCT/CH1993/000246 patent/WO1994009898A1/de active IP Right Grant
- 1993-10-18 CA CA002126685A patent/CA2126685C/en not_active Expired - Fee Related
- 1993-10-18 JP JP51051894A patent/JP3523254B2/ja not_active Expired - Fee Related
- 1993-10-18 EP EP93922486A patent/EP0625069B1/de not_active Expired - Lifetime
- 1993-10-18 DK DK93922486T patent/DK0625069T3/da active
- 1993-10-18 AT AT93922486T patent/ATE175132T1/de not_active IP Right Cessation
- 1993-10-18 HU HU9401329A patent/HU221308B1/hu not_active IP Right Cessation
- 1993-10-18 ES ES93922486T patent/ES2127835T3/es not_active Expired - Lifetime
- 1993-10-18 KR KR1019940702042A patent/KR100225983B1/ko not_active IP Right Cessation
- 1993-10-18 DE DE59309257T patent/DE59309257D1/de not_active Expired - Fee Related
- 1993-10-26 CN CN93119645A patent/CN1058864C/zh not_active Expired - Fee Related
-
1994
- 1994-06-22 US US08/264,007 patent/US5648096A/en not_active Expired - Fee Related
- 1994-06-23 FI FI943067A patent/FI943067A/fi not_active IP Right Cessation
-
1999
- 1999-02-26 GR GR990400601T patent/GR3029504T3/el unknown
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EP0102265A2 (de) * | 1982-07-29 | 1984-03-07 | The Stolle Research And Development Corporation | Injizierbares langwirkendes Mikroteilchen-Präparat zur Verabreichung entzündungshemmender Mittel |
JPS6067417A (ja) * | 1983-09-24 | 1985-04-17 | Tetsuo Kato | 生体内代謝性マイクロカプセルの製法 |
EP0315875A1 (de) * | 1987-11-11 | 1989-05-17 | Hoechst Aktiengesellschaft | Verfahren zur Herstellung von bioabbaubaren Mikrokapseln wasserlöslicher Peptide und Proteine sowie nach diesem Verfahren erhaltene Mikrokapseln |
EP0330180A1 (de) * | 1988-02-24 | 1989-08-30 | Biomaterials Universe, Inc. | Physiologisch aktive Substanzen enthaltende Mikrosphären des Polymilchsäuretyps sowie Verfahren zu deren Herstellung |
EP0505966A1 (de) * | 1991-03-25 | 1992-09-30 | Hoechst Aktiengesellschaft | Langwirkende bioabbaubare Mikropartikel und ein Verfahren zur Herstellung |
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R. BODMEIER ET AL.: "PREPARATION OF BIODEGRADABLE POLY( )LACTIDE MICROPARTICLES USING A SPRAY-DRYING TECHNIQUE", J. PHARM. PHARMACOL., vol. 40, 16 December 1987 (1987-12-16), pages 754 - 757, XP000615391 * |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0678035A4 (de) * | 1993-01-08 | 1997-02-26 | Csl Ltd | Impfstoffpräparate. |
EP0678035A1 (de) * | 1993-01-08 | 1995-10-25 | Csl Limited | Impfstoffpräparate |
EP0862420A1 (de) * | 1995-10-13 | 1998-09-09 | The Penn State Research Foundation | Synthese von arzneistoffnanopartikeln durch sprühtrocknung |
EP0862420A4 (de) * | 1995-10-13 | 1999-11-03 | Penn State Res Found | Synthese von arzneistoffnanopartikeln durch sprühtrocknung |
US6270795B1 (en) | 1995-11-09 | 2001-08-07 | Microbiological Research Authority | Method of making microencapsulated DNA for vaccination and gene therapy |
US6667294B2 (en) | 1995-11-09 | 2003-12-23 | Microbiological Research Authority | Microencapsulated DNA for vaccination and gene therapy |
US5783567A (en) * | 1997-01-22 | 1998-07-21 | Pangaea Pharmaceuticals, Inc. | Microparticles for delivery of nucleic acid |
US6482864B1 (en) | 1998-03-20 | 2002-11-19 | Takeda Chemical Industries, Ltd. | Sustained-release preparation of physiologically active polypeptide and production thereof |
US6309569B1 (en) | 1998-05-13 | 2001-10-30 | Microbiological Research Authority | Encapsulation of bioactive agents |
US6565777B2 (en) | 1998-05-13 | 2003-05-20 | Microbiological Research Authority | Encapsulation of bioactive agents |
US6406719B1 (en) | 1998-05-13 | 2002-06-18 | Microbiological Research Authority | Encapsulation of bioactive agents |
US6548302B1 (en) | 1998-06-18 | 2003-04-15 | Johns Hopkins University School Of Medicine | Polymers for delivery of nucleic acids |
US7087236B1 (en) | 1998-09-01 | 2006-08-08 | Merrion Research I Limited | Method for inducing a cell-mediated immune response and improved parenteral vaccine formulations thereof |
Also Published As
Publication number | Publication date |
---|---|
DK0625069T3 (da) | 1999-08-30 |
CA2126685C (en) | 2002-07-23 |
KR100225983B1 (ko) | 1999-10-15 |
CA2126685A1 (en) | 1994-05-11 |
JP3523254B2 (ja) | 2004-04-26 |
FI943067A0 (fi) | 1994-06-23 |
GR3029504T3 (en) | 1999-05-28 |
CN1058864C (zh) | 2000-11-29 |
HUT70418A (en) | 1995-10-30 |
ATE175132T1 (de) | 1999-01-15 |
DE59309257D1 (de) | 1999-02-11 |
JPH07502686A (ja) | 1995-03-23 |
HU9401329D0 (en) | 1994-08-29 |
HU221308B1 (en) | 2002-09-28 |
EP0625069B1 (de) | 1998-12-30 |
EP0625069A1 (de) | 1994-11-23 |
ES2127835T3 (es) | 1999-05-01 |
US5648096A (en) | 1997-07-15 |
FI943067A (fi) | 1994-06-23 |
CN1090172A (zh) | 1994-08-03 |
KR940703713A (ko) | 1994-12-12 |
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