CA2302601C - Transdermal therapeutic system comprising a reservoir-type pressure-sensitive adhesive layer and a back layer with uni-directional resilience - Google Patents
Transdermal therapeutic system comprising a reservoir-type pressure-sensitive adhesive layer and a back layer with uni-directional resilience Download PDFInfo
- Publication number
- CA2302601C CA2302601C CA002302601A CA2302601A CA2302601C CA 2302601 C CA2302601 C CA 2302601C CA 002302601 A CA002302601 A CA 002302601A CA 2302601 A CA2302601 A CA 2302601A CA 2302601 C CA2302601 C CA 2302601C
- Authority
- CA
- Canada
- Prior art keywords
- transdermal therapeutic
- therapeutic system
- backing layer
- layer
- backing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000010410 layer Substances 0.000 title claims abstract description 99
- 230000001225 therapeutic effect Effects 0.000 title claims abstract description 56
- 239000004820 Pressure-sensitive adhesive Substances 0.000 title claims abstract description 26
- 239000011241 protective layer Substances 0.000 claims abstract description 14
- 239000013013 elastic material Substances 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 7
- 208000002193 Pain Diseases 0.000 claims abstract description 5
- 239000011248 coating agent Substances 0.000 claims abstract description 5
- 238000000576 coating method Methods 0.000 claims abstract description 5
- 229940079593 drug Drugs 0.000 claims abstract description 5
- 239000013543 active substance Substances 0.000 claims description 35
- 239000000463 material Substances 0.000 claims description 26
- 239000004744 fabric Substances 0.000 claims description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- -1 polyethylene Polymers 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 229920000642 polymer Polymers 0.000 claims description 8
- 229920000728 polyester Polymers 0.000 claims description 7
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 claims description 6
- 229960001736 buprenorphine Drugs 0.000 claims description 6
- 238000004080 punching Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 230000001499 parasympathomimetic effect Effects 0.000 claims description 5
- 230000035699 permeability Effects 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 239000002759 woven fabric Substances 0.000 claims description 5
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 claims description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 4
- HJJPJSXJAXAIPN-UHFFFAOYSA-N arecoline Chemical compound COC(=O)C1=CCCN(C)C1 HJJPJSXJAXAIPN-UHFFFAOYSA-N 0.000 claims description 4
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 claims description 4
- ALOUNLDAKADEEB-UHFFFAOYSA-N dimethyl sebacate Chemical compound COC(=O)CCCCCCCCC(=O)OC ALOUNLDAKADEEB-UHFFFAOYSA-N 0.000 claims description 4
- WOZVHXUHUFLZGK-UHFFFAOYSA-N dimethyl terephthalate Chemical compound COC(=O)C1=CC=C(C(=O)OC)C=C1 WOZVHXUHUFLZGK-UHFFFAOYSA-N 0.000 claims description 4
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims description 4
- QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 4
- TVIDDXQYHWJXFK-UHFFFAOYSA-N n-Dodecanedioic acid Natural products OC(=O)CCCCCCCCCCC(O)=O TVIDDXQYHWJXFK-UHFFFAOYSA-N 0.000 claims description 4
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 239000011148 porous material Substances 0.000 claims description 4
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 claims description 4
- 229930013930 alkaloid Natural products 0.000 claims description 3
- 229960001231 choline Drugs 0.000 claims description 3
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 3
- 239000002329 esterase inhibitor Substances 0.000 claims description 3
- 239000005556 hormone Substances 0.000 claims description 3
- 229940088597 hormone Drugs 0.000 claims description 3
- 239000004745 nonwoven fabric Substances 0.000 claims description 3
- 229940055076 parasympathomimetics choline ester Drugs 0.000 claims description 3
- 150000003248 quinolines Chemical class 0.000 claims description 3
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 claims description 2
- RGCVYEOTYJCNOS-UHFFFAOYSA-N (4-cyano-2-methylphenyl)boronic acid Chemical compound CC1=CC(C#N)=CC=C1B(O)O RGCVYEOTYJCNOS-UHFFFAOYSA-N 0.000 claims description 2
- HPOIPOPJGBKXIR-UHFFFAOYSA-N 3,6-dimethoxy-10-methyl-galantham-1-ene Natural products O1C(C(=CC=2)OC)=C3C=2CN(C)CCC23C1CC(OC)C=C2 HPOIPOPJGBKXIR-UHFFFAOYSA-N 0.000 claims description 2
- LCFVJGUPQDGYKZ-UHFFFAOYSA-N Bisphenol A diglycidyl ether Chemical compound C=1C=C(OCC2OC2)C=CC=1C(C)(C)C(C=C1)=CC=C1OCC1CO1 LCFVJGUPQDGYKZ-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- LPCKPBWOSNVCEL-UHFFFAOYSA-N Chlidanthine Natural products O1C(C(=CC=2)O)=C3C=2CN(C)CCC23C1CC(OC)C=C2 LPCKPBWOSNVCEL-UHFFFAOYSA-N 0.000 claims description 2
- DRUKNYVQGHETPO-UHFFFAOYSA-N Nonanedioic acid dimethyl ester Natural products COC(=O)CCCCCCCC(=O)OC DRUKNYVQGHETPO-UHFFFAOYSA-N 0.000 claims description 2
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 claims description 2
- 229920001283 Polyalkylene terephthalate Polymers 0.000 claims description 2
- 239000004698 Polyethylene Substances 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 239000004743 Polypropylene Substances 0.000 claims description 2
- VNYBTNPBYXSMOO-UHFFFAOYSA-M Pyridostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=C[N+](C)=C1 VNYBTNPBYXSMOO-UHFFFAOYSA-M 0.000 claims description 2
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 claims description 2
- YIMQCDZDWXUDCA-UHFFFAOYSA-N [4-(hydroxymethyl)cyclohexyl]methanol Chemical compound OCC1CCC(CO)CC1 YIMQCDZDWXUDCA-UHFFFAOYSA-N 0.000 claims description 2
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 claims description 2
- 229960004373 acetylcholine Drugs 0.000 claims description 2
- 235000011037 adipic acid Nutrition 0.000 claims description 2
- 239000001361 adipic acid Substances 0.000 claims description 2
- 230000000202 analgesic effect Effects 0.000 claims description 2
- NZUPCNDJBJXXRF-UHFFFAOYSA-O bethanechol Chemical compound C[N+](C)(C)CC(C)OC(N)=O NZUPCNDJBJXXRF-UHFFFAOYSA-O 0.000 claims description 2
- 229960000910 bethanechol Drugs 0.000 claims description 2
- 229960004484 carbachol Drugs 0.000 claims description 2
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 claims description 2
- 150000005690 diesters Chemical class 0.000 claims description 2
- 229940014772 dimethyl sebacate Drugs 0.000 claims description 2
- 229960001446 distigmine Drugs 0.000 claims description 2
- GJHSNEVFXQVOHR-UHFFFAOYSA-L distigmine bromide Chemical compound [Br-].[Br-].C=1C=C[N+](C)=CC=1OC(=O)N(C)CCCCCCN(C)C(=O)OC1=CC=C[N+](C)=C1 GJHSNEVFXQVOHR-UHFFFAOYSA-L 0.000 claims description 2
- 229960003980 galantamine Drugs 0.000 claims description 2
- BGLNUNCBNALFOZ-WMLDXEAASA-N galanthamine Natural products COc1ccc2CCCC[C@@]34C=CCC[C@@H]3Oc1c24 BGLNUNCBNALFOZ-WMLDXEAASA-N 0.000 claims description 2
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- IYVSXSLYJLAZAT-NOLJZWGESA-N lycoramine Natural products CN1CC[C@@]23CC[C@H](O)C[C@@H]2Oc4cccc(C1)c34 IYVSXSLYJLAZAT-NOLJZWGESA-N 0.000 claims description 2
- NZWOPGCLSHLLPA-UHFFFAOYSA-N methacholine Chemical compound C[N+](C)(C)CC(C)OC(C)=O NZWOPGCLSHLLPA-UHFFFAOYSA-N 0.000 claims description 2
- 229960002329 methacholine Drugs 0.000 claims description 2
- 229960002362 neostigmine Drugs 0.000 claims description 2
- ALWKGYPQUAPLQC-UHFFFAOYSA-N neostigmine Chemical compound CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 ALWKGYPQUAPLQC-UHFFFAOYSA-N 0.000 claims description 2
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 claims description 2
- 229960001697 physostigmine Drugs 0.000 claims description 2
- 229960001416 pilocarpine Drugs 0.000 claims description 2
- 229920001748 polybutylene Polymers 0.000 claims description 2
- 229920000573 polyethylene Polymers 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229920001155 polypropylene Polymers 0.000 claims description 2
- 229960002151 pyridostigmine bromide Drugs 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 3
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 claims 1
- 239000011505 plaster Substances 0.000 abstract description 6
- 230000000052 comparative effect Effects 0.000 description 12
- 230000000694 effects Effects 0.000 description 10
- 238000012360 testing method Methods 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 229920006267 polyester film Polymers 0.000 description 6
- 230000002035 prolonged effect Effects 0.000 description 6
- 230000035807 sensation Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 230000004888 barrier function Effects 0.000 description 4
- 206010052428 Wound Diseases 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- JOOXCMJARBKPKM-UHFFFAOYSA-N 4-oxopentanoic acid Chemical compound CC(=O)CCC(O)=O JOOXCMJARBKPKM-UHFFFAOYSA-N 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 2
- 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 1
- 241000894006 Bacteria Species 0.000 description 1
- 229920002799 BoPET Polymers 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 206010070245 Foreign body Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- BARWIPMJPCRCTP-UHFFFAOYSA-N oleic acid oleyl ester Natural products CCCCCCCCC=CCCCCCCCCOC(=O)CCCCCCCC=CCCCCCCCC BARWIPMJPCRCTP-UHFFFAOYSA-N 0.000 description 1
- BARWIPMJPCRCTP-CLFAGFIQSA-N oleyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC BARWIPMJPCRCTP-CLFAGFIQSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000734 parasympathomimetic agent Substances 0.000 description 1
- 229940005542 parasympathomimetics Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 229920006254 polymer film Polymers 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940100640 transdermal system Drugs 0.000 description 1
- 230000005068 transpiration Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Dermatology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Medicinal Preparation (AREA)
- Materials For Medical Uses (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A transdermal therapeutic system (TTS), in particular a patch, is described, comprising - a redetachable protective layer, - a pressure-sensitive adhesive reservoir layer and - a backing layer with or without a coating of pressure-sensitive adhesive and featuring a unidirectionally, preferably longitudinally, elastic material having an elasticity of at least 20%. The TTS is particularly suitable for use as a multi-day plaster, for the treatment, for instance, of pain or of drug dependency.
Description
Transdermal therapeutic system with pressure-sensitive adhesive reservoir layer and unidirectionally elastic backing layer The invention relates to a transdermal therapeutic system, in particular an active substance patch, comprising a redetachable protective layer, a pressure-sensitive reservoir layer and a backing layer with or without a coating of pressure-sensitive adhesive. The invention also relates to a process for producing such a transdermal therapeutic system [occasionally abbreviated to TTS below]
and to the use thereof.
A TTS is a skin-applied administration form for active substances for delivery through the skin, and has the appearance of traditional patches. It ought to be distinguished from a topical active substance plaster - for example, a rheumatism plaster or a corn plaster. A TTS of this kind can include one or more active substances which are delivered continuously over a fixed period at a predetermined rate to the site of application ("Heilmann, Klaus: Therapeutische Systeme - Konzept and Realisation programmierter Arzneiverabreichung" [Therapeutic systems -design and implementation of programmed drug administration], 4th edition, 1984, Ferdinand-Enke-Verlag, Stuttgart). The fixed period referred to above is usually 24 hours. For the treatment of chronic disorders, however, it is necessary to administer medicaments for a longer period. It may therefore be appropriate to apply a TTS for a period longer than 24 hours, since this is more likely to result in constant plasma levels.
A typical such transdermal therapeutic system in the form of a patch is known from EP-B 0 430 019. It has a backing layer which is impermeable to the active substance, a pressure-sensitive adhesive reservoir layer, and a redetachable protective layer. The active-substance-impermeable backing layer can be composed of flexible or inflexible material. Substances which it is mentioned are used for producing such materials are polymer films or metal foils or else a composite comprising a film which has been coated with aluminium by vapour deposition. Where such systems are worn on the skin for a prolonged period, as is necessary (as mentioned above) for treating chronic disorders in particular, a pronounced sensation of a foreign body is perceived on the skin within a short time, owing to the relative rigidity of the TTS. This is extremely unpleasant for the user.
Another embodiment of such a TTS is described in US-A 5,246,705. The transdermal system it describes has an elastomeric backing layer havir_g a defined vapour transmission rate in the range from 0.1 to 20 g/mz/hr and a Young's modulus in the range of about 104 to 109 dynes/cm2.
Particularly preferred materials for the elastomeric backing layer are, for example, A-B-A block copolymers, the A blocks comprising styrene and the B blocks saturated hydrocarbon polymers such as, for instance, ethylene-butylene copolymers, ethylene-propylene copolymers, and the like. When the transdermal therapeutic systems as per the said US-A 5,246,705 are worn on the skin for a prolonged period, again, it is impossible to avoid the above-described sensation of a foreign body.
US-A 4,780,168 discloses a strip-like wound bandage for sealing wounds, which is fabricated from a woven or non-woven, polymer-based material, the said material having a planar stretching characteristic in the range from 0.5 to 110 [pounds/inch). Materials of such extensibility are, however, not immediately suitable as materials for backing layers of transdermal therapeutic systems. Either their extensibility is too low, in which case the unpleasant foreign-body sensation described above is felt when they are worn on the skin for a prolonged period, or else they are much too extensible, in which case the production of transdermal therapeutic systems is accompanied by the so-called curling effect, which is explained below.
During the production of the laminate from which the individual active substance patches are punched, the material for the backing layer comes under tensile stress and the resulting elastic return force means that, during punching, the opposite ends of the patches are each bent up. Owing to the reject rate during manufacture, this effect results in high costs, together with unnecessary environmental burden.
Aside from the abovementioned disadvantages, a material for the backing layer of a wound bandage is also unsuited to a TTS for other reasons too, such as the required impermeability to active substance.
The object of the invention is therefore to provide a transdermal therapeutic system which comprises a redetachable protective layer, a pressure-sensitive adhesive reservoir layer and a backing layer with or without a coating of pressure-sensitive adhesive and which avoids the aforementioned disadvantages. In particular, there should be no sensation of a foreign body on the skin in the course of prolonged wearing, even for periods of from several days to about 1 or 2 weeks. Furthermore, the production of the TTS should not be accompanied by the curling effect, so ensuring rational and inexpensive production.
and to the use thereof.
A TTS is a skin-applied administration form for active substances for delivery through the skin, and has the appearance of traditional patches. It ought to be distinguished from a topical active substance plaster - for example, a rheumatism plaster or a corn plaster. A TTS of this kind can include one or more active substances which are delivered continuously over a fixed period at a predetermined rate to the site of application ("Heilmann, Klaus: Therapeutische Systeme - Konzept and Realisation programmierter Arzneiverabreichung" [Therapeutic systems -design and implementation of programmed drug administration], 4th edition, 1984, Ferdinand-Enke-Verlag, Stuttgart). The fixed period referred to above is usually 24 hours. For the treatment of chronic disorders, however, it is necessary to administer medicaments for a longer period. It may therefore be appropriate to apply a TTS for a period longer than 24 hours, since this is more likely to result in constant plasma levels.
A typical such transdermal therapeutic system in the form of a patch is known from EP-B 0 430 019. It has a backing layer which is impermeable to the active substance, a pressure-sensitive adhesive reservoir layer, and a redetachable protective layer. The active-substance-impermeable backing layer can be composed of flexible or inflexible material. Substances which it is mentioned are used for producing such materials are polymer films or metal foils or else a composite comprising a film which has been coated with aluminium by vapour deposition. Where such systems are worn on the skin for a prolonged period, as is necessary (as mentioned above) for treating chronic disorders in particular, a pronounced sensation of a foreign body is perceived on the skin within a short time, owing to the relative rigidity of the TTS. This is extremely unpleasant for the user.
Another embodiment of such a TTS is described in US-A 5,246,705. The transdermal system it describes has an elastomeric backing layer havir_g a defined vapour transmission rate in the range from 0.1 to 20 g/mz/hr and a Young's modulus in the range of about 104 to 109 dynes/cm2.
Particularly preferred materials for the elastomeric backing layer are, for example, A-B-A block copolymers, the A blocks comprising styrene and the B blocks saturated hydrocarbon polymers such as, for instance, ethylene-butylene copolymers, ethylene-propylene copolymers, and the like. When the transdermal therapeutic systems as per the said US-A 5,246,705 are worn on the skin for a prolonged period, again, it is impossible to avoid the above-described sensation of a foreign body.
US-A 4,780,168 discloses a strip-like wound bandage for sealing wounds, which is fabricated from a woven or non-woven, polymer-based material, the said material having a planar stretching characteristic in the range from 0.5 to 110 [pounds/inch). Materials of such extensibility are, however, not immediately suitable as materials for backing layers of transdermal therapeutic systems. Either their extensibility is too low, in which case the unpleasant foreign-body sensation described above is felt when they are worn on the skin for a prolonged period, or else they are much too extensible, in which case the production of transdermal therapeutic systems is accompanied by the so-called curling effect, which is explained below.
During the production of the laminate from which the individual active substance patches are punched, the material for the backing layer comes under tensile stress and the resulting elastic return force means that, during punching, the opposite ends of the patches are each bent up. Owing to the reject rate during manufacture, this effect results in high costs, together with unnecessary environmental burden.
Aside from the abovementioned disadvantages, a material for the backing layer of a wound bandage is also unsuited to a TTS for other reasons too, such as the required impermeability to active substance.
The object of the invention is therefore to provide a transdermal therapeutic system which comprises a redetachable protective layer, a pressure-sensitive adhesive reservoir layer and a backing layer with or without a coating of pressure-sensitive adhesive and which avoids the aforementioned disadvantages. In particular, there should be no sensation of a foreign body on the skin in the course of prolonged wearing, even for periods of from several days to about 1 or 2 weeks. Furthermore, the production of the TTS should not be accompanied by the curling effect, so ensuring rational and inexpensive production.
This object is achieved in accordance with the invention by a transdermal therapeutic. system, in particular an active substance patch, which comprises a redetachable protective layer, a pressure-sensitive adhesive reservoir layer and a backing layer with or without a coating of pressure-sensitive adhesive, the backing layer being of a unidirectionally, especially longitudinally, elastic material having an elasticity of at least 20%.
Preferred embodiments of the TTS of the invention are subject-matter of the dependent claims.
In accordance with the invention, the TTS features not only a redetachable protective layer and a pressure-sensitive adhesive reservoir layer but also a backing layer which, optionally, is likewise coated with pressure-sensitive adhesive and which has a specifically defined unidirectional elasticity. With regard to the TTS of the invention, the elasticity is determined in accordance with the DIN standards 60 000 and 61 632 (April 1985), which are conventionally used for elasticity tests. Originally, these DIN standards do in fact apply to ideal bandages; the horizontal force extension unit used to test the elasticity can, however, be employed analogously for other materials as well. In accordance with the invention, the backing layer of the TTS is elastic in only one direction, i.e. in longitudinal or transverse direction. Relative to the longitudinal axis of the TTS, the transverse axis is that lying at right angles to it. In a circular TTS, the longitudinal and transverse axis are of course identical in length. In particular, the backing layer material used in accordance with the invention is unidirectionally longitudinally elastic.
Preferred embodiments of the TTS of the invention are subject-matter of the dependent claims.
In accordance with the invention, the TTS features not only a redetachable protective layer and a pressure-sensitive adhesive reservoir layer but also a backing layer which, optionally, is likewise coated with pressure-sensitive adhesive and which has a specifically defined unidirectional elasticity. With regard to the TTS of the invention, the elasticity is determined in accordance with the DIN standards 60 000 and 61 632 (April 1985), which are conventionally used for elasticity tests. Originally, these DIN standards do in fact apply to ideal bandages; the horizontal force extension unit used to test the elasticity can, however, be employed analogously for other materials as well. In accordance with the invention, the backing layer of the TTS is elastic in only one direction, i.e. in longitudinal or transverse direction. Relative to the longitudinal axis of the TTS, the transverse axis is that lying at right angles to it. In a circular TTS, the longitudinal and transverse axis are of course identical in length. In particular, the backing layer material used in accordance with the invention is unidirectionally longitudinally elastic.
In the other direction, the backing layer is nonelastic.
Nonelastic means that no elasticity can be found when testing by hand. In the case of measurement in accordance with DIN 61 632, then, the elasticity is less than 20%. In accordance with the invention, therefore, the elasticity in one direction - mainly the elastic direction - is above 20%.
Since the production of the patch involves it being punched out from a laminate, it would also be possible to conceive in principle of the TTS being "unidirectionally" elastic at an angle to the longitudinal direction of the patch.
Oblique elasticity of this kind is, however, the result of a superposition of elasticity in the transverse and longitudinal directions.
In the TTS of the invention, the elasticity of the unidirectionally elastic material used for the backing layer is preferably less than 150%. In a more preferred embodiment the elasticity is in the range from 20 to 80%, with particular preference in the range from 40 to 70%. The most preferred elasticity for a backing layer material, and, accordingly, that which is most advantageous for the achievement of the object on which the invention is based, lies within the range between 44 and 56%, always measured in accordance with DIN 61 632.
Preferred materials for the unidirectionally elastic backing layer are those which are microbially nondegradable. The material should be more than 90%, preferably more than 99%, microbially nondegradable. The degradability can be measured by conventional methods familiar to the person skilled in the art. Low degradability is particularly important in the case of TTSs which are to be worn on the skin for a prolonged period.
Nonelastic means that no elasticity can be found when testing by hand. In the case of measurement in accordance with DIN 61 632, then, the elasticity is less than 20%. In accordance with the invention, therefore, the elasticity in one direction - mainly the elastic direction - is above 20%.
Since the production of the patch involves it being punched out from a laminate, it would also be possible to conceive in principle of the TTS being "unidirectionally" elastic at an angle to the longitudinal direction of the patch.
Oblique elasticity of this kind is, however, the result of a superposition of elasticity in the transverse and longitudinal directions.
In the TTS of the invention, the elasticity of the unidirectionally elastic material used for the backing layer is preferably less than 150%. In a more preferred embodiment the elasticity is in the range from 20 to 80%, with particular preference in the range from 40 to 70%. The most preferred elasticity for a backing layer material, and, accordingly, that which is most advantageous for the achievement of the object on which the invention is based, lies within the range between 44 and 56%, always measured in accordance with DIN 61 632.
Preferred materials for the unidirectionally elastic backing layer are those which are microbially nondegradable. The material should be more than 90%, preferably more than 99%, microbially nondegradable. The degradability can be measured by conventional methods familiar to the person skilled in the art. Low degradability is particularly important in the case of TTSs which are to be worn on the skin for a prolonged period.
The reason for this is that, owing to the transpiration of the skin, a microclimate in which bacteria, fungi, spores etc. absolutely thrive develops directly below the section of skin covered by the TTS. Consequently, low microbial degradability, especially in the case of prolonged wearing, is extremely advantageous. The material of the backing layer can be a woven fabric, a nonwoven fabric or a film.
Where the backing layer comprises a polymer, the said polymer is selected advantageously from polyethylene, polypropylene or polyesters, especially polyalkylene terephthalates.
A number of polymeric materials may be mentioned by way of example for the backing layer. Advantageous polymeric materials which meet the above requirement of low microbial degradability are polyterephthalic diesters obtainable by the reaction of a starting material selected from ethylene glycol, 1,4-butanediol, 1,4-dihydroxymethylcyclohexane, terephthalic acid, isophthalic acid, adipic acid, azelaic acid, sebacic acid, dimethyl terephthalate, dimethyl azelate, dimethyl sebacate, bisphenol A diglycidyl ether, n-decane-1,10-dicarboxylic acid, polyethylene glycol and polybutylene glycol.
In the transdermal therapeutic system of the invention, it is likewise possible for a further separating layer to be arranged between backing layer and reservoir layer for the purpose, for example, of preventing active substance permeability. In this case, the backing layer on the skin-facing side, and/or the separating layer on the distal side, are/is likewise coated with pressure-sensitive adhesive.
For the effectiveness of a TTS of the invention it is advantageous for the backing layer to project beyond the _ 7 _ reservoir on all sides. This has the advantage that there are no losses of active substance in the lateral direction.
Furthermore, the TTS of the invention can be produced in a particularly inexpensive manner in this case, since the sections containing active substance can be punched separately. This avoids expensive, environmentally harmful, leftover waste pieces containing active substance. The backing layer of the TTS has a water vapour permeability of at least 0.1 g/m2/h, preferably from 1 to 20 g/m2/h.
Where a woven or nonwoven fabric or else a porous film is used, the porosity lies within the range from 10% to 50%.
Porosity here means the proportion of pores having an area of <_ 400 ~m2 as a percentage of the reference area in question. This relative pore area can be determined by measuring and counting the pores of any unextended reference area under the microscope or a thread counter.
If a woven fabric is used for the transdermal therapeutic system (TTS) of the invention, the backing layer has a number of warp threads in the range of 300-350, preferably in the range of 310-330, and/or a number of weft threads in the range from 100 to 140, preferably in the range from 120 to 130, measured in each case per 10 cm of unextended fabric.
The pressure-sensitive adhesive reservoir layer of the transdermal therapeutic system of the invention comprises at least one active substance. This substance is preferably selected from the group consisting of psychopharmaceuticals, analgesics and hormones. Particular substances which may be considered include estradiol as a hormone and buprenorphine as an analgesic. The psychopharmaceutical is preferably a parasympathomimetic.
_ g _ Particularly suitable parasympathomimetics are the following:
1. choline esters, e.g. acetylcholine, bethanechol, carbachol or methacholine;
2. alkaloids, e.g. arecoline and its derivatives, pilocarpine;
3. choline esterase inhibitors, e.g. demacarium bromide, distigmine bromide, neostigmine, physostigmine, pyridostigmine bromide, galanthamine.
These substances can of course also be used in combinations with one another. The active substance content is set in particular such that when the plaster is removed there is what is known as a pulloff effect. This effect is explained hereinbelow:
Where a TTS includes a backing layer of limited water vapour permeability, such as a PET film, the skin is unable to give off water vapour at the application site while the TTS is being worn. This water becomes incorporated in the skin. At the application site, therefore, the water content is higher than the physiobiological norm. A substance which is difficult for the skin to absorb (such as buprenorphine, for example) becomes incorporated into a deposit in the skin. When the TTS is pulled off, the skin gives off water vapour suddenly. As a result of removal of this water, there is a sudden increase in the concentration of the medicament to above the saturation concentration, since solvent is removed. A stable state is reached by the rapid emptying of the skin deposit. Therefore, as a result of the TTS being pulled off, there is a rapid increase in the plasma concentration of the active substance. The utilization of the pulloff effect is preferred for better utilization of active substance. In accordance with the _ g _ invention, therefore, the concentration of the active substance is set such that the abovementioned pulloff effect comes about.
The absolute level of active substance for achieving the pulloff effect cannot generally be defined validly with precision. It varies from one active substance to another and also depends on the embodiment of the TTS. Setting of the level can, however, be undertaken by the person skilled in the art without undue burden by means of routine experiments. In the case of buprenorphine, the level is about 5 - 15o by weight.
The pressure-sensitive adhesive reservoir layer may also include a water-absorbing polymer. In one preferred embodiment, the water-absorbing polymer is a polyvinylpyrrolidone. The polyvinylpyrrolidone preferably has a molecular weight in the range from 1 x 103 to 2 x 106. Such polyvinylpyrrolidones include Kollidon~.
For special purposes, moreover, such as for use in hospitals with many patients or for use in double blind studies where TTS containing active substance are compared with placebo TTS, it is preferred for the side of the TTS
that faces outwards - that is, away from the skin - to carry in the backing layer a marking/control element which is differentiated from the remaining area.
This element can differ from the remaining portion of the backing layer in its structure or in other properties, such as elasticity or porosity. By means of such a marking/control element the properties of the backing layer can be made different. For example, the elasticity of such an element can be greater than the elasticity of the remaining portion of the backing layer. If such a . CA 02302601 2000-03-03 marking/control element is specifically incorporated in one portion of the backing layer, then its relative elasticity - where desired - is preferably within a range situated about 20o below or about 20% above the elasticity of the remaining portion of the backing layer.
The marking/control element can also serve to distinguish the individual TTSs from one another in terms of their active substance content. This is done preferably by means of coloured marking, for example by means of a coloured thread or stripe. This is particularly advantageous if the TTS has to be held ready in large quantities at different dosages at one location: for example, a hospital with large numbers of patients.
The transdermal therapeutic system of the invention is particularly suitable for use as a mufti-day plaster owing to its backing layer, which is tailored to this requirement. Thus it can be used in particular to treat chronic pain or else to treat drug dependency.
The TTS of the invention is produced by means of conventional processes. In general, such a process comprises the steps of producing the individual TTSs by punching from a presupplied strip-like laminate comprising the unidirectionally elastic backing layer of the invention, an active substance layer and a redetachable protective layer.
In one particularly preferred process for producing the TTS
of the invention, the above steps are modified to the effect that, in a presupplied strip-like laminate having an optionally pressure-sensitive adhesive, unidirectionally elastic backing layer and a redetachable protective layer, pressure-sensitive adhesive active substance reservoir sections are inserted in sequence in the longitudinal direction, the backing layer is separated by punching and then in the spaces between the active substance reservoir sections the protective layer is separated. This specific process has the feature that it is highly advantageous from both economic and environmental standpoints. Indeed, the separate insertion of the active substance reservoir sections avoids the formation of waste comprising active substance (which is usually very expensive) and thus the need to dispose - again at great expense - of such waste. A
similar process is described in DE-B 41 10 027"
The invention is elucidated below with reference to a drawing and an exemplary embodiment. In the figures, Fig. 1 shows a plan view of the TTS of the invention;
Fig. 2 shows a section made at II-II through the TTS of Fig. 1.
Fig. 1 shows, diagrammatically, a plan view of a TTS of the invention. Lying atop the redetachable protective layer (1), which in the present case is rectangular, is the backing layer (5), which is coated with a pressure-sensitive adhesive devoid of active substance. It has the form of a rectangle with rounded corners. The punching line (la) outlines the form of the backing layer (5). It extends outside the laminate comprising the reservoir (2) and, optionally, a barrier or separating layer (3). The course of the punching line means that loss of active substance is avoided when the patch is punched out. Within the backing layer (5) it is possible to make out the contours of the reservoir (2) and of the optional barrier layer (3).
In the TTS shown, with the unidirectionally elastic backing layer (5), the latter protrudes beyond the abovementioned laminate on all sides. The reservoir is preferably rectangular in form. The rectangular form is preferred since it enables losses of active substance to be avoided when the reservoir is cut.
Fig. 2 is a cross section through II-II of Fig. 1. For clarity, the thicknesses of the layers have been exaggerated. The TTS features the reservoir (2), the removable protective layer (1) and also the optional barrier layer (3) and a further layer (4) of pressure-sensitive adhesive devoid of active substance, this layer (4) being necessary when a barrier layer (3) is present. In this depicted embodiment, the backing layer (5) and the pressure-sensitive adhesive layer (4) devoid of active substance protrude beyond the abovementioned laminate on all sides.
Example In order to produce the unidirectionally elastic backing layer of the invention, a woven polyester fabric having the following features was produced by means of the techniques known to the person skilled in the art.
TEST FEATURES UNIT Nominal MIN MAX X
WIDTH OF MATERIALmm 1500 1300 1390 1360 BASIS WEIGHT g/mz 100 95 103 100 (unextended) (DIN 53854 +
DIN 53884) EXTENSION
(longitudinal) % - - - -(transverse) % 50 46 52 48 (DIN 61632) THREADS
Per l0 cm unextended THREADS
Per 10 cm unextended In addition 49.175 kg of Duro-Tak* type 387-2054 {48.3% by weight solution) 4.450 kg of melted laevulinic acid and 6.675 kg of oleyl oleate were homogenized with stirring. Then 4.450 kg of Kollidon*
90F were added in portions. Following dilution with *=TM
6.800 kg of ethanol, the mixture was stirred at 170-190 rpm for 5 hours. Then 4.450 kg of buprenorphine base, suspended in 4.500 kg of ethyl acetate, were added. The mixture was diluted with 4.500 kg of ethyl acetate.
The mixture was stirred at 170 rpm for about 7 hours. It was then tested for homogeneity. When the composition was homogeneous it was devolatilized, with the stirrer switched off .
Following homogenization, the adhesive composition was applied to a siliconized polyester film. The organic solvents were removed by drying at normally 35°C to 80°C.
The laminate, comprising siliconized polyester film and buprenorphine-containing pressure-sensitive adhesive layer, was subsequently covered with a second polyester film 23 ~.m thick.
The siliconized polyester film was removed from the resulting active substance laminate. Subsequently, rectangles measuring 50 cm2 were punched out and were placed with their adhering face, at intervals of 3 cm, onto the siliconized face of a further 100 um polyester protective film. Atop these reservoir sections was placed the unidirectionally elastic, woven polyester fabric, which in this case was likewise coated with pressure-sensitive adhesive. Subsequently, individual longitudinally elastic patches were punched out. A wearing test was conducted on n=10 subjects using this TTS of the invention.
Comparative Example 1 In this example, a bidirectionally elastic woven polyester fabric was used instead of the unidirectionally elastic woven polyester fabric of the invention. The extensibility of this fabric (longitudinal and transverse extension) was 30% as measured in accordance with DIN 61632. Its basis weight was 109 g/m2. This material was a polyethylene terephthalate. In other respects, the TTSs produced in accordance with this comparative example were the same as those of the inventive example.
Using the TTSs according to this comparative example, a wear test was likewise conducted on n=10 subjects.
Comparative Example 2 TTSs were prepared in accordance with Example 1 and Comparative Example 1 but using a rigid polyester film (15 ~.m thick) of Hostaphan° RN 15, Hoechst AG, coated with pressure-sensitive adhesive, instead of a unidirectionally or bidirectionally elastic backing layer, respectively. In this case as well, a wear test was carried out with the resulting TTSs on n=10 subjects.
Evaluation The comparative wear test of the TTSs of Example 1, Comparative Example 1 and Comparative Example 2 gave the following result:
When polyester film was used as the backing layer (Comparative Example 2), a sensation of a foreign body occurred on the very first day. On the second day, creasing occurred and, beginning on the third day, the TTS became detached. The TTS of Example 1 and that of Comparative Example 1 were worn without problems by all 10 subjects, with no sensation of a foreign body, with no impairment of bond strength, and, furthermore, with no skin irritations, for at least seven days. In respect of wear comfort, therefore, the TTS of Example 1 and that of Comparative Example 1 are approximately equal. However, with regard to the production of the TTS of Comparative Example 1, complications in production occurred in a frequency of more than 50%, these complications being attributable predominantly to the curling effect.
Where the backing layer comprises a polymer, the said polymer is selected advantageously from polyethylene, polypropylene or polyesters, especially polyalkylene terephthalates.
A number of polymeric materials may be mentioned by way of example for the backing layer. Advantageous polymeric materials which meet the above requirement of low microbial degradability are polyterephthalic diesters obtainable by the reaction of a starting material selected from ethylene glycol, 1,4-butanediol, 1,4-dihydroxymethylcyclohexane, terephthalic acid, isophthalic acid, adipic acid, azelaic acid, sebacic acid, dimethyl terephthalate, dimethyl azelate, dimethyl sebacate, bisphenol A diglycidyl ether, n-decane-1,10-dicarboxylic acid, polyethylene glycol and polybutylene glycol.
In the transdermal therapeutic system of the invention, it is likewise possible for a further separating layer to be arranged between backing layer and reservoir layer for the purpose, for example, of preventing active substance permeability. In this case, the backing layer on the skin-facing side, and/or the separating layer on the distal side, are/is likewise coated with pressure-sensitive adhesive.
For the effectiveness of a TTS of the invention it is advantageous for the backing layer to project beyond the _ 7 _ reservoir on all sides. This has the advantage that there are no losses of active substance in the lateral direction.
Furthermore, the TTS of the invention can be produced in a particularly inexpensive manner in this case, since the sections containing active substance can be punched separately. This avoids expensive, environmentally harmful, leftover waste pieces containing active substance. The backing layer of the TTS has a water vapour permeability of at least 0.1 g/m2/h, preferably from 1 to 20 g/m2/h.
Where a woven or nonwoven fabric or else a porous film is used, the porosity lies within the range from 10% to 50%.
Porosity here means the proportion of pores having an area of <_ 400 ~m2 as a percentage of the reference area in question. This relative pore area can be determined by measuring and counting the pores of any unextended reference area under the microscope or a thread counter.
If a woven fabric is used for the transdermal therapeutic system (TTS) of the invention, the backing layer has a number of warp threads in the range of 300-350, preferably in the range of 310-330, and/or a number of weft threads in the range from 100 to 140, preferably in the range from 120 to 130, measured in each case per 10 cm of unextended fabric.
The pressure-sensitive adhesive reservoir layer of the transdermal therapeutic system of the invention comprises at least one active substance. This substance is preferably selected from the group consisting of psychopharmaceuticals, analgesics and hormones. Particular substances which may be considered include estradiol as a hormone and buprenorphine as an analgesic. The psychopharmaceutical is preferably a parasympathomimetic.
_ g _ Particularly suitable parasympathomimetics are the following:
1. choline esters, e.g. acetylcholine, bethanechol, carbachol or methacholine;
2. alkaloids, e.g. arecoline and its derivatives, pilocarpine;
3. choline esterase inhibitors, e.g. demacarium bromide, distigmine bromide, neostigmine, physostigmine, pyridostigmine bromide, galanthamine.
These substances can of course also be used in combinations with one another. The active substance content is set in particular such that when the plaster is removed there is what is known as a pulloff effect. This effect is explained hereinbelow:
Where a TTS includes a backing layer of limited water vapour permeability, such as a PET film, the skin is unable to give off water vapour at the application site while the TTS is being worn. This water becomes incorporated in the skin. At the application site, therefore, the water content is higher than the physiobiological norm. A substance which is difficult for the skin to absorb (such as buprenorphine, for example) becomes incorporated into a deposit in the skin. When the TTS is pulled off, the skin gives off water vapour suddenly. As a result of removal of this water, there is a sudden increase in the concentration of the medicament to above the saturation concentration, since solvent is removed. A stable state is reached by the rapid emptying of the skin deposit. Therefore, as a result of the TTS being pulled off, there is a rapid increase in the plasma concentration of the active substance. The utilization of the pulloff effect is preferred for better utilization of active substance. In accordance with the _ g _ invention, therefore, the concentration of the active substance is set such that the abovementioned pulloff effect comes about.
The absolute level of active substance for achieving the pulloff effect cannot generally be defined validly with precision. It varies from one active substance to another and also depends on the embodiment of the TTS. Setting of the level can, however, be undertaken by the person skilled in the art without undue burden by means of routine experiments. In the case of buprenorphine, the level is about 5 - 15o by weight.
The pressure-sensitive adhesive reservoir layer may also include a water-absorbing polymer. In one preferred embodiment, the water-absorbing polymer is a polyvinylpyrrolidone. The polyvinylpyrrolidone preferably has a molecular weight in the range from 1 x 103 to 2 x 106. Such polyvinylpyrrolidones include Kollidon~.
For special purposes, moreover, such as for use in hospitals with many patients or for use in double blind studies where TTS containing active substance are compared with placebo TTS, it is preferred for the side of the TTS
that faces outwards - that is, away from the skin - to carry in the backing layer a marking/control element which is differentiated from the remaining area.
This element can differ from the remaining portion of the backing layer in its structure or in other properties, such as elasticity or porosity. By means of such a marking/control element the properties of the backing layer can be made different. For example, the elasticity of such an element can be greater than the elasticity of the remaining portion of the backing layer. If such a . CA 02302601 2000-03-03 marking/control element is specifically incorporated in one portion of the backing layer, then its relative elasticity - where desired - is preferably within a range situated about 20o below or about 20% above the elasticity of the remaining portion of the backing layer.
The marking/control element can also serve to distinguish the individual TTSs from one another in terms of their active substance content. This is done preferably by means of coloured marking, for example by means of a coloured thread or stripe. This is particularly advantageous if the TTS has to be held ready in large quantities at different dosages at one location: for example, a hospital with large numbers of patients.
The transdermal therapeutic system of the invention is particularly suitable for use as a mufti-day plaster owing to its backing layer, which is tailored to this requirement. Thus it can be used in particular to treat chronic pain or else to treat drug dependency.
The TTS of the invention is produced by means of conventional processes. In general, such a process comprises the steps of producing the individual TTSs by punching from a presupplied strip-like laminate comprising the unidirectionally elastic backing layer of the invention, an active substance layer and a redetachable protective layer.
In one particularly preferred process for producing the TTS
of the invention, the above steps are modified to the effect that, in a presupplied strip-like laminate having an optionally pressure-sensitive adhesive, unidirectionally elastic backing layer and a redetachable protective layer, pressure-sensitive adhesive active substance reservoir sections are inserted in sequence in the longitudinal direction, the backing layer is separated by punching and then in the spaces between the active substance reservoir sections the protective layer is separated. This specific process has the feature that it is highly advantageous from both economic and environmental standpoints. Indeed, the separate insertion of the active substance reservoir sections avoids the formation of waste comprising active substance (which is usually very expensive) and thus the need to dispose - again at great expense - of such waste. A
similar process is described in DE-B 41 10 027"
The invention is elucidated below with reference to a drawing and an exemplary embodiment. In the figures, Fig. 1 shows a plan view of the TTS of the invention;
Fig. 2 shows a section made at II-II through the TTS of Fig. 1.
Fig. 1 shows, diagrammatically, a plan view of a TTS of the invention. Lying atop the redetachable protective layer (1), which in the present case is rectangular, is the backing layer (5), which is coated with a pressure-sensitive adhesive devoid of active substance. It has the form of a rectangle with rounded corners. The punching line (la) outlines the form of the backing layer (5). It extends outside the laminate comprising the reservoir (2) and, optionally, a barrier or separating layer (3). The course of the punching line means that loss of active substance is avoided when the patch is punched out. Within the backing layer (5) it is possible to make out the contours of the reservoir (2) and of the optional barrier layer (3).
In the TTS shown, with the unidirectionally elastic backing layer (5), the latter protrudes beyond the abovementioned laminate on all sides. The reservoir is preferably rectangular in form. The rectangular form is preferred since it enables losses of active substance to be avoided when the reservoir is cut.
Fig. 2 is a cross section through II-II of Fig. 1. For clarity, the thicknesses of the layers have been exaggerated. The TTS features the reservoir (2), the removable protective layer (1) and also the optional barrier layer (3) and a further layer (4) of pressure-sensitive adhesive devoid of active substance, this layer (4) being necessary when a barrier layer (3) is present. In this depicted embodiment, the backing layer (5) and the pressure-sensitive adhesive layer (4) devoid of active substance protrude beyond the abovementioned laminate on all sides.
Example In order to produce the unidirectionally elastic backing layer of the invention, a woven polyester fabric having the following features was produced by means of the techniques known to the person skilled in the art.
TEST FEATURES UNIT Nominal MIN MAX X
WIDTH OF MATERIALmm 1500 1300 1390 1360 BASIS WEIGHT g/mz 100 95 103 100 (unextended) (DIN 53854 +
DIN 53884) EXTENSION
(longitudinal) % - - - -(transverse) % 50 46 52 48 (DIN 61632) THREADS
Per l0 cm unextended THREADS
Per 10 cm unextended In addition 49.175 kg of Duro-Tak* type 387-2054 {48.3% by weight solution) 4.450 kg of melted laevulinic acid and 6.675 kg of oleyl oleate were homogenized with stirring. Then 4.450 kg of Kollidon*
90F were added in portions. Following dilution with *=TM
6.800 kg of ethanol, the mixture was stirred at 170-190 rpm for 5 hours. Then 4.450 kg of buprenorphine base, suspended in 4.500 kg of ethyl acetate, were added. The mixture was diluted with 4.500 kg of ethyl acetate.
The mixture was stirred at 170 rpm for about 7 hours. It was then tested for homogeneity. When the composition was homogeneous it was devolatilized, with the stirrer switched off .
Following homogenization, the adhesive composition was applied to a siliconized polyester film. The organic solvents were removed by drying at normally 35°C to 80°C.
The laminate, comprising siliconized polyester film and buprenorphine-containing pressure-sensitive adhesive layer, was subsequently covered with a second polyester film 23 ~.m thick.
The siliconized polyester film was removed from the resulting active substance laminate. Subsequently, rectangles measuring 50 cm2 were punched out and were placed with their adhering face, at intervals of 3 cm, onto the siliconized face of a further 100 um polyester protective film. Atop these reservoir sections was placed the unidirectionally elastic, woven polyester fabric, which in this case was likewise coated with pressure-sensitive adhesive. Subsequently, individual longitudinally elastic patches were punched out. A wearing test was conducted on n=10 subjects using this TTS of the invention.
Comparative Example 1 In this example, a bidirectionally elastic woven polyester fabric was used instead of the unidirectionally elastic woven polyester fabric of the invention. The extensibility of this fabric (longitudinal and transverse extension) was 30% as measured in accordance with DIN 61632. Its basis weight was 109 g/m2. This material was a polyethylene terephthalate. In other respects, the TTSs produced in accordance with this comparative example were the same as those of the inventive example.
Using the TTSs according to this comparative example, a wear test was likewise conducted on n=10 subjects.
Comparative Example 2 TTSs were prepared in accordance with Example 1 and Comparative Example 1 but using a rigid polyester film (15 ~.m thick) of Hostaphan° RN 15, Hoechst AG, coated with pressure-sensitive adhesive, instead of a unidirectionally or bidirectionally elastic backing layer, respectively. In this case as well, a wear test was carried out with the resulting TTSs on n=10 subjects.
Evaluation The comparative wear test of the TTSs of Example 1, Comparative Example 1 and Comparative Example 2 gave the following result:
When polyester film was used as the backing layer (Comparative Example 2), a sensation of a foreign body occurred on the very first day. On the second day, creasing occurred and, beginning on the third day, the TTS became detached. The TTS of Example 1 and that of Comparative Example 1 were worn without problems by all 10 subjects, with no sensation of a foreign body, with no impairment of bond strength, and, furthermore, with no skin irritations, for at least seven days. In respect of wear comfort, therefore, the TTS of Example 1 and that of Comparative Example 1 are approximately equal. However, with regard to the production of the TTS of Comparative Example 1, complications in production occurred in a frequency of more than 50%, these complications being attributable predominantly to the curling effect.
Claims (40)
1. A transdermal therapeutic system comprising a detachable protective layer;
a pressure-sensitive adhesive reservoir layer comprising at least one active substance;
and a backing layer comprising unidirectional elastic material having an elasticity of at least 20%, wherein the material is a woven fabric, and wherein said reservoir layer contains a water-absorbing polymer.
a pressure-sensitive adhesive reservoir layer comprising at least one active substance;
and a backing layer comprising unidirectional elastic material having an elasticity of at least 20%, wherein the material is a woven fabric, and wherein said reservoir layer contains a water-absorbing polymer.
2. The transdermal therapeutic system of claim 1 wherein the backing layer is a coating of pressure-sensitive adhesive.
3. The transdermal therapeutic system of claim 1 wherein the system is a patch.
4. The transdermal therapeutic system of claim 1 wherein the backing layer comprises longitudinally elastic material.
5. The transdermal therapeutic system of claim 1 wherein the elasticity of the backing layer is less than 150%.
6. The transdermal therapeutic system of claim 1 wherein the backing layer projects beyond the reservoir layer on all sides.
7. The transdermal therapeutic system of claim 2 further comprising a separating layer between the reservoir layer and the backing layer.
8. The transdermal therapeutic system of claim 1 wherein the elastic material of the backing layer has an elasticity of between 20-80%.
9. The transdermal therapeutic system of claim 8 wherein the elastic material of the backing layer has an elasticity of between 40-70%.
10. The transdermal therapeutic system of claim 9 wherein the elastic material of the backing layer has an elasticity of between 44-56%.
11. The transdermal therapeutic system of claim 1 wherein the material comprising the backing layer is more than 90% microbially nondegradable.
12. The transdermal therapeutic system of claim 11 wherein the material comprising the backing layer is more than 99% microbially nondegradable.
13. The transdermal therapeutic system of claim 1 wherein the backing layer comprises a material selected from the group consisting of a polyethylene, a polypropylene and a polyester.
14. The transdermal therapeutic system of claim 13 wherein the backing layer comprises a polyalkylene terephthalate.
15. The transdermal therapeutic system of claim 14 wherein the backing material is a polyterephthalic diester.
16. The transdermal therapeutic system of claim 15 wherein the backing material is a polyterephthalic acid diol ester obtained by the reaction of a starting material selected from the group consisting of ethylene glycol, 1,4-butanediol, 1,4-dihydroxymethylcyclohexane, terephthalic acid, isophthalic acid, adipic acid, azelaic acid, sebacic acid, dimethyl terephthalate, dimethyl azelate, dimethyl sebacate, bisphenol A diglycidyl ether, n-decane-1, 10-dicarboxylic acid, polyethylene glycol, and polybutylene glycol.
17. The transdermal therapeutic system of claim 1 wherein the reservoir layer comprises at least one active substance selected from the group consisting of a psychopharmaceutical, an analgesic and a hormone.
18. The transdermal therapeutic system of claim 1 wherein the water-absorbing polymer is a polyvinylpyrrolidone.
19. The transdermal therapeutic system of claim 18 wherein the polyvinylpyrrolidone has a molecular weight in the range of 1 × 10 3 to 2 × 10 6.
20. The transdermal therapeutic system of claim 1 wherein the backing layer facing outwardly has a differentiated marking element.
21. The transdermal therapeutic system of claim 20 wherein the marking element is a colored marking.
22. The transdermal therapeutic system of claim 21 wherein the colored marking is in strip form or a colored thread.
23. The transdermal therapeutic system of claim 20 wherein the marking element has an elasticity of between -20% to +20% relative to the elasticity of the remaining portion of the backing layer.
24. The transdermal therapeutic system of claim 1 wherein the backing layer has a water vapor permeability of at least 0.1 g/m2/h.
25. The transdermal therapeutic system of claim 24 wherein the backing layer, has a water vapor permeability of between 1 to 20 g/m2/h.
26. The transdermal therapeutic system of claim 1 wherein the backing layer has a number of warp threads in the range from 300 to 350 per 10 cm of unextended fabric.
27. Use of the transdermal therapeutic system according to claim 1 in the manufacture of a pharmaceutical delivery system for the treatment of pain or drug dependency.
28. Use of the transdermal therapeutic system according to claim 17 for the treatment of pain or drug dependency.
29. A method of producing the transdermal therapeutic system of claim 1 comprising the steps of inserting pressure-sensitive adhesive substance reservoir sections in a sequence in a longitudinal direction into a presupplied strip-like laminate comprising a detachable protective layer and a backing layer comprising a unidirectional backing material;
separating the backing layer by punching; removing the unwanted cut portion of the backing layers;
and separating the protective layer in the space between the active substance reservoir sections.
separating the backing layer by punching; removing the unwanted cut portion of the backing layers;
and separating the protective layer in the space between the active substance reservoir sections.
30. The transdermal therapeutic system of claim 1 wherein the backing layer comprises a material selected from the group consisting of a woven fabric, a nonwoven fabric and a film.
31. The transdermal therapeutic system of claim 17 wherein the active ingredient is selected from the group consisting of oestriol, buprenorphine and a parasympathomimetic.
32. The transdermal therapeutic system of claim 31, wherein the parasympathomimetic active ingredient is selected from the group consisting of choline esters, alkaloids and choline esterase inhibitors.
33. The transdermal therapeutic system of claim 32, wherein the choline esters are selected from the group consisting of acetylcholine, bethanechol, carbachol and methacholine.
34. The transdermal therapeutic system of claim 32, wherein the alkaloids are selected from the group consisting of arecholine and its derivatives and pilocarpine.
35. The transdermal therapeutic system of claim 32, wherein the choline esterase inhibitors are selected from the group consisting of demacarium bromide, distigmine bromide, neostigmine, physostigmine, pyridostigmine bromide and galanthamine.
36. The transdermal therapeutic system of claim 32 wherein the parasympathomimetic active ingredients are used in combination with each other.
37. The transdermal therapeutic system of claim 30 wherein the fabric or film comprises pores having a size less than or equal to 400 µm2 embracing an area proportion of between 10%
and 50% of said fabric or film.
and 50% of said fabric or film.
38. The transdermal therapeutic system of claim 30 wherein the fabric has a number of warp threads in the range of 300 to 350 per cm of unextended fabric and a number of weft threads in the range from 100 to 140 per 10 cm of unextended fabric.
39. The transdermal therapeutic system of claim 38 wherein the number of weft threads is in the range from 120 to 130.
40. Use of the transdermal therapeutic system according to claim 31 for the treatment of pain or drug dependency.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19738855.8 | 1997-09-05 | ||
DE19738855A DE19738855C2 (en) | 1997-09-05 | 1997-09-05 | Transdermal therapeutic system with adhesive reservoir layer and unidirectional elastic back layer |
PCT/EP1998/005321 WO1999012529A2 (en) | 1997-09-05 | 1998-08-21 | Transdermal therapeutic system comprising a reservoir-type pressure-sensitive adhesive layer and a back layer with uni-directional resilience |
Publications (2)
Publication Number | Publication Date |
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CA2302601A1 CA2302601A1 (en) | 1999-03-18 |
CA2302601C true CA2302601C (en) | 2006-06-13 |
Family
ID=7841309
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002302601A Expired - Lifetime CA2302601C (en) | 1997-09-05 | 1998-08-21 | Transdermal therapeutic system comprising a reservoir-type pressure-sensitive adhesive layer and a back layer with uni-directional resilience |
Country Status (14)
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US (2) | US6814976B1 (en) |
EP (1) | EP1009393B1 (en) |
JP (1) | JP3847088B2 (en) |
KR (1) | KR100515007B1 (en) |
AT (1) | ATE215364T1 (en) |
AU (1) | AU738033B2 (en) |
CA (1) | CA2302601C (en) |
DE (2) | DE19738855C2 (en) |
DK (1) | DK1009393T3 (en) |
ES (1) | ES2175792T3 (en) |
NO (1) | NO327605B1 (en) |
PT (1) | PT1009393E (en) |
SI (1) | SI1009393T1 (en) |
WO (1) | WO1999012529A2 (en) |
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-
1997
- 1997-09-05 DE DE19738855A patent/DE19738855C2/en not_active Expired - Fee Related
-
1998
- 1998-08-21 CA CA002302601A patent/CA2302601C/en not_active Expired - Lifetime
- 1998-08-21 SI SI9830189T patent/SI1009393T1/en unknown
- 1998-08-21 KR KR10-2000-7002344A patent/KR100515007B1/en not_active IP Right Cessation
- 1998-08-21 AT AT98948853T patent/ATE215364T1/en active
- 1998-08-21 DE DE59803647T patent/DE59803647D1/en not_active Expired - Lifetime
- 1998-08-21 AU AU95329/98A patent/AU738033B2/en not_active Ceased
- 1998-08-21 JP JP2000510427A patent/JP3847088B2/en not_active Expired - Lifetime
- 1998-08-21 US US09/486,266 patent/US6814976B1/en not_active Expired - Lifetime
- 1998-08-21 EP EP98948853A patent/EP1009393B1/en not_active Expired - Lifetime
- 1998-08-21 PT PT98948853T patent/PT1009393E/en unknown
- 1998-08-21 DK DK98948853T patent/DK1009393T3/en active
- 1998-08-21 WO PCT/EP1998/005321 patent/WO1999012529A2/en active IP Right Grant
- 1998-08-21 ES ES98948853T patent/ES2175792T3/en not_active Expired - Lifetime
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2000
- 2000-02-28 NO NO20001003A patent/NO327605B1/en not_active IP Right Cessation
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2004
- 2004-07-15 US US10/891,942 patent/US7384651B2/en not_active Expired - Fee Related
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AU738033B2 (en) | 2001-09-06 |
WO1999012529A3 (en) | 1999-05-27 |
JP3847088B2 (en) | 2006-11-15 |
NO20001003D0 (en) | 2000-02-28 |
NO20001003L (en) | 2000-02-28 |
ATE215364T1 (en) | 2002-04-15 |
US6814976B1 (en) | 2004-11-09 |
ES2175792T3 (en) | 2002-11-16 |
US20040253301A1 (en) | 2004-12-16 |
DE19738855A1 (en) | 1999-03-11 |
KR20010023691A (en) | 2001-03-26 |
EP1009393A2 (en) | 2000-06-21 |
AU9532998A (en) | 1999-03-29 |
DE59803647D1 (en) | 2002-05-08 |
SI1009393T1 (en) | 2002-10-31 |
DE19738855C2 (en) | 2001-01-04 |
NO327605B1 (en) | 2009-08-31 |
WO1999012529A2 (en) | 1999-03-18 |
KR100515007B1 (en) | 2005-09-14 |
JP2001515856A (en) | 2001-09-25 |
DK1009393T3 (en) | 2002-07-22 |
EP1009393B1 (en) | 2002-04-03 |
PT1009393E (en) | 2002-09-30 |
CA2302601A1 (en) | 1999-03-18 |
US7384651B2 (en) | 2008-06-10 |
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