NO302102B1 - Preparation of a Transdermal Therapeutic System - Google Patents
Preparation of a Transdermal Therapeutic System Download PDFInfo
- Publication number
- NO302102B1 NO302102B1 NO912851A NO912851A NO302102B1 NO 302102 B1 NO302102 B1 NO 302102B1 NO 912851 A NO912851 A NO 912851A NO 912851 A NO912851 A NO 912851A NO 302102 B1 NO302102 B1 NO 302102B1
- Authority
- NO
- Norway
- Prior art keywords
- active ingredient
- matrix
- reservoir
- layer
- therapeutic system
- Prior art date
Links
- 230000001225 therapeutic effect Effects 0.000 title claims description 28
- 238000002360 preparation method Methods 0.000 title claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 85
- 239000011159 matrix material Substances 0.000 claims description 68
- 239000000853 adhesive Substances 0.000 claims description 24
- 230000001070 adhesive effect Effects 0.000 claims description 24
- 238000004519 manufacturing process Methods 0.000 claims description 22
- 239000000463 material Substances 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 11
- 239000004753 textile Substances 0.000 claims description 6
- 238000005315 distribution function Methods 0.000 claims description 2
- 238000003825 pressing Methods 0.000 claims 1
- 239000010410 layer Substances 0.000 description 54
- 229960002715 nicotine Drugs 0.000 description 22
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 22
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 21
- 239000011888 foil Substances 0.000 description 10
- 239000012528 membrane Substances 0.000 description 10
- 239000013543 active substance Substances 0.000 description 9
- 239000012790 adhesive layer Substances 0.000 description 7
- 239000011241 protective layer Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 238000009826 distribution Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000004925 Acrylic resin Substances 0.000 description 4
- 229920000178 Acrylic resin Polymers 0.000 description 4
- 229920003149 Eudragit® E 100 Polymers 0.000 description 4
- 239000011149 active material Substances 0.000 description 4
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 4
- 125000005397 methacrylic acid ester group Chemical group 0.000 description 4
- 239000003094 microcapsule Substances 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 239000011505 plaster Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229920000728 polyester Polymers 0.000 description 3
- 239000011265 semifinished product Substances 0.000 description 3
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 description 2
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 2
- 235000013162 Cocos nucifera Nutrition 0.000 description 2
- 244000060011 Cocos nucifera Species 0.000 description 2
- 229920000742 Cotton Polymers 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- VIROVYVQCGLCII-UHFFFAOYSA-N amobarbital Chemical compound CC(C)CCC1(CC)C(=O)NC(=O)NC1=O VIROVYVQCGLCII-UHFFFAOYSA-N 0.000 description 2
- 229960005274 benzocaine Drugs 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- GLVVKKSPKXTQRB-UHFFFAOYSA-N ethenyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC=C GLVVKKSPKXTQRB-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 229960004391 lorazepam Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 2
- 229960001454 nitrazepam Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229920000058 polyacrylate Polymers 0.000 description 2
- 229920000193 polymethacrylate Polymers 0.000 description 2
- 229920001289 polyvinyl ether Polymers 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229940100640 transdermal system Drugs 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- VMEZXMFPKOMWHR-UHFFFAOYSA-N (dimethylamino)methyl prop-2-enoate Chemical compound CN(C)COC(=O)C=C VMEZXMFPKOMWHR-UHFFFAOYSA-N 0.000 description 1
- BFUXUGOZJVHVMR-UHFFFAOYSA-N 1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound N1CNS(=O)(=O)C2=CC(S(=O)(=O)N)=CC=C21 BFUXUGOZJVHVMR-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- VSKJLJHPAFKHBX-UHFFFAOYSA-N 2-methylbuta-1,3-diene;styrene Chemical compound CC(=C)C=C.C=CC1=CC=CC=C1.C=CC1=CC=CC=C1 VSKJLJHPAFKHBX-UHFFFAOYSA-N 0.000 description 1
- CPHGOBGXZQKCKI-UHFFFAOYSA-N 4,5-diphenyl-1h-imidazole Chemical compound N1C=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 CPHGOBGXZQKCKI-UHFFFAOYSA-N 0.000 description 1
- MUPQZWGSBCWCAV-UHFFFAOYSA-N 5-[2-(tert-butylamino)-1-hydroxyethyl]benzene-1,3-diol;sulfuric acid Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 MUPQZWGSBCWCAV-UHFFFAOYSA-N 0.000 description 1
- BKYKPTRYDKTTJY-UHFFFAOYSA-N 6-chloro-3-(cyclopentylmethyl)-1,1-dioxo-3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1CCCC1 BKYKPTRYDKTTJY-UHFFFAOYSA-N 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- 108010000437 Deamino Arginine Vasopressin Proteins 0.000 description 1
- BALXUFOVQVENIU-GNAZCLTHSA-N Ephedrine hydrochloride Chemical compound Cl.CN[C@@H](C)[C@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-GNAZCLTHSA-N 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 229920002292 Nylon 6 Polymers 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- 239000000026 Pentaerythritol tetranitrate Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- MJNIWUJSIGSWKK-BBANNHEPSA-N Riboflavin butyrate Chemical compound CCCC(=O)OC[C@@H](OC(=O)CCC)[C@@H](OC(=O)CCC)[C@@H](OC(=O)CCC)CN1C2=CC(C)=C(C)C=C2N=C2C1=NC(=O)NC2=O MJNIWUJSIGSWKK-BBANNHEPSA-N 0.000 description 1
- PPTYJKAXVCCBDU-UHFFFAOYSA-N Rohypnol Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F PPTYJKAXVCCBDU-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- MECHNRXZTMCUDQ-UHFFFAOYSA-N Vitamin D2 Natural products C1CCC2(C)C(C(C)C=CC(C)C(C)C)CCC2C1=CC=C1CC(O)CCC1=C MECHNRXZTMCUDQ-UHFFFAOYSA-N 0.000 description 1
- RMCARYIDWQXUND-UHFFFAOYSA-N [CH2-]C(=O)C.C(C)(=O)O Chemical compound [CH2-]C(=O)C.C(C)(=O)O RMCARYIDWQXUND-UHFFFAOYSA-N 0.000 description 1
- 239000002998 adhesive polymer Substances 0.000 description 1
- 229960005142 alclofenac Drugs 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 229960001301 amobarbital Drugs 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 1
- 229960003515 bendroflumethiazide Drugs 0.000 description 1
- HDWIHXWEUNVBIY-UHFFFAOYSA-N bendroflumethiazidum Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 HDWIHXWEUNVBIY-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 229920005549 butyl rubber Polymers 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- CBGUOGMQLZIXBE-XGQKBEPLSA-N clobetasol propionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CBGUOGMQLZIXBE-XGQKBEPLSA-N 0.000 description 1
- 229960004703 clobetasol propionate Drugs 0.000 description 1
- 229960003120 clonazepam Drugs 0.000 description 1
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- WTYGAUXICFETTC-UHFFFAOYSA-N cyclobarbital Chemical compound C=1CCCCC=1C1(CC)C(=O)NC(=O)NC1=O WTYGAUXICFETTC-UHFFFAOYSA-N 0.000 description 1
- 229960004138 cyclobarbital Drugs 0.000 description 1
- 229960003206 cyclopenthiazide Drugs 0.000 description 1
- 229960004281 desmopressin Drugs 0.000 description 1
- NFLWUMRGJYTJIN-NXBWRCJVSA-N desmopressin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSCCC(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(N)=O)=O)CCC(=O)N)C1=CC=CC=C1 NFLWUMRGJYTJIN-NXBWRCJVSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- OWMBTIRJFMGPAC-UHFFFAOYSA-N dimethylamino 2-methylprop-2-enoate Chemical compound CN(C)OC(=O)C(C)=C OWMBTIRJFMGPAC-UHFFFAOYSA-N 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- -1 domperdone Chemical compound 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 229960002061 ergocalciferol Drugs 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 229960001395 fenbufen Drugs 0.000 description 1
- ZPAKPRAICRBAOD-UHFFFAOYSA-N fenbufen Chemical compound C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 description 1
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 229960003469 flumetasone Drugs 0.000 description 1
- WXURHACBFYSXBI-GQKYHHCASA-N flumethasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-GQKYHHCASA-N 0.000 description 1
- 229960002200 flunitrazepam Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960002690 fluphenazine Drugs 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- MPGBPFMOOXKQRX-UHFFFAOYSA-N indenolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1C=CC2 MPGBPFMOOXKQRX-UHFFFAOYSA-N 0.000 description 1
- 229950008838 indenolol Drugs 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- KSMAGQUYOIHWFS-UHFFFAOYSA-N lofexidine Chemical compound N=1CCNC=1C(C)OC1=C(Cl)C=CC=C1Cl KSMAGQUYOIHWFS-UHFFFAOYSA-N 0.000 description 1
- 229960005209 lofexidine Drugs 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229960004815 meprobamate Drugs 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- OIXVKQDWLFHVGR-WQDIDPJDSA-N neomycin B sulfate Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)O[C@@H]1CO OIXVKQDWLFHVGR-WQDIDPJDSA-N 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- 229960000649 oxyphenbutazone Drugs 0.000 description 1
- HFHZKZSRXITVMK-UHFFFAOYSA-N oxyphenbutazone Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 HFHZKZSRXITVMK-UHFFFAOYSA-N 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960004321 pentaerithrityl tetranitrate Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- YZZCJYJBCUJISI-UHFFFAOYSA-N propatylnitrate Chemical compound [O-][N+](=O)OCC(CC)(CO[N+]([O-])=O)CO[N+]([O-])=O YZZCJYJBCUJISI-UHFFFAOYSA-N 0.000 description 1
- 229960003402 propatylnitrate Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- WTGQALLALWYDJH-WYHSTMEOSA-N scopolamine hydrobromide Chemical compound Br.C1([C@@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 WTGQALLALWYDJH-WYHSTMEOSA-N 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 229920006132 styrene block copolymer Polymers 0.000 description 1
- SKIVFJLNDNKQPD-UHFFFAOYSA-N sulfacetamide Chemical compound CC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 SKIVFJLNDNKQPD-UHFFFAOYSA-N 0.000 description 1
- 229960002673 sulfacetamide Drugs 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 230000008646 thermal stress Effects 0.000 description 1
- 238000007669 thermal treatment Methods 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- 230000001519 thymoleptic effect Effects 0.000 description 1
- 229960002044 tolmetin sodium Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 1
- 229960003386 triazolam Drugs 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
- 235000001892 vitamin D2 Nutrition 0.000 description 1
- 239000011653 vitamin D2 Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 239000002759 woven fabric Substances 0.000 description 1
Description
Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av et terapeutisk system for administrering av virksomme stoffer eller aktive bestanddeler til huden med et i forhold til huden fravendt sjikt; minst et depot for virksomt materiale; en fordelingsinnretning for den aktive bestanddel som står i forbindelse med depotet av aktiv bestanddel; en avgivelses-styringsinnretning for den aktive bestanddel som styrer avgivelse av denne samt en klebedyktig fikseringsinnretning for det terapeutiske system på huden. The present invention relates to a method for producing a therapeutic system for administering active substances or active ingredients to the skin with a layer facing away from the skin; at least one depot for active material; a distribution device for the active ingredient which is in connection with the depot of active ingredient; a release control device for the active ingredient which controls its release as well as an adhesive fixation device for the therapeutic system on the skin.
Foreliggende oppfinnelse er avdelt fra NO 173.168. The present invention is divided from NO 173,168.
Terapeutiske systemer for transdermal administrering av legemidler avgir en eller flere aktive bestanddeler i på forhånd bestemt grad kontinuerlig over et på forhånd fast bestemt tidsrom til et på forhånd fastsatt anvendelsespunkt. Therapeutic systems for the transdermal administration of drugs release one or more active ingredients in a predetermined amount continuously over a predetermined period of time to a predetermined application point.
Disse systemer er terapeutiske presisjonsinstrumenter som sikrer en kontinuerlig frigivning av aktiv bestanddel. These systems are therapeutic precision instruments that ensure a continuous release of active ingredient.
Den slags terapeutiske systemer kan oppvise både topisk og systemisk virkning og mangfoldet til de på denne måte administrerbare virksomme stoffer og deres forskjellige kjemiske, fysikalske og farmakologiske egenskaper stiller stadig nye krav til fremstilling av slike systemer. These kinds of therapeutic systems can exhibit both topical and systemic effects, and the diversity of the active substances that can be administered in this way and their different chemical, physical and pharmacological properties constantly place new demands on the production of such systems.
Vanligvis oppviser disse transdermale systemer minst et reservoar for aktiv bestanddel der denne foreligger i fast, flytende eller molekyldispers form, og et adhesjonssjikt gjennom hvilket systemet forbindes intimt med huden og gjennom hvilket transporten av aktiv bestanddel skjer, videre et styringsmembran og beskyttelses-dekksjikt som i det vesentlige er impermeable for den aktive bestanddel. Generally, these transdermal systems have at least one reservoir for the active ingredient, where this is in solid, liquid or molecularly dispersed form, and an adhesion layer through which the system is intimately connected to the skin and through which the transport of the active ingredient takes place, further a control membrane and protective cover layer as in the essential is impermeable to the active ingredient.
De kjente systemer er kompliserte i fremstilling og komplisert oppbygd. The known systems are complicated to manufacture and have a complicated structure.
Et problem ved de vanlige systemer ligger i å bearbeide flyktige aktive bestanddeler da fordamping av disse allerede under fremstillingen er vanskelig å kontrollere. A problem with the usual systems lies in processing volatile active ingredients, as evaporation of these already during production is difficult to control.
Termisk ømfintlig aktive bestanddeler er kun i begrenset grad anvendbare i systemer som fremstilles ved termiske metoder. Thermally sensitive active ingredients are only usable to a limited extent in systems produced by thermal methods.
Det er allerede forsøkt å innføre ren aktiv bestanddel i fin-krystallinsk form i et klebende polymerisat slik at den finfordelte finkrystallinske aktive bestanddel som depot-krystaller i den klebende matriks oppløses med tiden, se DE-OS 35 00 508. Denne fremgangsmåte egner seg dårlig for flyktige og termisk ømfintlige aktive bestanddel da metoden omfatter termiske behandlingstrinn. Attempts have already been made to introduce pure active ingredient in fine-crystalline form into an adhesive polymer so that the finely divided fine-crystalline active ingredient as depot crystals in the adhesive matrix dissolves over time, see DE-OS 35 00 508. This method is poorly suited for volatile and thermally sensitive active ingredients as the method includes thermal treatment steps.
Et annet forsøk på å forhøye kapasiteten til den slags terapeutiske systemer ligger i å omhylle depotet av aktiv bestanddel i mikrokapsler som omsluttes av en styringsmembran og å innleire dette i et klebesjikt (se US-PS 3 598 123 og 3 731 683). Fremstilling av den slags med regulerings-membraner omgitte mikrokapsler er meget komplisert og kostbar og lar seg ikke gjennomføre for alle aktive bestanddeler. I blandingen av mikrokapsler inneholdende aktive bestanddeler i et reservoarmateriale er en videre komplisert operasjon hvorved også mikrokapslene under bearbeidingen lett kan skades eller ødelegges, noe som fører til en ikke-tilfredsstillende konstant avgivelse av innholdet av aktiv bestanddel i det ferdige terapeutiske system. Fremgangsmåten i US-PS 3 598 123 er vanskelig å gjennomføre for flytende aktive bestanddel, spesielt når denne er flyktig. Another attempt to increase the capacity of such therapeutic systems lies in enveloping the depot of active ingredient in microcapsules which are enclosed by a control membrane and embedding this in an adhesive layer (see US-PS 3,598,123 and 3,731,683). Production of this type of microcapsules surrounded by regulatory membranes is very complicated and expensive and cannot be carried out for all active ingredients. In the mixture of microcapsules containing active ingredients in a reservoir material is a further complicated operation whereby the microcapsules can also be easily damaged or destroyed during processing, which leads to an unsatisfactory constant release of the content of active ingredient in the finished therapeutic system. The method in US-PS 3 598 123 is difficult to carry out for liquid active ingredient, especially when this is volatile.
Fra DE-PS 3 424 837 er det et depotplaster som lar seg anvende for flytende materialer samt en dekkfolie, en flytende aktiv bestanddel i et uthulet område i dekkfolien og et styringsmembran som dekker den aktive bestanddel, men er gjennomtrengelig for denne. Derved ligger det mellom dekkfolien og styringsmembranen en fordelingsanordning for aktiv bestanddel, nemlig en flor, som fordeler den aktive væske jevnt over styringsmembranet slik dette blir virksomt over et større flateområde. Ved depotplasteret fra DE-PS 3 424 837 er dekkfolie og styringsmembran sveiset sammen langs sine ytre kantområder for å forhindre at den flytende aktive bestanddel renner ut. From DE-PS 3 424 837 there is a transdermal patch which can be used for liquid materials as well as a cover foil, a liquid active ingredient in a hollowed out area in the cover foil and a control membrane which covers the active ingredient but is permeable to it. Thereby, there is a distribution device for active ingredient between the cover foil and the control membrane, namely a flor, which distributes the active liquid evenly over the control membrane so that it is effective over a larger surface area. In the transdermal patch from DE-PS 3 424 837, the cover foil and control membrane are welded together along their outer edge areas to prevent the liquid active ingredient from flowing out.
Det kjente depotplaster har dog mangler da væsken i plasteret er f rittf lytende og lett kan renne ut når klebe- hhv. sveisesømmene skades, og krever i tillegg til dette et kostbart styringsmembran som må tilveiebringes i tillegg til fordelingsanordningen for aktiv bestanddel, for kinetisk å styre administreringen av det virksomme stoff. However, the known transdermal patch has shortcomings as the liquid in the patch is free-flowing and can easily flow out when adhesive or the weld seams are damaged, and in addition to this requires an expensive control membrane which must be provided in addition to the distribution device for active ingredient, in order to kinetically control the administration of the active substance.
NO 173.168 tilveiebringer et nytt terapeutisk system med depot for aktiv bestanddel for administrering av denne, som samtidig er rimelig og lett kan fremstilles i forhold til systemene ifølge den kjente teknikk, og som også er egnet for administrering av flyktige og/eller termiske lite stabile komponenter. NO 173,168 provides a new therapeutic system with a depot for active ingredient for administration thereof, which is at the same time affordable and can be easily produced compared to the systems according to the known technique, and which is also suitable for the administration of volatile and/or thermally unstable components .
Dette oppnåes ifølge NO 173.168 ved et terapeutisk system som karakteriseres ved at fordelingsinnretningen for den aktive bestanddelen samt styringsinnretningen for denne er en reservoarmatriks som oppviser en eller flere rommelig definerte i forhold til hverandre anordnede adskilte virkestoffdepoter med en høyere konsentrasjon av aktiv bestanddel enn i reservoarmatriksen. Derved kan reservoar-matriksen ved fremstilling av det terapeutiske system være fritt for aktiv bestanddel og først anrikes på dette i løpet av tiden, under lagring av systemet, eller ved sterkt flyktige stoffer, under produksjonen. Det er altså en fordel ved NO 173.168 at nu også aktive bestanddeler som termisk er ustabile og/eller flyktige, uten termisk belastning kan innføres som et depot i transdermale systemer under fremstillingen. Arbeidsoperasjoner som blanding av reservoar-matriksmateriale med den aktive bestanddel faller bort, reservoarmatriksmaterialet mettes under lagring av det terapeutiske system med den aktive bestanddel ved romtempera-tur. På grunn av at fremstill ingsskrittene for aktiv bestanddel-mettet matriks faller bort, blir fremstillingen i vesentlig grad lettet. This is achieved according to NO 173,168 by a therapeutic system which is characterized by the fact that the distribution device for the active ingredient as well as the control device for this is a reservoir matrix which exhibits one or more spatially defined in relation to each other arranged separate active substance depots with a higher concentration of active ingredient than in the reservoir matrix. Thereby, the reservoir matrix during the production of the therapeutic system can be free of active ingredient and only be enriched with this over time, during storage of the system, or in the case of highly volatile substances, during production. It is therefore an advantage of NO 173,168 that now also active ingredients that are thermally unstable and/or volatile can be introduced without thermal stress as a depot in transdermal systems during manufacture. Work operations such as mixing reservoir matrix material with the active ingredient are omitted, the reservoir matrix material is saturated during storage of the therapeutic system with the active ingredient at room temperature. Due to the fact that the production steps for the active ingredient-saturated matrix are omitted, the production is considerably simplified.
I henhold til dette angår foreliggende oppfinnelse en fremgangsmåte for fremstilling av et terapeutisk system for avgivelse av aktiv bestanddel til huden med et fra huden vendt baksjikt; et aktivbestanddel-depot inneholdende en flytende aktiv bestanddel eller en flytende tilberedning av aktiv bestanddel; en matriks som styrer avgivelsen av den aktive bestanddel og en klebedyktig fikseringsinnretning for det terapeutiske system på huden, der aktivbestanddeldepotet oppviser minst et hjelpemateriale med støtte- og fordelingsfunksjon i form av et tekstil-flatemateriale, og er omgitt av matriksen på alle sider, og denne måte karakteriseres ved at den aktive bestanddel eller aktivbestanddel-preparatet i en på forhånd bestemt dose bringes inn i et tekstilt flatemateriale med på forhånd bestemt form og størrelse og sammen med dette umiddelbart bringes inn i en reservoar-matriks bestående av et eller flere matriks-sjikt, og så konfeksjonerer reservoar-matriksen, eller at det tekstile flatemateriale inneholdende aktiv bestanddel, umiddelbart omgis med en aktiv bestanddel ugjennomtrengelig omhylling og bringes inn i reservoar-matriksen på et senere tidspunkt efter fjerning av omhyllingen, hvorefter reservoar-matriksen konfeksjoneres. According to this, the present invention relates to a method for producing a therapeutic system for delivering an active ingredient to the skin with a back layer facing away from the skin; an active ingredient depot containing a liquid active ingredient or a liquid preparation of active ingredient; a matrix that controls the release of the active ingredient and an adhesive fixation device for the therapeutic system on the skin, where the active ingredient depot exhibits at least one auxiliary material with a support and distribution function in the form of a textile surface material, and is surrounded by the matrix on all sides, and this way is characterized by the fact that the active ingredient or active ingredient preparation in a predetermined dose is brought into a textile surface material with a predetermined shape and size and together with this is immediately brought into a reservoir matrix consisting of one or more matrix layers , and then the reservoir matrix is assembled, or that the textile surface material containing the active ingredient is immediately surrounded by an active ingredient impermeable casing and brought into the reservoir matrix at a later time after removal of the casing, after which the reservoir matrix is assembled.
På grunn av at det her kan anvendes en reservoarmatriks med en egen reguleringsfunksjon som blant annet kan bestemmes ved hjelp av migreringshastigheten for bestanddelen gjennom matriksen, kan man her utelate en styringsmembran som krever ytterligere fremgangsmåtetrinn og membranmaterialer ved fremstillingen. Derved kan depotet bestå av ren aktiv bestanddel som kan være fast eller flytende, men som også kan oppvise inerte hjelpestoffer. Med "inert" menes her at aktiv oppvise inerte hjelpestoffer. Med "inert" menes her at aktiv bestanddel og hjelpestoff ikke reagerer med hverandre, et "inert" hjelpestoff kan imidlertid også ha en fysiologisk funksjon, slik som for eksempel dimetylsulfoksyd og lignende som forhøyer hudens permeabilitet. Som den slags hjelpestoffer finner man også fortynningsmaterialer som gjør aktiv bestanddel-depotet uømfintlig overfor trykk-strekkbelast-ninger, samt konvensjonelle bærere. Due to the fact that a reservoir matrix can be used here with a separate regulation function which can be determined, among other things, with the help of the migration rate of the component through the matrix, a control membrane can be omitted here, which requires additional process steps and membrane materials during production. Thereby, the depot can consist of pure active ingredient which can be solid or liquid, but which can also contain inert excipients. By "inert" is meant here that active exhibit inert excipients. By "inert" is meant here that the active ingredient and excipient do not react with each other, an "inert" excipient may, however, also have a physiological function, such as, for example, dimethylsulfoxide and the like which increase the permeability of the skin. Diluting materials that make the active ingredient depot insensitive to compressive-tensile loads, as well as conventional carriers, can also be found as such excipients.
Som aktive bestanddeler av transdermal type kan anvendes for eksempel: As active ingredients of transdermal type can be used, for example:
- Nikotin - Nicotine
Kortikosteorider: hydrokortison, prednisolon, beklome-tason-propionat, flumetason, triamikinolon, triamikinolon-acetonid, fluokinolon, fluokinoln-acetonid, flukoinolon-acetonidacetat, klobetasol-propionat og andre, Corticosteroids: hydrocortisone, prednisolone, beclome tason propionate, flumetasone, triaquinolone, triaquinolone acetonide, fluoquinolone, fluoquinoln acetonide, flucoinolone acetonide acetate, clobetasol propionate and others,
Analgetiske, antiinflammatoriske midler: acetaminofen, Analgesic, anti-inflammatory agents: acetaminophen,
mefenaminosyre, flufenaminsyre, diklofenak, diklofenak-natrium-alklofenak, oksyfenbutazon, fenylbutanzon, ibuprofen, flurbiprofen, salicylsyre, 1-mentol, kamfer, mefenamic acid, flufenamic acid, diclofenac, diclofenac-sodium-alclofenac, oxyphenbutazone, phenylbutazone, ibuprofen, flurbiprofen, salicylic acid, 1-menthol, camphor,
sulindak-tolmetin-natrium, naproksen, fenbufen og andre, sulindac tolmetin sodium, naproxen, fenbufen and others,
Hypnotisk virksomme sedativer: fenobarbital, amobarbital, Hypnotically active sedatives: phenobarbital, amobarbital,
cyklobarbital, triazolam, nitrazepam, lorazepam, halo-peridol og andre, cyclobarbital, triazolam, nitrazepam, lorazepam, halo-peridol and others,
- Beroligende midler: flufenazin, tioridazin, lorazepam, flunitrazepam, klorpromazin og andre, - Antihypertensiver: pindolol, indenolol, nifedipin, lofeksidin, nipradinol, bukumolol og andre, - Antihypertensivt virkende diuretika: hydrotiazid, bendroflumetiazid, cyklopentiazid og andre, - Tranquilizers: fluphenazine, thioridazine, lorazepam, flunitrazepam, chlorpromazine and others, - Antihypertensives: pindolol, indenolol, nifedipine, lofexidine, nipradinol, bukumolol and others, - Antihypertensive diuretics: hydrothiazide, bendroflumethiazide, cyclopenthiazide and others,
Antibiotika: pencillin, tetracyklin, oksytetracyklin, Antibiotics: penicillin, tetracycline, oxytetracycline,
fradiomycinsulfat, erytromycin, kloramfenikol og andre, fradiomycin sulfate, erythromycin, chloramphenicol and others,
- Anestetika: lidokain, benzokain, etylaminobenzoat og andre, - Anesthetics: lidocaine, benzocaine, ethyl aminobenzoate and others,
Antimikrobielle midler: benzalkoniumklorid, nitofurazon, Antimicrobial agents: benzalkonium chloride, nitofurazone,
nystatin, acetosulfamin, klortrimazol og andre, nystatin, acetosulfamin, chlortrimazole and others,
Vitaminer: vitamin A, ergokalkiferol, klolekalkiferol, Vitamins: vitamin A, ergocalciferol, chlolecalciferol,
oktotiamin, riboflavinbutyrat og andre, octothiamine, riboflavin butyrate and others,
Antiepileptika: nitrazepam, meprobamat, klonazepam og Antiepileptics: nitrazepam, meprobamate, clonazepam and
andre, second,
Koronar-vasodilatorer: dipyridamol, erytrittetranitrat, Coronary vasodilators: dipyridamole, erythritol trinitrate,
pentaerytrit-tetranitrat, propatyl-nitrat og andre, Antihistaminer: difenyhydramin-hydroklorid, klorfenir-amin, difenylimidazol og andre, pentaerythritol tetranitrate, propatyl nitrate and others, Antihistamines: diphenyhydramine hydrochloride, chlorpheniramine, diphenylimidazole and others,
Antitussiver: dertrometorfan (hydrobromid), terbutalin (sulfat), efedrin (hydroklorid), salbutanol (sulfat), Antitussives: dertromethorphan (hydrobromide), terbutaline (sulfate), ephedrine (hydrochloride), salbutanol (sulfate),
isoproterenol (sulfat, hydroklorid) og andre, Seksualhormoner: progesteron og andre, isoproterenol (sulphate, hydrochloride) and others, Sex hormones: progesterone and others,
Tymoleptika: Doksepin og andre, Thymoleptics: Doxepin and others,
Ytterligere medikamenter: 5-fluoruracil, fentanyl, Additional drugs: 5-fluorouracil, fentanyl,
desmopressin, domperdon, skopolamin (hydrobromid), peptid desmopressin, domperdone, scopolamine (hydrobromide), peptide
og andre, and others,
selvfølgelig er denne oppsummering ikke fullstendig. Of course, this summary is not complete.
Med fordel kan også reservoarmatriksen av aktiv bestanddel være bygget opp lagvis, hvorved lagene kan være like eller forskjellige. Reservoarmatriksen kan være klebende, for eksempel et gummimateriale som styren/isopren/styren-blokkopolymerisat, silikongummi eller også syntetiske harpikser som poly(met)akrylat, polyuretan, polyvinyleter, polyester og lignende, en sammenfatning av egnede matrikse-materialer finnes for eksempel i DE-OS 35 Ot) 508. Det kan også være gunstig når reservoarmatriksen er klebende da men derved kan unngå å måtte tilveiebringe en separat klebende fikseringsinnretning i system, anvendelsen av en slik klebende matriks er blant annet avhengig av fordrageligheten for matriksmaterialet med den aktive bestanddel, klebende matriksmaterialer er kjent. Advantageously, the reservoir matrix of active ingredient can also be built up in layers, whereby the layers can be the same or different. The reservoir matrix can be adhesive, for example a rubber material such as styrene/isoprene/styrene block copolymer, silicone rubber or also synthetic resins such as poly(meth)acrylate, polyurethane, polyvinyl ether, polyester and the like, a summary of suitable matrix materials can be found, for example, in DE -OS 35 Ot) 508. It can also be beneficial when the reservoir matrix is adhesive then but thereby can avoid having to provide a separate adhesive fixation device in the system, the use of such an adhesive matrix depends, among other things, on the tolerability of the matrix material with the active ingredient, adhesive matrix materials are known.
Foretrukne ikke-klebende matriksmaterialer er: Preferred non-adhesive matrix materials are:
Polymerisater bestående av poly(met)akrylat, polyvinylpyrro-lidon, etylcellulose, hydroksypropylcelulose, hydroksypropyl-metylcellulosefatalat, polyvinylalkohol henholdsvis deres kopolymerisater med vinyllaurat eller malelnsyre, vinyl-acetat, henholdsvis disses kopolymerisater med vinyllaurat eller maleinsyre; polyvinyleter, butylkautsjuk og polykapro-laktam. Polymers consisting of poly(meth)acrylate, polyvinylpyrrolidone, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol or their copolymers with vinyl laurate or maleic acid, vinyl acetate or their copolymers with vinyl laurate or maleic acid; polyvinyl ether, butyl rubber and polycaprolactam.
For eksempel kan aktiv bestanddel-depotet henholdsvis flere slike anordnes mellom reservoarmaterialmatrikser og et mot huden vendende reservoarmatriks-sjikt hvorved tykkelsesfor-holdet for sjiktene fortrinnsvis ligger på X:Y = 1:1 ti 1:20 og fortrinnsvis 1:1 til 1:5. For example, the active ingredient depot or several such can be arranged between reservoir material matrices and a reservoir matrix layer facing the skin, whereby the thickness ratio for the layers is preferably X:Y = 1:1 to 1:20 and preferably 1:1 to 1:5 .
I andre tilfeller kan det være fornuftig når reservoar-matriksen eller også reservoarmatrikssjiktene av hvilke de er oppbygget, i det minste på en side er utstyrt med klebende belegg. In other cases, it may make sense when the reservoir matrix or also the reservoir matrix layers from which they are made up, at least on one side, are equipped with an adhesive coating.
Ved en ytterligere fordelaktig utførelsesform av systemet ifølge NO 173.168 kan den aktive depot være anordnet mellom reservoarmatriksen og bærersjiktet, noe som egner seg for fast, i form av legemer, påførte aktive bestanddeler. In a further advantageous embodiment of the system according to NO 173,168, the active depot can be arranged between the reservoir matrix and the carrier layer, which is suitable for solid, in the form of bodies, applied active ingredients.
Ved en foretrukket utførelsesform kan fikseringssjiktet være dannet av i reservoarmatriksen innarbeidede klebemiddel-områder som for eksempel tildannes ved hjelp av en omløpende kleberand eller klebepunkter. In a preferred embodiment, the fixing layer can be formed from areas of adhesive incorporated in the reservoir matrix, which are for example formed by means of a circumferential adhesive edge or adhesive points.
På samme måte er det mulig å tilveiebringe et adskillbart beskyttelsessjikt for den mot huden vendte flate av det terapeutiske system. In the same way, it is possible to provide a separable protective layer for the surface of the therapeutic system facing the skin.
Summen av aktiv bestanddel-mengder i depotet og i reservoar-matriksen ligger fortrinnsvis på ca. 20 ganger den terapeutisk nødvendige aktiv bestanddel-mengde. The sum of active ingredient quantities in the depot and in the reservoir matrix is preferably approx. 20 times the therapeutically necessary amount of active ingredient.
En spesielt foretrukket fremgangsmåte for fremstilling av den slags systemer medfører at reservoarmatriksen dannes av to reservoarmatrikssjikt som kan være like eller forskjellige og som anordnes mellom aktiv bestanddel-depotene. Derved kan reservoarmatrikssjiktene føyes sammen ved hjelp av trykk og/eller varme. Depotet kan også innføres under trykkanvendelse i reservoarmatriksen, for eksempel ved injeksjon av en på forhånd bestemt mengde eller inntrykking av en aktiv bestanddel i et mykt matrikssjikt. A particularly preferred method for producing such systems entails that the reservoir matrix is formed by two reservoir matrix layers which may be the same or different and which are arranged between the active ingredient depots. Thereby, the reservoir matrix layers can be joined together by means of pressure and/or heat. The depot can also be introduced under pressure into the reservoir matrix, for example by injecting a pre-determined amount or impressing an active ingredient into a soft matrix layer.
En ytterligere foretrukket fremgangsmåte består i fremstilling av minst en del av det terapeutiske system ved å strø på partikler. A further preferred method consists in producing at least part of the therapeutic system by sprinkling particles.
Det kan også fremstilles en flersjikts-aktiv-bestandel-matriks. Også dekk- og reservoarmatrikssjiktet kan føyes sammen under påvirkning av trykk eller varme. Reservoar-matrikssj iktet og/eller -sjiktene kan i det minste delvis fremstilles av flytende stoffer, for eksempel fra en dispersjon, en smelte eller en oppløsning. A multi-layer active ingredient matrix can also be produced. Also, the cover and reservoir matrix layer can be joined together under the influence of pressure or heat. The reservoir matrix layer and/or layers can be at least partially produced from liquid substances, for example from a dispersion, a melt or a solution.
Det terapeutiske system egner seg spesielt for lokal eller systemisk transdermal administrering av aktiv bestanddel i human- eller veterinærmedisinen eller kan også anvendes rent kosmetisk. The therapeutic system is particularly suitable for local or systemic transdermal administration of active ingredients in human or veterinary medicine or can also be used purely cosmetically.
Nedenfor følger illustrerende eksempler basert på de vedlagte tegninger av terapeutiske systemer der: Fig. 1 viser et snitt gjennom en foretrukket utførelsesform av et terapeutisk system; Fig. 2 viser et snitt gjennom en ytterligere foretrukket utførelsesform av et terapeutisk system der depotet av aktiv bestanddel befinner seg mellom dekksjiktet og reservoarmatriksen; Fig. 3 viser et snitt gjennom en ytterligere foretrukket utførelsesform av systemet der den aktive bestanddel ligger mellom matrikssjiktene; Fig. 4 viser et snitt gjennom et terapeutisk system med flere, i et plan anordnede depoter av aktiv bestanddel ; Fig. 5 viser et snitt gjennom et system med en sjiktformig Following are illustrative examples based on the attached drawings of therapeutic systems where: Fig. 1 shows a section through a preferred embodiment of a therapeutic system; Fig. 2 shows a section through a further preferred embodiment of a therapeutic system where the depot of active ingredient is located between the cover layer and the reservoir matrix; Fig. 3 shows a section through a further preferred embodiment of the system where the active ingredient lies between the matrix layers; Fig. 4 shows a section through a therapeutic system with several depots of active ingredient arranged in a plane; Fig. 5 shows a section through a system with a layered
aktiv bestanddel-depot; og active ingredient depot; and
Fig. 6 viser et snitt gjennom et banetildannet halvfabrikat Fig. 6 shows a section through a web-formed semi-finished product
ifølge oppfinnelsen. according to the invention.
I fig. 1 vises skjematisk et snitt gjennom et terapeutisk system som beskrevet, som festet til huden 18 ved hjelp av en festeinnretning 16, for eksempel et porøst klebemiddelsjikt eller lignende. På festeinnretningen 16 befinner seg reservoarmatriksen 12 som fortrinnsvis på fremstillingstids-punktet ikke inneholder aktiv bestanddel (metningen med aktiv bestanddel inntrer under lagringen). I reservoar-matriksen er det anordnet et depot 14 som her er fremstilt som et fast aktivt bestanddel-legeme 14 som oppløses i reservoarmatriksmaterialet og avgis via fikseringsanordningen 16 til huden 18. Det terapeutiske system avsluttes mot utsiden ved hjelp av. et dekksjikt 10 som er ugjennomtrengelig for den aktive bestanddel og fortrinnsvis også for fuktighet, og som samtidig utøver en bærende funksjon for systemet. In fig. 1 schematically shows a section through a therapeutic system as described, which is attached to the skin 18 by means of an attachment device 16, for example a porous adhesive layer or the like. On the fastening device 16 is the reservoir matrix 12 which preferably does not contain active ingredient at the time of manufacture (saturation with active ingredient occurs during storage). In the reservoir matrix, a depot 14 is arranged, which is here produced as a solid active component body 14 which dissolves in the reservoir matrix material and is released via the fixation device 16 to the skin 18. The therapeutic system is terminated towards the outside by means of. a cover layer 10 which is impermeable to the active ingredient and preferably also to moisture, and which at the same time performs a supporting function for the system.
I fig. 2 er det vist en ytterligere variant av systemet ved hvilket det på reservoarmatriks-sjiktet 12 ligger en aktiv bestanddel-depot 14 og som avdekkes av et støtte-bæresjikt 10. Fikseringsinnretningen er i denne tegning ikke vist, spesielt kan det her for eksempel dreie seg om en klebefolie eller lignende der hudkontaktflåtene til det terapeutiske system ligger tett an mot huden 18. Denne utførelsesform er i og for seg fordelaktig da fremstillingen er uhyre enkel, man må kun påføre definerte mengder aktiv bestanddel (elementer, (viskose) væske) på et på forhånd fremstilt matriks-sjikt og det hele må så avdekkes via et dekksjikt. In fig. 2 shows a further variant of the system in which there is an active component depot 14 on the reservoir matrix layer 12 and which is uncovered by a support carrier layer 10. The fixing device is not shown in this drawing, in particular it can for example be about an adhesive foil or the like where the skin contact surfaces of the therapeutic system are in close contact with the skin 18. This embodiment is in itself advantageous as the preparation is extremely simple, you only have to apply defined amounts of active ingredient (elements, (viscous) liquid) on a pre-made matrix layer and the whole thing must then be uncovered via a covering layer.
Fremgangsmåten for fremstilling av systemet i fig. 2 er meget kostnadsgunstig i forhold til systemet i fig. 1, det kan imidlertid kun anvendes når en generell inneslutning av det virksomme materialet i matriksen, for eksempel på grunn av flyktighet eller stor kontaktflate ikke er nødvendig. For eksempel kan dette benyttes for stoffer som oppløses lett i reservoaret av virkemiddel og som uten vanskeligheter diffunderer i dette slik at det ikke er nødvendig med noen stor kontaktflate mellom virkemiddel og reservoarmatriks. Fig. 3 viser en ytterligere foretrukket utførelsesform der et terapeutisk system ved hjelp av en aktiv bestanddel reservoar-matriksmateriale er festet ved hjelp av et klebemiddel-partikkelsjikt henholdsvis avsnitt av slike til huden 18. Aktiv bestanddel-reservoarsjiktene 12 består her av et øvre sjikt X og et nedre sjikt Y mellom hvilke virkemiddel, for eksempel i flytende form, er innbragt. Tilveiebringelse av to reservoarmatrikssjikt X og Y er fordelaktig i de tilfeller når fremstilling av et slikt system skjer ved at man i første omgang tilveiebringer den nedre aktive bestanddel-reservoar-sj ikt, eventuelt med allerede påkasjert dekkfolie eller lignende, og så påfører et på forhånd bestemt mønster av aktiv bestanddel-materiale, så legger den neste aktive bestanddel-reservoarsjikt X og på vanlig måte fullstendiggjør systemet ved påføring av dekksjiktet henholdsvis forskjellige klebemiddelsjikt. Det kan derfor også være fornuftig i første omgang å legge de to aktive bestanddel-reservoarsjikt X og Y på hverandre og derefter å sprøyte inn en på forhånd bestemt mengde aktiv bestanddel mellom de to reservoarsjikt og derved å redusere fordamping av den aktive bestanddel til et minimum. Fig. 4 viser en utførelsesform av det transdermale system med flere og i et plan anordnede aktive bestanddel-depoter 14 som befinner seg mellom et klebemiddelsjikt 16 og en reservoar-matriks 12, hvorved klebesjiktet 16 samtidig er festet til støttesjiktet 10. Systemet avsluttes av et fjernbart dekksjikt 19. The procedure for manufacturing the system in fig. 2 is very cost-effective compared to the system in fig. 1, it can, however, only be used when a general containment of the active material in the matrix, for example due to volatility or a large contact surface, is not necessary. For example, this can be used for substances that dissolve easily in the reservoir of active agent and which diffuse in this without difficulty, so that no large contact surface between active agent and reservoir matrix is necessary. Fig. 3 shows a further preferred embodiment in which a therapeutic system by means of an active ingredient reservoir matrix material is attached by means of an adhesive particle layer or sections of such to the skin 18. The active ingredient reservoir layers 12 here consist of an upper layer X and a lower layer Y between which the active agent, for example in liquid form, is introduced. Provision of two reservoir matrix layers X and Y is advantageous in cases where the production of such a system takes place by initially providing the lower active component reservoir layer, possibly with an already coated cover foil or the like, and then applying a determined pattern of active ingredient material, then he adds the next active ingredient reservoir layer X and in the usual way completes the system by applying the cover layer or different adhesive layers. It may therefore also be sensible in the first instance to place the two active ingredient reservoir layers X and Y on top of each other and then to inject a predetermined amount of active ingredient between the two reservoir layers and thereby reduce evaporation of the active ingredient to a minimum . Fig. 4 shows an embodiment of the transdermal system with several and arranged in a plane active ingredient depots 14 which are located between an adhesive layer 16 and a reservoir matrix 12, whereby the adhesive layer 16 is simultaneously attached to the support layer 10. The system ends with a removable cover layer 19.
I fig. 5 vises en ytterligere foretrukket utførelsesform av det system der et dekksjikt 10 ensidig er belagt med et klebemiddelsjikt 16 hvorpå aktiv bestanddel - eventuelt med hjelpestoff - som for eksempel stoffer for å lette forarbeid-barhet av de aktive béstanddeler (for eksempel tabletterings-hjelpemidler) eller bærematerialer som vevnader og lignende, er tilordnet. På det flataktige aktiv bestanddel-depot er det påført en reservoarmatriks som i sin tur er avdekket av en fjernbar beskyttelsesfolie. In fig. 5 shows a further preferred embodiment of the system where a cover layer 10 is coated on one side with an adhesive layer 16 on which active ingredient - possibly with auxiliary substance - such as substances to facilitate processability of the active constituents (for example tableting aids) or supporting materials such as woven fabrics and the like are assigned. A reservoir matrix is applied to the flat active ingredient depot, which in turn is covered by a removable protective foil.
I fig. 6 er det nu vist en forløper til en transdermalt system der man tyr til en foretrukket fremstillingsmetode. Et beskyttelsessjiktmateriale i form av en bane, for eksempel voksbelagt papir eller lignende, blir belagt med et reservoarmatriks-sjikt Y som her er fremstilt klebende, og som befinner seg på depotlegemet for virksomt materiale til-svarende et på forhånd bestemt mønster. Matriks-sjiktet Y er i sin tur belagt med et andre matriks-sj ikt X som for eksempel inneholder et annet materiale enn sjiktet Y. Det andre matriks-sj ikt Y blir så dekket av en dekkfolie 10. Langs pilretningen befinner det seg skillelinjer langs hvilke mellomproduktet ved fremstilling av de transdermale systemer kan kuttes opp/utstanses og derefter konfeksjoneres på vanlig måte. In fig. 6, a precursor to a transdermal system is now shown in which a preferred manufacturing method is used. A protective layer material in the form of a web, for example wax-coated paper or the like, is coated with a reservoir matrix layer Y which is here made adhesive, and which is located on the depot body for active material corresponding to a predetermined pattern. The matrix layer Y is in turn coated with a second matrix layer X which, for example, contains a different material than the layer Y. The second matrix layer Y is then covered by a cover foil 10. Along the direction of the arrow, there are dividing lines along in which the intermediate product in the manufacture of the transdermal systems can be cut up/punched out and then assembled in the usual way.
Typiske tykkelsesangivelser for de transdermale systemer er ved en total tykkelse på ca. 123 <m til 5550 <m, fortrinnsvis 285 <m - 1550 <m; dekksjiktets tykkelse: 8 - 150 <m, fortrinnsvis 15 - 100 <m; reservoartykkelse: 100 - 5000 <m, fortrinnsvis 200 - 1300 <m; beskyttelsessjiktets tykkelse: 15 Typical thickness specifications for the transdermal systems are for a total thickness of approx. 123 <m to 5550 <m, preferably 285 <m - 1550 <m; cover layer thickness: 8 - 150 <m, preferably 15 - 100 <m; reservoir thickness: 100 - 5000 <m, preferably 200 - 1300 <m; protective layer thickness: 15
- 400 <m, fortrinnsvis 70 - 150 <m. - 400 <m, preferably 70 - 150 <m.
Ved en spesiell anvendelsesform er det også mulig å kommer-sialisere den som "halvfabrikat" betegnede utførelsesform for å gjøre det mulig for eventuelle brukere å skille system-bestanddelene fra hverandre efter eget behov slik at halvfabrikatet tjener som et "forråd". In the case of a special form of application, it is also possible to commercialize the embodiment designated as "semi-finished product" in order to make it possible for possible users to separate the system components from each other according to their own needs so that the semi-finished product serves as a "storage".
De nedenfor følgende eksempler skal illustrere oppfinnelsen uten å begrense den. The following examples shall illustrate the invention without limiting it.
Eksempel 1 Example 1
Fremstilling av et nikotinplaster Production of a nicotine patch
Nikotinplasteret som for eksempel kan anvendes for avvenning fra røking kan i henhold til oppfinnelsen fremstilles som følger: En klebemasse bestående av 2,085 kg av en 40 %- ig oppløsning av den selvkryssbindende akrylatpolymer "Durotak 280 - 2416" i en blanding av eddiksyreetylester, etanol, heksan og metanol, 147 g av en akrylharpiks av dimetylaminometylakrylat og nøytral metakrylsyreester "Eudragit E 100" samt 100 g et blandet surt triglyserid av de fraksjonerte kokosfettsyre C3-C-LQ "Miglyol 812" påføres på et på en side med aluminium pådampet og tosidig abhesiv tildannet beskyttelsessjikt og oppløsningsmidlet fordampes ved 50 til 80°C. Det oppnås et sjikt på ca. 300 g/m2 . Fra det på denne måte fremstilte klebesjikt stanses det ut sirkler med en diameter på 65 mm hvorved de utragende renner overgitres og der det i midten påkasseres en pute av et flormateriale celluloserbomull 50.50 med en flatevekt på 80 g/m<2>av typen "Paratex 11/80" og med en diameter på 40 mm. Derefter påføres nikotin som virksomt materiale i en oppløsning av 140 g nikotin i 100 g av en akrylharpiks av dimetylaminometakrylat og nøytrale metakrylsyreestre "Eudragit E 100" i 102 mg doser/skive. Disse således fremstilte puter forbindes øyeblikkelig med et nikotinugjennomtrengelig dekksjikt (ensidig aluminium pådampet polyesterfolie med tykkelse 15 um) og forsegles i en på alle sider avtettet og tett pose. The nicotine patch, which can for example be used for quitting smoking, can be produced according to the invention as follows: An adhesive consisting of 2.085 kg of a 40% solution of the self-crosslinking acrylate polymer "Durotak 280 - 2416" in a mixture of acetic acid ethyl ester, ethanol, hexane and methanol, 147 g of an acrylic resin of dimethylaminomethyl acrylate and neutral methacrylic acid ester "Eudragit E 100" as well as 100 g of a mixed acidic triglyceride of the fractionated coconut fatty acids C3-C-LQ "Miglyol 812" are applied on one side with aluminum vaporized and double-sided abhesive formed protective layer and the solvent is evaporated at 50 to 80°C. A layer of approx. 300 g/m2. From the adhesive layer produced in this way, circles with a diameter of 65 mm are punched out, whereby the projecting channels are overlaid and in the middle a pad of a fluff material cellulose cotton 50.50 with a basis weight of 80 g/m<2> of the "Paratex" type is placed 11/80" and with a diameter of 40 mm. Nicotine is then applied as active material in a solution of 140 g of nicotine in 100 g of an acrylic resin of dimethylamino methacrylate and neutral methacrylic acid esters "Eudragit E 100" in 102 mg doses/disc. These cushions produced in this way are immediately connected with a nicotine-impermeable cover layer (one-sided aluminium-vaporized polyester foil with a thickness of 15 µm) and sealed in a sealed and tight bag on all sides.
Ved dette utførelseseksempel virker floret som støttevevnad, henholdsvis for å understøtte jevn fordeling av nikotin som inert hjelpemiddel i henhold til beskrivelsen. In this design example, the fleece acts as support tissue, respectively to support even distribution of nicotine as an inert aid according to the description.
Ved at det virksomme stoff hurtig påføres et matriks-sjikt og umiddelbart kan dekkes av en aktiv bestanddel-ugjennomtrengelig dekksjikt, er det for første gang mulig på tilfredsstillende måte å oppnå et godt dosert nikotinplaster. By the fact that the active substance is quickly applied to a matrix layer and can immediately be covered by an active ingredient-impermeable cover layer, it is possible for the first time in a satisfactory way to obtain a well-dosed nicotine patch.
Nikotin- frisetningsforsøk (in vitro) Nicotine release test (in vitro)
Et som i eksempel 1 fremstilt nikotinplaster dyppes efter avtrekking av beskyttelsessjiktet i 80 ml isotonisk koksalt-oppløsning ved 37°C og den frisatte nikotinmengde bestemmes efter fastlagte tidsrom ved hjelp av væskekromatografi. Volumet av fritt avgitt mengde ble valgt slik at det under hele forsøket ble opprettholdt "synke"-betingelser. A nicotine patch produced in example 1 is dipped after removal of the protective layer in 80 ml of isotonic sodium chloride solution at 37°C and the released amount of nicotine is determined after a fixed period of time using liquid chromatography. The volume of freely released amount was chosen so that "sinking" conditions were maintained throughout the experiment.
Man gjennomførte følgende målinger: The following measurements were carried out:
In vitro-frisatt nikotin/plaster: In vitro-released nicotine/patch:
efter 2 timer: 23,90 mg/plaster after 2 hours: 23.90 mg/plaster
efter 4 timer: 32,34 mg/plaster after 4 hours: 32.34 mg/patch
efter 8 timer: • 41,50 mg/plaster after 8 hours: • 41.50 mg/plaster
efter 24 timer: 56,54 mg/plaster after 24 hours: 56.54 mg/patch
Eksempel 2 Example 2
Fremstilling av et nikotinplaster Production of a nicotine patch
Et ytterligere nikotinplaster kan fremstilles som følger: A further nicotine patch can be prepared as follows:
En klebemasse, klebemasse 1, bestående av 1,9758 kg av en 40 %- ig oppløsning av en selvkryssbindende akrylatpolymer "Durotak 280 - 2526" i en blanding av eddiksyreetylester, etanol, heptan og metanol, 189,7 g av en akrylharpiks av dimetylaminoetylmetakrylat og nøytral metakrylsyreester "Eudragit E 100" samt 20 g av en blanding av surt triglyserid av den fraksjonerte kokosfettsyre Cg-C^Q"Miglyol 812" påføres et ensidig med aluminium pådampet og tosidig abhesiv utrystet beskyttelsessjikt og oppløsningsmidlet fordampes ved 50 til 80° C. Således oppnås det et sjikt med en tykkelse på ca. 440 g/m<2.>Ut fra dette klebemiddelsjikt stanser man ut sirkler med en diameter på 51 mm der de utoverhengende renner gitres av og det i midten påkasseres en sirkel av et florstoff av en fiberblanding celluloserbomull 70:30 med en flatevekt på 40 g/m<2>av typen "Paratex 111/40" og med en diameter på 42 mm. An adhesive, Adhesive 1, consisting of 1.9758 kg of a 40% solution of a self-crosslinking acrylate polymer "Durotak 280 - 2526" in a mixture of ethyl acetate, ethanol, heptane and methanol, 189.7 g of an acrylic resin of dimethylaminoethyl methacrylate and neutral methacrylic acid ester "Eudragit E 100" as well as 20 g of a mixture of acidic triglyceride of the fractionated coconut fatty acid Cg-C^Q "Miglyol 812" is applied to a one-sided with aluminum vaporized and two-sided adhesive unshaken protective layer and the solvent is evaporated at 50 to 80°C Thus, a layer with a thickness of approx. 440 g/m<2.>From this layer of adhesive, circles with a diameter of 51 mm are punched out, where the overhanging gutters are cut off and a circle of a fluffy fabric of a fiber mixture cellulose cotton 70:30 with a basis weight of 40 g/m<2>of the type "Paratex 111/40" and with a diameter of 42 mm.
Derefter påføres nikotin som aktiv bestanddel i oppløsning i form av 140 g nikotin i 100 g av en akrylharpiks av dimetylaminoetylmetakrylat og nøytral metakrylsyreestre "Eudragit E 100" i 46 mg doser. Disse således fremstilte "puter" lamineres øyeblikkelig med et nikotin ikke gjennomtrengelig dekksjikt (ensidig aluminium pådampet polyesterfolie med tykkelse 15 um belagt med ca. 110 g/m<2>klebemasse 1) og innsegles rundt det hele på i og for seg kjent måte. Nicotine is then applied as an active ingredient in solution in the form of 140 g of nicotine in 100 g of an acrylic resin of dimethylaminoethyl methacrylate and neutral methacrylic acid ester "Eudragit E 100" in 46 mg doses. These "pads" produced in this way are immediately laminated with a nicotine impermeable cover layer (one-sided aluminum vaporized polyester foil with a thickness of 15 µm coated with approx. 110 g/m<2>adhesive compound 1) and sealed around the whole in a manner known per se.
I dette utførelseseksempel virker floren som støttevevnad henholdsvis til understøttelse av den enhetlige fordeling av nikotin som inert hjelpestoff i henhold til beskrivelsen. In this design example, the flora acts as support tissue or to support the uniform distribution of nicotine as an inert excipient according to the description.
Idet en virkemiddeloppløsning hurtig kan påføres et matriks-sj ikt og umiddelbart overtrekkes med et dekksjikt er det for første gang mulig på tilfredsstillende måte å oppnå godt doserte nikotinplastre. As an active agent solution can be quickly applied to a matrix layer and immediately covered with a covering layer, it is for the first time possible to satisfactorily obtain well-dosed nicotine patches.
Nikotin- frisetningsforsøk (in vitro) Nicotine release test (in vitro)
Et som i eksempel 2 beskrevet nikotinplaster dyppes efter avtrekking av beskyttelsessjiktet i 80 ml isotonisk koksalt-oppløsning ved en temperatur over 37 °C og den frisatte nikotinmengde bestemmes efter fastlagte tidsrom ved hjelp av væskekromatografi. Volumet til frigivende medium velges slik at man over hele forsøksvarigheten oppnår "synke"-betin-gelser. A nicotine patch as described in example 2 is dipped after removing the protective layer in 80 ml of isotonic sodium chloride solution at a temperature above 37 °C and the released amount of nicotine is determined after a fixed period of time using liquid chromatography. The volume of releasing medium is chosen so that "sinking" conditions are achieved over the entire duration of the experiment.
Følgende målinger ble oppnådd: The following measurements were obtained:
In vitro-frisatt nikotin/plaster: In vitro-released nicotine/patch:
efter 2 timer: 5,1 mg/plaster after 2 hours: 5.1 mg/patch
efter 4 timer: 7,2 mg/plaster after 4 hours: 7.2 mg/plaster
efter 8 timer: 10,1 mg/plaster after 8 hours: 10.1 mg/plaster
efter 24 timer: 16,5 mg/plaster after 24 hours: 16.5 mg/patch
Selvfølgelig er oppfinnelsen ikke begrenset til de her gitte utførelsesformer, den begrenses kun av det som fremgår av de ledsagende krav. Of course, the invention is not limited to the embodiments given here, it is limited only by what appears in the accompanying claims.
Claims (5)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO912851A NO302102B1 (en) | 1986-08-28 | 1991-07-19 | Preparation of a Transdermal Therapeutic System |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19863629304 DE3629304A1 (en) | 1986-08-28 | 1986-08-28 | TRANSDERMAL THERAPEUTIC SYSTEM, ITS USE AND METHOD FOR THE PRODUCTION THEREOF |
PCT/DE1987/000372 WO1988001516A1 (en) | 1986-08-28 | 1987-08-20 | Transdermal therapeutic system, its use and production process |
NO882136A NO173168C (en) | 1986-08-28 | 1988-05-16 | DEVICE FOR DELIVERING ACTIVE INGREDIENTS TO THE SKIN |
NO912851A NO302102B1 (en) | 1986-08-28 | 1991-07-19 | Preparation of a Transdermal Therapeutic System |
Publications (3)
Publication Number | Publication Date |
---|---|
NO912851L NO912851L (en) | 1988-06-28 |
NO912851D0 NO912851D0 (en) | 1991-07-19 |
NO302102B1 true NO302102B1 (en) | 1998-01-26 |
Family
ID=27194773
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO912851A NO302102B1 (en) | 1986-08-28 | 1991-07-19 | Preparation of a Transdermal Therapeutic System |
Country Status (1)
Country | Link |
---|---|
NO (1) | NO302102B1 (en) |
-
1991
- 1991-07-19 NO NO912851A patent/NO302102B1/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
NO912851L (en) | 1988-06-28 |
NO912851D0 (en) | 1991-07-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA1312800C (en) | Transdermal therapeutic system, its use and process for the production thereof | |
US6139868A (en) | Transdermal therapeutic system, its use and production process | |
US6224900B1 (en) | Sealing bag for a transdermal therapeutic system | |
US4915950A (en) | Printed transdermal drug delivery device | |
USRE37934E1 (en) | Transdermal therapeutic system | |
US4460372A (en) | Percutaneous absorption enhancer dispenser for use in coadministering drug and percutaneous absorption enhancer | |
KR970008118B1 (en) | Transdermal therapeutic system | |
FI103478B (en) | Process for the preparation of a transdermal therapeutic system with enhanced flow of the active substance | |
IE52930B1 (en) | Dosage form for coadministering drug and percutaneous absorption enhancer | |
JPH0374205B2 (en) | ||
CZ284976B6 (en) | Flat therapeutical system, process of its preparation and use | |
US6110488A (en) | Transdermal therapeutic system, its use and production process | |
US6264977B1 (en) | Transdermal therapeutic system, its use and production process | |
EP0144486A2 (en) | Controlled-release drugsystem and process for preparing it | |
JPH0693921B2 (en) | Transdermal medicinal drug with gradual drug release | |
JPS6250447B2 (en) | ||
KR20000000640A (en) | Composition for percutaneous absorbing medication of non-steroidal aniphlogistic analgestic and making for percutaneous absorbing medication including composition | |
US6117448A (en) | Transdermal therapeutic system, its use and production process | |
NO302102B1 (en) | Preparation of a Transdermal Therapeutic System | |
NO173168B (en) | DEVICE FOR DELIVERING ACTIVE INGREDIENTS TO THE SKIN | |
JPS5984815A (en) | Pharmaceutical for prolonged release of chemical | |
SK277842B6 (en) | Therapeutic system for aplication of effective matters on skin method of its manufacture and its using | |
HRP920853A2 (en) | Transdermal therapeutic system releasing active substance | |
KR100272043B1 (en) | Percutaneous Absorption Agent for the Treatment of Alzheimer's Dementia | |
JPS62230720A (en) | Laminated pharmaceutical |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MK1K | Patent expired |