NO303107B1 - Process for Preparing a Transdermal Therapeutic System with Buprenorphine as an Active Ingredient - Google Patents
Process for Preparing a Transdermal Therapeutic System with Buprenorphine as an Active Ingredient Download PDFInfo
- Publication number
- NO303107B1 NO303107B1 NO905103A NO905103A NO303107B1 NO 303107 B1 NO303107 B1 NO 303107B1 NO 905103 A NO905103 A NO 905103A NO 905103 A NO905103 A NO 905103A NO 303107 B1 NO303107 B1 NO 303107B1
- Authority
- NO
- Norway
- Prior art keywords
- buprenorphine
- weight
- reservoir layer
- layer
- produced
- Prior art date
Links
- 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 title claims abstract description 43
- 229960001736 buprenorphine Drugs 0.000 title claims abstract description 43
- 230000001225 therapeutic effect Effects 0.000 title claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 239000004480 active ingredient Substances 0.000 title claims description 4
- 239000010410 layer Substances 0.000 claims abstract description 30
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 239000000853 adhesive Substances 0.000 claims abstract description 14
- 230000001070 adhesive effect Effects 0.000 claims abstract description 14
- 239000011241 protective layer Substances 0.000 claims abstract description 13
- 239000004014 plasticizer Substances 0.000 claims abstract description 11
- 239000013543 active substance Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 239000000463 material Substances 0.000 claims abstract description 5
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 claims description 16
- 229920000642 polymer Polymers 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 14
- 229920001577 copolymer Polymers 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 9
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 claims description 8
- 150000001298 alcohols Chemical class 0.000 claims description 8
- 239000002861 polymer material Substances 0.000 claims description 8
- 150000001991 dicarboxylic acids Chemical class 0.000 claims description 6
- 239000011888 foil Substances 0.000 claims description 6
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 5
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 5
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 5
- 238000004132 cross linking Methods 0.000 claims description 5
- IBMRTYCHDPMBFN-UHFFFAOYSA-N monomethyl glutaric acid Chemical compound COC(=O)CCCC(O)=O IBMRTYCHDPMBFN-UHFFFAOYSA-N 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 claims description 4
- SOGAXMICEFXMKE-UHFFFAOYSA-N alpha-Methyl-n-butyl acrylate Natural products CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 claims description 4
- 150000001735 carboxylic acids Chemical class 0.000 claims description 4
- -1 glycerol ester Chemical class 0.000 claims description 4
- 125000005397 methacrylic acid ester group Chemical group 0.000 claims description 4
- UOBSVARXACCLLH-UHFFFAOYSA-N monomethyl adipate Chemical compound COC(=O)CCCCC(O)=O UOBSVARXACCLLH-UHFFFAOYSA-N 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- KJIOQYGWTQBHNH-UHFFFAOYSA-N undecanol Chemical compound CCCCCCCCCCCO KJIOQYGWTQBHNH-UHFFFAOYSA-N 0.000 claims description 4
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 claims description 3
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
- 150000002314 glycerols Polymers 0.000 claims description 3
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 claims description 3
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 2
- 239000013522 chelant Substances 0.000 claims description 2
- 239000002131 composite material Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 150000002734 metacrylic acid derivatives Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical class CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 239000010936 titanium Substances 0.000 claims description 2
- 229910052719 titanium Inorganic materials 0.000 claims description 2
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 claims 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 claims 1
- 239000004372 Polyvinyl alcohol Substances 0.000 claims 1
- 229920006243 acrylic copolymer Polymers 0.000 claims 1
- 239000004411 aluminium Substances 0.000 claims 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims 1
- FACXGONDLDSNOE-UHFFFAOYSA-N buta-1,3-diene;styrene Chemical compound C=CC=C.C=CC1=CC=CC=C1.C=CC1=CC=CC=C1 FACXGONDLDSNOE-UHFFFAOYSA-N 0.000 claims 1
- 238000000265 homogenisation Methods 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 229920000468 styrene butadiene styrene block copolymer Polymers 0.000 claims 1
- 230000035515 penetration Effects 0.000 description 12
- 238000000338 in vitro Methods 0.000 description 11
- 239000000126 substance Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 206010012335 Dependence Diseases 0.000 description 4
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 229940127240 opiate Drugs 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229920005601 base polymer Polymers 0.000 description 3
- 230000036765 blood level Effects 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- UIQMVEYFGZJHCZ-SSTWWWIQSA-N Nalorphine Chemical compound C([C@@H](N(CC1)CC=C)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 UIQMVEYFGZJHCZ-SSTWWWIQSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 2
- 206010038678 Respiratory depression Diseases 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 229960000938 nalorphine Drugs 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LLVWLCAZSOLOTF-UHFFFAOYSA-N 1-methyl-4-[1,4,4-tris(4-methylphenyl)buta-1,3-dienyl]benzene Chemical compound C1=CC(C)=CC=C1C(C=1C=CC(C)=CC=1)=CC=C(C=1C=CC(C)=CC=1)C1=CC=C(C)C=C1 LLVWLCAZSOLOTF-UHFFFAOYSA-N 0.000 description 1
- ROGIWVXWXZRRMZ-UHFFFAOYSA-N 2-methylbuta-1,3-diene;styrene Chemical compound CC(=C)C=C.C=CC1=CC=CC=C1 ROGIWVXWXZRRMZ-UHFFFAOYSA-N 0.000 description 1
- XBIUWALDKXACEA-UHFFFAOYSA-N 3-[bis(2,4-dioxopentan-3-yl)alumanyl]pentane-2,4-dione Chemical compound CC(=O)C(C(C)=O)[Al](C(C(C)=O)C(C)=O)C(C(C)=O)C(C)=O XBIUWALDKXACEA-UHFFFAOYSA-N 0.000 description 1
- 229920000298 Cellophane Polymers 0.000 description 1
- XTJFFFGAUHQWII-UHFFFAOYSA-N Dibutyl adipate Chemical compound CCCCOC(=O)CCCCC(=O)OCCCC XTJFFFGAUHQWII-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241001539473 Euphoria Species 0.000 description 1
- 206010015535 Euphoric mood Diseases 0.000 description 1
- 206010053172 Fatal outcomes Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002367 Polyisobutene Polymers 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000002313 adhesive film Substances 0.000 description 1
- 239000012790 adhesive layer Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 210000003746 feather Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940124641 pain reliever Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920006267 polyester film Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920000346 polystyrene-polyisoprene block-polystyrene Polymers 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229920003048 styrene butadiene rubber Polymers 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 230000000007 visual effect 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
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Emergency Medicine (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Laminated Bodies (AREA)
Abstract
Description
Denne oppfinnelse vedrører en fremgangsmåte for fremstilling av et transdermalt terapeutisk system til administrering av buprenorfin (17-(cyklopropylmetyl)-ar- (1,1-dimetyletyl) -4, 5-epoksy-l8-l9-dihydro-3-hydroksy-6-metoksy-ar-metyl-6,14-etenormorfinan-7-metanol), til huden fra et virkestoff-ugjennomtrengelig baksjikt, et fastklebende reservoarsjikt og eventuelt et avtagbart beskyttelsessjikt. This invention relates to a method for producing a transdermal therapeutic system for the administration of buprenorphine (17-(cyclopropylmethyl)-ar-(1,1-dimethylethyl)-4,5-epoxy-18-19-dihydro-3-hydroxy-6 -methoxy-ar-methyl-6,14-ethenormorphinan-7-methanol), to the skin from an active ingredient-impermeable back layer, an adhesive reservoir layer and optionally a removable protective layer.
Buprenorfin er et partialsyntetisk opiat som har den fordel sammenlignet med andre forbindelser i denne substans-gruppe at det er mere virksomt. Dette betyr at det hos kreft-eller tumorpasienter med håpløs diagnose kan oppnås smertefri-het i sluttstadiet med dagdoser omkring 1 mg. Det er imidlertid to betydelige problemer med opiatene som buprenorfin ikke løser, nemlig avhengighetspotensialet og disse stoffenes dårlige biotilgjengelighet ved oral administrering. Således utgjør biotilgjengeligheten fra fordøyelseskanalen bare ca. 10%, og ved sublingual applikasjon bare ca. 50%. Buprenorphine is a partially synthetic opiate which has the advantage compared to other compounds in this substance group that it is more effective. This means that in cancer or tumor patients with a hopeless diagnosis, pain-freeness can be achieved in the final stage with daily doses of around 1 mg. However, there are two significant problems with the opiates that buprenorphine does not solve, namely the addiction potential and the poor bioavailability of these substances when administered orally. Thus, the bioavailability from the digestive tract is only approx. 10%, and with sublingual application only approx. 50%.
Den opprinnelige antagelse om buprenorfins lave avhengighetspotensiale etter dets innføring som smertemiddel, ble korrigert. Etter at misbruket hos medikamentavhengige har tiltatt, sorterer nå buprenorfinet under den tyske loven for bedøvelsesmidler. The original assumption about buprenorphine's low addiction potential after its introduction as a pain reliever was corrected. After the abuse by drug addicts has increased, buprenorphine now falls under the German law for anesthetics.
Blant fagfolk er det imidlertid i senere tid blitt hevdet at legemiddelformen bidrar til avhengighetspotensiale for et legemiddelpreparat. Dette lar seg lett etterpøve for sterkt virksomme analgetika i terapien for ekstremt store smerter. Among professionals, however, it has recently been claimed that the pharmaceutical form contributes to the addiction potential of a pharmaceutical preparation. This can easily be replicated for highly effective analgesics in the therapy for extremely severe pain.
Umiddelbart etter tilførselen er blodspeilet for smerte-middelet høyere enn nødvendig, og forårsaker eufori, men faller deretter ekspotensielt av og oppnår raskt et blodspeil som ikke lenger virker terapeutisk godt nok på smerten. På grunn av sine smerter begynner pasienten å lengte etter den neste dose, hvorved det iatrogent oppstår en avhengighet. Immediately after administration, the blood level for the painkiller is higher than necessary, causing euphoria, but then exponentially falls off and quickly reaches a blood level that no longer works therapeutically well enough on the pain. Because of their pain, the patient begins to long for the next dose, iatrogenically creating an addiction.
Også for buprenorfin og andre sterkt virksomme opiater ville en kontinuerlig infusjon være den valgte legemiddelform for ved hjelp av et konstant blodspeil å unngå at det iatrogent oppstår et slik sykelig begjær. En kontinuerlig infusjon kan imidlertid ikke gjennomføres og kontrolleres ved hjemmepleie uten legehjelp, og fører ofte til betennelser ved innføringsstedet for kanylen. Also for buprenorphine and other highly effective opiates, a continuous infusion would be the chosen form of medicine in order to avoid such a morbid desire arising iatrogenically with the help of a constant blood level. However, a continuous infusion cannot be carried out and controlled by home care without medical help, and often leads to inflammation at the insertion site of the cannula.
Heller ikke en oral depotform kan være det egnede legemiddelsystemet for buprenorfin, da det på grunn av den lave biotilgjengelighet ved oral administrering, sammenlignet med den nødvendige intravenøse dosering, vil måtte avgis en ca. 10-dobbelt mengde av virkestoff. Her gir imidlertid buprenorfin som partiell opiat-antagonist forsåvidt store problemer, da en pustedepresjon fremkalt ved en overdosering av virkestoffet ikke lar seg behandle ved å gi en antagonist, som f.eks. nalorfin, som er den vanlige motgift ved opiat-forgiftninger. Overdoseringer kan forekomme, da den orale biotilgjengelighet for buprenorfin riktignok er angitt til 10%, men kan være ganske mye høyere, da buprenorfin skal gis til en gruppe pasienter for hvilke det må regnes med leverfunksjonsforstyrrelser, slik at ganske mye mer enn 10% kan komme gjennom den første leverpassasjen umetabolisert. Nor can an oral depot form be the suitable drug system for buprenorphine, as due to the low bioavailability upon oral administration, compared to the necessary intravenous dosage, an approx. 10-fold amount of active ingredient. Here, however, buprenorphine as a partial opiate antagonist certainly causes major problems, as respiratory depression caused by an overdose of the active substance cannot be treated by giving an antagonist, such as e.g. nalorphine, which is the usual antidote for opiate poisoning. Overdoses can occur, as the oral bioavailability of buprenorphine is indeed stated at 10%, but can be quite a lot higher, as buprenorphine must be given to a group of patients for whom liver function disorders must be considered, so that quite a lot more than 10% can come through the first hepatic passage unmetabolized.
Dessuten er orale depotformer ikke i enhver henseende optimale, hvilket utviklingen på legemiddelmarkedet i de seneste årene tydelig viser. Generika med den samme in vitro-frigivelse som preparatene fra originalleverandøren er ikke like virksomme som nettopp disse originalpreparatene. Dette betyr at det ved ukontrollert frigivelse in vivo kan forekomme over- eller underdoseringer. Begge deler er for buprenorfin spesielt fatale. Dersom det underdoseres, vil pasienten lide av sterke smerter. Dersom det overdoseres, kan det i verste tilfelle føre til pustedepresjoner som ikke kan behandles med nalorfin, og derfor kan ha dødelig utgang. Moreover, oral depot forms are not optimal in every respect, which the development of the pharmaceutical market in recent years clearly shows. Generics with the same in vitro release as the preparations from the original supplier are not as effective as these original preparations. This means that with uncontrolled release in vivo, overdosing or underdosing can occur. Both parts are particularly fatal for buprenorphine. If it is underdosed, the patient will suffer from severe pain. If it is overdosed, in the worst case it can lead to respiratory depression that cannot be treated with nalorphine, and can therefore have a fatal outcome.
Det ble tidligere ikke tatt hensyn til at en oral depotform som ble beskadiget og derfor ikke forsinket, men med et slag frigjorde buprenorfin (på engelsk kjent blant fagfolk som "dosedumping"), ikke uiddelbart kan fjernes fra det menneskelige legeme. It was previously not taken into account that an oral depot form that was damaged and therefore not delayed, but with a stroke released buprenorphine (known in English among professionals as "dose dumping"), cannot be indivisible from the human body.
Alle hittil beskrevne forbehold mot en legemiddelform som frigir buprenorfin retardert, blir unngått ved hjelp av fordelene ved de transdermale terapisystemer, da medikamentet ikke må innføres i det menneskelige legeme ved hjelp av kanyler og derfor også kan anvendes av medisinske legfolk. Samtidig er det alltid sikret en legemiddeltilførsel ifølge ovennevnte ordning som til enhver tid kan avbrytes ved at systemet blir tatt bort. Et transdermalt terapeutisk system synes altså å være den legemiddelformen som bør velges for buprenorfin. All previously described caveats against a pharmaceutical form that releases buprenorphine in a delayed manner are avoided by means of the advantages of the transdermal therapy systems, as the drug does not have to be introduced into the human body by means of needles and can therefore also be used by medical professionals. At the same time, a drug supply is always ensured according to the above-mentioned arrangement, which can be interrupted at any time by the system being taken away. A transdermal therapeutic system thus seems to be the pharmaceutical form that should be chosen for buprenorphine.
Mot dette taler imidlertid at buprenorfin ved sin høye molekylvekt (molekylvekt 468), men fremfor alt ved sitt høye smeltepunkt og sin svært dårlige løselighet i vanlige organiske løsningsmidler og vann bare uttalt dårlig trenger igjennom den menneskelige hud, fordi en diffusjon som er forutsetning for gjennomtrengningen gjennom den menneskelige hud, fordrer løste substanser. Løseligheten kan imidlertid ikke forhøyes ved saltdannelse, fordi baser ikke blir resorbert i ionisert form. Inntil nå er det ikke lykkes å bringe buprenorfin transdermalt til resorpsjon i nødvendige mengder, selv om et TTS av ovenfor beskrevne grunner representerer den best mulige legemiddelform for dette virkestoffet. However, this is argued against by the fact that buprenorphine with its high molecular weight (molecular weight 468), but above all with its high melting point and its very poor solubility in common organic solvents and water, penetrates the human skin very poorly, because a diffusion which is a prerequisite for penetration through the human skin, requires dissolved substances. However, the solubility cannot be increased by salt formation, because bases are not resorbed in ionized form. Until now, it has not been successful in bringing buprenorphine transdermally to resorption in the necessary quantities, although for the reasons described above, a TTS represents the best possible pharmaceutical form for this active substance.
Dette gjelder i særlig grad EP 0 171 742 A3 og This applies in particular to EP 0 171 742 A3 and
WO 88/09676. Førstnevnte vedrører et preparat for transdermal administrering som kan inneholde buprenorfin ifølge krav 2 samt en andel dodekanol ifølge Tabell 3. WO 88/09676. The former relates to a preparation for transdermal administration which can contain buprenorphine according to claim 2 and a proportion of dodecanol according to Table 3.
Sistnevnte beskriver et preparat for transdermal administrering, som f.eks. ifølge krav 3 inneholder virkestoffet buprenorfin og fettsyreestere som gjennomtrengelighets-forsterkere. The latter describes a preparation for transdermal administration, which e.g. according to claim 3, the active substance contains buprenorphine and fatty acid esters as penetration enhancers.
Det er derfor en oppgave for denne oppfinnelse å tilveie-bringe en fremgangsmåte for fremstilling av et transdermalt terapeutisk system som kontrollert avgir og garanterer buprenorfin eller ett av dets farmasøytisk akseptable salter i løpet av et tidsrom på minst 24 timer, at buprenorfinet ikke i særlig grad spaltes under lagringen av det på forhånd fremstilte transdermale terapeutiske system, og sørger for at det utilstrekkelig hudgjennomtrengende buprenorfin i nødvendig utstrekning trenger igjennom den menneskelige hud in vivo. It is therefore a task for this invention to provide a method for the production of a transdermal therapeutic system which releases buprenorphine or one of its pharmaceutically acceptable salts in a controlled manner and guarantees that the buprenorphine does not to a great extent is cleaved during storage of the pre-manufactured transdermal therapeutic system, and ensures that the insufficiently skin-penetrating buprenorphine penetrates human skin in vivo to the necessary extent.
Denne oppgave blir ifølge oppfinnelsen løst på over-raskende måte ved hjelp av en fremgangsmåte til fremstilling av et transdermalt terapeutisk system for administrering av buprenorfin til huden, hvilket består av et virkestoff-ugjennomtrenglig bak-sjikt, et fastklebende reservoarsjikt og eventuelt et gjenavtagbart beskyttelsessjikt, og som karakteriseres ved at det til fremstilling av reservoarsjiktet homogeniseres en blanding av 20 til 90 vekt-% polymermateriale, 0,1 til 30 vekt-% mykgjører, valgt blant høyere alkoholer såsom dodekanol, undekanol oktanol, estere av karboksylsyrer, polyetoksylert alkohol, 0,1 til 20 vekt-% buprenorfinbase eller en av dens farmasøytisk akseptable salter, og 0,1 til 30 vekt-% løsningsmiddel for buprenorfinbase eller et av dens farmasøytisk akseptable salter, valgt blant monoestere av dikarboksylsyrer, under eventuell tilsetning av lett flyktige løsningsmider, og påføres på baksjiktet eller beskyttelsessjiktet, hvoretter lett flyktige løsningsmidler fjernes. According to the invention, this task is solved in a surprising way by means of a method for producing a transdermal therapeutic system for administering buprenorphine to the skin, which consists of an active substance impermeable back layer, an adhesive reservoir layer and optionally a removable protective layer, and which is characterized by homogenizing a mixture of 20 to 90% by weight polymer material, 0.1 to 30% by weight plasticizer, selected from higher alcohols such as dodecanol, undecanol octanol, esters of carboxylic acids, polyethoxylated alcohol, 0 .1 to 20% by weight of buprenorphine base or one of its pharmaceutically acceptable salts, and 0.1 to 30% by weight of solvent for buprenorphine base or one of its pharmaceutically acceptable salts, selected from monoesters of dicarboxylic acids, with the optional addition of easily volatile solvents, and applied to the backing or protective layer, after which volatile solvents feather nose.
Denne løsning er desto mer forbausende ettersom buprenorfin, som allerede nevnt, har en biotilgjengelighet på bare 50% når det gis sublingualt. Da den første leverpassasjen ved denne applikasjonsmåte blir omgått, kan den lave biotilgjengelighet bare tilbakeføres til substansens utilstrekkelige resorberbarhet gjennom munnens slimhinner. Et stoff som imidlertid bare vanskelig passerer munnens mukosa må imidlertid bare svært vanskelig kunne opptas gjennom den menneskelige hud. This solution is all the more surprising because, as already mentioned, buprenorphine has a bioavailability of only 50% when given sublingually. As the first liver passage is bypassed by this method of application, the low bioavailability can only be attributed to the substance's insufficient resorbability through the mucous membranes of the mouth. However, a substance that passes through the oral mucosa with difficulty must be able to be absorbed through the human skin with great difficulty.
Det virkestoff-ugjennomtrengelige baksjikt kan bestå av fleksibelt eller ikke-fleksibelt materiale. Substanser som kan anvendes til fremstilling av dette, er polymerfolier eller metallfolier som aluminiumfolie, som blir anvendt alene eller besjiktet med et polymert substrat. Det kan også anvendes flate konstruksjoner av tekstiler, når bestanddelene i reservoaret på grunn av sine fysikalske egenskaper ikke kan trenge gjennom disse. Ved en foretrukket utførelsesform er baksjiktet en kompositt av en folie med pådampet aluminium. The active ingredient-impermeable back layer can consist of flexible or non-flexible material. Substances that can be used to produce this are polymer foils or metal foils such as aluminum foil, which are used alone or coated with a polymeric substrate. Flat constructions made of textiles can also be used, when the constituents in the reservoir cannot penetrate these due to their physical properties. In a preferred embodiment, the back layer is a composite of a foil with evaporated aluminum.
Reservoarsjiktet består av en polymermatriks og virkestoffet, hvorved polymermatriksen sørger for at systemet blir holdt sammen. Den består av en grunnpolymer og eventuelt de vanlige tilsetningene. Valget av grunnpolymer retter seg etter buprenorfinets kjemiske og fysikalske egenskaper. Eksempler på polymerer er kautsjuk, kautsjuklignende, syntetiske homo-, ko- eller blokkpolymerer, polyakryl-syreestere og deres kopolymerer, polyuretaner og silikoner. I prinsippet kommer alle de polymerer på tale som kan anvendes ved fremstilling av klebemidler, og som er fysiologisk uskadelige. Spesielt foretrekkes slike som består av blokk-kopolymerer på basis av styren og 1,3-diener, polyisobutylener og polymerer av akrylat- og/eller metakrylat. The reservoir layer consists of a polymer matrix and the active substance, whereby the polymer matrix ensures that the system is held together. It consists of a base polymer and possibly the usual additives. The choice of base polymer is based on buprenorphine's chemical and physical properties. Examples of polymers are rubber, rubber-like, synthetic homo-, co- or block polymers, polyacrylic acid esters and their copolymers, polyurethanes and silicones. In principle, all the polymers that can be used in the production of adhesives, and which are physiologically harmless, come into question. Particular preference is given to those consisting of block copolymers based on styrene and 1,3-dienes, polyisobutylenes and polymers of acrylate and/or methacrylate.
Av blokk-kopolymerene på basis av styren og 1,3-diener anvendes ganske spesielt lineære styren-isopren- eller styren-butadien-blokk-kopolymerer. Of the block copolymers based on styrene and 1,3-diene, linear styrene-isoprene or styrene-butadiene block copolymers are particularly used.
Som polymerer på akrylatbasis foretrekkes selvtverrbindende akrylatkopolymerer av 2-etylheksylakrylat, vinylacetat og akrylsyre med respektive ikke-selvtverrbindende akrylatkopolymerer uten titanchelatestere. As acrylate-based polymers, self-crosslinking acrylate copolymers of 2-ethylhexyl acrylate, vinyl acetate and acrylic acid with respective non-self-crosslinking acrylate copolymers without titanium chelate esters are preferred.
Som polymerer for tilsetning til grunnpolymeren kommer polymetakrylater, estere av hydrert kolofonium og polyvinyler på tale. As polymers for addition to the base polymer, polymethacrylates, esters of hydrated rosin and polyvinyls come into question.
Som metakrylater foretrekkes kopolymerer på basis av dimetylaminoetylmetakrylater og nøytrale metakrylsyreestere. Som estere av hydrert kolofonium anvendes fortrinnsvis spesielt dennes metyl- og glycerolester. Som polyvinyler anvendes fortrinnsvis polyvinylpyrrolidoner og polyvinylalkoholer. As methacrylates, copolymers based on dimethylaminoethyl methacrylates and neutral methacrylic acid esters are preferred. As esters of hydrated rosin, its methyl and glycerol esters are preferably used in particular. Polyvinyl pyrrolidones and polyvinyl alcohols are preferably used as polyvinyls.
Typen av de vanlige tilsetninger avhenger av den anvendte polymer: ifølge sin funksjon kan de inndeles i f.eks. klebemidler, stabilisatorer, bærere og fyllstoffer. De fysiologisk uskadelige stoffene som kommer på tale herfor, er kjent for fagmannen. The type of the usual additives depends on the polymer used: according to their function, they can be divided into e.g. adhesives, stabilizers, carriers and fillers. The physiologically harmless substances that come into question here are known to the person skilled in the art.
Det har vist seg ifølge oppfinnelsen at en mykgjører er nødvendig i forbindelse med et løsningsmiddel for buprenorfin, for at buprenorfin skal kunne anvendes transdermalt. According to the invention, it has been shown that a plasticiser is necessary in connection with a solvent for buprenorphine, in order for buprenorphine to be used transdermally.
Valget av mykgjører retter seg etter polymeren. Spesielt egnet er høyere alkoholer som dodekanol, undekanol, oktanol, estere av karboksylsyrer, hvorved alkoholkomponenten også kan være en polyetoksylert alkohol, diestere av dikarboksylsyrer, f.eks. di-n-butyladipat samt triglycerider, spesielt middel-kjedede triglycerider av kapryl/kaprinsyrer fra kokosoljen. Ytterligere eksempler på egnede mykgjørere er flerverdige alkoholer f.eks. glycerol og propandiol-(1,2) som også kan foretres med polyetylenglykoler. The choice of plasticizer depends on the polymer. Particularly suitable are higher alcohols such as dodecanol, undecanol, octanol, esters of carboxylic acids, whereby the alcohol component can also be a polyethoxylated alcohol, diesters of dicarboxylic acids, e.g. di-n-butyl adipate as well as triglycerides, especially medium-chain triglycerides of caprylic/capric acids from the coconut oil. Further examples of suitable plasticizers are polyhydric alcohols, e.g. glycerol and propanediol-(1,2) which can also be etherified with polyethylene glycols.
Rollen til løsningsmiddelet for buprenorfinbasen blir vist ved eksemplene. Disse viser at løsningsmiddelet er en bestanddel av resepten som det ikke kan gis avkall på. Kombinasjonen mykgjører/løsningsmiddel ifølge beskrivelsen av oppfinnelsen skaper forutsetningen for penetrasjonen av buprenorfinbasen gjennom huden. The role of the solvent for the buprenorphine base is shown by the examples. These show that the solvent is a component of the prescription that cannot be dispensed with. The emollient/solvent combination according to the description of the invention creates the prerequisite for the penetration of the buprenorphine base through the skin.
Som løsningsmiddel for buprenorfin i matriks kommer monoesterne av dikarboksylsyrer, spesielt foretrukket monometylglutarat og monometyladipat, i betraktning. As a solvent for buprenorphine in the matrix, the monoesters of dicarboxylic acids, particularly preferred monomethyl glutarate and monomethyl adipate, come into consideration.
Reservoarsjiktet har en slik egenklebrighet at en varig kontakt med huden garanteres. Det løsbare beskyttelsessjiktet som står i berøring med reservoarsjiktet og blir fjernet før anvendelsen, består f.eks. av de samme materialer som blir benyttet til fremstilling av baksjiktet, forutsatt at de gjøres avtagbare, som f.eks. ved en silikonbehandling. Andre avtagbare beskyttelsessjikt er f.eks. polytetrafluoretylen, behandlet papir, cellofan, polyvinylklorid og lignende. Dersom lamintet ifølge oppfinnelsen før påføringen av beskyttelsessjiktet blir oppdelt i terapiegnede formater (plaster), så kan beskyttelsessjiktformatene som deretter skal påføres, ha en utoverstående ende, med hvis hjelp de lettere kan trekkes av fra plasteret. The reservoir layer has such an inherent stickiness that a lasting contact with the skin is guaranteed. The removable protective layer which is in contact with the reservoir layer and is removed before use, consists of e.g. of the same materials that are used to make the back layer, provided that they are made removable, such as e.g. by a silicone treatment. Other removable protective layers are e.g. polytetrafluoroethylene, treated paper, cellophane, polyvinyl chloride and the like. If the laminate according to the invention is divided into formats suitable for therapy (plasters) before the application of the protective layer, then the protective layer formats which are then to be applied can have a protruding end, with the help of which they can be more easily pulled off from the plaster.
Det transdermale terapeutiske system fremstilles ifølge oppfinnelsen idet virkestoffet sammen med bestanddelene i det fastklebende reservoarsjiktet, eventuelt i løsning, blir blandet sammen homogent og blir påført på det virkestoff-ugjennomtrengelige baksjiktet, hvorpå eventuelt løsnings-middelet eller løsningsmidlene blir fjernet. Deretter blir klebesjiktet forsynt med et tilsvarende beskyttelsessjikt. The transdermal therapeutic system is produced according to the invention in that the active substance together with the components of the adhesive reservoir layer, optionally in solution, are mixed together homogeneously and are applied to the active substance-impermeable back layer, whereupon the solvent or solvents are removed. The adhesive layer is then provided with a corresponding protective layer.
Også den omvendte vei, at klebeløsningen blir strøket på beskyttelsessjiktet, er i prinsippet mulig. Også i dette tilfellet fjerner man løsningsmidlene og tildekker deretter umiddelbart med baksjiktet. The reverse way, that the adhesive solution is applied to the protective layer, is also possible in principle. In this case too, the solvents are removed and then immediately covered with the backing layer.
Oppfinnelsen blir belyst ved følgende eksempler: The invention is illustrated by the following examples:
Eksempel I Example I
10,0 g av hver av glutarsyremonometylester, metanol og butanon og 15,0 g 1-dodekanol blir blandet under omrøring. Deretter tilsettes 10,0 g buprenorfinbase; det røres inntil fullstendig oppløsning av faststoffet (ca. 30 minutter, visuell kontroll). Deretter tilsettes under omrøring 133,0 g av en selvtverrbindende akrylatkopolymer av 2-etylheksylakrylat, vinylacetat og akrylsyre 46%-ig i en løsningsmiddel-blanding (etylacetat: heptan: isopropanol: toluen: acetylaceton 37 : 26 : 26 : 4 : 1); det homogeniseres. Deretter strøs inn under omrøring ytterligere 1,3 g aluminium-acetylacetonat og omrøres i 3 timer ved romtemperatur. Fordampningstapet blir utlignet. 10.0 g of each of glutaric acid monomethyl ester, methanol and butanone and 15.0 g of 1-dodecanol are mixed with stirring. Next, 10.0 g of buprenorphine base is added; it is stirred until complete dissolution of the solid (approx. 30 minutes, visual check). Then, while stirring, 133.0 g of a self-crosslinking acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate and acrylic acid 46% is added in a solvent mixture (ethyl acetate: heptane: isopropanol: toluene: acetylacetone 37 : 26 : 26 : 4 : 1); it is homogenized. A further 1.3 g of aluminum acetylacetonate is then sprinkled in while stirring and stirred for 3 hours at room temperature. The evaporation loss is compensated.
Resultatet blir 189,3 g av en 52,8 vekt-%-ig virkestoff-holdig kleberløsning som strykes ut med en 350/zm Rakel på en aluminisert og silikonisert polyetylenfolie. Etter at løsningsmidlene ble fjernet ved 30 minutters tørking til 60°C, blir klebefilmen dekket med en polyesterfolie på 15fim. Med egnet skjæreverktøy stanser man ut en flate på 16 cm<2>og fjerner kantene ved avgitring. Frigivelsen fra denne og de andre reseptureksemplene er angitt i tabellen; der er oppført både den kontrollerte frigivelse i en fysiologisk koksalt-løsning, samt også gjennom excidert gnagedyrhud. The result is 189.3 g of a 52.8% by weight active agent-containing adhesive solution which is spread with a 350/zm squeegee onto an aluminized and siliconized polyethylene foil. After the solvents have been removed by drying for 30 minutes at 60°C, the adhesive film is covered with a polyester film of 15 µm. With a suitable cutting tool, a surface of 16 cm<2> is punched out and the edges are removed by netting. The release from this and the other prescription examples is indicated in the table; there is listed both the controlled release in a physiological saline solution, as well as through excised rodent skin.
Alle videre eksempler blir utført etter det skjema som er angitt under Eksempel I. Først blandes alltid de flytende bestanddeler, deretter strøs buprenorfinbasen inn. Etter dennes oppløsning tilsetts eventuelt en metakrylatkopolymer på basis av dimetylaminoetylmetakrylat og nøytrale metakrylsyreestere, og etter deres oppløsning tilsettes kleber-løsningen. I den følgende tabell er oppført reseptur- All further examples are carried out according to the scheme indicated under Example I. The liquid ingredients are always mixed first, then the buprenorphine base is sprinkled in. After this is dissolved, a methacrylate copolymer based on dimethylaminoethyl methacrylate and neutral methacrylic acid esters is optionally added, and after their dissolution, the adhesive solution is added. The following table lists prescription
bestanddelene etter tørking. the components after drying.
Her betyr: Here means:
Akrylat: akrylatkopolymerer av 2-etylheksylakrylat, Acrylate: acrylate copolymers of 2-ethylhexyl acrylate,
vinylacetat og akrylsyre vinyl acetate and acrylic acid
Halvester: monometylester av glutar- (kjennetegnet ved G) respektive adipinsyre (kjennetegnet ved A) Halvester: monomethyl ester of glutaric acid (characterized by G) or adipic acid (characterized by A)
G.L. : polyetoksylert glycerol med C8/C10-etoksygrupper G. L. : polyethoxylated glycerol with C8/C10 ethoxy groups
Polymertilsetninger: b: kopolymer med basisk karakter på Polymer additives: b: copolymer with a basic character on
basis av dimetylaminoetylmetakrylat og nøytrale metakrylsyreestere n: kopolymer med nøytral karakter på basis av metakrylsyremetylester og metakrylsyrebutylester base of dimethylaminoethyl methacrylate and neutral methacrylic acid esters n: copolymer with neutral character based on methacrylic acid methyl ester and methacrylic acid butyl ester
PVP: polyvinylpyrrolidon PVP: polyvinylpyrrolidone
In vitro-frigivelsen ble bestemt i et rystevannbad ved37°C. Akzeptormediet var 100 ml fysiologisk koksaltløsning som ble fullstendig utvekslet etter 2, 4 og 8 timer. Konsentrasjonen ble bestemt etter 2, 4, 8 og 24 timer ved hjelp av HPLC. Penetrasjonen gjennom musehuden ble målt med diffusjonsceller ifølge Franz. The in vitro release was determined in a shaking water bath at 37°C. The acceptor medium was 100 ml of physiological saline solution which was completely exchanged after 2, 4 and 8 hours. The concentration was determined after 2, 4, 8 and 24 hours by HPLC. The penetration through mouse skin was measured with diffusion cells according to Franz.
Frigivelseskurvene ifølge Eksempel I er fremstilt i Fig. The release curves according to Example I are shown in Fig.
1 og 2. 1 and 2.
Interpretasjon av in vitro- resultatene Interpretation of the in vitro results
Eksemplene VII, XIV og XVII beviser nødvendigheten av å innarbeide en løsningsformidler med minst én sur gruppe i de transdermale systemene, da in vitro-penetrasjonen uten et slikt løsningsmiddel åpenbart avtar drastisk. In vitro-penetrasjonen ligger i alle tre eksemplene ved 0,1 mg/2,54 cm<2>x 25 h. På samme tid viser eksemplene I og XXI at det praktisk talt ikke spiller noen rolle for in vitro-penetrasjonen om det anvendes glutarsyre- eller adipinsyremonometylester. Eksempel XII tjener som belegg for at det i tillegg til løsningsformidleren også må anvendes en mykgjører, da in vitro-penetrasjonen uten en slik med 0,22 mg/2,54 cm<2>x 24 h bare ligger litt over den for systemene uten løsnings-formidler. Examples VII, XIV and XVII prove the necessity of incorporating a solubilizer with at least one acidic group in the transdermal systems, as the in vitro penetration without such a solvent obviously decreases drastically. In all three examples, the in vitro penetration is at 0.1 mg/2.54 cm<2>x 25 h. At the same time, examples I and XXI show that there is practically no effect on the in vitro penetration if used glutaric or adipic acid monomethyl ester. Example XII serves as proof that, in addition to the solvent, a plasticizer must also be used, as the in vitro penetration without one of 0.22 mg/2.54 cm<2>x 24 h is only slightly above that of the systems without solution mediator.
Eksemplene XIV, XIII, XX og XVIII tjener til undersøkelse av innflydelsen av mengden av halvester på in vitro-penetrasjonen; i denne rekkefølge ble halvesterandelen øket fra 0% via 2,5% og 5% til 10%. Derved steg in vitro-penetrasjonen gjennom musehuden fra 0,1 via 0,48 og 0,64 til 0,84 mg/2,54 cm<2>x 24 h. Etter tilsetning av halvester er økningen i in vitro-penetrasjonen tilnærmet lineær. Dette blir gjengitt i den følgende Fig. 3. Examples XIV, XIII, XX and XVIII serve to investigate the influence of the amount of half-ester on the in vitro penetration; in this order, the half-ester proportion was increased from 0% via 2.5% and 5% to 10%. Thereby, the in vitro penetration through mouse skin rose from 0.1 via 0.48 and 0.64 to 0.84 mg/2.54 cm<2>x 24 h. After addition of half-esters, the increase in in vitro penetration is approximately linear . This is reproduced in the following Fig. 3.
Sammenligningen av eksmplene X og XI viser at 1-dodekanol blir foretrukket som mykgjører. De øvrige eksempler viser hvordan polymertilsetningene virker på in vitro-penetrasjonen, da anvendelsen av disse stoffene er nødvendig for å sikre filmdannelse, klebekraft, adhesjon og kohesjon. The comparison of examples X and XI shows that 1-dodecanol is preferred as plasticizer. The other examples show how the polymer additives work on the in vitro penetration, as the use of these substances is necessary to ensure film formation, adhesive power, adhesion and cohesion.
Claims (12)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3939376A DE3939376C1 (en) | 1989-11-29 | 1989-11-29 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO905103D0 NO905103D0 (en) | 1990-11-26 |
| NO905103L NO905103L (en) | 1991-05-30 |
| NO303107B1 true NO303107B1 (en) | 1998-06-02 |
Family
ID=6394373
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO905103A NO303107B1 (en) | 1989-11-29 | 1990-11-26 | Process for Preparing a Transdermal Therapeutic System with Buprenorphine as an Active Ingredient |
Country Status (25)
| Country | Link |
|---|---|
| EP (1) | EP0430019B1 (en) |
| JP (1) | JPH0818984B2 (en) |
| KR (1) | KR950015061B1 (en) |
| AT (1) | ATE135205T1 (en) |
| AU (1) | AU632182B2 (en) |
| CA (1) | CA2030178C (en) |
| CZ (1) | CZ282557B6 (en) |
| DE (2) | DE3939376C1 (en) |
| DK (1) | DK0430019T3 (en) |
| ES (1) | ES2086353T3 (en) |
| FI (1) | FI100379B (en) |
| GR (1) | GR3020177T3 (en) |
| HR (1) | HRP930675B1 (en) |
| HU (1) | HU206266B (en) |
| IE (1) | IE73247B1 (en) |
| IL (1) | IL96243A (en) |
| MY (1) | MY105347A (en) |
| NO (1) | NO303107B1 (en) |
| NZ (1) | NZ236191A (en) |
| PL (1) | PL165396B1 (en) |
| PT (1) | PT96028B (en) |
| SI (1) | SI9012260B (en) |
| SK (1) | SK279687B6 (en) |
| YU (1) | YU47956B (en) |
| ZA (1) | ZA909544B (en) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5069909A (en) * | 1990-06-20 | 1991-12-03 | Cygnus Therapeutic Systems | Transdermal administration of buprenorphine |
| US5762952A (en) * | 1993-04-27 | 1998-06-09 | Hercon Laboratories Corporation | Transdermal delivery of active drugs |
| DE4446600A1 (en) * | 1994-12-24 | 1996-06-27 | Lohmann Therapie Syst Lts | Transdermal absorption of active ingredients from supercooled melts |
| US6344211B1 (en) | 1994-12-24 | 2002-02-05 | Lts Lohmann Therapie-Systeme Gmbh | Transdermal absorption of active substances from subcooled melts |
| JPH1036265A (en) * | 1996-07-19 | 1998-02-10 | Nitto Denko Corp | Buprenorphine percutaneous absorption preparation |
| DE19705138A1 (en) | 1997-02-11 | 1998-08-13 | Lohmann Therapie Syst Lts | Stretchy transdermal therapeutic system |
| US5968547A (en) * | 1997-02-24 | 1999-10-19 | Euro-Celtique, S.A. | Method of providing sustained analgesia with buprenorphine |
| DE19738855C2 (en) | 1997-09-05 | 2001-01-04 | Lohmann Therapie Syst Lts | Transdermal therapeutic system with adhesive reservoir layer and unidirectional elastic back layer |
| DE19828273B4 (en) * | 1998-06-25 | 2005-02-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing hormones and crystallization inhibitors |
| DE19850517B4 (en) | 1998-11-03 | 2004-02-12 | Lts Lohmann Therapie-Systeme Ag | Use of an active substance-containing transdermal therapeutic system in a combined treatment with and without ultrasound |
| DE19901085C2 (en) * | 1999-01-14 | 2003-12-18 | Lohmann Therapie Syst Lts | Transdermal therapeutic system with a self-adhesive matrix containing organic acid addition salts of morphine or morphine type alkaloids |
| DE19923551A1 (en) * | 1999-05-21 | 2000-11-30 | Lohmann Therapie Syst Lts | Pharmaceutical preparation with the active ingredient diamorphine and its use in a method for treating opiate addiction |
| DE10056014A1 (en) * | 2000-11-11 | 2002-05-16 | Beiersdorf Ag | Laminated plaster with active substance, used as transdermal therapeutic system, has impermeable barrier layer on side away from skin and separable carrier layer with adhesive on side towards skin |
| DE10056012A1 (en) * | 2000-11-11 | 2002-05-16 | Beiersdorf Ag | Carrier material for medical applications, preferably for transdermal therapeutic system, has aluminum film between carrier and self-adhesive coating |
| JP4194277B2 (en) | 2002-01-25 | 2008-12-10 | 久光製薬株式会社 | Method for producing pressure-sensitive adhesive molded body mainly composed of crosslinked polymer |
| AU2003283055A1 (en) * | 2002-08-09 | 2004-02-25 | Grunenthal Gmbh | Opioid-receptor antagonists in transdermal systems having buprenorphine |
| DE10237057A1 (en) * | 2002-08-09 | 2004-03-25 | Grünenthal GmbH | Transdermal therapeutic systems containing buprenorphine, useful in treating pain or urinary incontinence, also containing mu-, kappa- or delta-opioid receptor antagonist to reduce abuse potential |
| MXPA05010450A (en) | 2003-03-31 | 2005-11-04 | Titan Pharmaceuticals Inc | Implantable polymeric device for sustained release of dopamine agonist. |
| GEP20125454B (en) | 2003-07-25 | 2012-03-26 | Euro Celtique Sa | Treatment of drug dependence withdrawal |
| DE102004009903A1 (en) | 2004-02-26 | 2005-09-22 | Grünenthal GmbH | Patch with reduced skin irritation |
| EP1743638A1 (en) | 2005-07-15 | 2007-01-17 | Laboratorios Del Dr. Esteve, S.A. | Pharmaceutical formulations of substituted pyrazoline compounds |
| DE102006057083A1 (en) | 2005-12-05 | 2007-06-28 | Lg Electronics Inc. | Lighting device for a refrigerator |
| DE102006054731B4 (en) | 2006-11-21 | 2013-02-28 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system for administration of the active ingredient buprenorphine and use thereof in pain therapy |
| CA2815898C (en) | 2010-11-17 | 2018-12-18 | Hexal Ag | Transdermal therapeutic system comprising buprenorphine |
| DE102011076653A1 (en) | 2011-05-27 | 2012-11-29 | Acino Ag | Transdermal therapeutic system containing buprenorphine and an alpha hydroxy acid |
| AP4036A (en) * | 2011-12-12 | 2017-02-22 | Lohmann Therapie Syst Lts | Transdermal delivery system comprising buprenorphine |
| DE102012000369A1 (en) | 2012-01-11 | 2013-07-11 | Alfred E. Tiefenbacher (Gmbh & Co. Kg) | Transdermal therapeutic system with cholinesterase inhibitor |
| EP3106153A1 (en) | 2013-06-04 | 2016-12-21 | LTS LOHMANN Therapie-Systeme AG | Transdermal delivery system |
| DE102014013448A1 (en) | 2014-09-16 | 2016-03-17 | Alfred E. Tiefenbacher (Gmbh & Co. Kg) | Transdermal therapeutic system comprising buprenorphine |
| US9656441B2 (en) | 2015-01-08 | 2017-05-23 | Alfred E. Tiefenbacher ( Gmbh & Co. Kg) | Transdermal patch |
| EP3067050A1 (en) | 2015-03-13 | 2016-09-14 | Acino AG | Transdermal therapeutic system with an overtape comprising two adhesive layers |
| CN109045341A (en) * | 2018-05-07 | 2018-12-21 | 武汉兴嘉业堂医疗科技发展有限公司 | A kind of promoting blood circulation and stopping pain pressure sensitive adhesive and preparation method thereof, application |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4464378A (en) * | 1981-04-28 | 1984-08-07 | University Of Kentucky Research Foundation | Method of administering narcotic antagonists and analgesics and novel dosage forms containing same |
| JPS60123417A (en) * | 1983-12-07 | 1985-07-02 | Nitto Electric Ind Co Ltd | Drug delivery member |
| US4626539A (en) * | 1984-08-10 | 1986-12-02 | E. I. Dupont De Nemours And Company | Trandermal delivery of opioids |
| US4806341A (en) * | 1985-02-25 | 1989-02-21 | Rutgers, The State University Of New Jersey | Transdermal absorption dosage unit for narcotic analgesics and antagonists and process for administration |
| DE3634016A1 (en) * | 1986-04-17 | 1987-10-29 | Lohmann Gmbh & Co Kg | AREA-BASED THERAPEUTIC SYSTEM, METHOD FOR THE PRODUCTION THEREOF AND ITS USE |
| JPS632533A (en) * | 1986-06-23 | 1988-01-07 | Yamakawa Sangyo Kk | Molded sand for precision casting |
| CH672888A5 (en) * | 1986-11-07 | 1990-01-15 | Mepha Ag | |
| ES2036670T3 (en) * | 1987-03-09 | 1993-06-01 | Alza Corporation | COMPOSITION TO PREVENT A CONTACT ALLERGY BY SIMULTANEOUS ADMINISTRATION OF A CORTICOESTEROID WITH A SENSITIZING PHARMACY. |
| JPH02503672A (en) * | 1987-06-01 | 1990-11-01 | ワーナー‐ランバート・コンパニー | Fatty acids and their short chain esters as penetration enhancers in aqueous systems |
| DE3843237A1 (en) * | 1988-12-22 | 1990-07-05 | Lohmann Therapie Syst Lts | TRANSDERMAL THERAPEUTIC SYSTEM WITH AN ANTIADIPOSITUM AS AN ACTIVE INGREDIENT |
-
1989
- 1989-11-29 DE DE3939376A patent/DE3939376C1/de not_active Expired - Lifetime
-
1990
- 1990-11-01 AU AU65699/90A patent/AU632182B2/en not_active Expired
- 1990-11-05 MY MYPI90001939A patent/MY105347A/en unknown
- 1990-11-05 IL IL9624390A patent/IL96243A/en not_active IP Right Cessation
- 1990-11-13 CZ CS905598A patent/CZ282557B6/en not_active IP Right Cessation
- 1990-11-13 SK SK5598-90A patent/SK279687B6/en not_active IP Right Cessation
- 1990-11-16 CA CA002030178A patent/CA2030178C/en not_active Expired - Lifetime
- 1990-11-20 JP JP2312968A patent/JPH0818984B2/en not_active Expired - Lifetime
- 1990-11-20 AT AT90122120T patent/ATE135205T1/en not_active IP Right Cessation
- 1990-11-20 DE DE59010192T patent/DE59010192D1/en not_active Expired - Lifetime
- 1990-11-20 EP EP90122120A patent/EP0430019B1/en not_active Expired - Lifetime
- 1990-11-20 DK DK90122120.0T patent/DK0430019T3/en active
- 1990-11-20 ES ES90122120T patent/ES2086353T3/en not_active Expired - Lifetime
- 1990-11-22 NZ NZ236191A patent/NZ236191A/en unknown
- 1990-11-26 NO NO905103A patent/NO303107B1/en not_active IP Right Cessation
- 1990-11-27 YU YU226090A patent/YU47956B/en unknown
- 1990-11-27 SI SI9012260A patent/SI9012260B/en unknown
- 1990-11-28 KR KR1019900019329A patent/KR950015061B1/en not_active IP Right Cessation
- 1990-11-28 PT PT96028A patent/PT96028B/en not_active IP Right Cessation
- 1990-11-28 IE IE429090A patent/IE73247B1/en not_active IP Right Cessation
- 1990-11-28 PL PL90287989A patent/PL165396B1/en unknown
- 1990-11-28 ZA ZA909544A patent/ZA909544B/en unknown
- 1990-11-28 HU HU907677A patent/HU206266B/en unknown
- 1990-11-29 FI FI905892A patent/FI100379B/en active IP Right Grant
-
1993
- 1993-04-01 HR HRP-2260/90A patent/HRP930675B1/en not_active IP Right Cessation
-
1996
- 1996-06-06 GR GR960401538T patent/GR3020177T3/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NO303107B1 (en) | Process for Preparing a Transdermal Therapeutic System with Buprenorphine as an Active Ingredient | |
| US5240711A (en) | Transdermal therapeutic system comprising as active component buprenorphine | |
| JP3980633B2 (en) | Estradiol penetration enhancer | |
| JP3021661B2 (en) | Transdermal release devices for drug-containing adhesive composites | |
| FI115034B (en) | Process for preparing a non-recrystallizable estradiol-containing patch | |
| JPH08505632A (en) | Transdermal medical system with galantamine as active substance | |
| US20140276479A1 (en) | Transdermal drug delivery system with overlay | |
| WO2007099966A1 (en) | Transdermal absorption preparation | |
| US20090264806A1 (en) | Transdermal drug administration device | |
| WO2004110445A1 (en) | Phentanyl-containing adhesive patch for application to oral-cavity mucosa | |
| JPWO2009051217A1 (en) | Fentanyl-containing transdermal absorption preparation | |
| CZ277995A3 (en) | Pilocarpine controlled release system | |
| JP2602108B2 (en) | Transdermal drug having norpsoid ephedrine as active ingredient | |
| US5705186A (en) | Pharmaceutical composition for the systemic transdermal administration having the active substance morphine-6-glucuronide | |
| JP4167750B2 (en) | Transdermal absorption base and percutaneous absorption preparation containing the base | |
| JPH0413617A (en) | Patch | |
| KR20040044907A (en) | Transdermal administration of an enalapril ester | |
| JP3132838B2 (en) | Formulation for oral mucosa | |
| JP6864968B2 (en) | Patch | |
| JPH07316046A (en) | Transdermally absorbable preparation | |
| CN117899056A (en) | Transdermal patch containing lidocaine, and preparation method and application thereof | |
| CN115551489A (en) | Percutaneous absorption preparation containing antioxidant | |
| JPH05155759A (en) | Preparation for applying to oral cavity mucosa | |
| JPH06183956A (en) | Stable pharmaceutical preparation for application | |
| JPH05178762A (en) | Percutaneous and transmucosal absorption pharmacetical |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK1K | Patent expired |