HRP930675A2 - Process for the production of a transdermal therapeutic system containing buprenorphine as an active component - Google Patents
Process for the production of a transdermal therapeutic system containing buprenorphine as an active component Download PDFInfo
- Publication number
- HRP930675A2 HRP930675A2 HR930675A HRP930675A HRP930675A2 HR P930675 A2 HRP930675 A2 HR P930675A2 HR 930675 A HR930675 A HR 930675A HR P930675 A HRP930675 A HR P930675A HR P930675 A2 HRP930675 A2 HR P930675A2
- Authority
- HR
- Croatia
- Prior art keywords
- transdermal therapeutic
- therapeutic system
- buprenorphine
- acid
- polymer material
- Prior art date
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- 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 34
- 229960001736 buprenorphine Drugs 0.000 title claims abstract description 34
- 230000001225 therapeutic effect Effects 0.000 title claims abstract description 20
- 238000004519 manufacturing process Methods 0.000 title description 5
- 238000000034 method Methods 0.000 title description 4
- 239000010410 layer Substances 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 18
- 239000013543 active substance Substances 0.000 claims abstract description 13
- 239000011241 protective layer Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000000463 material Substances 0.000 claims abstract description 7
- 229920000642 polymer Polymers 0.000 claims description 18
- 229920001577 copolymer Polymers 0.000 claims description 12
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 claims description 8
- 239000002861 polymer material Substances 0.000 claims description 7
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 6
- 238000003860 storage Methods 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
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 5
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- 150000002148 esters Chemical class 0.000 claims description 5
- 239000011888 foil Substances 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- -1 glycerin ester Chemical class 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 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
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-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
- 239000012790 adhesive layer Substances 0.000 claims description 3
- 235000011037 adipic acid Nutrition 0.000 claims description 3
- 239000001361 adipic acid Substances 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
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 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
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- 150000002314 glycerols Polymers 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 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims 2
- 150000004702 methyl esters Chemical class 0.000 claims 2
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims 1
- 239000004372 Polyvinyl alcohol Substances 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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims 1
- 229920000346 polystyrene-polyisoprene block-polystyrene Polymers 0.000 claims 1
- 229920000468 styrene butadiene styrene block copolymer Polymers 0.000 claims 1
- 239000000853 adhesive Substances 0.000 abstract description 6
- 230000001070 adhesive effect Effects 0.000 abstract description 6
- 239000004014 plasticizer Substances 0.000 abstract description 3
- 230000035515 penetration Effects 0.000 description 13
- 238000000338 in vitro Methods 0.000 description 11
- 239000003814 drug Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 125000005397 methacrylic acid ester group Chemical group 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 229940127240 opiate Drugs 0.000 description 4
- 206010012335 Dependence Diseases 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
- 150000001298 alcohols Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-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 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 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
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 150000001991 dicarboxylic acids Chemical class 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 2
- IBMRTYCHDPMBFN-UHFFFAOYSA-N monomethyl glutaric acid Chemical compound COC(=O)CCCC(O)=O IBMRTYCHDPMBFN-UHFFFAOYSA-N 0.000 description 2
- 229960000938 nalorphine Drugs 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 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
- 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
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 239000002174 Styrene-butadiene Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229940035676 analgesics 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
- 229920005601 base polymer Polymers 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- MTAZNLWOLGHBHU-UHFFFAOYSA-N butadiene-styrene rubber Chemical compound C=CC=C.C=CC1=CC=CC=C1 MTAZNLWOLGHBHU-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001735 carboxylic acids Chemical class 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
- 238000013270 controlled release 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
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- 239000003974 emollient agent Substances 0.000 description 1
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- 230000008020 evaporation Effects 0.000 description 1
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- UOBSVARXACCLLH-UHFFFAOYSA-N monomethyl adipate Chemical compound COC(=O)CCCCC(O)=O UOBSVARXACCLLH-UHFFFAOYSA-N 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical class CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 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
- 230000000149 penetrating effect Effects 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
- 229920000307 polymer substrate Polymers 0.000 description 1
- 229920000193 polymethacrylate 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
- 239000005060 rubber Substances 0.000 description 1
- 239000011780 sodium chloride 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
- 239000011115 styrene butadiene Substances 0.000 description 1
- 229920003048 styrene butadiene rubber Polymers 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- KJIOQYGWTQBHNH-UHFFFAOYSA-N undecanol Chemical compound CCCCCCCCCCCO KJIOQYGWTQBHNH-UHFFFAOYSA-N 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
Izum se odnosi na postupak za izradu transdermalnog terapijskog sustava (TTS), koji kao aktivni sastojak sadrži (17-ciklopropilmetil)-α-(1,1-dimetiletil)-4,5-epoksi-18,19-dihidro-3-hidroksi-6-metoksi-α-metil-6,14-etenormorfinan-7-metanol). The invention relates to a procedure for the production of a transdermal therapeutic system (TTS), which as an active ingredient contains (17-cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy -6-methoxy-α-methyl-6,14-ethenormorphinan-7-methanol).
Buprenorphin je parcijalno sintetski opijat, čija prednost u odnosu na druge spojeve ove klase spojeva jest u višoj aktivnosti. Ovo znači da se oslobađanje od bolova kod pacijenata s rakom ili tumorom s nepovoljnom dijagnozom u završnom stadiju, može postići dnevnom dozom oko 1 mg. Ali dva značajna problema opijata Buprenorphin ne rješava, naime potencijalnu ovisnost i malu bioraspoloživost ovih tvari pri oralnom davanju. Tako iz gastrointestinalnog trakta bioraspoloživost iznosi približno samo 10%, a pri sublingualnoj primjeni također samo oko 50%. Prvobitna pretpostavka male potencijalne ovisnosti Buprenorphin-u poslije njegovog uvođenja kao sredstva protiv bola se ispravlja. Poslije povećanja zloupotrebe od strane ovisnika o drogi podliježe u međuvremenu Buprenorphin saveznom njemačkom zakonu o opojnim drogama Buprenorphine is a partially synthetic opiate, the advantage of which compared to other compounds of this class of compounds is higher activity. This means that pain relief in patients with cancer or a tumor with an unfavorable diagnosis in the final stage can be achieved with a daily dose of about 1 mg. But Buprenorphine does not solve two significant problems of opiates, namely potential addiction and low bioavailability of these substances when administered orally. Thus, bioavailability from the gastrointestinal tract is approximately only 10%, and with sublingual administration also only about 50%. The initial assumption of little potential addiction to Buprenorphine after its introduction as a pain reliever is being corrected. After increasing abuse by drug addicts, Buprenorphine is now subject to the Federal German Narcotics Act
Među stručnjacima se u nedavnoj prošlosti svakako zastupa teza da potencijalnoj ovisnosti o lijeku pridonosi oblik lijeka. Ovo se može lako potvrditi za jako aktivne analgetike u terapiji izvanredno visokih bolova Among experts, in the recent past, the thesis that the form of the drug contributes to potential addiction to the drug has certainly been advocated. This can be easily confirmed for highly active analgesics in the therapy of extremely high pain
Neposredno poslije davanja je razina u krvi sredstava protiv bola viša nego što je potrebno i uzrokuje euforiju, ali potom opada eksponencijalno i brzo dostiže razinu u krvi, koja više bol ne može uspješno liječiti. Zbog bolova počinje pacijent žudjeti za sljedećom dozom, čime se iatrogeno stvara navika Immediately after administration, the level in the blood of painkillers is higher than necessary and causes euphoria, but then it decreases exponentially and quickly reaches a level in the blood, which can no longer successfully treat the pain. Because of the pain, the patient begins to crave the next dose, which iatrogenically creates a habit
Trajna infuzija bi bila također i kod Buprenorphin-a i drugih jako aktivnih opijata izbor oblika lijeka da bi se ovo iatrogeno stvaranje navike izbjeglo konstantnom razinom u krvi. Trajna se pak infuzija ne može u kućnoj njezi provesti i kontrolirati bez liječničke pomoći i često vodi do upala na ulaznom mjestu kanile. Continuous infusion would also be the drug form choice for Buprenorphine and other highly active opiates to avoid this iatrogenic habit formation with a constant blood level. On the other hand, permanent infusion cannot be carried out and controlled in home care without medical help and often leads to inflammation at the cannula entrance site.
Također ni oralni depo oblik ne može biti za Buprenorphin podoban ljekovit sustav, budući da na temelju male bioraspoloživosti pri oralnom davanju se mora za usporedbu, za potrebno intravenozno doziranje dati približno desetostruka količina aktivne tvari. Ali ovdje Buprenorphin kao parcijalni opijat-antagonist pravi utoliko velike probleme, budući da se depresija disanja izazvana predoziranjem aktivne tvari ne može liječiti davanjem antagonista, nešto Nalorphin-a, antidotom izbora kod trovanja opijatima. Do predoziranja može doći, budući da je oralna bioraspoloživost dana doduše sa 10%, ali ova može biti apsolutno viša, budući se Buprenorphin treba davati krugu pacijenata kod koga se treba računati sa smetnjama jetre, tako da apsolutno više od 10% može prvim prolazom jetre izići nemetabolizirano. Also, the oral depot form cannot be a suitable medicinal system for Buprenorphine, since, based on the low bioavailability during oral administration, approximately ten times the amount of the active substance must be given for the necessary intravenous dosing. But here Buprenorphine as a partial opiate-antagonist causes all the bigger problems, since the respiratory depression caused by an overdose of the active substance cannot be treated by giving an antagonist, some Nalorphine, the antidote of choice in opiate poisoning. An overdose can occur, since the oral bioavailability is admittedly given as 10%, but this can be absolutely higher, since Buprenorphine should be given to a group of patients with liver disorders, so absolutely more than 10% can pass through the liver first. come out unmetabolized.
Osim toga oralni depo oblici nisu u svakom pogledu optimalni, kako jasno pokazuje razvoj na tržištu lijekova posljednjih godina. Generika sa istim oslobađanjem in-vitro kao preparati originalnih ponuditelja nemaju istu aktivnost baš kao ovi originalni preparati. Ovo znači, da nekontroliranim oslobađanjem in vivo može doći do pre ili nedovoljnog doziranja. I jedno i drugo je kod Buprenorphin-a naročito fatalno. Ako se ne dozira dovoljno, pacijent trpi jake bolove. Ako se predozira, može u najgorem slučaju doći do depresija disanja sa smrtnim ishodom, koje se ne mogu liječiti Nalorphin-om. In addition, oral depot forms are not optimal in every respect, as the development of the drug market in recent years clearly shows. Generics with the same in-vitro release as the original providers' preparations do not have the same activity as these original preparations. This means that uncontrolled release in vivo can lead to over or insufficient dosing. Both are particularly fatal with Buprenorphine. If it is not dosed enough, the patient suffers severe pain. If overdosed, in the worst case, respiratory depression with fatal outcome can occur, which cannot be treated with Nalorphin.
Do sada se nije uzimalo u obzir da oralni depo oblik, koji je oštećen i stoga ne usporava Buprenorphin, već ga odjednom oslobađa (u engleskom među stručnjacima poznato kao "dosedumping"), ne može se odmah odstraniti iz ljudskog tijela. Until now, it was not taken into account that the oral depot form, which is damaged and therefore does not slow down Buprenorphine, but releases it suddenly (known in English among experts as "dosedumping"), cannot be immediately removed from the human body.
Sva do sada opisana ograničenja protiv oblika lijeka koji usporeno oslobađa Buprenorphin se izbjegavaju prednostima transdermalnih terapijskih sustava, budući da se medikament ne mora preko kanile unositi u ljudsko tijelo i stoga ga mogu upotrijebiti i medicinski laici. Istovremeno je osiguran dovod lijeka prema 0. redu, koji se skidanjem sustava u svako doba može prekinuti. Transdermalni terapijski sustav se čini dakle za Buprenorphin kao izbor oblika lijeka All the limitations described so far against the slow-release form of buprenorphine are avoided by the advantages of transdermal therapeutic systems, since the medication does not have to be introduced into the human body through a cannula and can therefore be used by medical laymen. At the same time, the supply of medicine according to the 0th row is ensured, which can be interrupted at any time by removing the system. The transdermal therapeutic system seems therefore for Buprenorphine as the choice of drug form
Ali tome nasuprot, Buprenorphin zbog njegove visoke molekularne mase (m.m. 463) i prije svega pak zbog njegove visoke točke topljenja i njegove veoma loše otopljivosti u organskim otapalima u upotrebi i vodi prodire samo izrazito loše kroz ljudsku kožu, budući da difuzija, pretpostavka je za prodiranje kroz ljudsku kožu, zahtijeva otopljene supstance. Ali otopljivost se ne smije povisiti stvaranjem soli, budući se baze ne apsorbiraju u ioniziranom obliku. Do danas se nije uspjelo Buprenorphin transdermalno dovesti do resorpcije u potrebnoj količini, iako iz gore opisanih razloga TTS za ovu aktivnu tvar predstavlja najbolji mogući oblik lijeka. But in contrast, due to its high molecular weight (m.m. 463) and above all due to its high melting point and its very poor solubility in organic solvents in use and water, Buprenorphine penetrates only extremely poorly through human skin, since diffusion is a prerequisite for penetration through human skin requires dissolved substances. But the solubility must not be increased by forming salts, since bases are not absorbed in ionized form. To date, it has not been possible to resorb Buprenorphine transdermally in the required amount, although for the reasons described above, TTS represents the best possible form of the drug for this active substance.
Stoga je zadatak izuma izrada postupka za izradu trensdermalnog terapijskog sustava, koji Buprenorphin ili jednu od njegovih farmaceutski prihvatljivih soli u tijeku vremenskog intervala od najmanje 24 sata kontrolirano otpušta i jamči da se Buprenorphin u tijeku skladištenja unaprijed izrađenog transdermalnog terapijskog sustava ne raspada znatno i osigurava da nedovoljno prolazan kroz kožu, Buprenorphin prodire u potrebnoj mjeri in vivo kroz ljudsku kožu. Therefore, the task of the invention is to create a method for making a transdermal therapeutic system, which releases Buprenorphine or one of its pharmaceutically acceptable salts in a controlled manner over a time interval of at least 24 hours and guarantees that Buprenorphine does not significantly decompose during storage of the pre-made transdermal therapeutic system and ensures that insufficiently penetrating through the skin, Buprenorphine penetrates to the required extent in vivo through human skin.
Ovaj zadatak se prema izumu na iznenađujući način rješava postupkom za izradu transdermalnog terapijskog sustava za davanje Buprenorphin-a na koži, koji se sastoji iz zadnjeg sloja nepropusnog za aktivnu tvar, sloja spremnika koji se priljubljuje na kožu i u datom slučaju ponovo odvojivog zaštitnog sloja, i naznačen je time, što se za izradu sloja spremnika homogenizira smjesa od 20 do 90 mas.-% polimernog materijala, 0,1 do 30 mas.% omekšivača, 0,1 do 20 mas.-% Buprenorphin baze ili jedne od njegovih farmaceutski prihvatljivih soli i 0,1 do 30 mas.-% otapala za bazu aktivne tvari uz eventualni dodatak lako isparljivih otapala i nanese na zadnji sloj ili zaštitni sloj, poslije čega se lako isparljiva otapala odstranjuju. According to the invention, this task is solved in a surprising way by a process for creating a transdermal therapeutic system for administering Buprenorphine on the skin, which consists of a last layer impermeable to the active substance, a container layer that adheres to the skin and, in a given case, a removable protective layer, and it is indicated that for the production of the tank layer, a mixture of 20 to 90 wt.-% polymer material, 0.1 to 30 wt.% plasticizer, 0.1 to 20 wt.-% Buprenorphine base or one of its pharmaceutically acceptable compounds is homogenized salt and 0.1 to 30 wt.-% solvent for the base of the active substance with the possible addition of easily volatile solvents and applied to the last layer or protective layer, after which the easily volatile solvents are removed.
Ovo rješenje je utoliko čudnovatije, budući da Buprenorphin, kako je spomenuto, ima dan sublingvalno bioraspoloživost od samo 50%. Pošto se kod ove vrste primjene prvi prolaz kroz jetru, zaobilazi, može se mala bioraspoloživost svesti na nedovoljnu sposobnost resorpcije tvari usnom sluzokožom. Ali tvar, koja sluzokožu usta prolazi samo teško, upravo se teško prima od strane ljudske kože. This solution is all the more strange, since Buprenorphine, as mentioned, has a given sublingual bioavailability of only 50%. Since the first pass through the liver is bypassed with this type of application, the low bioavailability can be reduced to the insufficient ability to resorb the substance through the oral mucosa. But the substance, which passes the mucous membrane of the mouth only with difficulty, is precisely absorbed by the human skin.
Zadnji sloj nepropustan za aktivnu tvar može se sastojati od fleksibilnog ili nefleksibilnog materijala. Tvari, koje se mogu primijeniti za njegovu izradu, su polimerne folije ili metalne folije, kao aluminijske folije, koje se primjenjuju same ili obložene pomoću polimernog supstrata. Mogu se primijeniti također i tekstilni ravni proizvodi, ako sastojci spremnika na osnovu njihovog fizičkog svojstva ne mogu proći kroz njih. Kod oblika izvođenja koji se pretpostavlja zadnji sloj je spojni materijal na primjer iz folije na koju je aluminij nanesen u parnom stanju. The back layer impermeable to the active substance can consist of a flexible or non-flexible material. Materials that can be used for its production are polymer foils or metal foils, such as aluminum foils, which are applied alone or coated with a polymer substrate. Textile flat products can also be used, if the contents of the container cannot pass through them due to their physical properties. In the assumed embodiment, the last layer is a connecting material, for example, from a foil on which aluminum has been applied in a vapor state.
Sloj spremnika se sastoji iz polimerne matrice i aktivne tvari, pri čemu polimerna matrica jamči povezanost sustava. On se sastoji iz osnovnog polimera i u danom slučaju uobičajenih dodataka. Izbor osnovnog polimera se ravna prema kemijskim i fizikalnim svojstvima Buprenorphin-a. Primjeri polimera su kaučuk, kaučuku slični, sintetski mono-, ko- ili blokpolimeri, esteri poliakrilne kiseline i njeni kopolimeri, poliuretani i silikoni. Načelno dolaze u obzir svi polimeri, koji se mogu upotrijebiti za izradu priljubljujućih ljepila i fiziološki nisu sumnjivi. Naročito se pretpostavljaju takvi koji se sastoje od blok polimera na bazi stirola i 1,3-diena, poliizobutilena, polimeri na bazi akrilata i/ili metakrilata. The container layer consists of a polymer matrix and an active substance, whereby the polymer matrix guarantees the connection of the system. It consists of a basic polymer and, in a given case, the usual additives. The choice of base polymer is based on the chemical and physical properties of Buprenorphine. Examples of polymers are rubber, rubber-like, synthetic mono-, co- or block polymers, polyacrylic acid esters and their copolymers, polyurethanes and silicones. In principle, all polymers that can be used for the production of adherent adhesives and are physiologically not suspicious come into consideration. In particular, those consisting of block polymers based on styrene and 1,3-diene, polyisobutylene, polymers based on acrylates and/or methacrylates are assumed.
Od blok kopolimera na bazi stirola i 1,3-diena sasvim posebno se stavljaju linearni stirol-izopren ili stirol-butadien blok polimeri. Of the block copolymers based on styrene and 1,3-diene, linear styrene-isoprene or styrene-butadiene block polymers are quite special.
Kao polimeri na bazi akrilata se pretpostavljaju samoumreženi akrilatkopolimeri iz 2-etilheksilakrilata, vinilacetata i akrilne kiseline odn. akrilatkopolimeri bez titanhelatestera koji nisu samoumreženi. Self-crosslinked acrylate copolymers from 2-ethylhexylacrylate, vinyl acetate and acrylic acid are assumed to be acrylate-based polymers. acrylate copolymers without titanium chelatesters that are not self-crosslinked.
Kao polimeri, koji se dodaju osnovnom polimeru, dolaze u obzir polimetakrilati, esteri hidriranog kolofonija i polivinili. Kao metakrilati se pretpostavljaju kopolimeri na bazi dimetil-aminoetilmetakrilata i neutralnih estera metakrilne kiseline. Kao esteri hidriranog kolofonija u prvom redu se primjenjuju naročito njegovi metil i glicerin esteri. Kao polivinili se stavljaju prvenstveno polivinil pirolidoni i polivinil alkoholi. Vrsta uobičajenih dodataka zavisi od stavljenog polimera: prema njihovoj funkciji mogu se podijeliti na primjer u sredstva koja čine ljepljivost, stabilizatore, nosive materije i punila. Stručnjaku su poznate fiziološki nesumnjive supstance koje ovdje dolaze u obzir. Prema izumu se pokazalo da potreban omekšivač u svezi sa Buprenorphin-om da bi se Buprenorphin mogao transdermalno primjenjivati. As polymers, which are added to the basic polymer, polymethacrylates, hydrogenated rosin esters and polyvinyls come into consideration. Methacrylates are assumed to be copolymers based on dimethyl-aminoethyl methacrylate and neutral methacrylic acid esters. As esters of hydrogenated rosin, especially its methyl and glycerine esters are used in the first place. Polyvinyl pyrrolidones and polyvinyl alcohols are used primarily as polyvinyls. The type of common additives depends on the added polymer: according to their function, they can be divided, for example, into adhesives, stabilizers, carriers and fillers. Physiologically unquestionable substances that come into consideration here are known to the expert. According to the invention, it has been shown that a softener is required in connection with Buprenorphine in order for Buprenorphine to be administered transdermally.
Izbor omekšivača se ravna prema polimeru. Naročito su podobni viši alkoholi kao dodekanol, undekanol, oktanol i esteri karbonskih kiselina pri čemu alkoholna komponenta može biti također i polietoksilirani alkohol, diesteri dikarbonskih kiselina, na primjer di-n-butiladipat kao i trigliceridi, naročito trigliceridi srednjeg lanca kapril/kaprinskih kiselina kokosovog ulja. Daljnji primjeri za pogodan omekšivač su viševalentni alkoholi, npr. glicerin i propandiol-(1,2) i dr., koji mogu biti također i eterificirani polietilenglikolima. The choice of plasticizer depends on the polymer. Particularly suitable are higher alcohols such as dodecanol, undecanol, octanol and esters of carboxylic acids, whereby the alcoholic component can also be polyethoxylated alcohol, diesters of dicarboxylic acids, for example di-n-butyldidipate, as well as triglycerides, especially triglycerides of the medium chain caprylic/capric acids of coconut oil. Further examples of suitable softeners are polyvalent alcohols, for example glycerin and propanediol-(1,2), etc., which can also be etherified with polyethylene glycols.
Uloga otapala za Buprenorphin bazu se potvrđuje primjerima. Oni pokazuju da je otapalo sastojak od koga se ne može odustati u recepturi. Kombinacija omekšivača/otapala prema učenju izuma stvara pretpostavku za prodiranje Buprenorphin baze kroz kožu. Kao otapala za Buprenorphin u matrici dolaze u obzir takvi sa najmanje jednom kiselom grupom. Naročito su podobni monoesteri dikarbonskih kiselina, npr. monomerilglutarat i monometiladipat. Načelno dolaze u obzir sve kiseline, koje Buprenorphin u dovoljnoj mjeri otapaju, a da ne dolazi do potpunog stvaranja soli, pošto se u posljednjem slučaju ne može više računati s prodiranjem kroz kožu. The role of the solvent for the Buprenorphine base is confirmed by examples. They show that the solvent is an indispensable ingredient in the recipe. The emollient/solvent combination according to the teachings of the invention creates a prerequisite for penetration of the Buprenorphine base through the skin. Solvents for Buprenorphine in the matrix are those with at least one acidic group. Particularly suitable are monoesters of dicarboxylic acids, eg monomeryl glutarate and monomethyl adipate. In principle, all acids that dissolve Buprenorphine to a sufficient extent, without complete formation of salts, are considered, since in the latter case, penetration through the skin can no longer be counted on.
Sloj spremnika ima takvu vlastitu ljepljivost da se osigurava trajan dodir za kožu. Odvojivi zaštitni sloj, koji stoji u dodiru sa slojem spremnika i odstranjuje se prije primjene, sastoji se na primjer od istih materijala, kako se oni koriste za izradu zadnjeg sloja, uz pretpostavku da se učine odvojivim, kao npr. silikonskom obradom. Drugi odvojivi zaštitni slojevi su npr. politetrafluoretilen, obrađeni papir, celofan, polivinil klorid i dr. The container layer has such an inherent tackiness that it ensures a permanent contact with the skin. The removable protective layer, which is in contact with the container layer and is removed before application, consists for example of the same materials as those used to make the last layer, assuming that they are made separable, such as by silicone treatment. Other removable protective layers are, for example, polytetrafluoroethylene, treated paper, cellophane, polyvinyl chloride, etc.
Ako se laminat prema izumu prije nanošenja zaštitnog sloja podijeli u terapijski pogodne formate (flasteri), tada formati zaštitnog sloja koji trebaju nanijeti imaju ispuštene krajeve, čijom se pomoći mogu lakše skidati sa flastera. Transdermalni terapijski sustav prema izumu se izrađuje tako što se aktivna tvar zajedno sa sastojcima sloja spremnika koji se lijepi priljubljujući se u danom slučaju homogeno pomiješan u otopini i premaže na zadnji sloj nepropustan za aktivnu tvar, poslije čega se u danom slučaju otapalo ili otapala odstrani/odstrane. Zatim se ljepljivi sloj opskrbljuje zaštitnim slojem. Također je načelno moguć i obratni put da se premaže otopina ljepila na zaštitni sloj. Također i u ovom slučaju se odstranjuju otapala i zatim se pokriva zadnjim slojem. If the laminate according to the invention is divided into therapeutically suitable formats (patches) before applying the protective layer, then the formats of the protective layer to be applied have dropped ends, with the help of which they can be more easily removed from the patch. The transdermal therapeutic system according to the invention is made by mixing the active substance together with the ingredients of the container layer that adheres to each other homogeneously in a solution and is coated on the last layer impermeable to the active substance, after which the solvent or solvents are removed in the given case. from side. Then the adhesive layer is supplied with a protective layer. In principle, it is also possible to apply the adhesive solution to the protective layer in the opposite way. Also in this case the solvents are removed and then it is covered with the last layer.
Izum se objašnjava sljedećim primjerima: The invention is explained with the following examples:
Primjer I Examples
Po 10,0 g monometilestera glutarne kiseline, metanola i butanona i 15,0 g 1-dodekanola se uz miješanje pomiješa. Zatim se unese 10,0 g Buprenorphin baze; miješa se do potpunog otapanja čvrste tvari (pribl. 30 min, vizuelna kontrola). Zatim se uz miješanje doda 133,0 g samoumreženog akrilatkopolimera iz 2-etilheksil akrilata, vinilacetata i 46%tne akrilne kiseline u smjesi otapala (etilacetat: heptan: izopropanol: toluol: acetilaceton 37 : 26 : 26 : 4 : 1); homogenizira se. Poslije toga se uz miješanje dodatno pospe 1,3 g aluminij acetilacetonata i miješa 3 sata dugo na temperaturi okoline. Gubitak isparavanja se nadoknađuje. 10.0 g each of glutaric acid monomethylester, methanol and butanone and 15.0 g of 1-dodecanol are mixed with stirring. Then 10.0 g of Buprenorphine base is introduced; it is mixed until the solid substance is completely dissolved (approx. 30 min, visual control). Then, with stirring, 133.0 g of self-crosslinked acrylate copolymer from 2-ethylhexyl acrylate, vinyl acetate and 46% acrylic acid is added in a solvent mixture (ethyl acetate: heptane: isopropanol: toluene: acetylacetone 37 : 26 : 26 : 4 : 1); it is homogenized. After that, 1.3 g of aluminum acetylacetonate is additionally sprinkled with stirring and stirred for 3 hours at ambient temperature. Evaporation loss is compensated.
Nastaje 189,3 g 52,8 %-tne otopine ljepila koja sadrži aktivnu tvar, koja se premazuje pomoću 350 µm razmaka za nanošenje na aluminiziranu ili silikoniziranu polietilensku foliju. Poslije toga se odstranjuje otapalo 30 minutnim sušenjem do 60ºC, pokrije ljepljivi sloj poliesterskom folijom 15 µm. Sa podobnim alatom za rezanje izrezuju se površine od 16 cm2 i izrezivanjem se odvajaju rubovi. Oslobađanje ovoga i drugih primjera recepture su navedeni u Tabeli; tamo su navedeni kako kontrolirano oslobađanje u fiziološkoj otopini kuhinjske soli tako i kroz izrezanu kožu glodavaca. 189.3 g of a 52.8% adhesive solution containing the active substance is produced, which is coated using a 350 µm gap for application to an aluminized or siliconized polyethylene film. After that, remove the solvent by drying for 30 minutes at 60ºC, cover the adhesive layer with a 15 µm polyester film. Areas of 16 cm2 are cut with a suitable cutting tool and the edges are separated by cutting. The release of this and other recipe examples are listed in the Table; both controlled release in saline and through excised rodent skin are reported there.
Svi daljnji primjeri se izrađuju prema shemi pod Primjerom I. Najprije se uvijek izmiješaju tekući sastojci, potom se pospe Buprenorphin. Poslije njegovog rastvaranja se u datom slučaju dodaje metakrilatni kopolimer na bazi dimetilaminoetilmetakrilata i neutralnih estera metakrilne kiseline i poslije njihovog otapanja dodaje otopina ljepila. U sljedećoj Tabeli su navedeni sastojci recepture poslije sušenja. Pri tom znače: All further examples are made according to the scheme under Example I. The liquid ingredients are always mixed first, then Buprenorphine is sprinkled. After its dissolution, a methacrylate copolymer based on dimethylaminoethyl methacrylate and neutral methacrylic acid esters is added in the given case, and after their dissolution, the glue solution is added. The following table lists the ingredients of the recipe after drying. At the same time, they mean:
Akrilat: akrilatkopolimer iz 2-etilheksilakrilata, vinil acetata i akrilne kiseline Acrylate: acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate and acrylic acid
Poluester: monometilester glutarne (označen pomoću G) odn. adipinske kiseline (označen pomoću A) Half-ester: monomethyl ester of glutarine (marked by G) or adipic acid (marked by A)
G.L.: polietoksilirani glicerin sa C8/C10-etoksigrupama G.L.: polyethoxylated glycerin with C8/C10-ethoxy groups
Polimerni dodaci: b: kopolimer sa baznim karakterom na bazi dimetilaminoetilmetakrilata i neutralnih estera metakrilne kiseline Polymer additives: b: copolymer with basic character based on dimethylaminoethyl methacrylate and neutral methacrylic acid esters
n: kopolimer sa neutralnim karakterom na bazi estera metakrilne kiseline i butilestera metakrilne kiseline n: copolymer with a neutral character based on methacrylic acid ester and methacrylic acid butyl ester
PVP: polivinilpirolidon PVP: polyvinylpyrrolidone
in vitro oslobađanje se određuje u posudi mućkalici na 37ºC. Akceptorska sredina su bili 100 ml fiziološke otopine kuhinjske soli, koji su potpuno izmijenjeni poslije 2, 4 i 8 sati. Koncentracije se određuje poslije 2, 4 i 8 i 24 sata pomoću HPLC. Prodiranje na koži miševa je mjereno Franz’ovim difuzionim stanicama. in vitro release is determined in a shaker container at 37ºC. The acceptor medium was 100 ml of a physiological solution of kitchen salt, which was completely changed after 2, 4 and 8 hours. Concentrations are determined after 2, 4 and 8 and 24 hours using HPLC. Penetration on the skin of mice was measured with Franz diffusion cells.
Krivulje oslobađanja prema Primjeru I su predstavljene na Slici 1 i 2. The release curves of Example I are presented in Figures 1 and 2.
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Tumačenje in vitro rezultata Interpretation of in vitro results
Primjeri VII, XIV i XVII potvrđuju potrebu da se u transdermalne sustave umiješa posredno otapalo sa najmanje jednom kiselom grupom, budući da bez takvog otapala očigledno drastično opada in vitro prodiranje. In vitro prodiranje kod sva tri Primjera jest oko 0,1 mg/2,54 cm2 x h. Istovremeno Primjeri I i XXI pokazuju da praktično ne igra za in vitro prodiranje nikakvu ulogu, da li je stavljen monometil ester glutarne kiseline ili adipinske kiseline. Primjer XII služi kao dokaz za to, da se pored posrednika otapala mora staviti još omekšivač, jer bez takvog je in vitro prodiranje sa 0,22 mg/2,54 cm2 x 24 h samo malo iznad prodiranja sustava bez otapala posrednika. Examples VII, XIV and XVII confirm the need to mix an intermediate solvent with at least one acidic group into the transdermal systems, since without such a solvent the in vitro penetration obviously drops drastically. In vitro penetration in all three Examples is about 0.1 mg/2.54 cm2 x h. At the same time, Examples I and XXI show that whether monomethyl ester of glutaric acid or adipic acid is used does not play any role for in vitro penetration. Example XII serves as proof that a softener must be added in addition to the solvent mediator, because without it the in vitro penetration with 0.22 mg/2.54 cm2 x 24 h is only slightly above the penetration of the system without the solvent mediator.
Primjeri XIV, XIII, XX i XVIII služe istraživanju utjecaja količine poluestera na in vitro prodiranje; u ovom redoslijedu je povišavan udio poluestera od 0 % preko 2,5 % i 5 % na 10 %. Na taj način se povisilo in vitro prodiranje na koži miša od 0,1 preko 0,48 i 0,64 na 0,84 mg/2,54 cm2 x 24 h. Poslije dodavanja poluestera je povećanje in vitro prodiranja približno linearno. Ovo se prikazuje na sljedećoj Slici 3. Examples XIV, XIII, XX and XVIII serve to investigate the influence of the amount of half-ester on in vitro penetration; in this order, the proportion of half-esters was increased from 0% over 2.5% and 5% to 10%. In this way, the in vitro penetration on mouse skin increased from 0.1 over 0.48 and 0.64 to 0.84 mg/2.54 cm2 x 24 h. After the addition of the half-ester, the increase in in vitro penetration is approximately linear. This is shown in the following Figure 3.
Usporedba Primjera X i XI pokazuje, da se kao omekšivač pretpostavlja 1-dodekanol. Ostali Primjeri pokazuju, kako se odnose na in vitro penetraciju polimerni dodaci, budući da je stavljanje ovih tvari potrebno da bi se garantirali stvaranje filma, sila lijepljenja, adhezija i kohezija. A comparison of Examples X and XI shows that 1-dodecanol is assumed as a softener. Other Examples show how polymer additives relate to in vitro penetration, since the addition of these substances is necessary to guarantee film formation, adhesive force, adhesion and cohesion.
Claims (11)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| DE3939376A DE3939376C1 (en) | 1989-11-29 | 1989-11-29 | |
| YU226090A YU47956B (en) | 1989-11-29 | 1990-11-27 | PROCEDURE FOR MAKING A TRANSDERMAL THERAPY SYSTEM WITH BUPRENORPHINE AS THE ACTIVE INGREDIENT |
Publications (2)
| Publication Number | Publication Date |
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| HRP930675A2 true HRP930675A2 (en) | 1994-10-31 |
| HRP930675B1 HRP930675B1 (en) | 1999-10-31 |
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| HRP-2260/90A HRP930675B1 (en) | 1989-11-29 | 1993-04-01 | Process for the preparation of transdermal therapeutic system with buprenorphine as an active substance |
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| 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) |
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| IE (1) | IE73247B1 (en) |
| IL (1) | IL96243A (en) |
| MY (1) | MY105347A (en) |
| NO (1) | NO303107B1 (en) |
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| PL (1) | PL165396B1 (en) |
| PT (1) | PT96028B (en) |
| SI (1) | SI9012260B (en) |
| SK (1) | SK279687B6 (en) |
| YU (1) | YU47956B (en) |
| ZA (1) | ZA909544B (en) |
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| 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 |
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| 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 |
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| 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 |
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| US9656441B2 (en) | 2015-01-08 | 2017-05-23 | Alfred E. Tiefenbacher ( Gmbh & Co. Kg) | Transdermal patch |
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| 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 |
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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
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1993
- 1993-04-01 HR HRP-2260/90A patent/HRP930675B1/en not_active IP Right Cessation
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1996
- 1996-06-06 GR GR960401538T patent/GR3020177T3/en unknown
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