NO178784B - Process for the preparation of a transdermal therapeutic system with norpseudoephedrine as active ingredient - Google Patents
Process for the preparation of a transdermal therapeutic system with norpseudoephedrine as active ingredient Download PDFInfo
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- NO178784B NO178784B NO895173A NO895173A NO178784B NO 178784 B NO178784 B NO 178784B NO 895173 A NO895173 A NO 895173A NO 895173 A NO895173 A NO 895173A NO 178784 B NO178784 B NO 178784B
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- polymer material
- layer
- norpseudoephedrine
- weight
- reservoir layer
- Prior art date
Links
- DLNKOYKMWOXYQA-IONNQARKSA-N cathine Chemical compound C[C@H](N)[C@@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-IONNQARKSA-N 0.000 title claims abstract description 15
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 229960003609 cathine Drugs 0.000 title claims abstract description 14
- 230000001225 therapeutic effect Effects 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 title claims description 11
- 239000004480 active ingredient Substances 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title description 2
- 239000010410 layer Substances 0.000 claims abstract description 30
- 239000013543 active substance Substances 0.000 claims abstract description 19
- 239000011241 protective layer Substances 0.000 claims abstract description 14
- 239000002861 polymer material Substances 0.000 claims abstract description 11
- 239000000853 adhesive Substances 0.000 claims abstract description 7
- 230000001070 adhesive effect Effects 0.000 claims abstract description 7
- 239000004014 plasticizer Substances 0.000 claims description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- -1 glycerol ester Chemical class 0.000 claims description 10
- 229920000642 polymer Polymers 0.000 claims description 9
- 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 8
- 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 8
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 8
- 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 8
- 150000002148 esters Chemical class 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 229920001400 block copolymer Polymers 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- XTJFFFGAUHQWII-UHFFFAOYSA-N Dibutyl adipate Chemical compound CCCCOC(=O)CCCCC(=O)OCCCC XTJFFFGAUHQWII-UHFFFAOYSA-N 0.000 claims description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 2
- 229920002367 Polyisobutene Polymers 0.000 claims description 2
- 150000001298 alcohols Chemical group 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 150000003626 triacylglycerols Chemical class 0.000 claims description 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 claims 2
- MTAZNLWOLGHBHU-UHFFFAOYSA-N butadiene-styrene rubber Chemical compound C=CC=C.C=CC1=CC=CC=C1 MTAZNLWOLGHBHU-UHFFFAOYSA-N 0.000 claims 1
- 239000000470 constituent Substances 0.000 claims 1
- 239000011888 foil Substances 0.000 description 7
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- 230000036765 blood level Effects 0.000 description 4
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229960002179 ephedrine Drugs 0.000 description 3
- 210000004051 gastric juice Anatomy 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 229920000573 polyethylene Polymers 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002313 adhesive film Substances 0.000 description 2
- 239000012790 adhesive layer Substances 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229920005601 base polymer Polymers 0.000 description 2
- 235000019864 coconut oil Nutrition 0.000 description 2
- 239000003240 coconut oil Substances 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 235000003642 hunger Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000011505 plaster Substances 0.000 description 2
- 229920000468 styrene butadiene styrene block copolymer Polymers 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
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 description 1
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229920000298 Cellophane Polymers 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000219823 Medicago Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000002998 adhesive polymer Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229920006317 cationic polymer Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 210000003736 gastrointestinal content Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000005397 methacrylic acid ester group Chemical group 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 235000015816 nutrient absorption Nutrition 0.000 description 1
- 235000006286 nutrient intake Nutrition 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000021962 pH elevation Effects 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920006267 polyester film Polymers 0.000 description 1
- 229920001296 polysiloxane 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
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 229940100640 transdermal system Drugs 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
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Oppfinnelsen vedrører en fremgangsmåte for fremstilling av et transdermalt terapeutisk system som inneholder norpseudoefedrin som aktiv bestanddel. The invention relates to a method for producing a transdermal therapeutic system containing norpseudoephedrine as active ingredient.
Den kjemiske gruppen amfetaminene, hvortil hører mange antiadiposita, ble oppdaget allerede i 30-årene, men først forordnet som middel mot tretthet. Først senere erkjente man at disse legemidlene har enda en annen terapeutisk nyttbar effekt - de reduserer sultfølelsen. Ved målrettet legemiddel-syntese lyktes det å utvikle substanser, hvorved reduksjonen av sultfølelsen kommer i forgrunnen, mens de stimulerende komponentene blir lagret i bakgrunnen. Dessuten må ved an-vendelser av antiadiposita av denne typen tas hensyn til følgende synspunkter: - De må ikke kombineres med visse andre medikamenter (og ikke med alkohol). The chemical group amphetamines, to which many anti-adipocytes belong, was discovered as early as the 1930s, but was first prescribed as a remedy for fatigue. Only later was it recognized that these drugs have yet another therapeutically useful effect - they reduce the feeling of hunger. Through targeted drug synthesis, it was possible to develop substances, whereby the reduction of the feeling of hunger comes to the fore, while the stimulating components are stored in the background. In addition, the following points of view must be taken into account when using anti-adiposity drugs of this type: - They must not be combined with certain other drugs (and not with alcohol).
Man må være på vakt mot at det utvikler seg tilvenning You have to be on guard against the development of habituation
og mot faren for sykelig begjær. and against the danger of morbid desire.
Intravenøse injeksjoner må unngås på grunn av fåren for induksjon av blodspeiltopper. Intravenous injections must be avoided because of the risk of inducing blood count peaks.
Lovgivere og farmasøytisk industri tar hensyn på samme måte, idet for det første flytende legemiddelformer er under-lagt reseptplikt, mens de faste legemidlene tilhører OTC-sektoren; for det andre imidlertid også ved utvikling av orale depotformer som senker doseringen av antiadiposita, men hvis blodspeil kan holdes konstant. Da i senere tid den tesen fremholdes blant medisinere at legemiddelformen bidrar til avhengighetsforhold av et virkestoff (et konstant blodspeil er betydelig gunstigere enn den raske vekslingen av blodspeiltopper med overdose til tidsintervaller med under-forsyning), ligger det nær å utvikle slike retardformer som enda bedre enn orale depotformer oppnår et konstant konsen-trasjonsnivå. For selv om de vanlige orale depotformene er galenisk-teknologiske mesterverk, som under in vitro-betingelser, dvs. i den kunstige mage- resp. tarmsaften oppnår optimale frigjøringsprofiler, kan de allikevel ikke garantere noe konstant blodspeil, da farmakoreserpsjonen fra gastrointestinaltrakten blir avgjørende påvirket av mage-uttømmingstiden, som ved næringsopptak blir forsinket av-hengig av volumet og av næringssammensetningen. Dessuten forekommer det ved næringsopptak pH-verdiforskyvninger i magen og ved innblandingen av magesaften med matvellingen en reduksjon av diffusjonsvirksomme gradienter. Betydningen av pH-verdibetingelsene i magen for den gastrale reserpsjonen understrekes også ved undersøkelser, hvorved magesaften ble alkalisert. Således ble det påvist i dyreforsøk at etter alkalisering av mageinnholdet med NaHC03 til pH: 8,0, blir resorpsjonen fra magen ved svake syrer redusert tilsvarende deres pKa-verdi, og ved svake baser forhøyet. Da amfetaminene er middels sterke baser (pka-verdi for D-norpseudoefedrin: 8,9), er effekten av den pH-verdiavhengige resorpsjonen riktignok ikke sterkt utpreget, men på ingen måte neglisjer-bar. Legislators and the pharmaceutical industry take account in the same way, as, firstly, liquid medicinal forms are subject to a prescription, while the solid medicinals belong to the OTC sector; secondly, however, also through the development of oral depot forms that lower the dosage of anti-adiposity, but whose blood levels can be kept constant. Since in recent times the thesis has been advanced among medics that the pharmaceutical form contributes to dependence on an active substance (a constant blood level is significantly more favorable than the rapid alternation of blood level peaks with overdose to time intervals with under-supply), it is close to developing such retarded forms that are even better than oral depot forms achieve a constant concentration level. Because even though the usual oral depot forms are Galenic-technological masterpieces, which under in vitro conditions, i.e. in the artificial stomach or the intestinal juice achieves optimal release profiles, they still cannot guarantee a constant blood level, as the pharmacoresorption from the gastrointestinal tract is decisively affected by the gastric emptying time, which is delayed during nutrient absorption depending on the volume and the nutrient composition. In addition, there are pH value shifts in the stomach during nutrient intake and when the gastric juice is mixed with the food gruel, there is a reduction in diffusion-active gradients. The importance of the pH value conditions in the stomach for the gastric resorption is also emphasized by investigations, whereby the gastric juice was alkalized. Thus, it was demonstrated in animal experiments that after alkalinization of the stomach contents with NaHC03 to pH: 8.0, the absorption from the stomach of weak acids is reduced corresponding to their pKa value, and of weak bases is increased. As the amphetamines are medium strong bases (pka value for D-norpseudoephedrine: 8.9), the effect of the pH value-dependent resorption is admittedly not strongly pronounced, but by no means negligible.
For å oppnå en mest mulig konstant virkestoffkonsentra-sjon egner seg innsatsen av såkalte terapeutiske systemer som er definert som en legemiddelholdig anordning, resp. en av-givelsesform som avgir et legemiddel eller flere med forut-bestemt hastighet kontinuerlig i løpet av et fastlagt tidsrom på et bestemt anvendelsessted (se Heilmann, "Therapeutische Systeme", 4. opplag, Enke Verlag Stuttgart 1984, s. 26). Et oralt terapeutisk system, som beskrevet eksempelvis i EP 0 237 159, er imidlertid ingen løsning av det beskrevne pro-blem, da middels sterke baser løser seg bedre i den sure magesaften enn i den nøytrale. Derved blir frigjøringen pH-verdiavhengig. In order to achieve the most possible constant active substance concentration, the use of so-called therapeutic systems which are defined as a drug-containing device, resp. a delivery form which releases one or more drugs at a predetermined rate continuously during a determined period of time at a determined site of application (see Heilmann, "Therapeutische Systeme", 4th edition, Enke Verlag Stuttgart 1984, p. 26). An oral therapeutic system, as described for example in EP 0 237 159, is not, however, a solution to the described problem, as moderately strong bases dissolve better in the acidic gastric juice than in the neutral one. Thereby, the release becomes pH value-dependent.
I US-PS 4 292 301 er allerede beskrevet den transdermale administrering av efedrin fra en ikke-klebende polymermatriks, dog tilkommer efedrinen bare en svak virkning som antiadipositum. In US-PS 4 292 301, the transdermal administration of ephedrine from a non-adhesive polymer matrix has already been described, although the ephedrine only has a weak effect as an anti-adipose.
I EP 0 195 643 A3 beskrives fremstilling av et transdermalt plaster som kan inneholde pseudoefedrin. Bærermassen består av over 10% polymer, f.eks. av en kationisk polymer, så som amberlitt, samt en gelerende Zellulosepolymer. Det fremstilles en transdermal anordning med baksjikt og beskyttelsessjikt. EP 0 195 643 A3 describes the production of a transdermal patch which can contain pseudoephedrine. The carrier mass consists of more than 10% polymer, e.g. of a cationic polymer, such as amberlite, as well as a gelling cellulose polymer. A transdermal device with a back layer and a protective layer is produced.
I EP 0 261 402 Al beskrives et transdermalt system på basis av akrylatpolymerer. Systemet kan f.eks. inneholde efedrin. Tilberedningen fremstilles ved å løse opp innholds-stoffene, og omfatter et beskyttelsessjikt og et baksjikt. EP 0 261 402 Al describes a transdermal system based on acrylate polymers. The system can e.g. contain ephedrine. The preparation is made by dissolving the ingredients, and comprises a protective layer and a backing layer.
Det er derfor en oppgave for oppfinnelsen å tilveie-bringe norpseudoefedrin som antiadipositum resp. et middel i en form, hvori sammenlignet med de orale depotformene blir oppnådd et svært forbedret konstant virkestoffspeil, for dermed å overvinne ulempene ved teknikkens stand. It is therefore a task for the invention to provide norpseudoephedrine as an anti-adipose or a remedy in a form, in which, compared to the oral depot forms, a much improved constant active substance level is achieved, in order to overcome the disadvantages of the state of the art.
Denne oppgaven løses ifølge oppfinnelsen på overraskende måte ved at det tilveiebringes et transdermalt terapeutisk system for administrering av et antiadipositum til huden fra et virkestoffugjennomtrengelig baksjikt, et reservoarsjikt og eventuelt et gjenavtagbart beskyttelsessjikt, hvor reservoarsjiktet er fastklebende og inneholder 10-90 vektprosent polymermateriale, 0-30 vektprosent mykner og 0,1-20 vektprosent norpseudoefedrin. According to the invention, this task is solved in a surprising way by providing a transdermal therapeutic system for administering an anti-adipose agent to the skin from an active substance impermeable back layer, a reservoir layer and possibly a removable protective layer, where the reservoir layer is adhesive and contains 10-90 percent by weight polymer material, 0- 30 weight percent plasticizer and 0.1-20 weight percent norpseudoephedrine.
Denne løsningen er desto mer overraskende, ettersom norpseudoefedrin må appliseres i dagsdoser som ved transdermale systemer vanligvis ikke kan oppnås i akseptable mengder. This solution is all the more surprising, as norpseudoephedrine must be applied in daily doses which, with transdermal systems, cannot usually be achieved in acceptable amounts.
Gjenstand for oppfinnelsen er en fremgangsmåte for fremstilling av et transdermalt terapeutisk system for administrering av et antiadipositum som virkestoff til huden, bestående av et virkestoffugjennomtrengelig baksjikt, et reservoarsjikt og eventuelt et gjenavtagbart beskyttelsessj ikt, karakterisert ved at norpseudoefedrin i løsning blandes homogent med bestanddelene i reservoarsjiktet, at blandingen påføres det virkestoffugjennomtrengelige baksjiktet, løsningsmidlet fjernes, og deretter påføres et beskyttelsessjikt på reservoarsjiktet, hvorved reservoarsjiktet er fastklebende og inneholder 10-90 vektprosent polymermateriale, opptil 30 vektprosent mykner og 0,1-20 vektprosent norpseudoefedrin, idet polymermaterialet velges fra gruppen bestående av blokk-kopolymerer på basis av styren og 1,3-diener, polyisobutylener, polymerer på akrylat- og/eller metakrylatbasis og estere av hydrogenert kolofonium, og myknere velges fra gruppen bestående av vicinale alkoholer og estere. The object of the invention is a method for the production of a transdermal therapeutic system for administering an anti-adipose as an active substance to the skin, consisting of an active substance impermeable back layer, a reservoir layer and possibly a removable protective layer, characterized in that norpseudoephedrine in solution is mixed homogeneously with the components in the reservoir layer , that the mixture is applied to the active substance impermeable back layer, the solvent is removed, and then a protective layer is applied to the reservoir layer, whereby the reservoir layer is adhesive and contains 10-90 weight percent polymer material, up to 30 weight percent plasticizer and 0.1-20 weight percent norpseudoephedrine, the polymer material being selected from the group consisting of of block copolymers based on styrene and 1,3-dienes, polyisobutylenes, polymers based on acrylate and/or methacrylate and esters of hydrogenated rosin, and plasticizers are selected from the group consisting of vicinal alcohols and esters.
En bærer for anvendelse ved transdermal administrering av et antiadipositum består av et virkestoffugjennomtrengelig baksjikt, et fastklebende sjikt som er egnet til opptak av et virkestoff, såvel som eventuelt et gjenavtagbart beskyttelsessjikt, hvor reservoarsjiktet er fastklebende og inneholder 50-100 vektprosent polymermateriale, såvel som 0-50 vektprosent mykner. A carrier for use in transdermal administration of an anti-adipose agent consists of an active substance impermeable back layer, an adhesive layer which is suitable for absorption of an active substance, as well as possibly a removable protective layer, where the reservoir layer is adhesive and contains 50-100 percent by weight of polymer material, as well as 0 -50 weight percent plasticizer.
Derved kan det virkestoffugjennomtrengelige baksjikt bestå av fleksibelt eller ikke-fleksibelt materiale. Substanser som kan anvendes til dets fremstilling er polymer-folier eller metallfolier, som aluminiumfolie som blir anvendt alene eller besjiktet med et polymert substrat. Det kan også anvendes flate tekstilformer når bestanddelene i reservoaret ikke kan trenge igjennom dem på grunn av deres fysikalske egenskaper. Ved en foretrukket utførelsesform er baksjiktet et sammensatt stoff av en folie som er pådampet aluminium. Thereby, the active substance impermeable back layer can consist of flexible or non-flexible material. Substances that can be used for its production are polymer foils or metal foils, such as aluminum foil which is used alone or coated with a polymeric substrate. Flat textile forms can also be used when the components in the reservoir cannot penetrate them due to their physical properties. In a preferred embodiment, the back layer is a composite material of a foil that has been vaporized aluminum.
Reservoarsjiktet består av en polymermatriks og virkestoffet, hvorved polymermatriksen har den egenskapen at den sørger for samholdet i systemet. Den består av en grunn-polymer og eventuelt de vanlige tilsetningene. Valget av grunnpolymeren retter seg etter de kjemiske og fysikalske egenskapene av det anvendte virkestoffet. Av blokk-kopoly-merene på basis av styren og 1,3-diener anvendes ganske spesielt lineære styren-isopren-blokk-kopolymerer. The reservoir layer consists of a polymer matrix and the active substance, whereby the polymer matrix has the property that it ensures the cohesion of the system. It consists of a base polymer and possibly the usual additives. The choice of the base polymer is based on the chemical and physical properties of the active substance used. Of the block copolymers based on styrene and 1,3-diene, linear styrene-isoprene block copolymers are particularly used.
Som polymerer på akrylatbasis foretrekkes akrylat-kopolymerer av 2-etylheksylakrylat, vinylacetat og akrylsyre med, resp. uten titanchelatester. Som metakrylater foretrekkes kopolymerer på basis av dimetylaminoetylmetakrylat og nøytrale metakrylsyreestere. Som estere av hydrert kolofonium anvendes fortrinnsvis spesielt dennes metyl- og glycerolester. As acrylate-based polymers, acrylate copolymers of 2-ethylhexyl acrylate, vinyl acetate and acrylic acid with, resp. without titanium chelates. As methacrylates, copolymers based on dimethylaminoethyl methacrylate and neutral methacrylic acid esters are preferred. As esters of hydrated rosin, its methyl and glycerol esters are preferably used in particular.
Typen av de mulige tilsetningene avhenger av den anvendte polymeren og virkestoffet. Etter sin funksjon lar de seg inndele i myknere, klebehjelpemidler, stabilisatorer, bærestoffer for diffusjons- og penetrasjonsregulerende til-setninger eller fyllstoffer. De fysiologisk ufarlige stoffene som kommer på tale for dette, er kjent for fagmannen. Reservoarsjiktet har en slik egenklebrighet at det er sikret varig kontakt med huden. The type of possible additives depends on the polymer used and the active ingredient. According to their function, they can be divided into plasticizers, adhesive aids, stabilizers, carriers for diffusion and penetration regulating additives or fillers. The physiologically harmless substances that come into question for this are known to the person skilled in the art. The reservoir layer has such an inherent stickiness that permanent contact with the skin is ensured.
Som eksempler på egnede myknere er å nevne diestere av dikarboksylsyrer, f.eks.a di-n-butyladipat, såvel som triglycerider, spesielt kapryl/kaprinsyrens triglycerider med midlere kjedelengde fra kokosolje. Ytterligere eksempler på en egnet mykner er glycerol, propandiol (1,2) og andre. Examples of suitable plasticizers include diesters of dicarboxylic acids, e.g. di-n-butyl adipate, as well as triglycerides, especially caprylic/capric acid triglycerides with medium chain length from coconut oil. Further examples of a suitable plasticizer are glycerol, propanediol (1,2) and others.
Det avtagbare beskyttelsessjiktet som er i berøring med reservoarsjiktet og som blir fjernet før anvendelsen, består eksempelvis av de samme materialene som ble anvendt ved fremstilling av baksjiktet, forutsatt at det gjøres avtagbart, som f.eks. ved en silikonbehandling. Andre avtagbare beskyttelsessj ikt er f.eks. polytetrafluoretylen, behandlet papir, cellofan, polyvinylklorid og andre. Dersom laminatet ifølge oppfinnelsen blir oppdelt i terapiriktige formater (plaster) før påføringen av beskyttelsessjiktet, så kan de beskyttelsessjiktformatene som da skal påføres, ha en utover-gående ende, ved hvis hjelp de lettere kan trekkes av fra plasteret. The removable protective layer which is in contact with the reservoir layer and which is removed before use, for example consists of the same materials that were used in the production of the back layer, provided that it is made removable, such as e.g. by a silicone treatment. Other removable protective layers are e.g. polytetrafluoroethylene, treated paper, cellophane, polyvinyl chloride and others. If the laminate according to the invention is divided into therapy-appropriate formats (plasters) before the application of the protective layer, then the protective layer formats that are then to be applied can have an outward-protruding end, with the help of which they can be more easily pulled off from the plaster.
Som antiadipositum anvendes ifølge oppfinnelsen norpseudoefedrin, da det har det minste avhengighets-potensiale av alle antiadiposita. According to the invention, norpseudoephedrine is used as anti-adiposit, as it has the least addiction potential of all anti-adiposits.
Det transdermale terapeutiske systemet ifølge oppfinnelsen fremstilles idet virkestoffet sammenblandes homogent, eventuelt i løsning, med bestanddelene i det fastklebende reservoarsjiktet og påføres på det virkestoffugjennomtrengelige baksjiktet, hvorpå eventuelt løsemidlet eller løsemidlene blir fjernet. Deretter forsynes klebe-sjiktet med et tilsvarende beskyttelsessjikt. The transdermal therapeutic system according to the invention is produced by mixing the active substance homogeneously, possibly in solution, with the components in the adhesive reservoir layer and applying it 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.
Oppfinnelsen belyses ved følgende eksempler: The invention is illustrated by the following examples:
Reseptureksempel l: Prescription example l:
4,3 g n-heptan og 15,7 g butanon blandes sammen. Deri løses 4,0 g norpseudoefedrin, fri base. Etter fullstendig oppløsning av virkestoffet tilsetter man porsjonsvis 23,5 g av en glycerolester av fullstendig hydrert kolofonium, 15,5 g av en lineær styren-butadien-styren-blokk-kopolymer, 3,9 g metylester av hydrert kolofonium og 3,1 g av kapryl/kaprin-syrens triglycerider fra kokosolje ("triglycerider med midlere kjedelengde" DAB 8). Under utelukkelse av lys rører man til fullstendig oppløsning (ca. 8 timer) og stryker ut den oppnådde løsningen med en 3 00 ^m avstrykningskniv på en aluminisert og silikonisert polyetylenfolie. 4.3 g of n-heptane and 15.7 g of butanone are mixed together. 4.0 g of norpseudoephedrine, free base, are dissolved in it. After complete dissolution of the active ingredient, 23.5 g of a glycerol ester of fully hydrated rosin, 15.5 g of a linear styrene-butadiene-styrene block copolymer, 3.9 g of methyl ester of hydrated rosin and 3.1 g are added in portions of caprylic/capric acid triglycerides from coconut oil ("medium chain triglycerides" DAB 8). Under the exclusion of light, the mixture is stirred until complete dissolution (approx. 8 hours) and the resulting solution is spread with a 300 µm spreader knife on an aluminized and siliconized polyethylene foil.
Etter at løsningsmidlet er blitt fjernet ved 25 minutters tørking ved 50°C i tørkekanal, tildekker man klebefilmen med en polyesterfolie på 15 ^m. Med egnet skjæreverktøy stanser man ut plater på 16 cm<2>, resp. 50 cm<2>, og fjerner kantene ved avgitring. Frigjøringskurvene in vitro er gjengitt i fig. 1. De viser den kontrollerte frigjøringen av virkestoffet fra et 16 cm<2> plaster i fysiologisk koksalt-løsning. Dessuten ble et 50 cm2 plaster båret av en frisk frivillig i 12 timer, hvilket plaster inneholdt 52 mg norpseudoefedrin ved en flatevekt på 130 g/m<2>. Etter fjernin-gen av systemet ble restinnholdet i plasteret bestemt til ca. 17 mg, slik at ca. 35 mg/50 cm2 har diffundert gjennom den menneskelige hud i løpet av 12 timer. After the solvent has been removed by drying for 25 minutes at 50°C in a drying channel, the adhesive film is covered with a polyester film of 15 µm. With a suitable cutting tool, you punch out sheets of 16 cm<2>, resp. 50 cm<2>, and removes the edges by de-gridding. The release curves in vitro are reproduced in fig. 1. They show the controlled release of the active substance from a 16 cm<2> plaster in physiological saline solution. In addition, a 50 cm2 patch was worn by a healthy volunteer for 12 hours, which patch contained 52 mg of norpseudoephedrine at a basis weight of 130 g/m<2>. After the removal of the system, the residual content of the patch was determined to be approx. 17 mg, so that approx. 35 mg/50 cm2 has diffused through the human skin within 12 hours.
Dermed overskrides den verdi som kreves terapeutisk. Thus, the value required therapeutically is exceeded.
Reseptureksempel 2: Recipe example 2:
25 g butanon og 15 g etylacetat blandes sammen. Deri løses 10,0 g norpseudoefedrin, fri base. Etter fullstendig oppløsning av virkestoffet tilsetter man porsjonsvis 17,5 g av en glycerolester av fullstendig hydrert kolofonium og 22,5 g av en lineær styren-butadien-styren-blokk-kopolymer. Under utelukkelse av lys rører man til fullstendig oppløsning (ca. 8 timer) og stryker ut den oppnådde løsningen med en 350 /im avstrykningskniv på en aluminisert og silikonisert polyetylenfolie (tykkelse: 100 jum) . 25 g of butanone and 15 g of ethyl acetate are mixed together. 10.0 g of norpseudoephedrine, free base, are dissolved in it. After complete dissolution of the active ingredient, 17.5 g of a glycerol ester of fully hydrated rosin and 22.5 g of a linear styrene-butadiene-styrene block copolymer are added in portions. Under the exclusion of light, the mixture is stirred until complete dissolution (approx. 8 hours) and the resulting solution is spread with a 350 µm scraper knife on an aluminized and siliconized polyethylene foil (thickness: 100 µm).
Etter at løsningsmidlet er blitt fjernet ved 25 minutters tørking ved 50°C i tørkekanal, belegger man klebefilmen med en polyetylenfolie (tykkelse: 15 nm). Med egnet skjæreverktøy stanser man ut flater på 16 cm<2> og fjerner kantene ved avgitring. Frigjøringskurven in vitro er gjengitt i fig. 2. Den viser den kontrollerte frigjøringen av virkestoffet fra et 16 cm<2> plaster i fysiologisk koksalt-løsning. Dessuten ble in vitro-penetrasjonen på eksidert musehud bestemt. Den er 9,8 mg/16 cm<2> x 24 timer og ligger derved, uten myknertilsetning, i samme størrelsesorden som reseptureksempel 1. After the solvent has been removed by drying for 25 minutes at 50°C in a drying channel, the adhesive film is coated with a polyethylene foil (thickness: 15 nm). With a suitable cutting tool, you punch out surfaces of 16 cm<2> and remove the edges by netting. The release curve in vitro is reproduced in fig. 2. It shows the controlled release of the active substance from a 16 cm<2> patch in physiological saline solution. Moreover, the in vitro penetration on excised mouse skin was determined. It is 9.8 mg/16 cm<2> x 24 hours and is therefore, without plasticizer addition, in the same order of magnitude as recipe example 1.
Claims (9)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3843237A DE3843237A1 (en) | 1988-12-22 | 1988-12-22 | TRANSDERMAL THERAPEUTIC SYSTEM WITH AN ANTIADIPOSITUM AS AN ACTIVE INGREDIENT |
Publications (4)
| Publication Number | Publication Date |
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| NO895173D0 NO895173D0 (en) | 1989-12-21 |
| NO895173L NO895173L (en) | 1990-06-25 |
| NO178784B true NO178784B (en) | 1996-02-26 |
| NO178784C NO178784C (en) | 1996-06-05 |
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| NO895173A NO178784C (en) | 1988-12-22 | 1989-12-21 | Process for the preparation of a transdermal therapeutic system with norpseudoephedrine as active ingredient |
Country Status (23)
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| EP (1) | EP0374725B1 (en) |
| JP (1) | JP2602108B2 (en) |
| KR (1) | KR950015055B1 (en) |
| AT (1) | ATE93147T1 (en) |
| AU (1) | AU614208B2 (en) |
| CA (1) | CA2006425C (en) |
| CS (1) | CS8907193A3 (en) |
| DD (1) | DD290581A5 (en) |
| DE (2) | DE3843237A1 (en) |
| DK (1) | DK651089A (en) |
| ES (1) | ES2045369T3 (en) |
| FI (1) | FI95772C (en) |
| HU (1) | HU203280B (en) |
| IE (1) | IE63878B1 (en) |
| IL (1) | IL92678A (en) |
| MY (1) | MY105074A (en) |
| NO (1) | NO178784C (en) |
| NZ (1) | NZ231909A (en) |
| PH (1) | PH25854A (en) |
| PL (1) | PL163292B1 (en) |
| PT (1) | PT92650B (en) |
| YU (1) | YU47075B (en) |
| ZA (1) | ZA899879B (en) |
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| DE3939376C1 (en) * | 1989-11-29 | 1991-05-08 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg, 5450 Neuwied, De | |
| DE4342893C2 (en) * | 1993-12-16 | 1999-09-23 | Lohmann Gmbh & Co Kg | Reversible adhesive, residue-free removable pressure sensitive adhesive, process for its production and use as re-adhesive pressure sensitive adhesive articles |
| US6719997B2 (en) | 2000-06-30 | 2004-04-13 | Dermatrends, Inc. | Transdermal administration of pharmacologically active amines using hydroxide-releasing agents as permeation enhancers |
| US6673363B2 (en) | 1999-12-16 | 2004-01-06 | Dermatrends, Inc. | Transdermal and topical administration of local anesthetic agents using basic enhancers |
| US6602912B2 (en) | 2000-06-30 | 2003-08-05 | Dermatrends, Inc. | Transdermal administration of phenylpropanolamine |
| EP1239846A2 (en) * | 1999-12-16 | 2002-09-18 | Dermatrends, Inc. | Transdermal administration of phenylpropanolamine |
| KR100956865B1 (en) * | 2009-08-10 | 2010-05-11 | 주식회사 라이트론 | Slide pressure packing type linear lighting apparatus |
| EP3532037A4 (en) * | 2016-10-31 | 2020-10-21 | The Corporation Of Mercer University | Transdermal delivery of phenethylamine monoamine releasers |
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|---|---|---|---|---|
| US4291015A (en) * | 1979-08-14 | 1981-09-22 | Key Pharmaceuticals, Inc. | Polymeric diffusion matrix containing a vasodilator |
| JPS57116011A (en) * | 1981-01-08 | 1982-07-19 | Nitto Electric Ind Co Ltd | Pharmaceutical preparation |
| ATE42901T1 (en) * | 1984-03-05 | 1989-05-15 | Nitto Denko Corp | ADHESIVE MEDICATION FOR PERCUTANEOUS ABSORPTION. |
| JPS60185713A (en) * | 1984-03-05 | 1985-09-21 | Nitto Electric Ind Co Ltd | Percutaneous preparation and its production |
| US4692462A (en) * | 1985-03-18 | 1987-09-08 | Menley & James Laboratories, Ltd. | Compositions and method of controlling transdermal penetration of topical and systemic agents |
| DE3629304A1 (en) * | 1986-08-28 | 1988-03-24 | Lohmann Gmbh & Co Kg | TRANSDERMAL THERAPEUTIC SYSTEM, ITS USE AND METHOD FOR THE PRODUCTION THEREOF |
| DE3743945A1 (en) * | 1987-09-01 | 1989-03-09 | Lohmann Gmbh & Co Kg | DEVICE FOR DELIVERING SUBSTANCES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
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1988
- 1988-12-22 DE DE3843237A patent/DE3843237A1/en active Granted
-
1989
- 1989-12-13 IL IL9267889A patent/IL92678A/en not_active IP Right Cessation
- 1989-12-14 EP EP89123091A patent/EP0374725B1/en not_active Expired - Lifetime
- 1989-12-14 DE DE8989123091T patent/DE58905320D1/en not_active Expired - Fee Related
- 1989-12-14 MY MYPI89001760A patent/MY105074A/en unknown
- 1989-12-14 ES ES89123091T patent/ES2045369T3/en not_active Expired - Lifetime
- 1989-12-14 AT AT89123091T patent/ATE93147T1/en not_active IP Right Cessation
- 1989-12-18 AU AU46843/89A patent/AU614208B2/en not_active Ceased
- 1989-12-19 CS CS897193A patent/CS8907193A3/en unknown
- 1989-12-19 YU YU240589A patent/YU47075B/en unknown
- 1989-12-19 FI FI896097A patent/FI95772C/en not_active IP Right Cessation
- 1989-12-19 IE IE407789A patent/IE63878B1/en not_active IP Right Cessation
- 1989-12-20 PH PH39752A patent/PH25854A/en unknown
- 1989-12-20 NZ NZ231909A patent/NZ231909A/en unknown
- 1989-12-20 DK DK651089A patent/DK651089A/en not_active Application Discontinuation
- 1989-12-21 PT PT92650A patent/PT92650B/en not_active IP Right Cessation
- 1989-12-21 ZA ZA899879A patent/ZA899879B/en unknown
- 1989-12-21 NO NO895173A patent/NO178784C/en unknown
- 1989-12-21 CA CA002006425A patent/CA2006425C/en not_active Expired - Fee Related
- 1989-12-21 DD DD89336084A patent/DD290581A5/en not_active IP Right Cessation
- 1989-12-21 HU HU896721A patent/HU203280B/en not_active IP Right Cessation
- 1989-12-22 JP JP1331442A patent/JP2602108B2/en not_active Expired - Lifetime
- 1989-12-22 KR KR1019890019229A patent/KR950015055B1/en not_active IP Right Cessation
- 1989-12-22 PL PL89282948A patent/PL163292B1/en unknown
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