NO311783B1 - Transdermalt terapeutisk system for frigjöring av 17-<beta>- östradiol og fremgangsmåte for fremstilling derav - Google Patents
Transdermalt terapeutisk system for frigjöring av 17-<beta>- östradiol og fremgangsmåte for fremstilling derav Download PDFInfo
- Publication number
- NO311783B1 NO311783B1 NO19951765A NO951765A NO311783B1 NO 311783 B1 NO311783 B1 NO 311783B1 NO 19951765 A NO19951765 A NO 19951765A NO 951765 A NO951765 A NO 951765A NO 311783 B1 NO311783 B1 NO 311783B1
- Authority
- NO
- Norway
- Prior art keywords
- estradiol
- relative humidity
- therapeutic system
- transdermal therapeutic
- equilibrium
- Prior art date
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Classifications
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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- A—HUMAN NECESSITIES
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- 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
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- 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
- A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
-
- 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
- A61K9/7092—Transdermal patches having multiple drug layers or reservoirs, e.g. for obtaining a specific release pattern, or for combining different drugs
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Description
Denne oppfinnelse vedrører et transdermalt terapeutisk system for frigjøring av 17-Ii-østradiol og eventuelt ytterli--gere virkestoffer gjennom huden på det menneskelige legemet.
Transdermale terapeutiske systemer (TTS) er allerede innført i markedet for legemiddelterapien av en rekke sykdom-mer. Også TTS med virkestoffet 17-Ii-østradiol har i mellomti-den oppnådd gode resultater i handelen og i terapien som terapeutikum for klimakteriumplager, i senere tid også mot osteoporose. Systemene beskrevet i EP 0 421 454 inneholder østradiol i en vannsvellbar akrylatpolymer under tilsetning av "krystallisasjonshemmere" og klebriggjørende harpikser. Påvirkningen av løseligheten av østradiol gjennom forskjellig vanndamptrykk ble imidlertid ikke erkjent, og følgelig finnes det heller ikke noen resept for den korrekte innstilling av konsentrasjonen av østradiol.
En ulempe ved de kjente systemene er nødvendigheten av å måtte anvende såkalte "enhancere". Det dreier seg her i regelen om flytende tilsetningsstoffer som forbedrer resorp-sjonsegenskapene til den menneskelige hud, og dermed også muliggjør opptaket av virkestoffet østradiol fra en tilstrekkelig liten TTS-flate. Særlig de lett flyktige enhancere som den i tilfellet østradiol regelmessig anvendte etanol fører til problemer med> den altfor sterke oppmykning av klebesjikt-ene i TTS, og gjør det fremfor alt nødvendig med ytterligere plasskrevende rom i systemet, hvilket fører til at TTS får uakseptabelt store flater, hhv. uakseptabel tykkelse.
Under tilsetning av bestemte mindre flyktige, for det meste også mindre aktive enhancere er det allikevel mulig å fremstille matrikssystemer som inneholder virkestoffet og de resorpsjonsforsterkende komponenter i ett eller noen få mono-littiske sjikt. US 4.863.738 er således et eksempel blant flere, hvori det gjøres krav på påføring av virkestoffer, f.eks. østradiol sammen med en bestemt enhancer (her glycerolmonooleat) i en vilkårlig TTS-matriks i vilkårlig konsentra-sjon. Imidlertid er det ifølge teknikkens stand heller ikke med slike TTS mulig å oppnå noen tilfredsstillende terapi, da enten de utvalgte enhancere er for dårlig forlikelige med huden eller TTS-systemene pga. den fremdeles altfor svake strømning gjennom huden må ha uakseptabelt store flater. Et ytterligere problem er det faktum at tallrike reseptur-varianter av slike systemer har tendens til omkrystallisering av tilsynelatende uforutsigbare årsaker, og derved taper en stor del av sin terapeutiske aktivitet.
Konsentrasjonsangivelser tilsvarende teknikkens stand finnes f.eks. i GB 2 138 286 (mellom 0,01% østradiol og met-ningsløseligheten i løsningsmidlet), i EP 0 421 454 (0,5% til 10% i polymeren) eller i BE 899 444 (mellom 20% og metning).
Følgelig er det oppgaven for denne oppfinnelse å tilvei-ebringe et akseptabelt tynt og med hensyn til flaten lite TTS, som ikke inneholder noen lettflyktige enhancere, i løpet av lagringstiden ikke lider noen aktivtetstap ved omkrystallisering og allikevel har en høy strømningshastighet med hensyn på flaten (mg/cm<2>/time) på huden.
Denne oppgave løses ifølge oppfinnelsen ved et transdermalt terapeutisk system, inneholdende virkestoffet 17-15-østradiol og eventuelt ytterligere'virkestoffer, med sjiktvis oppbygging av et i alt vesentlig fuktighetsugjennomtrengelig baksjikt, ett eller flere matrikssjikt og eventuelt et klebesjikt, ved at konsentrasjonen av den løste østradiol i alle matrikssjikt og eventuelt i klebesjiktet ligger mellom sin metningskonsentrasjon i tørr tilstand og sin metnings-konsentras j on i fuktig tilstand, hvorved med begrepet "tørr tilstand" skal forstås at grunnmaterialet står i likevekt med en gassfase med mindre enn 10% relativ luftfuktighet og med begrepet "fuktig tilstand" at grunnmaterialet står i likevekt med en gassfase med mer enn 90% relativ luftfuktighet.
Ytterligere verdifulle egenskaper for det transdermale terapeutiske system gir seg gjennom dettes utforming tilsvarende underkravene, hvorved det i løpet av lagringen fordelaktig har en likevektsfuktighet inntil 40% relativ luftfuktighet. Derved har overraskende alle matrikssjikt og ved tilstedeværelse av et klebesjikt også dette i fuktighetslikevekt med inntil 10% relativ luftfuktighet en minst 50% høyere løselig-het for virkestoffet 17-li-østradiol, enn i fuktighetslikevekt med minst 90% relativ luftfuktighet. Det er fordelaktig når - alle matrikssjikt og ved tilstedeværelse av et klebesjikt at disse består av en akrylsyreesterkopolymer med en løselighet for virkestoffet 17-Ii-østradiol mellom 0,2 og 2,0 (g/g), bestemt i fuktighetslikevekt med 10% relativ luftfuktighet. Hensiktsmessig vil ett eller flere av matrikssjiktene eller ved tilstedeværelse av et klebesjikt også dette inneholde ett eller flere stoffer fra gruppen av klebemidler, hudgjennomtrengningsforbedrende tilsetninger, fyllstoffer, løselighets-forbedringsmidler eller tilsetningsstoffer svellbare i vann.-Derved kan det alltid i ett eller flere sjikt av matriksen og/eller i et klebesjikt inneholdes følgende komponenter: Som bestanddel av hefteklebmidlet klebriggjørende harpikser som kolofonium og dets derivater, polyterpenharpikser fra a- eller ft-pinen, alifatiske, aromatiske eller alkylaromatiske hydrokarbonharpikser, melamin-formaldehyd-harpikser, fenol-harpikser, hydroabietylalkohol og deres blandinger.
Som fyllstoffer karbonater, fosfater, silikater, sulfater og oksyder av jordalkalimetallene, sinkoksyd, silisiumoksyder, cellulose og dens derivater, talkum eller titandioksyd, men også tungtløselige sukker (-derivater), som f.eks. laktose eller stivelsesderivater som cyklodekstrin.
Som løselighetsforbedrende tilsetninger hhv. hudgjennom-trengningsforbedringsmidler acetylaceton, acetyltributyl-citrat, acetyltrietylcitrat, avokadoolje, bomullsfrøolje, benzylalkohol, butylstearat, cetyllaktat, cetylpalmitat, cetylstearat, cetylstearylalkohol/cetylalkohol, klorbutanol, cineol, decylmetylsulfoksyd, decyloleat, dibutylftalat, di-etylenglykolmonoetyleter, dietylftalat, dietylsebacat, di-isopropyladipat, dimetylftalat, dimetylsulfoksyd, dioktyl-adipat, dipropylenglykol, glycerolmonooleat, glycerolmono-stearat, stearylalkohol, jordnøttolje, etyllaktat, etyl-linolat, etyl-(9,12,15)-linolenat, eugenol, farnesol, gly-cerol, glycerolacetylester, glycerolstearat, glykoldistearat, glyoksal, heksadekanol, heksylenglykol, vaselin, petrolatum, isobutylstearat, isocetylstearat, isodecyloleat, isopropyl-lanolat, isopropylmyristat/isopropylpalmitat, isopropyl-stearat, isostearylneopentanoat, laurinsyredietanolamid, limonen, linolensyre, linolsyredietanolamid, mandelolje, mentol, myntolje, myristyllaktat, myristylmyristat, myristyl-stearat, m-tolylacetat, nellikolje, oktyldodekanol, oktyl-palmitat, oktylstearat, oljesyredietanolamid, oleylalkohol, oleyloleat, olivenolje, parafin, flytende = mineralolje, petroleum, peppermintolje, fenyletylalkohol, isostearinsyre, oktansyre, propylenkarbonat, propylenglykol, rizinusolje/- hydrert/raffinert, saflorolje, squalan, squalen, triacetin, glyceroltriacetat, trietylcitrat, undecylensyre, propylenglykol, propandiol, 1,3-butylenglykol, (+)-fenchon, ammonium-lauryletersulfat, kolsyre, kolesterol, kaliumstearat, lecitin, glycerolhydroksystearat, mono- og diglycerid av spisefett-syrer, natriumkaprylat, natriumlauryletersulfat, Na-/K-salter av spisefettsyrene, Na-laurylsulfat, PEG-(2)-stearat, natrium-sulfosuccinat, polyglycerolestere av spisefettsyrene, poly-oksyetylenalkyleter, cetomakrogol, polyoksyetylenfettsyre-sorbitanester, propylenglykolstearat, sorbitanfettsyreester, stearinsyredietanolamid.
Som i vann svellbare tilsetninger som stivelse og dens derivater, agar-agar, alginsyre, arabinogalaktan, galakto-mannan, cellulose og dens derivater, karragen, dekstran, traganth og flere andre gummityper av planteopprinnelse, samt i vann løselige eller svellbare, syntetiske polymerer som polyvinylpyrrolidon, polyvinylalkohol, polyakrylsyre eller polyakrylamid, for bare å nevne noen. Polypeptider som gela-tin, albumin, kollagen eller eggehvite.
Som krystallisasjonshemmere ftalsyreestere, adipinsyre-estere, mono-, di- og triglyceridér, estere av høyere fettsyrer, langkjedede alkoholer og deres derivater, derivater av nonylfenol hhv. av oktylfenol, derivater av fettsyrer, derivater av sorbit og av mannit, ikke-ionogene tensider, polyoksy-etylenalkyletere, derivater av rizinusoljen, sitosterin og polyvinylpyrrolidon, samt ytterligere stoffer kjent for fagmannen.
Prinsippet ifølge oppfinnelsen opptrer på sammenlignbar måte også ved andre grunnmaterialer for transdermale terapeutiske systemer. Hertil er fremfor alt den korrekte innstil- - ling av østradiol-konsentrasjonen viktig. Denne må være høyere enn metningskonsentrasjonen i fuktig tilstand, men lavere enn metningskonsentrasjonen under tørre betingelser. Til fremstilling av systemer ifølge oppfinnelsen er det også nødvendig på forhånd å utføre eksperimentelle løselighets-bestemmelser. Da polymerenes vannopptaksevne er høyst forskjellig og også temperaturavhengig, ville en beskrivelse av tilstandene "fuktig" og "tørr" ved absolutte konsentrasjonsangivelser av vann i grunnmaterialet ikke beskrive forholdene presist nok. Det er snarere nødvendig å ta til hjelp det i farmasien vanlige begrep ekvivalentfuktighet. Dermed betegnes den fuktighet som et materiale antar i likevekt med en på forhånd innstilt relativ luftfuktighet i omgivelsene. Hensiktsmessig gjennomføres østradiolløselighetsbestemmelsen derfor i såkalte hygrostater, hvori et hjelpemateriale med kjent ekvivalentfuktighet (saltløsninger, silikagel, fosfor-pentoksyd osv.) blir lagret sammen med prøven i en innelukket beholder over en viss tid (dager til uker).
I vedlagte eksempel 1 ble det anvendt praksisnære varian-ter av slike hygrostater, og med deres hjelp ble det anvendt ekvivalentfuktigheter fra ca. 0 til 1%, men sikkert under 10% relativ luftfuktighet - tørr tilstand - (silikagel) hhv. ca. 97 - 98% - fuktig tilstand - (såkalt fysiologisk koksalt-løsning).
Den metode for løselighetsbestemmelse som anvendes ved disse forsøk må tilpasses av fagmannen til det aktuelle problem. En enkel mulighet er den som er beskrevet i eksempel 1.
Her ble det laget testformuleringer med forskjellige høye virkestoffinnhold og lagret under fuktighetskontrollerte betingelser. Deretter ble det enten visuelt eller mikro-skopisk bestemt om virkestoffet nu foreligger fullstendig løst eller tvert i mot utfelt.
Ekvivalentfuktighet under 40% relativ luftfuktighet fordelaktig for fremstillings- og lagringsfremgangsmåten, kan foruten ved anvendelse av hygrostat-prinsippet også enkelt oppnås ved tilstrekkelig avskjerming (forpakning) av godset fra den omgivende luft.
En fremgangsmåte til fremstilling av TTS ifølge oppfinnelsen er forutsett tilsvarende bemerkningene i kravene 6 til 8.
Eksempel 1:
Til bestemmelse av påvirkningen av løseligheten av 17 —li — østradiol ved forskjellig lagringsfuktighet ble det først trukket frem følgende virkestoffholdige klebrige sjikt (sjikttykkelse tilsvarende ca. 60 um) :
Sjiktene ble for beskyttelse av overflatene kasjert luftboblefritt mellom en 15 um tykk PETP-membran og et objekt-glass (76 x 26 mm).
Prøvene ble forseglet sammen med den nødvendige fuktig-hetsregulerende innretning (se nedenfor) i forseglbart inn-pakningsmateriale (papir/aluminium/etylenvinylacetat) og lagret ved romtemperatur i 1 år.
Fuktighetsregulatoer:
1. "Fuktig": innlagte striper av platevatt, dynket med ca.
1 ml 0,9% natriumkloridløsning i vann.
2. "Tørr": ca. 10 småkorn av blågel, ca. 1 g.
Da hver prøve A-H ble lagret under begge betingelser, fikk man 16 forskjellige prøver til observasjon.
Etter utløp av lagertiden ble prøvene undersøkt på ut-fellinger av virkestoffet. Derved ble utelukkende mikrosko-pisk feilfritt erkjennbare krystaller som opptrer på overfla-ten, ansett som "omkrystallisasjon".
Konsentrasjonsområdet, hvori prinsippet ifølge oppfinnelsen kan benyttes, ligger alstå mellom 0,6 og 1,3% østradiol (g</>g)<.>
Eksempel 2:
Fremstilling av et system ifølge oppfinnelsen:
1,0 g 17-Ii-østradiol
60,0 g Cariflex R TR 1107 (Styrol-isopren-styrol-blokkopolymer)
138,0 g Foral R 85 (termoplastisk esterharpiks) av kolofoniumderivater)
200,0 g benzin (kokeomårde 80 til 100°C)
omrøres ved romtemperatur i en sylindrisk glassbeholder inntil det oppnås en jevn suspensjon, og besjiktes deretter på et kontinuerlig arbeidende besjiktingsanlegg til 100 ym tykk, silikonisert polyesterfolie slik at det oppnås en sjikttykkelse på 100 g/m<2> (i forhold til den løsemiddelfrie andel).
Utstrykningen tørkes hver gang i 4 min. ved 40°C, 60°C, 80°C og ved 120°C. Deretter legges straks en 15 um tykk polyester-, folie luftboblefritt under valsetrykk på det tørkede sjikt (til kasjering).
Ved utstansing med Henkelhulljern oppnås transdermale systemer pa 16 cm .
Med det transdermale terapisystem ifølge oppfinnelsen oppnås følgende fordelaktige virkninger:
gode resorpsjonsegenskaper for den menneskelige hud,
god forlikelighet med huden, tilstrekkelig virkestoffstrøm gjennom huden ved aksepta-bel flate (cm<2>) av TTS,
ingen omkrystallisering av virkestoffet under lagringen.
Claims (8)
1. Transdermalt terapeutisk system inneholdende virkestoffet 17-Ii-østradiol og eventuelt ytterligere virkestoffer, med sjiktvis oppbygging av et i alt vesentlig fuktighetsugjennomtrengelig samt virkestoffugjennomtrengelig baksjikt, ett eller flere matrikssjikt og ved tilstedeværelse av ikke-klebrige matrikssjikt et klebesjikt, karakterisert ved at konsentrasjonen av den oppløste østradiol i alle matrikssjikt og ved tilstedeværelse av et klebesjikt i dette ligger mellom sin metningskonsentrasjon i tørr tilstand og sin metningskonsentrasjon i fuktig tilstand, hvorved det med begrepet "tørr tilstand" skal forstås at grunnmaterialet står i likevekt med en gassfase med mindre enn 10% relativ luftfuktighet, og med begrepet "fuktig tilstand", at grunnmaterialet står i likevekt med en gassfase med mer enn 90% relativ luftfuktighet.
2. Transdermalt terapeutisk system ifølge krav 1, karakterisert ved at det i løpet av frem-stillingen og lagringen har en likevektsfuktighet inntil 40% relativ luftfuktighet.
3. Transdermalt terapeutisk system ifølge krav 1 eller 2,
karakterisert ved at alle matrikssjikt og ved tilstedeværelse av et klebesjikt også dette i fuktighetslikevekt med inntil 10% relativ luftfuktighet har en minst 50% høyere løselighet for virkestoffet 17-Ii-østradiol enn i fuktighetslikevekt med minst 90% relativ luftfuktighet.
4. Transdermalt terapeutisk system ifølge krav 3, karakterisert ved at alle matrikssjikt og ved tilstedeværelse av et klebesjikt også dette består av en akrylsyreesterkopolymer med en løselighet for virkestoffet 17-Ii-østradiol mellom 0,2 og 2,0% (g/g), bestemt i fuktighetslikevekt med 10% relativ luftfuktighet.
5. Transdermalt terapeutisk system ifølge ett eller flere av de foregående krav,
karakterisert ved at ett eller flere matrikssjikt eller ved tilstedeværelse av et klebesjikt også dette inneholder ett eller flere stoffer fra gruppen av klebemidler, hudgjennomtrengningsforbedrende tilsetninger, fyllstoffer, løselighetsforbedringsmidler eller tilsetningsstoffer svellbare i vann.
6. Fremgangsmåte til fremstilling av det transdermale terapeutiske system ifølge kravene 1 til 5, karakterisert ved at virkestoffet ved romtemperatur blir omrørt sammen med bestanddeler av matriks-sjiktet hhv. klebejsiktet, samt med ett eller flere tilsetningsstoffer fra gruppen av klebemidler, hudgjennomtrengningsforbedrende tilsetninger, fyllstoffer, løselighets-forbedringsmidler og/eller tilsetningsstoffer svellbare i vann inntil det oppnås en jevn suspensjon og deretter blir be-sjiktet på en dehesivt utrustet folie, slik at resultatet blir en sammenligningsvis tynn sjikttykkelse, hvorpå påstrykningen blir tørket noen minutter ved trinnvis hevet temperatur, til sist ved ca. 120°C, og på det tørkede sjikt øyeblikkelig blir pålagt en dekkfolie luftboblefritt under valsetrykk og denne dermed blir tilkasjert, hvoretter det til slutt blir utstanset enkelte transdermale systemer med definert flateinnhold.
7. Fremgangsmåte ifølge krav 6,
karakterisert ved å påføre besjiktningen på den dehesivt utrustede folie med en besjiktingsmasse på ca. 100 g/m<2> i forhold til den løsningsmiddeltrie andel.
8. Fremgangsmåte ifølge krav 6 eller 7, karakterisert ved å gjennomføre tørkingen av sjiktet hver gang i ca. 4 min. ved hhv. 40°C, 60°C, 80°C og 120°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4237453A DE4237453C1 (no) | 1992-11-06 | 1992-11-06 | |
| PCT/EP1993/002971 WO1994010984A1 (de) | 1992-11-06 | 1993-10-27 | TRANSDERMALES THERAPEUTISCHES SYSTEM ZUR ABGABE VON 17-β-ESTRADIOL UND VERFAHREN ZU SEINER HERSTELLUNG |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO951765L NO951765L (no) | 1995-05-05 |
| NO951765D0 NO951765D0 (no) | 1995-05-05 |
| NO311783B1 true NO311783B1 (no) | 2002-01-28 |
Family
ID=6472230
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO19951765A NO311783B1 (no) | 1992-11-06 | 1995-05-05 | Transdermalt terapeutisk system for frigjöring av 17-<beta>- östradiol og fremgangsmåte for fremstilling derav |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US5912008A (no) |
| EP (1) | EP0716599B1 (no) |
| JP (1) | JP3237016B2 (no) |
| KR (1) | KR100306946B1 (no) |
| AT (1) | ATE164516T1 (no) |
| AU (1) | AU678408B2 (no) |
| CA (1) | CA2147172C (no) |
| CZ (1) | CZ286907B6 (no) |
| DE (2) | DE4237453C1 (no) |
| DK (1) | DK0716599T3 (no) |
| ES (1) | ES2117152T3 (no) |
| FI (1) | FI113339B (no) |
| HR (1) | HRP931360B1 (no) |
| HU (1) | HU221847B1 (no) |
| IL (1) | IL107395A (no) |
| MY (1) | MY118171A (no) |
| NO (1) | NO311783B1 (no) |
| NZ (1) | NZ257137A (no) |
| PL (1) | PL174604B1 (no) |
| SI (1) | SI9300581A (no) |
| SK (1) | SK279911B6 (no) |
| WO (1) | WO1994010984A1 (no) |
| YU (1) | YU69693A (no) |
| ZA (1) | ZA938257B (no) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE95059T1 (de) * | 1989-02-28 | 1993-10-15 | Teijin Ltd | Pflaster sowie dessen herstellung. |
| EP0695177B1 (de) * | 1993-04-20 | 1998-02-18 | Hexal Ag | Wirkstoffplaster |
| DE4429664C2 (de) * | 1994-08-20 | 1997-09-11 | Lohmann Therapie Syst Lts | Estradiol-TTS mit wasserbindenden Zusätzen und Verfahren zu seiner Herstellung |
| US5906830A (en) * | 1995-09-08 | 1999-05-25 | Cygnus, Inc. | Supersaturated transdermal drug delivery systems, and methods for manufacturing the same |
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| US9855211B2 (en) | 2013-02-28 | 2018-01-02 | Novan, Inc. | Topical compositions and methods of using the same |
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-
1992
- 1992-11-06 DE DE4237453A patent/DE4237453C1/de not_active Revoked
-
1993
- 1993-10-21 MY MYPI93002178A patent/MY118171A/en unknown
- 1993-10-25 IL IL10739593A patent/IL107395A/xx not_active IP Right Cessation
- 1993-10-27 JP JP51165094A patent/JP3237016B2/ja not_active Expired - Lifetime
- 1993-10-27 SK SK580-95A patent/SK279911B6/sk not_active IP Right Cessation
- 1993-10-27 ES ES93923559T patent/ES2117152T3/es not_active Expired - Lifetime
- 1993-10-27 AT AT93923559T patent/ATE164516T1/de active
- 1993-10-27 CA CA002147172A patent/CA2147172C/en not_active Expired - Lifetime
- 1993-10-27 WO PCT/EP1993/002971 patent/WO1994010984A1/de active IP Right Grant
- 1993-10-27 NZ NZ257137A patent/NZ257137A/en not_active IP Right Cessation
- 1993-10-27 DK DK93923559T patent/DK0716599T3/da active
- 1993-10-27 AU AU53386/94A patent/AU678408B2/en not_active Expired
- 1993-10-27 KR KR1019950701791A patent/KR100306946B1/ko not_active IP Right Cessation
- 1993-10-27 DE DE59308360T patent/DE59308360D1/de not_active Expired - Lifetime
- 1993-10-27 HU HU9501318A patent/HU221847B1/hu active IP Right Grant
- 1993-10-27 EP EP93923559A patent/EP0716599B1/de not_active Expired - Lifetime
- 1993-10-27 PL PL93308532A patent/PL174604B1/pl unknown
- 1993-10-27 CZ CZ19951162A patent/CZ286907B6/cs not_active IP Right Cessation
- 1993-11-03 YU YU69693A patent/YU69693A/sh unknown
- 1993-11-04 HR HRP4237453.7A patent/HRP931360B1/xx not_active IP Right Cessation
- 1993-11-05 SI SI9300581A patent/SI9300581A/sl unknown
- 1993-11-05 ZA ZA938257A patent/ZA938257B/xx unknown
-
1995
- 1995-05-03 FI FI952115A patent/FI113339B/fi not_active IP Right Cessation
- 1995-05-05 NO NO19951765A patent/NO311783B1/no not_active IP Right Cessation
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1997
- 1997-06-16 US US08/876,427 patent/US5912008A/en not_active Expired - Lifetime
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| MK1K | Patent expired |