NO325621B1 - Forbindelser, sammensetninger inneholdende nevnte forbindelser i kombinasjon med et aktivt midddel, doseringsenhetsform samt fremgangsmater for fremstilling av nevnte sammensetninger - Google Patents
Forbindelser, sammensetninger inneholdende nevnte forbindelser i kombinasjon med et aktivt midddel, doseringsenhetsform samt fremgangsmater for fremstilling av nevnte sammensetninger Download PDFInfo
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- NO325621B1 NO325621B1 NO19974495A NO974495A NO325621B1 NO 325621 B1 NO325621 B1 NO 325621B1 NO 19974495 A NO19974495 A NO 19974495A NO 974495 A NO974495 A NO 974495A NO 325621 B1 NO325621 B1 NO 325621B1
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- active agent
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- biologically active
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Description
Foreliggende oppfinnelse vedrører forbindelser og sammensetninger inneholdende nevnte forbindelser i kombinasjon med et aktivt middel. Nevnte sammensetninger er egnet for levering av nevnte aktive midler, og spesielt biologiske eller kjemiske aktive midler, så som for eksempel bioaktive peptider og lignende. Disse forbindelsene blir anvendt som bærere for å lette levering av et middel til et mål. Bærerene er modifiserte aminosyrer og er velegnet for dannelse av ikke-kovalente blandinger med biologiske aktive midler for oral administrering til dyr. Fremgangsmåter for fremstilling av slike sammensetninger er også beskrevet.
Konvensjonelle midler for levering av aktive midler er ofte meget begrenset av biologiske, kjemiske og fysiske barrierer. Disse barrierene kommer ofte fra miljøet som de blir levert gjennom, miljøet til målet for levering eller selve målet.
Biologiske eller kjemiske aktive midler er spesielt utsatte for slike barrierer. For eksempel ved levering til dyr av farmasøytiske eller terapeutiske midler blir barrierer pålagt kroppen. Eksempler på fysiske barrierer er hud og forskjellige organmembraner som må bli passert før de når et mål. Kjemiske barrierer innbefatter, men er ikke begrenset til, pH variasjoner, lipid bilag og degraderingsenzymer.
Disse barrierene er av spesiell betydning ved konstruering av orale leveringssystemer. Oral levering av mange biologiske eller kjemiske aktive midler vil være den rette veien for administrering til dyr om ikke for biologiske, kjemiske og fysiske barrierer så som variering av pH i mave-tarm (GI) kanalen, kraftfulle fordøyelsesenzymer og aktiv middel impermeable mave-tarm membraner. Blant de mange midlene som vanligvis ikke er egnet for oral administrering er biologiske eller kjemiske aktive peptider, så som kalsitonin og insulin; polysakkarider, og spesielt mukopolysakkarider inkludert, men ikke begrenset til heparin; heparinoider; antibiotika; og andre organiske forbindelser. Disse midlene blir hurtig ineffektive eller blir ødelagt i mave-tarm kanalen av sur hydrolyse, enzymer eller lignende.
Tidligere fremgangsmåter for oral administrering mottagelig for farmasøytiske midler har vært basert på koadministrering av adjuvants (for eksempel resorcinoler og ikke-ioniske overflateaktive midler så som polyoksyetylenoleyleter og n-heksadecylpolyetyleneter) for og kunstig øke permeabiliteten til tarmveggene, samt koadministrering av enzymatiske inhibitorer (for eksempel bukspyttkjerteltrypsininhibitorerm diisopropylfluorfosfat (DFF) og trasylol) for å inhibere enzymatisk degradering.
Liposomer er også blitt beskrevet som medikamentleveringssystemer for insulin og heparin. Se for eksempel US-PS 4.239.754; Patel et al. (1976), FEBS Letters, Vol. 62, s. 60; og Hashimoto et al. (1979), Endocrinology Japan, Vol. 26, s. 337.
Bredspektret anvendelse av slike medikamentleveringssystemer er utelukket på grunn av (1) systemene krever toksiske mengder av adjuvants eller inhibitorer; (2) egnede lavmolekylvektsmidler, dvs. aktiv last, er ikke tilgjengelige; (3) systemene utviser dårlig stabilitet og utilstrekkelig oppbevaringstid; (4) systemene kan vanskelig fremstilles; (5) systemene beskytter ikke det aktive middelet (lasten); (6) systemene endrer det aktive middelet negativt; eller (7) systemene svikter når det gjelder å muliggjøre eller fremme absorpsjon av det aktive middelet.
Mikrosfærer av kunstige polymerer av blandede aminosyrer (proteinoider) er blitt anvendt for levering av farmasøytiske midler. For eksempel beskriver US-PS 4.925.673 medikament-inneholdende proteinoidmikrosfære bærere som fremgangsmåter for fremstilling og anvendelse derav. Disse proteinoid mikrosfærer er nyttige for levering av et antall aktive midler.
Det er fortsatt et behov innenfor fagområdet for enkle, billige leveringssystemer som lett kan bli fremstilt og som kan levere et bredt spekter av aktive midler.
Sammensetninger som er nyttige for levering av aktive midler er beskrevet. Disse sammensetningene innbefatter minst et aktivt middel, foretrukket et biologisk eller kjemisk aktivt middel, og minst en av følgende forbindelser:
eller salter derav.
Det er blitt oppdaget at organiske syreforbindelser og deres salter, med en aromatisk amidgruppe, med en hydroksygruppe substituert i ortho posisjon på den aromatiske ringen og en lipofil kjede som dannes rundt 4 karbonatomer til omtrent 20 atomer i kjeden er nyttige som bærere for levering av aktive midler. I en foretrukket form kan den lipofile kjeden ha 5 til 20 karbonatomer.
Sammensetninger som omfatter bærerforbindelsene diskutert ovenfor og aktive midler er blitt vist å være effektive for levering av aktive midler til valgte biologiske systemer. Disse sammensetningene innbefatter minst et aktivt middel, som er fortrinnsvis et biologisk eller kjemisk aktivt middel, og minst en bærerforbindelse.
Videre betraktet i foreliggende oppfinnelse er doseringsenhetsformer som innbefatter disse sammensetningene.
Også betraktet er en fremgangsmåte for fremstilling av disse sammensetningene som omfatter blanding av minst et aktivt middel med minst en forbindelse som beskrevet ovenfor, og eventuelt, en doseringsbærer.
Disse ikke-toksiske forbindelsene kan bli administrert oralt til dyr som del av et leveringssystem ved sammenblanding eller miksing av forbindelser med et aktivt middel før administrering. Figur 1 er en grafisk illustrasjon av resultatene til subkutan injeksjon av rhGH sammensetningen i rotter. Figur 2 er en grafisk illustrasjon av resultatene til sublingual (SL), intranasal (IN) og intrakolon (IC) dosering av rhGH i rotter. Figur 3 er en grafisk illustrasjon av resultatene til intrakodondosering av heparinlevering med forbindelsen XXXI bæreren.
De spesifikke sammensetningene ifølge foreliggende oppfinnelse innbefatter et aktivt middel og en modifisert aminosyre. Disse sammensetningene kan bli anvendt for å levere forskjellige aktive midler gjennom forskjellige biologiske, kjemiske og fysiske barrierer og er spesielt egnede for levering av aktive midler som er utsatt for miljømessig degradering. Sammensetningene ifølge oppfinnelsen er spesielt nyttige for levering eller administrering av biologiske eller kjemiske aktive midler til et hvilket som helst dyr så som fugler; pattedyr, så som primater og spesielt mennesker; og insekter.
Andre fordeler ifølge oppfinnelsen innbefatter anvendelse av billige råmaterialer som er lette å fremstille. Sammensetningene og formuleringsmetodene ifølge foreliggende oppfinnelse er kostnadseffektive, enkle å fremstille og kan tilpasses industriell oppskalering for kommersiell produksjon.
Subkutan, sublingual og intranasal koadministrering av et aktivt middel, så som et rekombinant humant veksthormon (rhGH) og leveringsmidler og spesielt proteiner, beskrevet heri resulterer i en øket biotilgjengelighet av det aktive middelet sammenlignet med administrering av aktivt middel alene. Et lignende resultat blir oppnådd ved koadministrering av laksekalsitonin med leveringsmidler, i rotter. Data som understøtter disse funnene er presentert i eksemplene.
Aktive midler
Aktive midler egnede for anvendelse i foreliggende oppfinnelse innbefatter biologiske eller kjemiske aktive midler, inkludert, men ikke begrenset til, duftmidler, samt andre aktive midler så som for eksempel kosmetiske midler.
Biologiske eller kjemiske aktive midler innbefatter, men er ikke begrenset til, pesticider, farmakologiske midler og terapeutiske midler. For eksempel, biologiske eller kjemiske aktive midler egnede for anvendelse i foreliggende oppfinnelse innbefatter, men er ikke begrenset til, peptider, og spesielt små peptider; hormoner og, spesielt hormoner som i seg i selv ikke passerer gjennom eller bare en fraksjon av den administrerte dosen passerer gjennom mave-tarm slimhinnen og/eller er mottagelig for kjemisk spaltning av syrer og enzymer i mave-tarm kanalen; polysakkarider, og spesielt blandinger av mukopolysakkarider; karbohydrater; lipider eller en hvilken som helst kombinasjon derav. Ytterligere eksempler innbefatter, men er ikke begrenset til, humane veksthormoner; bovine veksthormoner; vekstfrigjørende hormoner; interferoner, interleukin-1, insulin, heparin og spesielt heparin med lav molekylvekt; kalsitonin; erytropoietin, atriell naturetisk faktor; antigener, monoklonale antistoffer, somatostatin, adrenokortikotropin, gonadotropin frigjørende hormon; oksytocin, vasopressin, kromolyn natrium (natrium eller dinatrium kromoglyeat); vankomycin; desferrioksamin (DFO)m paratyroid hormon anti-mikrobielle midler, inkludert, men ikke begrenset til anti-soppmidler; eller en hvilken som helst kombinasjon derav.
Modifiserende aminosyrer
Betegnelsene modifisert aminosyre er anvendt som en benevnelse på de ovendefinerte bærer forbindelser som er aminosyrer som er blitt modifisert ved acylering av en fri amingruppe med et acyleringsmiddel som reagerer med den frie aminogruppen som er tilstede.
Aminosyrer i modifisert form kan bli anvendt for å levere aktive midler inkludert, men ikke begrenset til biologiske eller kjemiske aktive midler så som for eksempel farmakologiske og terapeutiske midler.
Modifiserte aminosyrer blir vanligvis fremstilt ved modifisering av aminosyren eller en ester derav. Mange av disse forbindelsene blir fremstilt ved acylering med midler som har formelen hvor: R^ er den hensiktsmessige resten for å tilveiebringe modifikasjonen indikert i sluttproduktet,
Y er
og X er en avspaltbar gruppe. Typiske avspaltbaregrupper innbefatter, men er ikke begrenset til, halogener så som for eksempel klorin, bromin og iodid. I tillegg utgjør korresponderende anhydrider modifiserende midler.
Mange av forbindelsene ifølge foreliggende oppfinnelse kan lett bli fremstilt fra aminosyrer ved fremgangsmåter som er kjente for fagfolk basert på foreliggende beskrivelse. For eksempel er forbindelsene I-VU avledet fra aminosmørsyre; og forbindelsene XI-XXVI er avledet fra aminokaprylsyre. For eksempel kan de modifiserte aminosyreforbindelsene ovenfor bli fremstilt ved omsetning av enkelt aminosyrer med hensiktsmessige modifiseirngsmiddel som reagerer med den frie aminodelen som er tilstede i aminosyrene for å danne amider. Beskyttelsesgruppen kan bli anvendt for å unngå uønskede sidereaksjoner som ellers er kjent for fagfolk innenfor dette området.
Aminosyren kan bli løst opp i vandig alkalisk oppløsning av et metallhydroksid, for eksempel natrium eller kaliumhydroksid, og oppvarmet ved en temperatur varierende mellom omtrent 5°C og omtrent 70°C, fortrinnsvis mellom omtrent 10°C og omtrent
40°C, i en periode som varierer mellom omtrent 1 time og omtrent 4 timer, fortrinnsvis omtrent 2,5 timer. Mengden av alkali anvendt pr ekvivalent NH2 grupper i aminosyren varierer generelt mellom omtrent 1,25 og omtrent 3 mmol, fortrinnsvis mellom omtrent 1,5 og omtrent 2,25 mmol pr ekvivalent NHtø. pH til oppløsningen varierer generelt mellom omtrent 8 og omtrent 13, fortrinnsvis varierende mellom omtrent 10 og omtrent 12.
Deretter blir hensiktsmessige aminosyremodifiserende middel tilsatt til aminosyreoppløsningen med omrøring. Temperaturen til blandingen blir opprettholdt ved en temperatur som generelt varierer mellom omtrent 5°C og omtrent 70°C, fortrinnsvis mellom omtrent 10°C og omtrent 40°C, i en periode som varierer mellom omtrent 1 og omtrent 4 timer. Mengden av aminosyremodifiserende middel anvendt i relasjon til mengden av aminosyren er basert på antall mol totalt fri NH2 i aminosyren. Generelt blir det aminomodifiserende middelet anvendt i en mengde som varierer mellom omtrent 0,5 og omtrent 2,5 mol ekvivalenter, fortrinnsvis mellom omtrent 0,75 og omtrent 1,25 ekvivalenter, pr molar ekvivalent total NH2 gruppe i aminosyren.
Reaksjonen blir stoppet ved justering av pH til blandingen med en egnet syre, for eksempel, konsentrert saltsyre, helt til pH er mellom omtrent 2 og omtrent 3. Blandingen separeres ved henstand ved romtemperatur for å danne et gjennomsiktig øvre lag og et hvitt eller off white presipitat. Det øvre laget blir fjernet og den modifiserte aminosyren blir samlet fra det nederste laget ved filtrering eller dekantering. Rå modifisert aminosyre blir deretter oppløst i vann ved en pH som varierer mellom 9 og omtrent 13, fortrinnsvis mellom omtrent 11 og omtrent 13. Uoppløselige materialer blir fjernet ved filtrering og filtratet tørket i vakuum. Utbyttet av modifisert aminosyre varierer generelt mellom omtrent 30 og omtrent 60% og vanligvis omtrent 45%.
Om ønskelig kan aminosyreestere, så som for eksempel benzyl, metyl eller etylestere av aminosyreforbindelser bli anvendt for å fremstille de modifiserte aminosyrene ifølge oppfinnelsen. Aminosyreester, oppløst i et egnet organisk oppløsningsmiddel så som dimetylformamid, pyridin eller tetrahydrofuran blir omsatt med hensiktsmessige aminomodifiserende middel ved en temperatur som varierer mellom omtrent 5°C og omtrent 70°C, fortrinnsvis omtrent 25°C, i en periode som varierer mellom omtrent 7 og omtrent 24 timer. Mengde av aminomodifiserende middel anvendt i forhold til aminosyreesteren er den samme som beskrevet ovenfor for aminosyrene. Denne reaksjonen kan bli utført med eller uten en base så som for eksempel trietylamin eller diisopropyletylamin.
Deretter blir reaksjonsoppløsningsmiddelet fjernet under negativt trykk og esterfunksjonaliteten blir fjernet ved hydrolysering av modifisert aminosyreester med en egnet alkalisk oppløsning, for eksempel IN natriumhydroksid, ved en temperatur varierende mellom omtrent 50°C og omtrent 80°C, fortrinnsvis omtrent 70°C, i en tidsperiode tilstrekkelig for å hydrolysere ut estergruppen og danne modifisert aminosyre som har en fri karboksylgruppe. Hydrolyseblandingen blir deretter avkjølt til romtemperatur og surgjort, for eksempel vandig 25% saltsyreoppløsning, til en pH som varierer mellom omtrent 2 og omtrent 2,5. Den modifiserte aminosyren presipiteres ut av oppløsningen og blir isolert ved konvensjonelle midler så som filtrering eller dekantering. Benzylestere kan bli fjernet ved hydrogenering i et organisk oppløsningsmiddel ved anvendelse av en overgangsmetallkatalysator.
Den modifiserte aminosyren kan bli renset ved omkrystallisering eller ved fraksjonering på faste kolonnebærere. Egnede omkrystalliseringsoppløsningsmiddelsystemer innbefatter acetonitril, metanol og tetrahydrofuran. Fraksjoneringen kan bli utført på en egnet fast kolonnebærer så som aluminiumoksid, ved anvendelse av metanol/n-propanolblandinger som mobil fase; revers fase kolonnebærere ved anvendelse av trifluoreddiksyre/acetonitrilblandingen som mobil fase; og ionebytte kromatografi ved anvendelse av vann som mobil fase. Når anionbyttekromatografi blir utført blir det fortrinnsvis anvendt en påfølgende O-500 mM natriumkloirdgradient. I en alternativ fremgangsmåte kan modifiserte aminosyrer som har formelen
hvor Y er
og R<1>, R<2>, og R<3> er de passende rester; kan bli fremstilt ved
(a) omsetning i vann og tilstedeværelse av en base, en forbindelse som har formelen
med en forbindelse som har formelen
hvor Y, R<1>, R<2> og R<3> er som vist ovenfor og X er en avspaltbar gruppe.
Forbindelse CXXV kan bli fremstilt, for eksempel ved fremgangsmåten beskrevet i Olah et al., Synthesis, 537-538 (1979).
Forbindelsen XXXI ble fremstilt som beskrevet i skjema I fra 10-undecen-l-ol, 1, ved en tretrinns prosedyre i et totalt utbytte på 31%. Alkylering av fthalimid med alkanol, 1, under Mitsunobu betingelser, etterfulgt av omsetning med hydrazin ga 1-aminoundec-1 O-ene, 2, i 66% utbytte. Aminet ble derivatisert med O-acetylsalicyloylklorid og resulterende alken, 3, ble oksidert til syren ved anvendelse av kaliumpermanganat. Fjerning av acetat, etterfulgt av sur presipitering ga forbindelsen XXXI i 47% utbytte basert på amin 2.
Leveringss<y>stemer
Sammensetningene ifølge foreliggende oppfinnelse kan innbefatte en eller flere aktive midler.
I en utførelsesform kan de ovendefinerte bærer forbindelsene bli anvendt direkte som en leveringsbærer ved å blande en eller flere av forbindelsene med det aktive middelet før administrering.
I en alternativ utførelsesform kan forbindelsene bli anvendt for å danne mikrosfærer inneholdende det aktive middelet. Disse forbindelsene er spesielt nyttige for oral administrering av visse biologiske-aktive midler, for eksempel, små peptidhormoner, som i seg selv, ikke passerer eller bare en liten fraksjon av administrert dose passerer gjennom mave-tarm slimhinnen og/eller er mottagelige for kjemisk spaltning av syre og enzymer i mave-tarm kanalen.
Dersom modifiserte aminosyrer skal bli omdannet til mikrosfærer blir blandingen
eventuelt oppvarmet til en temperatur som varierer mellom omtrent 20 og omtrent 50°C, fortrinnsvis omtrent 40°C, helt til de modifiserte aminosyrene er oppløste. Den endelige oppløsningen inneholder fra omtrent 1 mg og til omtrent 2000 mg av forbindelsen pr ml oppløsning, fortrinnsvis mellom omtrent 1 og omtrent 500 mg pr ml. Konsentrasjonen av det aktive middelet i sluttoppløsningen varierer og er avhengig av nødvendig dosering for behandling. Når det er nødvendig kan den nøyaktige konsentrasjonen bli bestemt ved for eksempel revers fase HPLC analyse.
Når forbindelsene blir anvendt å fremstille mikrosfærer utgjør en annen nyttig prosedyre følgende: forbindelser blir løst opp i deionisert vann i en konsentrasjon som varierer mellom omtrent 75 og omtrent 200 mg/ml, fortrinnsvis omtrent 100 mg/ml ved en temperatur mellom omtrent 25°C og omtrent 60°C, fortrinnsvis omtrent 40°C. Partikkelformig materiale som er igjen i oppløsningen kan bli fjernet ved konvensjonelle metoder så som filtrering.
Deretter blir forbindelsen opprettholdt ved en temperatur på omtrent 40°C, blandet 1:1 ( V/ V) med en vandig sur oppløsning (også ved omtrent 40°C) som har en syrekonsentrasjon som varierer mellom omtrent 0,05 N og omtrent 2 N, fortrinnsvis omtrent 1,7 N. Den resulterende blandingen blir videre inkubert ved 40°C i en tidsperiode som er effektiv for mikrosfæredannelse, som observert ved lysmikroskopi. Ved utførelse av oppfinnelsen er den foretrukne rekkefølgen for tilsetningen å tilsette forbindelse til den vandige sure oppløsningen.
Egnede syrer for mikrosfæredannelse innbefatter en hvilken som helst syre som ikke (a) negativt påvirker de modifiserte aminosyrene, polyaminosyren eller peptidene for
eksempel, initiere eller propagere kjemisk nedbrytning; (b) interferere med mikrosfæredannelse; (c) interferere med mikrosfæreinnkorporering av aktivt middel lasten; og (d) negativt reagere med aktivt middel lasten.
Foretrukne syrer for anvendelse i dette aspektet innbefatter eddiksyre, sitronsyre, saltsyre, fosforsyre, malinsyre og maleinsyre.
Et mikrosfærestabiliserende additiv kan bli innkorporert i den vandige sure oppløsningen eller inn i forbindelsen eller lasteoppløsningen før mikrosfæredannelsesprosessen. I noen aktive midler vil tilstedeværelse av slike additiver fremme stabiliteten og/eller dispergerbarheten til mikrosfærene i oppløsningen.
Stabiliserende additiver kan bli anvendt i en konsentrasjon som varierer mellom omtrent 0,1 og 5% (W/V), fortrinnsvis omtrent 0,5% (W/V). Egnede, men ikke-begrensende, eksempler på mikrosfærestabiliserende additiver innbefatter gummiakasia, gelatin, metylcellulose, polyetylenglykol, polypropylenglykol, karboksylsyrer og salter derav, og polylysin. Foretrukne stabiliserende additiver er gummiakasia, gelatin og metylcellulose.
Under ovennevnte betingelser danner forbindelsesmolekylene hule eller faste matrisetypemikrosfærer hvor lasten blir fordelt i en bærermatrise eller kapseltypemikrosfærer som innkapsler flytende eller fast last. Dersom forbindelsen blir dannet i nærvær av et oppløselig materiale, for eksempel, et farmasøytisk middel i ovennevnte vandige syreoppløsning, vil dette materialet bli innkapslet i mikrosfærene. På denne måten kan man innkapsle farmakologiske aktive materialer så som peptider, proteiner og polysakkarider samt ladede organiske molekyler, for eksempel, antimikrobielle midler, som normalt har dårlig biotilgjengelighet via den orale veien. Mengden av farmasøytisk middel som kan bli innkorporert av mikrosfæren er avhengig av et antall faktorer som innbefatter konsentrasjonen til middelet i oppløsningen, samt affiniteten som lasten har for bæreren. Forbindelse mikrosærene endrer ikke de fysiologiske eller biologiske egenskapene til det aktive middelet. Innkapslingsprosessen endrer ikke de farmakologiske egenskapene til det aktive middelet. Et hvilket som helst farmakologisk middel kan bli innkorporert i mikrosfærene. Systemet er spesielt fordelaktig for levering av kjemiske eller biologiske midler som ellers vil bli ødelagt eller gjort mindre effektive ved tilstander som oppstår i kroppen til dyret som blir administrert, før mikrosfæren når målsonen (dvs. området hvor innholdet av mikrosfæren skal bli frigjort) og for levering av farmakologiske midler som blir dårlig absorbert i mave-tarm kanalen. Målsoner kan variere avhengig av medikamentet som blir anvendt.
Partikkelstørrelsen til mikrosfæren spiller en viktig rolle for bestemmelse av frigjøring av det aktive middelet i det målsøkte området til mave-tarm kanalen. Foretrukne mikrosfærer har diametere på omtrent < 0,1 mikroner og omtrent 10 mikroner, fortrinnsvis mellom omtrent 0,5 mikroner og omtrent 5 mikroner. Mikrosfærer er tilstrekkelig små for å frigjøre effektivt det aktive middelet ved det målsøkte området i mave-tarm kanalen så som for eksempel mellom maven og tarmen. Små mikrosfærer kan også bli administrert parenteralt ved å bli suspendert i en hensiktsmessig bærervæske (for eksempel isotonisk saltvann) og injisert direkte i sirkulasjonssystemet, intramuskulært eller subkutant. Administreringsmetoden valgt vil selvfølgelig variere avhengig av kravet til aktivt middel som blir administrert. Store aminosyremikrosfærer (>50 mikroner) pleier å være mindre effektive som orale leveringssystemer.
Størrelsen på mikrosfærene dannet av kontaktende forbindelser med vann eller en vandig oppløsning inneholdende aktive midler kan bli kontrollert ved å manipulere forskjellige fysiske eller kjemiske parametere, så som pH, osmolaritet eller ionestyrken til innkapslingsoppløsningen, størrelsen på ionene i oppløsningen og utifrå valg av syre anvendt i innkapslingsprosessen.
Administreringsblandingene blir dannet ved blanding av en vandig oppløsning av bæreren med en vandig oppløsning av det aktive ingredienset like før administreringen. Alternativt kan bæreren og det biologiske eller kjemiske aktive ingredienset bli blandet sammen i løpet av fremstillingsprosessen. Oppløsningene kan eventuelt inneholder additiver så som fosfatbuffer salter, sitronsyre, eddiksyre, chelatin og gummiakasi.
Stabiliserende additiver kan bli innkorporert i bæreroppløsningen. For noen medikamenter vil tilstedeværelse av slike additivere fremme stabiliteten og dispergerbarheten til middelet i oppløsningen.
Stabiliserende additiver kan bli anvendt ved en konsentrasjon som varierer mellom omtrent 0,1 og 5% (w/v), fortrinnsvis omtrent 0,5% (w/v). Egnede, men ikke-begrensende, eksempler på stabiliserende additiver innbefatter gummiakasi, gelatin, metylcellulose, polyetylenglykol, karboksylsyrer og salter derav, og polylysin. Foretrukne stabiliserende additiver er gummiakasi, gelatin og metylcellulose.
Mengden av aktivt middel er en mengde som effektivt kan oppnå formålet til det bestemte aktive middelet. Mengden i sammensetningen er vanligvis en farmakologisk eller biologisk effektiv mengde. Mengden kan derimot være mindre enn en farmakologisk eller biologisk effektiv mengde når sammensetningen blir anvendt i en doseringsenhetsform, så som en kapsel, en tablett eller en væske, fordi doseringsenhetsformen kan inneholde en mengde av bærer/biologisk eller kjemisk aktivt middelsammensetninger eller kan inneholde en inndelt farmakologisk eller biologisk effektiv mengde. De totale effektive mengdene kan deretter bli administrert i kumulative enheter inneholdende totalt farmakologiske eller biologiske eller kjemiske aktive mengder av biologisk eller farmakologisk aktivt middel.
Den totale mengden av aktivt middel, og spesielt biologisk eller kjemisk aktivt middel, som kan bli anvendt kan bli bestemt av fagfolk innenfor dette området. Det er derimot overraskende blitt oppdaget at når det gjelder noen biologiske eller kjemiske aktive midler tilveiebringer anvendelsen av de for tiden beskrevne bærere ekstremt effektiv levering, spesielt i oral, intranasal, sublingual, intraduodenal eller subkutane systemer. Lavere mengder av biologisk eller kjemisk aktivt middel enn de som blir anvendt i tidligere doseringsenhetsformer eller leveringssystemer kan bli administrert til individet mens det fortsatt oppnår samme blodnivåer og terapeutiske effekter.
Mengden av bærer i foreliggende sammensetning er en leveringseffektiv mengde og kan bli bestemt for en bestemt bærer eller biologisk eller kjemisk aktivt middel ifølge fremgangsmåten kjent for fagfolk innenfor dette området.
Doseringsenhetsformer kan også innbefatte hvilke som helst av eksipienter; fortynningsmidler; oppløsningsmidler; smøremidler; plastifiserende midler; farvestoffer og doseringsbærere, inkludert, men ikke begrenset til vann, 1,2-propandiol, etanol, olivenolje eller en hvilken som helst kombinasjon derav.
Administrering av foreliggende sammensetninger eller doseringsenhetsformer er fortrinnsvis oral eller ved intraduodenal injeksjon.
Leveringssammensetningene ifølge foreliggende oppfinnelse kan også innbefatte en eller flere enzyminhibitorer. Slike enzyminhibitorer innbefatter, men er ikke begrenset til, forbindelser som aktinonin eller epiaktinonin og derivater derav. Disse forbindelsene har formlene angitt nedenfor:
Derivater av disse forbindelsene er beskrevet i US-PS 5.206.384. Aktinoninderivatene har formelen:
hvor R<5> er sulfoksymetyl eller karboksyl eller en substituert karboksygruppe valgt fra karboksamid, hydroksaminokarbonyl og alkoksykarbonylgruppe; og R<*>> er hydroksyl, alkoksy, hydroksyamino eller sulfoksyaminogruppe. Andre enzyminhibitorer innbefatter, men er ikke begrenset til, aprotinin (Trasylol) og Bowman-Birk inhibitor.
Forbindelsene og sammensetningene ifølge oppfinnelsen er nyttige for administrering av biologiske eller kjemiske aktive midler til et hvilket som helst dyr så som fugler; pattedyr, så som primater og spesielt mennesker; og insekter. Systemet er spesielt fordelaktig for levering av kjemiske eller biologiske eller kjemiske aktive midler som ellers blir ødelagt eller blir mindre effektive av tilstander som oppstår før det aktive middelet når målsonen (dvs. området hvor det aktive middelet til leveringssammensetningen skal bli frigjort) og innenfor kroppen til dyret som de blir administrert til. Forbindelsene og sammensetningene ifølge foreliggende oppfinnelse er spesielt nyttige i oralt administrerende aktive midler, spesielt de som vanligvis ikke kan administreres oralt.
Følgende eksempler illustrerer oppfinnelsen. Alle deler er gitt i vekt dersom ikke annet er angitt.
Eksempel 1
Forbindelse XIX ble fremstilt som følger:
en 3 1 tre-halset rundbunnet flaske ble utstyrt med en mekanisk øvre rører og et termometer, og flasken ble avkjølt i et isbad. En oppløsning av 8-aminokaprylsyre (100,0 g, 0,65 mol) i 2 M vandig natriumhydroksid (1,41) ble applisert i den rundbunnede flasken. Temperaturen til oppløsningen ble oppbevart ved omtrent 5°C og O-acetylsalicyloylklorid (198,6 g, 0,76 mol, 1,2 ekv.) ble tilsatt porsjonsvis over 7 timer. Blandingen ble omrørt ved 5°C i 12 timer for å tilveiebringe en gul homogen oppløsning. Oppløsningen ble surgjort med 1 M saltsyre til pH 6,8 og ble ekstrahert med etylacetqt (2 x 600 ml). pH til det vandige laget ble på ny jusert til 6,3 og ble ytterligere ekstrahert med etylacetat (2 x 600 ml). De organiske lagene ble kombinert, tørket over vannfri natriumsulfat, filtrert og avdampet under redusert tykk. Resten ble på ny oppløst i minimalt volum 2 M vandig natriumhydroksid og pH til oppløsningen var mellom 9,5 og 10. Blandingen ble surgjort ved omrøring med 1 M saltsyre til pH på omtrent 6,2, og et fast stoff ble dannet. Det faste stoffet ble filtrert, vasket med vann (3 x 300 ml) og omkrystallisert fra 55% metanol/vann (v/v) for å tilveiebringe forbindelse XVUJ som et off-white fast stoff (99,7 g, 57%).
Egenskapene er oppført nedenfor.
Smp. 116-117°C, <l>H NMR (300 MHz, DMSO-d6) 5: 12,70 (1H, br s), 11,95 (1H, br s) 8,81 (1H, t), 7,82 (1H, m), 7,38 (1H, m), 6,84 (2H, m), 2,36 (2H, q), 2,18 (2H, t), 1,50 (4H, br, m), 1,28 (6H, m), Analyse beregnet for C15H21NO4: C, 64,50; H 7,58; IN, 5,02. Funnet: C, 64,26; H, 7,81; N, 4,93.
Lignede prosedyrer ble anvendt for å fremstille forbindelsene IV, XXVII og XXVUJ.
Egenskapene er oppført nedenfor.
Forbindelse IV: Analyse beregnet for: Ci 1H13NO4: C, 59,9, H 5,87, N, 6,27
funnet: C, 58,89, H, 5,85, N, 6,07. <l>H NMR (300MHz, DMSO-d6): 8 1,8 (2H, m 2,3 (2H, t) 3,1 (2H, q) 6,9 (2H, t) 7,4 (1H, t) 7,8 (1H, d) 8,85 (1H, t) 12,0 (1H, s) 12,15 (1H, s)
Forbindelse XXVII: Analyse beregnet for Ci8H27NO4: C, 67,25, H, 8,48, N, 4,36
funnet: C, 67,23, H, 8,57, N, 4,20. <*>H NMR (300 MHz, DMSO-d6): 8 1,22-1,26 (m, 12H), 1,45-1,51 (m, 4H), 2,16 (t, 2H), 3,25 (qt, 2H, 6,85 (t, 2H), 7,37 (t, 1H), 7,81 (d, 1H), 8,79 (t, 1H), 11,95 (s, 1H), 12,72 (s, 1H)
Forbindelse XXVHI: <t>ø NMR (300 MHz, DMSO-d6): 8 1,26 (8H, br m), 1,49 (4H,
m), 2,17 (2H, t), 3,26 (2H, m), 6,86 (2H, m), 7,37 (1H, m), 7,83 (1H, m), 8,80 (1H, t), 11,95 (1H, s), 12,73 (1H, s).
Eksempel IA
En alternativ syntese av forbindelse XTX var som følger:
En 5 1 tre-halset rundbunnet flaske ble utstyrt med en varmekappe, en øvre mekanisk rører, en tilsetningstrakt og et termometer. Reaksjonen ble utført under en argonatmosfære. Hydroksylamin-O-sulfonsyre (196,7 g, 1,74 mol, 1,10 ekv.) og maursyre (11) ble tilført i en rundbunnet flaske og omrørt for å danne en hvit oppslemming. En oppløsning av cyklooktanon (200,0 g, 1,58 mol, 1,0 ekv.) i maursyre (600 ml) ble dråpevis tilsatt til den hvite oppslemmingen via tilsetningstrakten. Etter tilsetning ble tilsetningstrakten erstattet av en tilbakeløpskondensator, og reaksjonen ble oppvarmet til tilbakeløp (indre temperatur omtrent 105°C) i 1 time for å tilveiebringe en brun oppløsning. Etter at oppløsningen var avkjølt til romtemperatur ble den helt inn i en blanding av mettet vandig ammoniumklorid (1,5 1) og vann (1,5 1). Den vandige blandingen ble ekstrahert med kloroform (3 x 1200 ml). Kombinerte kloroformlag ble overført til en beholder, og mettet natriumbikarbonat (21) ble sakte tilsatt. Kloroformlaget ble deretter separert, tørket over vannfri natriumsulfat og avdampet under redusert trykk for å tilveiebringe en brun olje. Oljen ble plassert i en 500 ml rundbunnet flaske med en magnetisk rører. Den rundbunnede flasken ble plassert i et silikonoljebad og ble utstyrt med et kort stykke vakuum destillasjonshode utstyrt med et termometer. En Cow-type mottaker ble koblet til tre 250 ml flasker. 2-azacyklononanon (145 g, 65%, smp. 64-69°C) ble oppnådd ved vakuum destillasjon (fraksjon med hodetemperatur varierte fra 80 til 120°C ved trykk mellom 3,0 og 3,4 mmHg).
En 5 1 tre-halset rundbunnet flaske ble utstyrt med en varmekappe, en over hode mekanisk rører, en tilbakeløpskondensator og et 29 termometer. En suspensjon av 2-azacyklononanon (83 g, 0,59 mol, 1,0 ekv.) i 5 M vandig natriumhydroksid (650 ml, 3,23 mol, 5,5 ekv.) ble tilført i den rundbunnede flasken. Blandingen ble oppvarmet til tilbakeløp (indre temperatur omtrent 110°C) i 4 timer for å tilveiebringe en klar gul oppløsning. Varmekappen og tilbakeløpskondensatoren ble fjernet. Etter at oppløsningen var avkjølt til romtemperatur ble den fortynnet med vann (650 ml) og ytterligere avkjølt i et isbad. Finmalt O-acetylsalicyloylklorid (114,7 g, 0,59 mol, 1,0 ekv.) ble porsjonsvis tilsatt til oppløsningen med omrøring og fortsatt avkjøling i over 1 time. Etter ytterligere 30 minutter ble isbadet fjernet og omrøringen ble fortsatt ved romtemperatur i 21 timer for å tilveiebringe en brunaktig gul oppløsning. Den omrørte blandingen ble surgjort med 2M svovelsyre (omtrent 850 ml) til en pH på omtrent 1, og et gult fast stoff ble dannet. Det faste stoffet ble samlet ved filtrering og ble løst opp i varm etanol (1,7 1). Aktivert trekull (omtrent 5 g) ble tilsatt til metanol, og oppløsningen ble omrørt i 10 minutter. Aktivert trekull ble fjernet ved filtrering og trekullresten ble vasket med ytterligere 300 ml metanol. Vann (21) ble tilsatt til de kombinerte filtratene (dvs. 2 L metanol) og et off-white fast stoff presipiterte ved henstand ved 4°C over natt. Råproduktet ble filtrert og ble omkrystallisert fra 65% metanol/vann (v/v) for å tilveiebringe forbindelse XIX (69,1 g, 42%) som off-white fast stoff.
Egenskapene er oppført nedenfor:
Smp. 116-117°C; HPLC, <*>H NMR og analyse beregnet for C15H21NO4: C, 64,50; H, 7,58; N, 5,02. Funnet: C, 64,26; H, 7,71; N, 4,93.
Eksempel 2
Forbindelse XXXI ble fremstilt som følger:
l-aminoundec-10-ene. En blanding av 10-undecene-l-ol (5,00 g, 29,36 mmol, 1 ekv.) trifenylfosfin (7,70 g, 29,36 mmol, 1 ekv.) og fthalimid (4,32 g, 29,36 mmol, 1 ekv.) i tørr tetrahydrofuran (THF, 30 ml) ble omfattende omrørt under argon. Dietylazodikarboksylat (DEAD, 5,11 g, 29,36 mmol, 1 ekv.) ble fortynnet med THF (12 ml) og tilsatt dråpevis med sprøyte. Etter tilsetningen ble reaksjonen omrørt ved romtemperatur i 4 timer. Oppløsningsmiddelet ble avdampet under vakuum og eter (30 ml) ble tilsatt for å presipitere trifenylfosfinoksid og hydrazindikarboksylat som ble fjernet ved filtrering. Presipitatet ble skylt med eter (2 x 30 ml) og kombinerte filtrater ble avdampet for å tilveiebringe et gult fast stoff. Det gule faste stoffet ble trituert med varme heksaner (3 x 50 ml) og filtrert. Kombinerte heksaner ble avdampet for å tilveiebringe l-fthalimidylundec-10-ene som gul voks.
Den gule voksen ble løst opp i etanolisk oppløsning (38 ml) og hydrazinhydrat (1,47 g,
1 ekv., 29,36 mmol). Blandingen ble oppvarmet ved tilbakeløp i 2 timer. Etter at blandingen ble avkjølt til romtemperatur ble konsentrert saltsyre (30 ml) tilsatt og det faste stoffet ble filtrert gjennom et sintret glassfilter. Resten ble vasket med vann (50 ml) og de kombinerte filtratene ble avdampet for å tilveiebringe et gult fast stoff. Det gule faste stoffet ble på nytt oppløst i IM NaOH (100 ml) og ekstrahert med eter (2 x 50 ml). Eter ble tørket og avdampet for å tilveiebringe en gul olje. Oljen ble renset ved Kugelrohr destillasjon (ca 0,1 mmHg, 100°C) for å tilveiebringe l-aminoundec-10-ene (2) som en lysegul olje (3,29 g, 66%).
Egenskapene er oppført nedenfor.
<t>ø NMR (300 MHz, DMSO-d6); 8 1,23 (14H, br m), 1,99 (2H, m), 2,48 (2H, m), 4,94 (2H, m), 5,77 (1H, m). l-(O-acetylsalicyloylamino)undec-10-ene. O-acetylsalicyloylklorid (3,82 g, 19,25 mmol, 1 ekv.) i THF (30 ml) ble avkjølt i et isbad. Trietylamin (1,95 g, 19,25 mmol, 1 ekv.) etterfulgt av l-aminoundec-10-ene (3,26 g, 19,25 mmol, 1 ekv.) i THF (10 ml) ble tilsatt med sprøyte. Isbadet ble fjernet og reaksjonen ble omrørt ved romtemperatur i 3,5 timer. Etter fjerning av oppløsningsmiddelet ble resten løst opp i EtOAc (50 ml) og vasket med vann (2 x 30 ml). Det organiske laget ble tørket og avdampet for å tilveiebringe l-(O-acetylsalicyloyl-amino)undec-10-ene som en farveløs olje, i et kvantitativt utbytte, 6,59 g.
Egenskapene er oppført nedenfor.
<*>H NMR (300 MHz, DMSO-d6: 8 1,26 (12H, br s), 1,47 (2H, m), 1,99 (2H,m), 2,19 (3H,s), 3,15 (2H, q), 4,95 (2H, m), 5,78 (1H, m), 7,15 (1H, m), 7,30 (1H, m), 7,50 (2H, m), 8,24 (lH,t).
Forbindelse XXXI
l-(O-acetylsalicyloylamino)under-10-ene (6,59 g, 19,25 mmol, 1 ekv.) i diklormetan (108 ml) ble tilsatt til en blanding av vann (108 ml), svovelsyre (9M, 13 ml), iseddiksyre (2,16 ml) og metyltrialkyl(Cg-Cio)arnmoniumklorid (0,32 g) (Adogen® 464, tilgjengelig fra Aldrich Chemical Co.). Blandingen ble omfattende omrørt i et isbad og kaliumpermanganat (9,13 g, 57,75 mmol, 3 ekv.) ble tilsatt i porsjoner over 1,5 timer. Etter tilsetningen ble isbadet fjernet og den resulterende fiolette oppløsningen ble omrørt ved romtemperatur i 20 timer. Oppløsningen ble avkjølt i et isbad og natriumbisulfitt (6,8 g) ble tilsatt for å dissipere overskudd permanganat. Det organiske laget ble separert og det vandige laget ble ekstrahert med etylacetat (2 x 50 ml). Kombinerte organiske lag ble vasket med saltvann (50 ml), tørket og avdampet.
Natriumhydroksid (2M, 50 ml) ble tilsatt til resten og omrørt i 30 min. Oppløsningen ble fortynnet med vann (50 ml), vasket med eter (50 ml) og surgjort til pH 1 med 2M saltsyre. Et fast stoff ble dannet og samlet ved filtrering. Omkrystallisering av det faste stoffet fra 65% MeOH/r^O ga XXXI som et brunt fast stoff (2,78 g, 47% basert på aminet).
Egenskapene er oppført nedenfor.
<*>H NMR (300 MHz, DMSO-d6): 81,24 (10H, br m), 1,51 (4H, m), 2,17 (2H, t), 3,27 (2H, m), 6,86 (2H, m), 7,37 (1H m), 7,82 (1H, m), 8,80 (1H, t), 11,95 (1H, s), 12,72 (1H, s).
De andre forbindelsene ifølge oppfinnelsen kan lett bli fremstilt ved å følge fremgangsmåtene beskrevet i eksemplene 1-2.
Eksemplene 5- 15 - In vivo vurdering av rekombinant veksthormin i rotter Doseringssammensetninger ble fremstilt ved blanding av modifiserte aminosyrer og rekombinant humant veksthormon (rhGH) som oppført i tabell 1 nedenfor i en fosfatbufferoppløsning ved en pH på omtrent 7-8.
Rottene ble administrert doseringssammensetningen ved sublingual, oral føring, intraduodenal administrering eller kolonadministrering. Leveringen ble vurdert ved anvendelse av en ELISA analyse for rhGH fra Medix Biotech, Inc. For intrakolonadministrering ble en prøve fremstilt og dosert til fastende rotter ved 25 mg/kg av bærer i en buffret oppløsning inneholdende propylenglykol (0-50%) og 1 mg/kg rhGH.
Resultatene er illustrert i tabell 1 nedenfor.
Sammenlignende eksempel 5A
rhGH (6 mg/ml) ble administrert ved oral føring til en rotte, og leveringen ble vurdert ifølge fremgangsmåten i eksempel 5.
Resultatene er illustrert i tabell 1 nedenfor.
Eksemplene 16- 27 - In vivo vurdering av rekombinant veksthormon i rotter
Preparerin<g> av doseringsoppløsningene.
Leveringsmidlene ble rekonstituert med destillert vann og justert til pH 7,2-8,0 med enten vandig saltsyre eller vandig natriumhydroksid. En stamoppløsning av rhGH ble dannet ved blanding av rhGH, D-mannitol og glycin og ved oppløsning av denne blandingen i 2% glycerol/vann. Stamoppløsningen ble deretter tilsatt til leveringsmiddeloppløsningen. Flere leveringsmidler til aktivt middel forhold ble studert.
In vivo eksperimenter
Hann-Sprague-Dawley rotter med vekt på 200-250 g ble fastet i 24 timer og administrert ketamin (44 mg/kg) og klorpromazin (1,5 mg/kg) minutter før doseringen. Rottene ble administrert en av doseringsoppløsningene beskrevet ovenfor ved subkutan injeksjon, intranasal installering og sublingual innstillering. Blodprøvene ble samlet i serier fra halearterien for serurnkalsiurnkonsentrasjonsbestemmelse eller serum rhGH konsentrasjoner. Dosen til rhGH administrert i disse eksperimentene var 0,1 mg/kg.
Serum rhGH konsentrasjonene ble kvantifisert i et rhGH enzym immunoanalysetestsett. Resultatene er angitt i tabell 2 og figurene 1 og 2.
I figur 2 representerer sirklene responsen etter SL dosering av en vandig oppløsning av forbindelse XIX og rhGH. Firkantene representerer responsen etter gjendosering av en vandig oppløsning av forbindelsen XIX og rhGH. Trianglene representerer responsen etter IC dosering av en vandig oppløsning av forbindelsen XIX og rhGH. Dosen av forbindelsen XIX var 25 mg/kg og dosen til rhGH var 1 mg/kg.
Sammenlignbart eksempel 16A
rhGH (1 mg/kg) ble administrert ved oral føring til en rotte og leveringen ble vurdert ifølge fremgangsmåten i eksempel 16.
Resultatene er illustrert i tabell 2 nedenfor.
Eksemplene 28- 33 - In vivo vurdering av interferon i rotter
Doseringssammensetningene ble fremstilt ved blanding av modifiserte aminosyreforbindelser og interferon a2b som oppført i tabell 3 nedenfor i en Trizma® hydrokloridbufferoppløsning (Tris-HCl) ved en pH på omtretn 7-8. Propylenglykol (0-25%) ble tilsatt som et solubiliserende middel, om nødvendig.
Rottene ble administrert doseringsammensetningen ved oral føring, intraduodenal administrering eller intrakolon administrering. Leveringen ble vurdert ved anvendelse av en ELISA analyse for human interferon a fra Biosource, Inc.
Resultater av intrakolon administreringen er illustrert i tabell 3 nedenfor.
Sammenlignende eksempel 28A
Inferferon a2b (250 ug/kg) ble administrert intrakolon til rotter, og leveringen ble vurdert ifølge fremgangsmåten i eksempel 14.
Resultatene er illustrert i tabell 3 nedenfor.
Eksemplene 34- 37 - In vivo vurdering av laksekalsitonin i rotter Doseringssammensetningene ble dannet ved blanding av modifiserte aminosyrer og laksekalsitonin som oppført i tabell 4 nedenfor. 400 mg bærer ble tilsatt til 2,9 ml 25% vandig propylenglykol. Den resulterende oppløsningen ble omrørt, og pH ble justert til 7,2 med natriumhydroksid (1,0 N). Vann ble tilsatt for å bringe totalvolumet til 2,0 ml. Prøven hadde en endelig bærerkonsentrasjon på 200 mg/ml. Kalsitonin (10 ug) ble tilsatt til oppløsningen. Total kalsitonin konsentrasjon var 2,5 ug/ml.
For hver prøve ble en gruppe fastende rotter bedøvd. Rottene ble administrert doseringssammensetningen ved oral føring, intrakolon installasjon eller intraduodenal administrering. Blodprøvene ble samlet i serie fra halevenen. Serumkalsium ble bestemt ved testing med et kalsiumsett (Sigma Chemical Company, St. Louis, Missouri, USA).
Resultatene er illustrert i tabell 4 nedenfor.
Eksemplene 38- 43 - In vivo vurdering av laksekalsitonin i rotter
Preparering av doserin<g>soppløsnin<g>
Leveringsmidlene ble gjenopprettet med destillert vann og justert til pH 7,2-8,0 med enten vandig saltsyre eller vandig natriumhydroksid. En stamoppløsning av sCT ble dannet ved oppløsning av sCT i sitronsyre (0,085N). Stamoppløsningen ble deretter tilsatt til leveringsmiddeloppløsningen. Flere forskjellige leveringsmidler til aktivt middel forhold ble studert.
In vivo eksperimenter
Hann Sprague-Dawley rotter med vekt på 200-250 g ble fastet i 24 timer og ble administrert ketamin (44 mg/kg) og klorpromazin (1,5 mg/kg) 15 minutter før doseringen. Rottene ble administrert en av doseringsoppløsningene beskrevet ovenfor ved subkutan injeksjon. Blodprøvene ble samlet i serie fra halearterien for serumkalsium konsentrering.
Serumkalsiumkonsentreringer ble kvantifisert ved o-cresolfthalein komplekson metoden (Sigma) ved anvendelse av et UV/VIS spektrofotometer (Perkin Eimer). Resultatene er gitt i tabell 5.
Eksempel 38A
Laksekalsitonin ble administrert ved oral føring til rotter, og leveringen ble vurdert ifølge fremgangsmåten i eksempel 38.
Resultatene er angitt i tabell 5 nedenfor.
Eksemplene 44- 50 - In vivo vurdering av heparin i rotter
Doseringssammensetningene ble dannet ved blanding av modifiserte aminosyrer og heparin som oppført i tabell 4.1 et reagensrør ble en 900 mg bærer løst opp i 3 ml propylenglykol og 0,299 g natriumheparin ble løst opp i 3 ml vann. Oppløsningene ble blandet ved vortex behandling. Natriumhydroksid (10 M) ble tilsatt til den resulterende blandingen helt til en oppløsning ble oppnådd. pH ble deretter justert til 7,4 +/-0.5 med konsentrert saltsyre og den endelige oppløsningen ble sonikert ved 40°C i 30 minutter.
En gruppe av fastende, ikke-bedøvde rotter ble administrert doseringssammensetningene ved oral føring. Blodprøvene ble samlet ved hjertepunktur etterfulgt av administrering av ketamin (44 mg/kg). Heparinaktiviteten ble bestemt ved anvendelse av aktivert deltromboplastin tid (APTT) ifølge fremgangsmåten til Henry, J.B., Clinical Diagnosis and Management by Laboratory Methods; Philadelphia, PA; WB Saunders (1979). Resultatene er illustrert i tabell 6 nedenfor.
Sammenlignende eksempel 44A
Heparin (100 mg/kg) ble administrert ved oral føring til rotter, og heparinaktiviteten ble bestemt ifølge fremgangsmåten i eksempel 44.
Resultatene er illustrert i tabell 6 nedenfor.
Eksempel 51
Fremgangsmåten i eksempel 44 ble fulgt, med erstatning av lav molekylvekt heparin med heparin og varierende mengder av propylenglykol og vann for oppløsning etter behov.
Eksemplene 50- 58 - In vivo vurdering av parathyroid hormon i rotter
Preparering av doseringsoppløsninger.
Leveringsmidlene ble rekonstituert med destillert vann og/eller propylenglykol og justert til en tilsynelatende pH på 7,2-8,0 med enten vandig saltsyre eller vandig natriumhydroksid. En stamoppløsning av parathyroidhormon ble dannet ved oppløsning av parathyroidhormon i vann. Parathyroidhormonoppløsningen ble deretter tilsatt til leveringsmiddeloppløsningen. Flere forskjellige leveringsmiddel til aktivt middelforhold ble studert.
In vivo eksperimenter
Hann Sprague-Dawley rotter med vekt på 200-250 g ble fastet i 24 timer og tilført ketamin (44 mg/kg) og klorpromazin (1,5 mg/kg) 15 minutter før dosering. Rottene ble administrert en av doseringsoppløsningene beskrevet ovenfor ved oral føring eller intrakolon installasjon. Blodprøver ble samlet i serie fra halearterien for serumbestemmelse av parathyroidhormonkonsentrasjonen. Serumparathyroid hormon konsentrasjonene ble kvantifisert i et parathyroid hormon radioimmunoanalysetestsett.
In vivo oral administrering
Oral administrering av oppløsninger inneholdende parathyroidhormon (PTH) og ikke-a-aminosyreleveringsmidler ble testet in vivo i rotter. Testresultatet viser en betydelig økning i den orale biotilgjengeligheten av parathyroidhormonet sammenlignet med lignende administrering av aktivt middel alene. Data er presentert i tabell 7.
Claims (22)
1.
Forbindelse, karakterisert ved at den blir valgt fra gruppen bestående av
hvor hvor hvor eller salter derav.
2.
Sammensetning, karakterisert ved at den omfatter (a) et aktivt middel; og (b) en forbindelse valgt fra gruppen bestående av
hvor hvor hvor eller salter derav.
3.
Sammensetning ifølge krav 2, karakterisert ved at det aktive midlet er valgt blant gruppen bestående av et biologisk aktivt middel og et kjemisk aktiv middel.
4.
Sammensetning ifølge krav 3, karakterisert ved at det biologiske aktive midlet er valgt fra gruppen bestående av et peptid, et mukopolysakkarid, et karbohydrat, et lipid, et pesticid eller en hvilken som helst kombinasjon derav.
5.
Sammensetning ifølge krav 4, karakterisert ved at nevnte biologiske aktive middel er valgt fra gruppen bestående av humant veksthormon, bovint veksthormon, vekst hormon-firgjørende hormon, et interferon, interleukin-II, insulin, heparin, kalsitonin, erytropoietin, atriell naturetisk faktor, et antigen, et monoklonalt antistoff, somatostatin, adrenokortikotropin, gonadotropin frigjørende hormon, oksytosin, vasopressin, kromolyn natrium, vankomycin, parathyroid hormon, desferrioksamin (DFO), eller en hvilken som helst kombinasjon derav.
6.
Sammensetning ifølge krav 2, karakterisert ved at den er egnet for oral, intranasal, sublingval, intraduodonal, intramuskulær, eller subkutan administrering til et dyr med behov for et aktivt middel.
7.
Sammensetning ifølge krav 6, karakterisert ved at det aktivemidlet er et biologisk aktivt middel og sammensetningen er egnet for oral administrering til et dyr.
8.
Doseringsenhetsform, karakterisert ved at den omfatter (A) en sammensetning som definert i krav 2; og (B) (a) en eksipient, (b) et fortynningsmiddel, (c) et oppløsningsmiddel, (d) et smøremiddel, (e) et plastifiserende middel, (f) et farvemiddel, (g) en doseringsbærer eller (h) en hvilken som helst kombinasjon derav.
9.
Doseringsenhetsform ifølge krav 8, karakterisert ved at den omfatter en tablett, en kapsel eller en væske.
10.
Fremgangsmåte for fremstilling av en sammensetnig, karakterisert ved at den omfatter sammenblanding av (A) minst ett bilogisk aktivt middel, (B) minst en forbindelse ifølge krav 1 og (C) eventuelt en doseringsbærer.
11.
Forbindelse ifølge krav 1, karakterisert ved at den har formelen
eller salter derav.
12.
Sammensetning ifølge krav 3, karakterisert ved at den omfatter: (a) en forbindelse med formelen
eller et salt derav; og (b) et biologisk aktivt middel.
13.
Sammensetning ifølge krav 12, karakterisert ved at det biologisk aktive midlet er heparin.
14.
Forbindelse ifølge krav 1, karakterisert ved at den har formelen
i
eller salter derav.
15.
Sammensetning ifølge krav 3, karakterisert ved at den omfatter: (a) en forbindelse med formelen
eller et salt derav; og (b) et biologisk aktivt middel.
16.
Sammensetning ifølge krav 15, karakterisert ved at det biologisk aktive midlet er et humant veksthormon.
17.
Sammensetning ifølge krav 15, karakterisert ved at det biologisk aktive midlet er interferon.
18.
Sammensetning ifølge krav 15, karakterisert ved at det biologisk aktive midlet er calcitonin.
19.
Sammensetning ifølge krav 18, karakterisert ved at det biologisk aktive midlet er salmon calcitonin.
20.
Sammensetning ifølge krav 15, karakterisert ved at det biologisk aktive midlet er heparin.
21.
Sammensetning ifølge hvilket som helst av kravene 12,13 og 15 til 20, karakterisert ved at den er egnet for oral administrering.
22.
Sammensetning ifølge krav 3, karakterisert ved at den omfatter en forbindelse med formelen
eller et salt derav;
og parathyroid hormon.
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- 1995-03-31 US US08/414,654 patent/US5650386A/en not_active Expired - Lifetime
-
1996
- 1996-04-01 JP JP52975196A patent/JP3647041B2/ja not_active Expired - Lifetime
- 1996-04-01 WO PCT/US1996/004580 patent/WO1996030036A1/en active IP Right Grant
- 1996-04-01 NZ NZ307319A patent/NZ307319A/en not_active IP Right Cessation
- 1996-04-01 RU RU97118224/04A patent/RU2203268C2/ru active
- 1996-04-01 CA CA002214323A patent/CA2214323C/en not_active Expired - Lifetime
- 1996-04-01 PT PT96913778T patent/PT817643E/pt unknown
- 1996-04-01 TR TR97/01071T patent/TR199701071T2/xx unknown
- 1996-04-01 PL PL96322494A patent/PL188523B1/pl unknown
-
1997
- 1997-09-29 NO NO19974495A patent/NO325621B1/no not_active IP Right Cessation
- 1997-09-29 FI FI973828A patent/FI121748B/fi not_active IP Right Cessation
-
1998
- 1998-12-02 HK HK98112664A patent/HK1017995A1/xx not_active IP Right Cessation
-
2003
- 2003-05-19 JP JP2003140962A patent/JP2003313157A/ja active Pending
-
2006
- 2006-12-13 JP JP2006335831A patent/JP2007077170A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
JP2003313157A (ja) | 2003-11-06 |
NO974495L (no) | 1997-11-28 |
JP3647041B2 (ja) | 2005-05-11 |
RU2203268C2 (ru) | 2003-04-27 |
FI973828A0 (fi) | 1997-09-29 |
US5650386A (en) | 1997-07-22 |
HK1017995A1 (en) | 1999-12-10 |
JP2002506418A (ja) | 2002-02-26 |
CA2214323A1 (en) | 1996-10-03 |
NZ307319A (en) | 1999-10-28 |
FI121748B (fi) | 2011-03-31 |
PL322494A1 (en) | 1998-02-02 |
PT817643E (pt) | 2007-05-31 |
MX9707088A (es) | 1997-11-29 |
FI973828A (fi) | 1997-09-29 |
CA2214323C (en) | 2008-07-29 |
PL188523B1 (pl) | 2005-02-28 |
TR199701071T2 (xx) | 1999-03-22 |
WO1996030036A1 (en) | 1996-10-03 |
JP2007077170A (ja) | 2007-03-29 |
NO974495D0 (no) | 1997-09-29 |
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