NO315027B1 - Antitumor-preparater inneholdende taxan-derivater - Google Patents
Antitumor-preparater inneholdende taxan-derivater Download PDFInfo
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- NO315027B1 NO315027B1 NO19951327A NO951327A NO315027B1 NO 315027 B1 NO315027 B1 NO 315027B1 NO 19951327 A NO19951327 A NO 19951327A NO 951327 A NO951327 A NO 951327A NO 315027 B1 NO315027 B1 NO 315027B1
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- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Description
Foreliggende oppfinnelse angår kombinasjoner av taxol, Taxotére og deres analoger og terapeutiske stoffer som kan benyttes ved behandling av neoplastiske sykdommer.
Taxol, Taxotére og deres analoger, som oppviser interessante antitumorale og anti-leukemiske egenskaper, er spesielt brukbare ved behandling av ovarie-, bryst- eller lungekreft.
Fremstillingen av taxol, Taxotére og deres derivater er for eksempel gjenstand for de europeiske patenter EP 0 253 738 og EP 0 253 739 samt den internasjonale søknad PCT WO 9209589.
Generelt ligger de benyttede doser som avhenger av egne faktorer hos personen som behandles, mellom 1 og 10 mg/kg ved intraperitoneal administrering og mellom 1 og 3 ml/kg ved intravenøs administrering.
I en forsøksrapport fra University Hospital, Groningen, Holland, (van Putten et al.) er det vist at en kombinasjon av docetaxel (Taxotére) og carboplatin (et koordinasjons-kompleks av platina) gir en forbedret, terapeutisk virkning ved behandling av pasienter med ikke-småcellet lungecancer (NSCLC).
I en intern forsøksrapport fra Rhone-Poulenc Rorer S.A. (Bissery et al., 1996) er det vist at en kombinasjon av docetaxel (Taxotére) og irinotecan (en topoisomeraseinhibitor) oppviser en synergistisk virkning mot brystadenokarcinom.
I en erklæring av dr. A. Riva, inngitt den 21. august 1998, i forbindelse med US SN 08/967036, er det vist at en kombinasjon av Taxotére og doxorubicin (et antibiotikum) gir en synergistisk virkning ved behandling av pasienter med metastatisk lungecancer.
Det er nu funnet, og det er gjenstand for oppfinnelsen, at effektiviteten til taxol, Taxotére og deres analoger, betydelig kan forbedres når de administreres i forbindelse med minst et stoff som er terapeutisk brukbart ved anti-cancer-behandling med en virknings-mekanisme som er identisk med eller forskjellig fra den ti) taxan-derivatene.
Foreliggende oppfinnelse angår således kombinasjoner av Taxotére med minst ett terapeutisk stoff som er brukbart ved behandling av neoplastiske sykdommer, og disse kombinasjoner karakteriseres ved at det terapeutiske stoff er valgt blant alkyleringsmidler, antimetabolitter, vinca-alkaloider, épidofyllotoksiner, antibiotika, topoisome-
rase-inhibitorer og koordinasjonskomplekser av platina.
Blant de stoffer som kan benyttes i forbindelse med eller i kombinasjon med taxol, Taxotére og deres analoger, kan nevnes alkyleringsmidler som cyklofosfamid, ifosfamid, mefalan, heksametylmelamin, tiotépa eller dikarbacin, antimetabolitter, for eksempel pyrimidinanaloger som 5-fluoracil eller cytarabin eller dennes analoger som 2-fluor-desoksytidin eller folsyreanaloger som metotrexat, idatrexat eller trimetrexat, sopp-gifter, for eksempel vinca-alkaloider som vinblastin eller vincristin eller deres syntese-analoger som navelbin, eller estramustin eller taxoider, epidofilotoksiner som etopsid eller teniposid, antibiotika som daunorubicin, doxorubicin, bléomycin eller mitomycin, enzymer som L-asparaginase, topo-isomerase-inhibitorer som camptotécin-derivater valgt blant CPT-11 og topotécan eller pyridobenzoindol-derivater eller forskjellige midler som pro-carbacin, mitoxantron, koordinasjonskomplekser av platina som cis-platin eller carboplatin, biologisk respons-modifikatorer eller vekst-faktor-inhibitorer som interferoner eller inter-leukiner.
Aktiviteten til produktene avhenger av de benyttede doser og det er derfor mulig å benytte forhøyede doser og å øke aktiviteten mens man reduserer toksisitetsfenomenene eller forsinker deres opptreden i forbindelse med taxol, Taxotére, deres analoger eller deres kombinasjoner med andre terapeutisk aktive stoffer som vekst-faktorer av typen hématopoYetin-forbindelser som G-CSF eller GM-CSF eller visse interleukiner.
Kombinasjonene eller forbindelsene ifølge oppfinnelsen tillater å unngå eller å forsinke de pleiotropiske motstandsfenomener eller muskelmedikamentresistens-fenomenene.
Mere spesielt angår oppfinnelsen sambruk av taxol, Taxotére og deres analoger med vinca-alkaloider, cyklofosfamid, 5-fluoruracil, doxorubicin, cisplatin og étoposid.
Den forbedrede effektivitet av kombinasjonen ifølge oppfinnelsen kan påvises ved be-stemmelse av en terapeutisk synergisme.
Effektiviteten for en kombinasjon ifølge oppfinnelsen kan også karakteriseres ved en addisjon av virkningen av hver bestanddel.
En kombinasjon manifesterer en terapeutisk synergisme hvis den er terapeutisk over-legen den ene eller andre av bestanddelene benyttet ved sin optimale dose [T.H. Corbett et coil. "Cancer Treatment Reports", 66,1187 (1982)].
For å påvise effektiviteten for en kombinasjon kan det være nødvendig å sammenligne den tolererte maksimale dose for kombinasjonen med den tolererte maksimale dose for hver av bestanddelene isolert i det angjeldende studium. Denne effektivitet kan kvantifi-seres, for eksempel ved logiQ av cellene som drepes og som bestemmes i henhold til følgende formel:
der T - C betyr vekstforsinkelsen for cellene som er den midlere tid i dager for at tumorene i den behandlede gruppe (T) og tumorene fra sammenligningsgruppen (C) har nådd en på forhånd bestemt verdi (for eksempel 1 g) og Tj betyr tiden i dager som er nødven-dig for en dobling av tumor-volumet hos referansedyrene. [T.H. Corbett et coil. "Cancer", 40, 2660.2680 (1977); F.M. Schabel et coil., "Cancer Drug Development", Part B, "Methods in Cancer Research", 17,3-51, New York, Academic Press Inc. (1979)]. Et produkt anses som aktivt hvis log^o for de drepte celler er lik eller større enn 0,7. Et produkt anses som meget aktivt hvis logjø for de drepte celler er 2,8.
Kombinasjonen, benyttet i den egentlige maksimalt tolererte dose, der hver av bestanddelene er tilstede i en mengde generelt lik eller større enn den tolererte maksimale dose, manifesterer en terapeutisk synergi når logiø for drepte celler er større enn verdien for logio for drepte celler for den beste bestanddel når denne administreres alene.
Effektiviteten for kombinasjonene på faste tumorer kan bestemmes eksperimentelt på følgende måte: Dyrene som underkastes forsøkene, generelt mus, podes bilateralt, subkutant, med 30 til 60 mg av et fragment av en tumor på dag 0. Dyrene som bærer tumorene blandes før de underkastes forskjellige behandlinger og kontroller. Når det gjelder behandling av avan-serte tumorer lar man tumoren utvikle seg til den ønskede størrelse, dyr med utilstrekke-lig utviklede tumorer eller mineres. De valgte dyr fordeles vilkårlig for å underkaste dem kontroller og behandlinger. Dyr som ikke bærer tumorer kan likeledes underkastes de samme behandlinger som bærerdyrene for derved å kunne skille den toksiske virkning fra den egentlige virkning på tumoren. Kjemoterapien begynner vanligvis 3 til 22 dager efter poding i henhold til typen tumor og dyrene observeres hele dagen. De forskjellige dyregrupper veies 3 eller 4 ganger pr. uke inntil det maksimale vekt-tap er nådd hvorefter gruppene veies minst 1 gang pr. uke inntil slutten av prøven.
Tumorene måles to eller tre ganger pr. uke inntil tumoren har nådd ca. 2 gram eller inntil dyrets død hvis dette inntrer før tumoren når 2 gram. Dyrene underkastes autopsi efter avlivning. Den antitumorale aktivitet bestemmes som en funksjon av de forskjellige registrerte parametre.
For å studere kombinasjonene på leukemier blir dyrene podet med et bestemt antall celler og den antitumorale aktivitet bestemmes ved økningen av overlevelsestiden for mus som behandles i forhold til sammenligningsmus. Et produkt anses som aktivt hvis tids-økningen for overlevelse er over 27 % og det anses som meget aktivt hvis den er over 75 % når det gjelder leukemi P388.
Som eksempel gies i de følgende tabeller verdier som er oppnådd med kombinasjon av Taxotére og forskjellige kjemoterapeutiske midler som cyklofosfamid (alkyleringsmid-del), 5-fluor-uracil (antimetabolitt), étoposid (hemisyntesemiddel for podofyllotoksin) og vincristin (vinca-alkaloid) som benyttes i optimal dose. Foreliggende oppfinnelse angår også produkter inneholdende Taxotére og minst ett terapeutisk brukbart stoff som angitt ovenfor ved behandling av neoplastiske sykdommer som kombinasjonspreparater for en samtidig, separat eller tidsforskutt anvendelse ved anticancerterapi.
Produktene som utgjør kombinasjonen kan administreres samtidig, separat eller på tidsforskutt måte for å oppnå den maksimale kombinasjonseffektivitet; hver administrering kan ha en variabel varighet som tillater en hurtig total administrering ved kontinuerlig perfusjon.
Dette har ifølge oppfinnelsen som resultat at kombinasjonene ikke kun er begrenset til de som oppnås ved den fysiske sammenføring av bestanddelen men også den som tillater en separert administrering som kan være samtidig eller forskutt i tid.
Produktene ifølge oppfinnelsen er fortrinnsvis produkter som kan administreres parente-ralt. Imidlertid kan produktene administreres oralt eller inlraperetonealt når det gjelder loco-regionalc terapier.
Produktene for parenteral administrering cr generelt farmasøytisk godtagbare, sterile oppløsninger eller suspensjoner som eventuelt kan fremstille ekstermporalt på bruks-øyeblikket. For fremstilling av ikke-vandige oppløsninger eller suspensjoner kan man benytte naturlige, vegitabilske oljer som olivenolje, sesamolje eller paraffinolje eller injiserbare organiske estere som etyloleat. De vandige, sterile oppløsninger kan bestå av en oppløsning av produktet i vann. De vandige oppløsninger egner seg for intravenøs administrering hvis pH-verdien justeres riktig eller hvis det oppnås isotonisitet, for eksempel ved en tilstrekkelig mengde natriumklorid eller glucose. Steriliseringen kan gjennomføres ved oppvarming eller på en hvilken som helst annen måte som ikke end-rer preparatet. Kombinasjonen kan også foreligge i form av liposomer eller i form av en forbindelse med bærere som cyklodekstriner eller polyetylenglykoler.
Produktene for oral eller intraperetoneal-administrering er fortrinnsvis vandige oppløs-ninger eller suspensjoner.
I kombinasjonene ifølge oppfinnelsen der anvendelsen av bestanddelene kan være samtidig, separat eller forskutt i tid, er det særlig fordelaktig at mengden av taxan-derivat utgjør 10 til 90 vekt-% av kombinasjonen idet denne mengde kan variere som funksjo-nen av arten av det benyttede substrat, den tilsiktede effektivitet og typen av cancer som skal behandles.
Kombinasjonene ifølge oppfinnelsen er spesielt brukbare ved behandling av bryst-, ovarie- eller lungekreft. Spesielt kan de oppvise den fordel at de tillater bruk av bestanddelene ved lavere doser enn når de benyttes alene.
Det følgende eksempel skal illustrere oppfinnelsen.
Eksempel
På i og for seg kjent måte fremstilles, for intravenøs administrering, ampuller på 10 cm<3 >inneholdende 10 mg Taxotére.
Man fremstiller, på i og for seg kjent måte, for intravenøs administrering, ampuller på
5 cm3 inneholdende 100 mg étoposid.
Disse oppløsninger administreres samtidig, efter hensiktsmessig fortynning, ved perfusjon.
Behandlingen kan gjentas flere ganger pr. dag eller pr. uke inntil det er oppnådd en par-tiell eller total remisjon eller helbredelse.
Claims (10)
1.
Kombinasjoner av Taxotére med minst ett terapeutisk stoff som er brukbart ved behandling av neoplastiske sykdommer, karakterisert ved at det terapeutiske stoff er valgt blant alkyleringsmidler, antimetabolitter, vinca-alkaloider, épidofyllotoksiner, antibiotika, topoisomerase-inhibitorer og koordinasjonskomplekser av platina.
2.
Kombinasjon ifølge krav 1, karakterisert ved at alkyleringsmidlene er valgt blant cyklofosfamid, ifosfamid, melfalan, heksametylmelamin, tiotépa eller decarbazin.
3.
Kombinasjoner ifølge krav 1, karakterisert ved at antimetabolittene er valgt blant 5-fluoruracil, cytarabin og folsyreanaloger valgt blant métotrexat, idatrexat eller trimetrexat.
4.
Kombinasjoner ifølge krav 1, karakterisert ved at vinca-alkaloidene også omfatter deres syntetiske eller semisyntetiske analoger.
5.
Kombinasjon ifølge krav 1, karakterisert ved at epidofyllotoksinene er valgt blant etoposid og teniposid.
6.
Kombinasjoner ifølge krav 1, karakterisert ved at antibiotikumet er valgt blant daunorubicin, doxorubicin, bléomycin eller mitomycin.
7.
Kombinasjoner ifølge krav 1, karakterisert ved at topoisomerase-inhibitorene er valgt blant kamptotesin og derivater derav valgt blant CPT-11 og topotécan og derivater av pyridobenzoindol.
8.
Kombinasjon ifølge krav 1, karakterisert ved at koordinasjonskomplekser av platina er valgt blant cisplatin og carboplatin.
9.
Kombinasjoner ifølge et hvilket som helst av kravene 1 til 8, karakterisert ved at de inneholder 10 til 90 vekt-% Taxotére.
10.
Produkter inneholdende Taxotére og minst et terapeutisk brukbart stoff som angitt i et av kravene 1 til 9 ved behandling av neoplastiske sykdommer som kombinasjonspreparater for en samtidig, separat eller tidsforskutt anvendelse ved anticancerterapi.
Applications Claiming Priority (2)
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FR9213525A FR2697752B1 (fr) | 1992-11-10 | 1992-11-10 | Compositions antitumorales contenant des dérivés du taxane. |
PCT/FR1993/001096 WO1994010995A1 (fr) | 1992-11-10 | 1993-11-08 | Compositions antitumorales contenant des derives du taxane |
Publications (3)
Publication Number | Publication Date |
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NO951327L NO951327L (no) | 1995-04-05 |
NO951327D0 NO951327D0 (no) | 1995-04-05 |
NO315027B1 true NO315027B1 (no) | 2003-06-30 |
Family
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO19951327A NO315027B1 (no) | 1992-11-10 | 1995-04-05 | Antitumor-preparater inneholdende taxan-derivater |
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US (13) | US5728687A (no) |
EP (4) | EP1295597A1 (no) |
JP (1) | JP3974938B2 (no) |
KR (2) | KR100334051B1 (no) |
AT (2) | ATE165002T1 (no) |
AU (1) | AU680845B2 (no) |
CA (1) | CA2149055C (no) |
CZ (2) | CZ288033B6 (no) |
DE (2) | DE69330724T2 (no) |
DK (2) | DK0667771T3 (no) |
ES (2) | ES2163076T3 (no) |
FI (1) | FI952248A0 (no) |
FR (1) | FR2697752B1 (no) |
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HU (1) | HU223773B1 (no) |
MX (1) | MX9306924A (no) |
NO (1) | NO315027B1 (no) |
NZ (1) | NZ257585A (no) |
PL (1) | PL173951B1 (no) |
PT (1) | PT827745E (no) |
RU (1) | RU2131250C1 (no) |
SK (1) | SK282867B6 (no) |
TW (1) | TW386877B (no) |
WO (1) | WO1994010995A1 (no) |
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1992
- 1992-11-10 FR FR9213525A patent/FR2697752B1/fr not_active Expired - Lifetime
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1993
- 1993-11-02 ZA ZA938182A patent/ZA938182B/xx unknown
- 1993-11-05 MX MX9306924A patent/MX9306924A/es not_active IP Right Cessation
- 1993-11-06 TW TW082109299A patent/TW386877B/zh not_active IP Right Cessation
- 1993-11-08 EP EP02028931A patent/EP1295597A1/fr not_active Withdrawn
- 1993-11-08 US US08/424,470 patent/US5728687A/en not_active Expired - Lifetime
- 1993-11-08 HU HU9501372A patent/HU223773B1/hu active IP Right Grant
- 1993-11-08 AU AU54253/94A patent/AU680845B2/en not_active Expired
- 1993-11-08 PL PL93308902A patent/PL173951B1/pl unknown
- 1993-11-08 ES ES97117252T patent/ES2163076T3/es not_active Expired - Lifetime
- 1993-11-08 JP JP51178394A patent/JP3974938B2/ja not_active Expired - Lifetime
- 1993-11-08 DE DE69330724T patent/DE69330724T2/de not_active Expired - Lifetime
- 1993-11-08 CZ CZ19951193A patent/CZ288033B6/cs not_active IP Right Cessation
- 1993-11-08 EP EP93924682A patent/EP0667771B1/fr not_active Expired - Lifetime
- 1993-11-08 PT PT97117252T patent/PT827745E/pt unknown
- 1993-11-08 EP EP01101665A patent/EP1093811A1/fr not_active Ceased
- 1993-11-08 NZ NZ257585A patent/NZ257585A/en not_active IP Right Cessation
- 1993-11-08 DE DE69318033T patent/DE69318033T2/de not_active Expired - Lifetime
- 1993-11-08 AT AT93924682T patent/ATE165002T1/de active
- 1993-11-08 WO PCT/FR1993/001096 patent/WO1994010995A1/fr active IP Right Grant
- 1993-11-08 KR KR1019950701848A patent/KR100334051B1/ko not_active IP Right Cessation
- 1993-11-08 AT AT97117252T patent/ATE205083T1/de active
- 1993-11-08 SK SK595-95A patent/SK282867B6/sk not_active IP Right Cessation
- 1993-11-08 CA CA002149055A patent/CA2149055C/fr not_active Expired - Lifetime
- 1993-11-08 KR KR1020017011197A patent/KR20030096445A/ko active Search and Examination
- 1993-11-08 EP EP97117252A patent/EP0827745B1/fr not_active Expired - Lifetime
- 1993-11-08 ES ES93924682T patent/ES2114620T3/es not_active Expired - Lifetime
- 1993-11-08 DK DK93924682T patent/DK0667771T3/da active
- 1993-11-08 DK DK97117252T patent/DK0827745T3/da active
- 1993-11-08 RU RU95112842A patent/RU2131250C1/ru active
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1995
- 1995-04-05 NO NO19951327A patent/NO315027B1/no not_active IP Right Cessation
- 1995-05-09 FI FI952248A patent/FI952248A0/fi not_active Application Discontinuation
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1997
- 1997-11-10 US US08/967,036 patent/US5908835A/en not_active Expired - Lifetime
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1998
- 1998-04-16 GR GR970403093T patent/GR3026666T3/el unknown
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1999
- 1999-08-10 US US09/371,520 patent/US6214863B1/en not_active Expired - Lifetime
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2000
- 2000-02-18 US US09/506,902 patent/US6239167B1/en not_active Expired - Lifetime
- 2000-11-08 CZ CZ20004149A patent/CZ290120B6/cs not_active IP Right Cessation
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2001
- 2001-09-06 GR GR20010400691T patent/GR3036537T3/el unknown
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2002
- 2002-04-30 US US10/134,391 patent/US20020197245A1/en not_active Abandoned
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2003
- 2003-04-25 US US10/422,823 patent/US7989489B2/en not_active Expired - Fee Related
- 2003-12-30 US US10/747,372 patent/US8124650B2/en not_active Expired - Fee Related
- 2003-12-30 US US10/747,206 patent/US7994212B2/en not_active Expired - Fee Related
- 2003-12-30 US US10/747,279 patent/US8101652B2/en not_active Expired - Fee Related
- 2003-12-30 US US10/747,410 patent/US20040152673A1/en not_active Abandoned
- 2003-12-30 US US10/747,207 patent/US20040157786A1/en not_active Abandoned
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2005
- 2005-06-10 US US11/149,178 patent/US20050226940A1/en not_active Abandoned
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2011
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