NO328734B1 - Anvendelse av ibandroninsyre for fremstilling av medikamenter til behandling og prevensjon av osteoprose - Google Patents
Anvendelse av ibandroninsyre for fremstilling av medikamenter til behandling og prevensjon av osteoprose Download PDFInfo
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- NO328734B1 NO328734B1 NO20044195A NO20044195A NO328734B1 NO 328734 B1 NO328734 B1 NO 328734B1 NO 20044195 A NO20044195 A NO 20044195A NO 20044195 A NO20044195 A NO 20044195A NO 328734 B1 NO328734 B1 NO 328734B1
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- Prior art keywords
- pharmaceutically acceptable
- ibandronic acid
- osteoporosis
- drug
- salts
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Classifications
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- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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Description
Foreliggende oppfinnelse vedrører anvendelsen av (1-hyd-roksy-3-(N-metyl-N-pentyl)aminopropyliden-1,1,-bisfonfonin-syre (ibandroninsyre) eller farmasøytisk akseptable salter derav for fremstilling av medikamenter til forebygging eller behandling av forstyrrelser særpreget ved patologisk økning i benresorpsjon, spesielt for å forhindre og be-handle osteoporose, og hvor medikamentet omfatter de trekk som er nevnt i krav 1.
Ben tjener primært som en støtte, og ben er følgelig ofte ansett å være et enkelt byggemateriale. Ben er imidlertid et komplisert biomateriale tilpasset til en bred variasjon av behov, stimulanser og skader som den blir utsatt for. Endoproteser er tilgjengelige som erstatninger for ben og ledd. Endoproteser, selv når biomekanisk svært forfinet, har ikke en aktiv effekt på miljø- og belastningsfaktorer.
Et mangfold av forstyrrelser hos mennesker og pattedyr innebærer eller er assosiert med unormal benresorpsjon. Slike forstyrrelser inkluderer, men er ikke begrenset til, osteoporose, Pagets sykdom, periprostetisk bentap eller osteo-lyse, og hyperkalsemi av ondartet og metastatisk bensykdom. Den meste vanlige av disse forstyrrelsene er osteoporose, som er den mest vanlige manifestering som forekommer post-menopausalt hos kvinner. På grunn av osteoporose, så vel som andre forstyrrelser assosiert med bentap, er kroniske lidelser, er det antatt at egnet terapi vil vanligvis kreve kronisk behandling.
Bisfosfonater, det vil si bisfosfoninsyrer eller farmasøy-tisk akseptable salter derav, er syntetiske analoger av na-turlig forekommende pyrofosfat. På grunn av sin markerte affinitet for fastfasekalsiumfosfat, binder bisfosfonater kraftig til benmineral. Farmakologisk aktive bisfosfonater er godt kjent på fagområdet og er sterke hemmere av benresorpsjon og er derfor nyttige ved behandlingen og forhindring av sykdommer som innebærer unormal benresorpsjon, spesielt osteoporose, Pagets sykdom, hyperkalsemi ved ondar-tethet, og metastatisk og metaboliske benforstyrrelser.
Bisfosfonater som farmasøytiske agenser er for eksempel beskrevet i EP-A-170,228, EP-A-197,478, EP-A-22,751; EP-A-252,504, EP-A-252,505, EP-A-258,618, EP-A-350,002, EP-A-273, 190, WO-A-90/00798, etc.
Farmasøytiske former for bisfosfonater som er i dag på mar-kedet er orale formuleringer (tabletter eller kapsler) eller løsninger for intravenøs injeksjon eller infusjon. De er godt tolerert systemisk når administrert ved terapeu-tiske doser. Bisfosfonater som en klasse er imidlertid ir-riterende for hud og slimhinnemembraner og bivirkninger i fordøyelsessystemet kan oppstå når de gis på en kontinuer-lig basis oralt, som for eksempel uheldige tilstander i spiserøret eller forstyrrelser i den gastrointestinale ka-nalen. Følgelig, og på grunn av sin lave orale biotil-gjengelighet, har den orale administrasjonsveien frem til i dag, måttet følge besværlige anbefalinger for bruk av pasi-enten.
Bisfosfonater kan klassifiseres i to grupper med forskjel-lige virkningsmoduser. Ibandronat tilhører den sterke nit-rogeninneholdende bisfosfonatgruppen [Russell RGG, Rogers MJ. Bisphosphonates: From the laboratory to the clinic and back again. Bone 25(1):97-106 (1999); Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith JC. Cellular Molecular mechanisms of action of bisphosphonates. Cancer 88(12) Suppl: 2961-2978 (2000)]. Ibandronat er en av de mest kraftfulle bisfosfonater som i dag er under klinisk utvikling i osteoporose og metastatiske bensykdommer. Ibandronat er 2, 10, 50 og 500 ganger mer kraftfull enn henholdsvis risedronat, alendronat, pamidronat, og klodro-nat i dyremodeller av benresorpsjon [Muhlbauer R.C., F. Bauss, R. Schenk, M. Janner, E. Bosies, K. Strein, og H. Fleisch. BM 21.0955, a potent new bisphosphonate to inhibit bone resorption. J. Bone Miner. REs. 6: 1003-1011 (1991)].
Ibandronat hemmer benresorpsjon uten å hemme minerali-seringen (Miihlbauer R.C., F. Bauss, R. Schenk, M. Janner, E. Bosies, K. Strein, og H. Fleisch. BM 21.0955, a potent new bisphosphonate to inhibit bone resorption. J. Bone Miner. Res. 6; 1003-1011 (1991)). Det har vært vist å senke osteoklastaktivitet, og således hemmer bendestruksjon. Ved høye doser re-duserer den også antallet osteoklaster (Miihlbauer R.C., F. Bauss, R. Schen, M. Janner, E. Bosies, K. Strein, og H. Fleisch. BM 21.0955, a potent new bisphosphonate to inhibit bone resoption. J. Bone Miner. Res. 6; 1003-1011 (1991)).
Som beskrevet blir bisfosfonater akseptert å gi sterk effekt ved håndteringen av osteoporose. Gitte administra-sjonsbegrensninger assosiert med lav oral biotilgjengelig-het og faren for gastrointestinale effekter foreligger imidlertid en klar åpning for en kur som byr på forbedret beleilighet og fleksibilitet, som fører til et høyere an-vendelighetsnivå og bedre pasient behandling/tilfredsstill-het. Intermitterende kurer slik som for eksempel en ukent-lig administrasjon, har vært beskrevet på fagområdet, men slike intermitterende behandlinger fører ikke til de øns-kede resultatene.
Det har nå blitt funnet at forhindringen eller behandlingen av forstyrrelser særpreget ved patologisk økning i benresorpsjon slik som osteoporose, kan forbedres ved månedlig administrasjon av 150 mg av et bisfonsfonat eller farmasøy-tisk akseptabelt salt derav, spesielt ved en månedlig administrasjon av ibandronat, det vil si ibandroninsyre eller et farmasøytisk akseptabelt salt derav.
Foreliggende oppfinnelse vedrører således anvendelsen av ibandroninsyre eller et farmasøytisk akseptabelt salt derav, for fremstillingen av medikamenter for forebygging eller behandling av lidelser særpreget ved patologisk økning i benresorpsjon, hvori medikamentet a) omfatter en effektiv dose på omkring 150 mg ibandroninsyre eller et akseptabelt salt derav og b) medikamentet er tilrettelagt for å bli administrert oralt en dag per måned.
Før det kliniske ibandronat utviklingsprogrammet ble stilt ferdig, hadde ingen bisfosfonat vist mulig benbruddreduk-sjonseffektivitet med et medikamentfritt interval lengre enn den daglige administrasjon. I korthet kan det opplyses at det er ganske uventet at fordelen ved redusert benbrudd kan oppnås fra månedlig administrasjon av oral ibandronat med en enkel tablett administrasjonsplan.
Ibandroninsyre eller farmasøytisk akseptable salter derav kan således anvendes for fremstillingen av et medikament for forhindring eller behandling av forstyrrelser særpreget ved patologisk økning i benresorpsjon, for eksempel osteoporose .
Uttrykket "farmasøytisk akseptabel" som benyttet heri betyr saltene eller chelaterende agenser som er akseptable med hensyn til toksisitet.
Uttrykket "farmasøytisk akseptabelt salt" viser til ammoniakksalter, alkaliske metallsalter slik som kalium og natrium (inkludert mono-, di- og tri-natrium) salter (som er foretrukket) , jordalkalimetallsalter slik som kalsium og magnesiumsalter, salter med organiske baser slik som dicykloheksylaminsalter, N-metyl-D-glukamin, og salter med amino-syrer slik som arginin, lysin og lignende.
Uttrykket "forstyrrelser særpreget ved patologisk økning i benresorpsjon" viser til medisinsk beskrevne lidelser med eller uten en identifiserbar årsak (slik som post-menopau-sal osteoporose, idiopatisk juvenil osteoporose, osteoporose assosiert med Klinefelter's syndrom, mannlig osteoporose, osteoporose grunnet ernæringsfaktorer, organtrans-plantasjons relatert osteoporose, immobilitet assosiert osteoporose, betennelsestilstander og kortikosteroid indusert osteoporose).
Uttrykket "medikament" viser til en farmasøytisk sammensetning. Uttrykket omfatter enkelt- eller flerlags admini-strasjonsopplegg.
Medikamentet blir fortrinnsvis administrert på en dag per måned. Medikamentet blir fortrinnsvis administrert som en enkel dose.
Uttrykket "effektiv dose" viser til omtrent 50 til omtrent 250 mg, mest foretrukket til omtrent 100 til omtrent 150 mg, av ibandroninsyre eller et farmasøytisk akseptabelt salt derav. Som bemerket kan den effektive dosen være enkel dose.
"Bisfosfoninsyrer og farmasøytisk akseptable salter derav" som farmasøytiske agenser er beskrevet i for eksempel US patentnumrene 4,509,612, 4,666,895, 4,719,203, 4,777,163, 5,002,937, 4,971,958 og 4,958,839 og i europeisk patent-søknader nr. 252,504 og 252,505.
Fremgangsmåter for fremstilling av bisfosfoninsyrer og far-masøytisk akseptable salter derav kan finnes i, for eksempel US patentnumrene 3,962,432, 4,054,598, 4,267,108, 4,327,039, 4,407,761, 4,621,077, 4,624,947, 4,746,654, 4,922,077, 4,970,335, 5,019,651, 4,761,406, 4,876,248; i J. Org. Chem. 32, 4111 (1967) og europeisk patentsøknad 252,504. Eksempler på basesalter av bisfosfoninsyrer inkluderer ammoniakksalter, alkaliske metallsalter slik som kalium og natrium (inkludert mono-, di- og tri-natrium) salter (som er foretrukket), jordalkalimetallsalter slik som kalsium- og magnesiumsalter, salter med organiske baser slik som dicykloheksylaminsalter, N-metyl-D-glukamin, og salter med aminosalter slik som arginin, lysin og lignende. Ikke-toksiske, fysiologisk akseptable salter er foretrukket. Saltene kan fremstilles ved fremgangsmåter kjent på fagområdet, slik som beskrevet i europeisk patentsøknad 252,504 eller i US patentnummer 4,922,077.
Medikamentet omfatter fortrinnsvis 150 mg ibandroninsyre eller et farmasøytisk akseptabelt salt derav. Medikamentet blir fortrinnsvis administrert som en enkel dose.
Ibandroninsyre(l-hydroksy-3-(N-metyl-N-pentyl)aminopropyli-den-1,1-bisfosfoninsyre) eller fysiologisk kompatible salter derav er spesielt foretrukket, for eksempel ibandroninsyre, mononatriumsalt, monohydrat.
Ibandroninsyre og de farmasøytisk akseptable saltene kan administreres alene eller i kombinasjon med andre benaktive stoffer, enten i fastkombinasjoner eller separat både fy-sisk og i tid, inkludert hormoner, slik som et steroidhor-mon, for eksempel et østrogen; en partiell østrogenagonist, eller østrogen-gestagenkombinasjon; en kalsitonin eller analog eller derivat derav, for eksempel laks, ål eller hu-man kalsitonin paratyroidhormon eller analoger derav, for eksempel PTH (1-84), PTH (1-34), PTH (1-36), PTH (1-38), PTH (1-31)NH2 eller PPTS 893; en SERM (Selektiv østrogenre-septormodulator), for eksempel raloksifen, lasofoksifen, TSE-434, FC1271, tibolon, vitamin D eller en analog. Slike ytterligere benaktive stoffer kan administreres oftere enn bisfosfonatet.
Egnede farmasøytiske sammensetninger er kjent på fagområdet og har vært beskrevet for eksempel i US patent nr. 6,143,326 og 6,294,196.
For fremstillingen av tabletter, belagte tabletter, dragéer eller harde gelatinkapsler, kan ibandroninsyre blandes sam-men med farmasøytisk inerte, uorganiske eller organiske eksipienser. Eksempler på egnede eksipienser for tabletter,
dragéer eller harde gelatinkapsler inkluderer laktose,
maisstivelse eller derivater derav, talkum eller stearinsyre eller salter derav.
Farmasøytiske sammensetninger kan også inneholde konser-veringsmidler, solubiliseringsmidler, stabiliseringsmidler, fuktemidler, emulgeringsmidler, søtestoffer, fargemidler, luktemidler, salter for variasjon av osmotisk trykk, buf-fere, belegningsagenser eller antioksidanter. De kan også inneholde andre terapeutisk nyttige agenser. Den farmasøy-tiske sammensetningen er fortrinnsvis en filmbelagt tablett hvori tablettkjernen omfatter 150 mg ibandroninsyre eller et farmasøytisk akseptabelt salt derav som definert ovenfor og en eller flere farmasøytisk akseptable eksipienser valgt fra gruppen bestående av laktose, polyvinylpyrrolidon, mikrokrystallinsk cellulose, krospovidon, stearinsyre, silikondioksid og tablettkjernen omfatter en eller flere farma-søytisk akseptable eksipienser valgt fra gruppen bestående av hydroksypropylmetylcellulose, titandioksid, talkum og polyetylenglykol 6.000. Disse sammensetningene er kjent på fagområdet og beskrevet for eksempel i US patent nr. 6,143,326 og 6,294,196.
Oppfinnelsen vil nå bli forklart med henvisning til eksem-plifiserte utførelser.
Eksempler
Eksempel 1: Farmasøytisk sammensetning
Eksemplet viser sammensetningen av en 50 mg tablett. Sammensetningen og fremstilling av disse tablettene er kjent på fagområdet og beskrevet i for eksempel i US patentnumrene 6,143,326 og 6,294,196.
Andre sammensetningene kan fremstilles ved å justere ingre-diensene ifølge mengden bisfosfonat, for eksempel ibandroninsyre, mononatriumsalt, monohydrat.
Claims (5)
1. Anvendelse av en ibandroninsyre eller farmasøytisk akseptabelt salt derav for fremstilling av et medikament egnet for forebygging eller behandling av forstyrrelser særpreget ved patologisk økning i benresorpsjon hvori medikamentet a) omfatter en effektiv dose på omkring 150 mg ibandroninsyre eller et farmasøytisk akseptabelt salt derav; og b) medikamentet er tilrettelagt for å bli administrert oralt en dag per måned.
2. Anvendelse ifølge krav 1 hvor sykdommen er osteoporose .
3. Anvendelse ifølge krav 1 eller 2, hvori ibandroninsy-ren foreligger i form av sitt mononatriumsalt, monohydrat.
4. Anvendelse ifølge et hvilket som helst av kravene 1 til 3, hvori medikamentet er en filmbelagt tablett hvori tablettkjernen omfatter 150 mg ibandroninsyre eller et far-masøytisk akseptabelt salt derav som definert i kravene 1 til 3, og en eller flere farmasøytisk akseptable eksipienser valgt fra gruppen bestående av laktose, polyvinylpyrrolidon, mikrokrystallinsk cellulose, krospovidon, stearinsyre, silikondioksid og tablettkjernen omfatter en eller flere farmasøytisk akseptable eksipienser valgt fra gruppen bestående av hydroksypropylmetylcellulose, titandioksid, talkum og polyetylenglykol 6.000.
5. Anvendelse ifølge et hvilket som helst av kraven 1 til 4, hvori medikamentet blir administrert som en enkel dose.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP02010136 | 2002-05-10 | ||
| PCT/EP2003/004629 WO2003095029A1 (en) | 2002-05-10 | 2003-05-02 | Bisphosphonic acid for the treatment and prevention of osteoporosis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO20044195L NO20044195L (no) | 2004-10-01 |
| NO328734B1 true NO328734B1 (no) | 2010-05-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20044195A NO328734B1 (no) | 2002-05-10 | 2004-10-01 | Anvendelse av ibandroninsyre for fremstilling av medikamenter til behandling og prevensjon av osteoprose |
| NO20100477A NO331024B1 (no) | 2002-05-10 | 2010-03-31 | Anvendelse av risendroninsyre for forebygging eller behandling av osteoporose |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20100477A NO331024B1 (no) | 2002-05-10 | 2010-03-31 | Anvendelse av risendroninsyre for forebygging eller behandling av osteoporose |
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| US20070148228A1 (en) * | 1999-02-22 | 2007-06-28 | Merrion Research I Limited | Solid oral dosage form containing an enhancer |
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| WO2003055496A1 (en) * | 2001-12-21 | 2003-07-10 | The Procter & Gamble Company | Method for the treatment of bone disorders |
| WO2003086415A1 (en) * | 2002-04-05 | 2003-10-23 | Merck & Co., Inc. | Method for inhibiting bone resorption with an alendronate and vitamin d formulation |
| KR20120065435A (ko) | 2002-05-10 | 2012-06-20 | 에프. 호프만-라 로슈 아게 | 골다공증 치료 및 예방용 비스포스폰산 |
| BR0309691A (pt) † | 2002-12-20 | 2005-08-02 | Hoffmann La Roche | Formulação de ibandronato em alta dose |
| US20050261250A1 (en) * | 2004-05-19 | 2005-11-24 | Merck & Co., Inc., | Compositions and methods for inhibiting bone resorption |
| EP1713489B1 (en) * | 2004-08-23 | 2011-01-19 | Teva Pharmaceutical Industries Ltd | Crystalline form of ibandronate sodium and processes for preparation thereof |
| ES2712644T3 (es) * | 2005-02-01 | 2019-05-14 | Atnahs Pharma Uk Ltd | Uso médico del polimorfo A de Ibandronato |
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| US20070049557A1 (en) * | 2005-08-24 | 2007-03-01 | Hashim Ahmed | Solid pharmaceutical dosage forms comprising bisphosphonates and modified amino acid carriers |
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| AU2007335156A1 (en) * | 2006-12-20 | 2008-06-26 | Mylan Pharmaceuticals Ulc | Pharmaceutical composition comprising a hot-melt granulated lubricant |
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| EP2210596A1 (en) | 2009-01-22 | 2010-07-28 | Laboratorios Liconsa, S.A. | Pharmaceutical composition of ibandronate sodium salt or a hydrate thereof |
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| WO2001015703A1 (en) * | 1999-09-02 | 2001-03-08 | Merck & Co., Inc. | Method for inhibiting bone resorption |
| WO2001082903A1 (en) * | 2000-04-28 | 2001-11-08 | Lipocine, Inc. | Enteric coated formulation of bisphosphonic acid compounds and associated therapeutic methods |
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