HRP20020169A2 - Pharmaceutical formulations and use thereof in the prevention of stroke, diabetes and/or congestive heart failure - Google Patents
Pharmaceutical formulations and use thereof in the prevention of stroke, diabetes and/or congestive heart failure Download PDFInfo
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Description
Područje izuma
Predloženi izum se odnosi na upotrebu inhibitora sistema renin-angiotenzin RAS) ili njegovog farmaceutski prihvatljivog derivata za proizvodnju lijeka za prevenciju udara kapi, dijabetesa i/ili kongestivnog otkazivanja srca (CHF). Predloženi izum se odnosi, nadalje, na metodu prevencije i/ili liječenja udara kapi, dijabetesa i/ili CHF-a, koja uključuje davanje terapeutski učinkovite količine inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata pacijentu kojem je potrebna takova prevencija i/ili liječenje.
Pozadina izuma
Spojevi koji interferiraju s RAS-om su dobro poznati u struci i oni se upotrebljavaju za liječenje kardiovaskularnih bolesti, posebno arterijske hipertenzije i otkazivanja srca. Načelno, RAS se može omesti inhibicijom enzima koji sintetiziraju angiotenzine ili blokiranjem odgovarajućih receptora na mjestima efektora. Danas su raspoloživi inhibitori enzima koji pretvara angiotenzin (e. angiotenzin converting enzime, ACE) i antagonisti tipa l receptora angiotenzina II (AT II).
ACE inhibitori su spojevi koji inhibiraju pretvorbu angiotenzina I u aktivan angiotenzin II kao i opadanje aktivnog vazodilatora bradikinina. Ova obadva mehanizma dovode do vazodilatacije. Takovi spojevi su bili opisani,
na primjer, u EP 158927, EP 317878, US 4,743,450, i US 4,857,520.
Ramipril (obznanjen u EP-A-079022) je ACE inhibitor dugotrajnog djelovanja. Njegov aktivan metabolit je slobodna ramiprilat-di-kiselina, koja se dobije in vivo nakon davanja ramiprila. Poznato je da kod hipertenzivnih pacijenata davanje ramiprila uzrokuje smanjenje periferne arterijske rezistencije i time smanjenje krvnog tlaka bez kompenzacijskog porasta brzine rada srca. On se sada upotrebljava za liječenje hipertenzije i CHF-a. Osim toga, pokazalo se je da ramipril smanjuje smrtnost kod pacijenata s kliničkim znakovima kongestivnog otkazivanja srca nakon preživljavanja akutnog miokardijalnog infarkta. Za ramipril se je preporučalo da ima dodatnu prednost u odnosu prema drugim ACE inhibitorima zbog njegove istaknute inhibicije ACE-a u tkivima čije djelovanje ima posljedicu zaštite organa, npr. srca, bubrega i krvnih žila.
Spojevi koji interferiraju s RAS-om, uključiv ACE inhibitore i AT II antagoniste, sada se upotrebljavaju za liječenje raznih kardiovaskularnih poremećaja, posebno kod pacijenata koji pokazuju visok krvni tlak. Upotreba spomenutih spojeva u prevenciji kardiovaskularnih poremećaja je mnogo rjeđa, a upotreba spomenutih spojeva u prevenciji udara kapi, dijabetesa i/ili CHF-a je do sada nepoznata.
Sažetak izuma
Predloženi izum se odnosi na upotrebu inhibitora RASa ili njegovog farmaceutski prihvatljivog derivata za proizvodnju lijeka za prevenciju udara kapi, posebno kod pacijenata koji pokazuju normalan ili nizak krvni tlak.
Predloženi izum se odnosi nadalje na upotrebu inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata za proizvodnju lijeka za prevenciju dijabetesa.
Predloženi izum također se odnosi na upotrebu inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata za proizvodnju lijeka za prevencija razvoja CHF-a kod pacijenata kod kojih još ne postoji CHF, tj. koji još nemaju znakova ili simptoma CHF-a.
Drugi oblik izuma je metoda za prevencija udara kapi, dijabetesa i/ili CHF-a, koja uključuje davanje terapeutski učinkovite količine inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata pacijentu kojem je potrebna takova prevencija.
Također, drugi oblik izuma je farmaceutska formulacija koja se upotrebljava za prevencija udara kapi, dijabetesa i/ili CHF-a, koja sadrži terapeutski učinkovitu količinu inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata.
Daljnji oblik izuma je upotreba inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata u prevenciji udara kapi, dijabetesa i/ili CHF-a davanjem inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata pacijentu kojem je potrebna takova prevencija.
Opis izuma u pojedinostima
Iznenađujuće je pronađeno da se kardiovaskularni i metabolički poremećaji, kao što je udar, dijabetes i CHF, mogu spriječiti upotrebom inhibitora RAS-a, posebno ACE inhibitora koji ometa sintezu angiotenzina II. Predloženi izum je posebno iznenađujući time što posebno pacijenti s uglavnom zadržanom funkcijom srca i/ili oni koji pokazuju normalan ili nizak krvni tlak imaju značajnu korist od preventivnog djelovanja inhibitora RAS. Izum opisuje novu metodu za prevenciju poremećaja kao što je udar, dijabetes i/ili CHF davanjem inhibitora RAS-a.
Pacijenti koji pokazuju normalan ili nizak krvni tlak su poznati kao normotenzivni pacijenti. Primjeri smjernica koje definiraju vrijednosti krvnog tlaka za različite skupine pacijenta, a koje uključuju različitu starost, uključuju smjernice koje su izdale WHO i JNC (USA) . Za predloženi izum, prikladna definicija normalnog ili niskog krvnog tlaka može se naći u JNC VI, što je ovdje uvršteno kao literatura.
Prema predloženom izumu, "udar kapi7' uključuje fatalni i ne-fatalni udar kapi.
Prema predloženom izumu, "dijabetes" uključuje obadva tipa dijabetesa, dijabetes I koji je također poznat kao dijabetes ovisan o inzulinu, dijabetes meilitus (IDMM), i tip II dijabetesa, koji je također poznat kao dijabetes melitus koji nije ovisan o inzulinu (NIDDM).
Prema predloženom izumu, "inhibitor sistema renin-angiotenzina (RAS) ili njegov farmaceutski prihvatljiv derivat uključuje svaki spoj koji sam po sebi ili nakon davanja blokira negativne učinke angiotenzina II na vaskulaturu smanjenjem sinteze angiotenzina II ili blokiranjem njegovog učinka na receptoru.
Prema predloženom izumu, "inhibitor enzima koji pretvara angiotenzin (AGE) ili njegov farmaceutski prihvatljiv derivat uključuje svaki spoj koji sam po sebi ili nakon davanja ometa sintezu angiotenzina II.
Ako inhibitor RAS-a upotrijebljen prema predloženom izumu ima više asimetričnih ugljikovih atoma, on zbog toga može postojati u više stereokemijskih oblika. Predloženi izum uključuje smjese izomera kao i pojedinačne stereoizomere. Predloženi izum uključuje, nadalje, geometrijske izomere, rotacijske izomere, enantiomere, racemate i diastereomere.
Tamo gdje se to može primijeniti, inhibitori RAS-a mogu se upotrijebiti u neutralnom obliku, npr. kao karboksilna kiselina, ili u obliku soli, ponajprije u obliku farmaceutski prihvatljive soli kao što je natrijeva, kalijeva, amonijeva, kalcijeva ili magnezijeva sol spoja. Tamo gdje je to moguće, gore navedeni spojevi mogu se upotrijebiti u obliku estera koji mogu hidrolizirati.
Prema predloženom izumu, inhibitori RAS-a uključuje njihove sve predlijekove, bez obzira jesu li oni aktivni in vitro ili nisu. Stoga, dakle, iako takovi zaštićeni derivati kao takovi ne moraju imati farmakološko djelovanje, oni se mogu dati npr. parenteralno ili oralno, i nakon toga se mogu metabolizirati in vivo u oblik farmakološki aktivnih inhibitora RAS-a. Prednosni primjeri su ramipril, koji se metabolizira u ramiprilat, i kandesartan cileksetil, koji se metabolizira u kandesartan. Inhibitori RAS-a uključuju AGE inhibitore, AT II antagoniste, koji su također poznati kao angiotenzin receptor blokeri (ARBs), renin antagoniste, i inhibitore vazopeptidaze (VPIs).
Pojam "inhibitori vazopeptidaze" obuhvaća takozvane NEP/ACE inhibitore (koji se također navode kao selektivni ili neutralni inhibitori endopeptidaze dvostrukog djelovanja) koji djeluju inhibitorski prema neutralnoj endopeptidazi (NEP) i koji djeluju inhibitorski prema enzimu koji pretvara angiotenzin (ACE).
Pojam "renin antagonisti" obuhvaća inhibitore renina. Prema predloženom izumu, RAS inhibitori mogu pokazati dugotrajno djelovanje, djelovanje srednjeg trajanja ili kratkotrajno djelovanje.
ACE inhibitori ili njihovi farmaceutski prihvatljivi derivati, uključiv aktivne metabolite, koji se mogu upotrijebiti za prevenciju udara kapi, dijabetesa i/ili CHF-a uključuje, ali nisu ograničeni samo na slijedeće spojeve:
alacepril, alatriopril, altiopril kalcij, ankovenin, benazepril, benazepril hidroklorid, benazeprilat, benzoil-kaptopril, kaptopril, kaptopril-cistein, kaptopril-glutation, ceranapril, ceranopril, ceronapril, cilazaprit, cilazaprilat, delapril, delapril-di-kiselina, enalapril, enalaprilat, enapril, epikaptopril, foroksimitin, fosfenopril, fosenopril, fosenopril natrij, fosinopril, fosinopril natrij, fosinoprilat, fosinoprilna kiselina, glikopril, hemorfin-4, idrapril, imidapril, indolapril, indolaprilat, libenzapril, lizinopril, liciumin A, liciumin B, miksanpril, moeksipril, moeksiprilat, moveltipril, muracein A, muracein B, muracein C, pentopril, perindopril, perindoprilat, pivalopril, pivopril, kvinapril, kvinapril hidroklorid, kvinaprilat, ramipril, ramiprilat, spirapril, spirapril hidroklorid, spiraprilat, spiropril, spiropril hidroklorid, temokapril, temokapril hidroklorid, teprotid, trandolapril, trandolaprilat, utibapril, zabicipril, zabiciprilat, zofenopril i zofenoprilat.
Prednosni ACE inhibitori za upotrebu prema predloženom izumu jesu kamipril, ramiprilat, lisinopril, enafapril i enalaprilat. ACE inhibitori za upotrebu prema predloženom izumu kojima se daje još veću prednost jesu ramipril i ramiprilat. Informacije o ramiprilu i ramiprilatu mogu se naći npr. u Merckovom popisu, 12. izdanje, 1996, str. 1394-1395.
AT II antagonisti ili njihovi farmaceutski prihvatljivi derivati, uključiv aktivne metabolite, koji se mogu upotrijebiti za prevenciju udara kapi, dijabetesa i/ili CHF-a, uključuju ali nisu ograničeni samo na one koji su opisani u publikacijama europskih patentnih prijava br. 253310, 323841, 324377, 399731, 400974, 401030, 403158, 403159, 407102, 407342,409332. 411507, 411766, 412594, 412848, 415886, 419048, 420237, 424317, 425211, 425921, 426021, 427463, 429257, 430300, 430709, 432737, 434038, 434249, 435827, 437103. 438869, 442473, 443568, 443983, 445811, 446062, 449699, 450566. 453210, 454511, 454831, 456442, 456442, 456510, 459136, 461039. 461040, 465323, 465368, 467207, 467715, 468372, 468470, 470543. 475206, 475898, 479479, 480204, 480659, 481448, 481614, 483683, 485929, 487252, 487745, 488532, 490587. 490820, 492105, 497121. 497150, 497516, 498721, 498722, 498723, 499414, 499415, 499416, 500297, 500409, 501269, 501892, 502314, 502575, 502725, 503162, 503785, 503838, 504888, 505098, 505111, 505893. 505954. 507594, 508393, 508445, 508723, 510812, 510813, 511767, 511791, 512675, 512676, 512870, 513533, 513979, 514192, 514193, 514197, 514198, 514216, 514217, 515265, 515357, 515535, 515546, 515548, 516392, 517357, 517812, 518033, 518931, 520423, 520723, 520724, 521768, 522038, 523141, 526001, 527534, i 528762. Svi ostali antagonisti uključuju one koji su opisani u publikacijama međunarodnih patentnih prijava br. WO 91/00277, WO 91/00281, WO 91/11909, WO 91/11999, WO 91/12001,
WO 91/12002, WO 91/13063, 91/15209, WO 91/15479, WO 91/16313, WO 91/17148, WO 91/18888, WO 91/19697, WO 91/19715, WO 92/00067, WO 92700068, WO 92/00977, WO 92/02510, WO 92/04335, WO 92/04343, WO 92705161, WO 92/06081, WO 92/07834, WO 92/07852, WO 92/09278, WO 92/09600, WO 92/10189, WO 92/11255, WO 92/14714, WO 92/16523, WO 92/16552, WO 92/17469, WO 92/18092, WO 92/19211, WO 92/20651, WO 92/20660, WO 92/20687. WO 92/21666, WO 92/22533, WO 93/00341, WO 93/01177, WO 93/03018, WO 93/03033 i WO 93/03040. Sadržaji gore spomenutih europskih i međunarodnih patentnih prijava ovdje su uvršetni kao literatura.
Prednosni AT II antagonisti ili njihovi farmaceutski prihvatljivi derivati za upotrebu prema predloženom izumu uključuju, ali nisu ograničeni samo na spojeve slijedećih generičkih naziva: kandesartan, kandesartan cileksetil, josartan, valsartan, irbesartan, tasosartan, telmisartan i eprosartan.
Posebno prednosni AT II antagonisti ili njihovi farmaceutski prihvatljivi derivati za upotrebu prema predloženom izum jesu kandesartan i kandesartan cileksetil. Kandesartan i kandesartan cileksetil su poznati iz europskog patenta br. 459 136 BI, US 5,196,444 i US 5,703,110 tvrtke Takeda Chemical Industries. Kandesartan cikeksetil sada proizvode i prodaju širom svijeta tvrtke AstraZeneca i Takeda npr. pod trgovačim nazivima Atacand®, Amias® i Blopress®.
NEP/ACE-inhibitori ili njihovi farmaceutski prihvatljivi derivati, uključiv aktivne metabolite, koji se mogu upotrijebiti za prevenciju udara kapi, dijabetesa i/ili CHF-a uključuju, ali nisu ograničeni samo na one spojeve koji su opisani u U.S. patentima br. 5,508,272, 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516, 5,552,397, 4,749,688, 5,504,080, 5,612,359, 5,525,723, 5,430,145, i 5,679,671, i u europskim patentnim prijavama 0481522, 0534263, 0534396, 0534492 i 0671172.
Prednosni NEP/ACE inhibitori za upotrebu prema predloženom izumu su oni koji su označeni kao prednosni u gornjim U.S. patentima i europskim patentnim prijavama i ti dokumenti su ovdje uvršteni kao literatura. Posebnu prednost daje se NEP/ACE inhibitoru omapatrilatu (koji je obznanjen u U.S. patentu br. 5,508,272), ili MDL 100240 (koji je obznanjen u U.S. patentu br. 5,430,145).
Inhibitori renina ili njihovi farmaceutski prihvatljivi derivati, uključiv njihove aktive metabolite, koji se mogu upotrijebiti za prevenciju udara kapi, dijabetesa i/ili CHF-a uključuju, ali nisu ograničeni samo na slijedeće spojeve: enalkrein; RO 42-5892; 65317; CP80794; ES 1005; ES 8891; SQ 34017; CGP 29287; CGP 38560;
SR 43845; U-71038; 62198; i 64662.
Farmaceutske formulacije
U drugom obliku, predloženi izum se odnosi na farmaceutske formulacije koje kao aktivan sastojak sadrže RAS inhibitor ili njegov farmaceutski prihvatljiv derivat ili njegov predlijek, uključiv njegove metabolite, u upotrebi za prevenciju udara kapi, dijabetesa i/ili kongestivnog otkazivanja srca (CHF).
Za kliničku upotrebu, RAS inhibitor se formulira u farmaceutsku formulaciju za oralno, intravensko, supkutano, trahejalno, bronhijalno, intranazalno, pulmonalno, transdermalno, bukalno, rektalno, parenteralno ili za davanje na neki drugi način. Farmaceutska formulacija može sadržavati inhibitor u mješavini s farmaceutski prihvatljivim pomoćnim sredstvom, sredstvom za razredivanje i/ili nosačem.
Za pripravu farmaceutskih formulacija predloženog izuma aktivan sastojak se može pomiješati s krutim, praškastim sastojcima kao što su laktoza, saharoza, sorbitol, manitol, škrob, amilopektin, derivati celuloze, želatina, ili drugi prikladan sastojak, kao i sa sredstvima za dezintegraciju i lubrikantima kao što su magnezijev stearat, kalcijev stearat, natrijev stearil fumarat i polietilen glikolni voskovi. Smjesu se zatim može preraditi u granule ili isprešati u tablete.
Aktivan sastojak se može odvojeno prethodno pomiješati s drugim ne-aktivnim sastojcima i zatim se može pomiješati u oblik formulacije.
Meke želatinske kapsule se mogu proizvesti kao kapsule koje sadrže smjesu aktivnog sastojka prema izumu, biljno ulje, mast ili drugi prikladan nosač za želatinske kapsule. Tvrde želatinske kapsule mogu sadržavati granule aktivnih
sastojaka. Tvrde želatinske kapsule mogu također sadržavati aktivne sastojke u kombinaciji s krutim praškastim sastojcima kao što su laktoza, saharoza, sorbitol, manitol, krumpirov škrob, kukuruzni škrob, amilopektin, derivati celuloze ili želatina.
Jedinično doziranje za rektalno davanje može se proizvesti (i) u obliku čepića koji sadrže aktivnu tvar pomiješanu s neutralnom masnom osnovnom; (ii) u obliku želatinskih rektalnih kapsula koje sadrže aktivnu tvar pomiješanu s biljnim uljem, parafinskim uljem ili s drugim prikladnim nosačem za želatinske rektalne kapsule/ (iii) u obliku mikro klistira gotovih za upotrebu/ ili (iv) u obliku suhe mikro klistirne formulacije koju se pripravlja u prikladnom otapalu neposredno prije davanja.
Tekući pripravci se mogu proizvesti u obliku sirupa ili suspenzija, npr. otopina ili suspenzija koje sadrže aktivne sastojke, a ostatak se sastoji, na primjer, od šećera ili šećernog alkohola i mješavine etanola, vode, glicerola, propilen glikola i polietilen glikola. Po želji, takovi pripravci mogu sadržavati bojila, začine, konzervanse, saharin i karboksimetil celulozu ili druga sredstva za zgušnjavanje. Tekući pripravci se također mogu proizvesti u obliku suhog praha koji se miješa s prikladnim otapalom prije upotrebe.
Otopine za parenteralno davanje mogu se proizvesti kao otopine formulacije prema izumu u farmaceutski prihvatljivom otapalu. Te otopine mogu također sadržavati stabilizatore, konzervanse i/ili pufere. Otopine za parenteralno davanje se mogu također proizvesti kao suhi pripravak koji se miješa s prikladnim otapalom prije upotrebe.
Ukupna količina aktivnog sastojka povoljno se kreće u rasponu od približno 0,1% (masa/masa) do približno 95% (masa/masa) formulacije, povoljno od 0,5% do 50% (masa/masa) i prednosno od 1% do 25% (masa/masa).
Farmaceutske formulacije mogu sadržavati između pribl. 0,1 mg i pribl. 1000 mg aktivnog sastojka, ponajprije između l mg i 100 mg aktivnog sastojka.
Doziranje aktivnog sastojka za aplikaciju ovisit će o dotičnoj indikaciji, starosti, težini i spolu pacijenta i može ga odrediti liječnik. Doziranje će biti povoljno u rasponu od približno 0,01 mg/kg do približno 20 mg/kg, ponajprije između 0,1 mg/kg i 10 mg/kg.
Tipična dnevna doza aktivnog sastojka mijenja se u širokom rasponu i ovisit će o raznim faktorima kao što je dotična indikacija, način davanja, starost, težina i spol pacijenta i može ju odrediti liječnik. Općenito, doziranje, a posebno oralno i parenteralno doziranje bit će u rasponu od približno 0,1 do približno 100 mg dnevno aktivne tvari, ponajprije između l i 50 mg dnevno aktivne tvari.
Slijedeći primjer predviđen je za ilustraciju izuma i ne ograničava ga ni na koji način.
PRIMJER
Za ispitivanje učinka ACE inhibitora ramiprila u usporedbi s placebom u smanjenju kardiovaskularanih slučajeva provedeno je kliničko ispitivanje u velikom mjerilu.
Studija je provedena u 267 centara u 19 zemalja tijekom perioda od šest godina i uključila je 9.541 sudionika koji su bili kardiovaskularni slučajevi visokog rizika zbog povijesti prethodne ishemijske srčane bolesti, udara kapi, periferne arterijske bolesti ili pojedinci s dijabetesom.
Sistolički krvni tlak pri uključenju pacijenata bio je u prosjeku 138 mm Hg i stoga su pacijenti bili normotenzivni na početku proučavanja. Nakon jednog mjeseca terapije s ramiprilom ili s placeboom, sistolički krvni tlak se je smanjio za 5,48 mm Hg, odnosno 1,59 mm Hg.
Primarna završna točka proučavanja bio je miokardijalni infarkt (MI), udar kapi i kardiovaskularna (CV) smrt (mortalitet).
Proučavanje je zaustavljeno ranije zbog vrlo jasne redukcije u kombiniranoj završnoj točki kardiovaskularne smrti, srčanog napada i udara kapi kod pacijenata koji su uzimali ramipril. Osim gornje koristi, također je došlo do smanjenja između četvrtine do petine potreba za postupcima revaskularizacije (kao što je operacija ugradnje koronarnog arterijskog premoštenja, angioplastija balona, itd.) i dijabetskih komplikacija.
U skupini pacijenata koji su primali ramipril bilo je jasno 32%-tno smanjenje pacijenata kod kojih je došlo do razvoja udara kapi, i to je iznenađujuće jer pacijenti su bili normotenzivni kad su uzeti u proučavanje.
Broj pacijenata kod kojih je došlo do razvoja CHF-a značajno se je smanjio za 21% u skupini koja je primala ramipril, što je neočekivano jer ti pacijenti nisu pokazivali znakove ili simptome CHF-a na početku proučavanja.
Također je izneđujuće značajno smanjenje od 36% razvoja dijabetesa u skupini koja je primala ramipril.
Kratice
ACE = enzim koji pretvara angiotenzin (e. angiotenzin converting enzime),
AT II = angiotenzin II tip 1 receptor, CHF = kongestivno otkazivanje srca,
IDMM = o inzulinu ovisan dijabetes (insulin-dependent, dijabetes mellitus) ,
JNC = Joint National Committee,
MI = miokardijalni infarkt,
NIDDM = dijabetes melitus koji ne ovisi o inzulinu (non-insulin-dependent dijabetes mellitus),
WHO = World Healt Organization, (Svjetska zdravstvena organizacija).
Claims (28)
1. Upotreba inhibitora ili sistema renin-angiotenzina (RAS) ili njihovih farmaceutski prihvatljivih derivata, naznačena time, da se oni koriste za proizvodnju lijeka za prevenciju udara kapi.
2. Upotreba inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata, naznačena time, da se oni koriste za proizvodnju lijeka za prevenciju udara kapi kod pacijenata koji pokazuju normalan ili snižen krvni tlak.
3. Upotreba inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata, naznačena time, da se on koristi za proizvodnju lijeka za prevenciju dijabetesa.
4. Upotreba inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata, naznačena time, da se on koristi za proizvodnju lijeka za prevenciju razvoja kongestivnog otkazivanja srca (CHF) kod pacijenata kod kojih ranije nije bilo CHF-a.
5. Upotreba prema bilo kojem prethodnom zahtjevu, naznačena time, da inhibitor RAS-a je inhibitor enzima koji pretvara angiotenzin (ACE) ili angiotenzin II tip 1 receptor (AT II) antagonist ili farmaceutski prihvatljiv derivat bilo kojeg od njih.
6. Upotreba prema zahtjevu 5, naznačena time, da ACE inhibitor ili njegov farmaceutski prihvatljiv derivat je odabran iz skupine koju čine alacepril, alatriopril, altiopril kalcij, ankovenin, benazepril, benazepril hidroklorid, benazeprilat, benzoilkaptopril, kaptopril, kaptopril-cistein, kaptopril-glutation, keranapril, keranopril, keronapril, cilazapril, cilazaprilat, delapril, delapri1-di-kiselina, enalapril, enalaprilat, enapril, epikaptopril, foroksimitin, fosfenopril, fosenopril, fosenopril natrij, fosinopril, fosinapril natrij, fosinoprilat, fosinoprilna kiselina, glikopril, hemorfin-4, idrapril, imidapril, indolapril, indolaprilat, libenzapril, lizinopril, liciumin A, liciumin B, miksanpril, moeksipril, moeksiprilat, moveltipril, muracein A, muracein B, muracein C, pentopril, perindopril, perindoprilat, pivalopril, pivopril, kvinapril, kvinapril hidroklorid, kvinaprilat, ramipril, ramiprilat, spirapril, spirapril hidroklorid, spiraprilat, spiropril, spiropril hidroklorid, temokapril, temokapril hidroklorid, teprotid, trandolapril, trandolaprilat, utibapril, zabicipril, zabiciprilat, zofenopril i zofenoprilat.
7. Upotreba prema zahtjevu 6, naznačena time, da ACE inhibitor je odabran iz skupine koju čine ramipril, ramiprilat, lisinopril, enalapril i enaiaprilat.
8. Upotreba prema zahtjevu 5, naznačena time, da AT II antagonist ili njegov farmaceutski prihvatljiv derivat je odabran iz skupine koju čine kandesartan, kandesartan cileksetil, losartan, valsartan, irbesartan, tasosartan, telmisartan i eprosartan.
9. Upotreba prema zahtjevu 8, naznačena time, da AT II antagonist ili njegov farmaceutski prihvatljiv derivat je odabran iz skupine koju čine kandesartan i kandesartan cileksetil.
10. Metoda prevencije udara kapi, naznačena time, da uključuje davanje terapeutski učinkovite količine inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata pacijentu kojem je potrebna takova prevencija.
11. Metoda prevencije udara kapi kod pacijenata koji pokazuju normalan ili nizak krvni tlak, naznačena time, da uključuje davanje terapeutski učinkovite količine inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata pacijentu kojem je potrebna takova prevencija.
12. Metoda prevencije dijabetesa, naznačena time, da uključuje davanje terapeutski učinkovite količine inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata pacijentu kojem je potrebna takova prevencija.
13. Metoda prevencije razvoja CHF-a kod pacijenata kod kojih ranije nije bilo CHF-a, naznačena time, da uključuje davanje terapeutski učinkovite količine inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata pacijentu kojem je potrebna takova prevencija.
14. Metoda prevencije prema bilo kojem zahtjevu 10 do 13, naznačena time, da inhibitor RAS-a je ACE inhibitor ili AT II antagonist ili njihov farmaceutski prihvatljiv derivat.
15. Metoda prevencije prema zahtjevu 14, naznačena time, da ACE inhibitor ili njegov farmaceutski prihvatljiv derivat je odabran iz skupine koju čine alacepril, alatriopril, altiopril kalcij, ankovenin, benazepril, benazepril hidroklorid, benazeprilat, benzoilkaptopril, kaptopril, kaptopril-cistein, kaptopril-glutation, keranapril, keranopril, keronapril, cilazapril, cilazaprilat, delapril, delapril-di-kiselina, enalapril, enalaprilat, enapril, epikaptopril, foroksimitin, fosfenopril, fosenopril, fosenopril natrij, fosinopril, fosinapril natrij, fosinoprilat, fosinoprilna kiselina, glikopril, hemorfin-4, idrapril, imidapril, indolapril, indolaprilat, libenzapril, lizinopril, liciumin A, liciumin B, miksanpril, moeksipril, moeksiprilat, moveltipril, muracein A, muracein B, muracein C, pentopril, perindopril, perindoprilat, pivalopril, pivopril, kvinapril, kvinapril hidroklorid, kvinaprilat, ramipril, ramiprilat, spirapril, spirapril hidroklorid, spiraprilat, spiropril, spiropril hidroklorid, temokapril, temokapril hidroklorid, teprotid, trandolapril, trandolaprilat, utibapril, zabicipril, zabiciprilat, zofenopril i zofenoprilat.
16. Metoda prevencije prema zahtjevu 15, naznačena time, da ACE inhibitor je odabran iz skupine koju čine ramipril, ramiprilat, lisinopril, enalapril i enalaprilat.
17. Metoda prevencije prema zahtjevu 14, naznačena time, da AT II antagonist ili njegov farmaceutski prihvatljiv derivat je odabran iz skupine koju čine kandesartan, kandesartan cileksetil, losartan, valsartan, irbesartan, tasosartan, telmisartan i eprosartan.
18. Metoda prevencije prema zahtjevu 17, naznačena time, da AT II antagonist ili njegov farmaceutski prihvatljiv derivat je odabran iz skupine koju čine kandesartan i kandesartan cileksetil.
19. Farmaceutska formulacija za upotrebu u prevenciji udara kapi, dijabetesa i/ili CHF-a, naznačena time, da sadrži terapeutski učinkovitu količinu inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata.
20. Farmaceutska formulacija prema zahtjevu 19, naznačena time, da inhibitor RAS-a je AGE inhibitor ili AT II antagonist ili farmaceutski prihvatljiv derivat bilo kojeg od njih.
21. Farmaceutska formulacija prema zahtjevu 20, naznačena time, da ACE inhibitor je odabran iz skupine koju čine ramipril, ramiprilat, lisinopril, enalapril i enalaprilat.
22. Farmaceutska formulacija prema zahtjevu 20, naznačena time, da AT II antagonist ili njegov farmaceutski prihvatljiv derivat je odabran iz skupine koju čine kandesartan, kandesartan cileksetil, losartan, valsartan, irbesartan, tasosartan, telmisartan i eprosartan.
23. Farmaceutska formulacija prema bilo kojem zahtjevu 19 do 22, naznačena time, da je ona u mješavini s farmaceutski prihvatljivim pomoćnim sredstvom, sredstvom za razrjeđivanje i/ili nosačem.
24. Farmaceutska formulacija prema bilo kojem zahtjevu 19 do 23, naznačena time, da ona ima oblik jediničnog doziranja.
25. Upotreba inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata, naznačena time, da se on koristi u prevenciji udara kapi, dijabetesa i/ili CHF-a davanjem inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata pacijentu kojem je potrebna takova prevencija.
26. Upotreba prema zahtjevu 25, naznačena time, da inhibitor RAS-a je AGE inhibitor ili AT II antagonist ili farmaceutski prihvatljiv derivat bilo kojeg od njih.
27. Upotreba prema zahtjevu 26, naznačena time, da ACE inhibitor je odabran iz skupine koju čine ramipril, ramiprilat, lisinopril, enalapril i enalaprilat.
28. Upotreba prema zahtjevu 26, naznačena time, da AT II antagonist ili njegov farmaceutski prihvatljiv derivat je odabran iz skupine koju čine kandesartan, kandesartan cileksetil, losartan, valsartan, irbesartan, tasosartan, telmisartan i eprosartan.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9903028A SE9903028D0 (sv) | 1999-08-27 | 1999-08-27 | New use |
| PCT/EP2000/008341 WO2001015673A2 (en) | 1999-08-27 | 2000-08-25 | Pharmaceutical formulations and use thereof in the prevention of stroke, diabetes and/or congestive heart failure |
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| Publication Number | Publication Date |
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| HRP20020169A2 true HRP20020169A2 (en) | 2005-10-31 |
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| HR20020169A HRP20020169A2 (en) | 1999-08-27 | 2000-08-25 | Pharmaceutical formulations and use thereof in the prevention of stroke, diabetes and/or congestive heart failure |
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| US (6) | US20060194868A1 (hr) |
| EP (4) | EP1437131B1 (hr) |
| JP (1) | JP4843172B2 (hr) |
| KR (2) | KR20020060167A (hr) |
| CN (2) | CN100408093C (hr) |
| AT (2) | ATE554761T1 (hr) |
| AU (3) | AU7648400A (hr) |
| BG (2) | BG66115B1 (hr) |
| BR (1) | BR0013540A (hr) |
| CA (1) | CA2382387C (hr) |
| CY (2) | CY1112987T1 (hr) |
| CZ (1) | CZ303433B6 (hr) |
| DE (1) | DE60023518T3 (hr) |
| DK (3) | DK1212081T4 (hr) |
| EE (1) | EE05130B1 (hr) |
| ES (3) | ES2525699T3 (hr) |
| HR (1) | HRP20020169A2 (hr) |
| HU (1) | HU229107B1 (hr) |
| IL (1) | IL148126A (hr) |
| ME (1) | MEP28208A (hr) |
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| NO (2) | NO329245B1 (hr) |
| NZ (1) | NZ571901A (hr) |
| PL (1) | PL353066A1 (hr) |
| PT (2) | PT1925303E (hr) |
| RS (1) | RS52907B (hr) |
| RU (2) | RU2272651C2 (hr) |
| SE (1) | SE9903028D0 (hr) |
| SI (3) | SI1925303T1 (hr) |
| SK (1) | SK288239B6 (hr) |
| TR (5) | TR200202463T2 (hr) |
| UA (2) | UA76702C2 (hr) |
| WO (1) | WO2001015673A2 (hr) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| NZ517468A (en) * | 1999-08-30 | 2004-02-27 | Aventis Pharma Gmbh | Use of inhibitors of the renin-angiotensin system in the prevention of cardiovascular events |
| CA2441838A1 (en) * | 2001-03-26 | 2002-10-03 | Kotobuki Pharmaceutical Co., Ltd. | Isoquinuclidine derivatives, method of manufacturing the same and therapeutic agents containing these compounds |
| EP1438043A2 (en) * | 2001-10-17 | 2004-07-21 | Aventis Pharma Deutschland GmbH | Method of reducing type 2 diabetes in high risk patients |
| US6844361B2 (en) | 2002-02-04 | 2005-01-18 | Aventis Pharma Deutschland Gmbh | Pharmaceutical composition comprising a sodium hydrogen exchange inhibitor and an angiotensin converting enzyme inhibitor |
| DE10230272A1 (de) * | 2002-07-05 | 2004-01-22 | Solvay Pharmaceuticals Gmbh | AT1-Rezeptorantagonisten zur Prävention von Folgeschlaganfällen |
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2000
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- 2000-08-25 SI SI200030766T patent/SI1212081T2/sl unknown
- 2000-08-25 KR KR1020087007837A patent/KR20080035703A/ko not_active Ceased
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2002
- 2002-01-16 YU YU3602A patent/YU3602A/sh unknown
- 2002-01-18 BG BG106319A patent/BG66115B1/bg unknown
- 2002-01-18 BG BG11047909A patent/BG110479A/bg unknown
- 2002-02-21 ZA ZA200201471A patent/ZA200201471B/xx unknown
- 2002-02-21 NO NO20020850A patent/NO329245B1/no not_active IP Right Cessation
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2005
- 2005-08-17 AU AU2005203694A patent/AU2005203694A1/en not_active Abandoned
- 2005-09-08 RU RU2005128124/15A patent/RU2378018C2/ru not_active IP Right Cessation
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2006
- 2006-02-20 UA UAA200601774A patent/UA88270C2/ru unknown
- 2006-05-02 US US11/415,137 patent/US20060194868A1/en not_active Abandoned
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2008
- 2008-02-07 US US12/027,938 patent/US20080125472A1/en not_active Abandoned
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2009
- 2009-02-12 AU AU2009200551A patent/AU2009200551B2/en not_active Ceased
- 2009-06-16 US US12/457,589 patent/US20090258919A1/en not_active Abandoned
- 2009-11-10 US US12/615,588 patent/US20100267798A1/en not_active Abandoned
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2010
- 2010-04-20 NO NO20100569A patent/NO20100569L/no not_active Application Discontinuation
- 2010-12-01 US US12/957,777 patent/US20110263619A1/en not_active Abandoned
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2012
- 2012-07-24 CY CY20121100657T patent/CY1112987T1/el unknown
- 2012-11-09 US US13/673,852 patent/US20130317047A1/en not_active Abandoned
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2014
- 2014-12-23 CY CY20141101082T patent/CY1115869T1/el unknown
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