ME00181B - Farmaceutske formulacije inhibitora renin-angiotenzin sistema (ras) i njihova primjena - Google Patents
Farmaceutske formulacije inhibitora renin-angiotenzin sistema (ras) i njihova primjenaInfo
- Publication number
- ME00181B ME00181B MEP-2008-282A MEP28208A ME00181B ME 00181 B ME00181 B ME 00181B ME P28208 A MEP28208 A ME P28208A ME 00181 B ME00181 B ME 00181B
- Authority
- ME
- Montenegro
- Prior art keywords
- pharmaceutically acceptable
- acceptable derivative
- prevention
- inhibitor
- ras
- Prior art date
Links
- 206010019280 Heart failures Diseases 0.000 title claims abstract description 37
- 206010007559 Cardiac failure congestive Diseases 0.000 title claims abstract description 36
- 230000002265 prevention Effects 0.000 title claims abstract description 35
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 15
- 229940078123 Ras inhibitor Drugs 0.000 claims abstract description 31
- 229960003401 ramipril Drugs 0.000 claims abstract description 23
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- 238000000034 method Methods 0.000 claims abstract description 15
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- 239000003112 inhibitor Substances 0.000 claims abstract description 11
- 230000036454 renin-angiotensin system Effects 0.000 claims abstract description 10
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- 239000005541 ACE inhibitor Substances 0.000 claims description 23
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- QKIVRALZQSUWHH-SFYZADRCSA-N (1s,2r)-2-[[2-(hydroxyamino)-2-oxoethyl]-methylcarbamoyl]cyclohexane-1-carboxylic acid Chemical compound ONC(=O)CN(C)C(=O)[C@@H]1CCCC[C@@H]1C(O)=O QKIVRALZQSUWHH-SFYZADRCSA-N 0.000 claims description 3
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Abstract
Ovaj pronalazak se odnosi na upotrebu nekog inhibitora renin-angiotenzin sistema (RAS) ili njegovog farmaceutski prihvatljivog derivata, posebno ramiprila ili ramiprilata, u proizvodnji medikamenta za prevenciju šloga, dijabetsa i/ili kongestivne srčane insuficijencije (CHF). Ovaj pronalazak se dalje odnosi na postupak prevencije i/ili liječenja šloga, dijabetsa i/ili CHF, uključujući davanje terapeutski efektivne količine nekog inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata, posebno ramiprilia ili ramiprilata, pacijentima kojima je potrebna takva prevencija i/ili liječenje.
Description
Farmaceutske formulacije i njihova upotreba u prevenciji šloga, dijabetesa i/ili kongestivne srčane insuficijencije
POLJE PRONALASKA
Ovaj pronalazak se odnosi na upotrebu nekog inhibitora renin-angiotenzin sistema (RAS) ili njegovih farmaceutski prihvatljivih derivata u proizvodnji medikamenata za prevenciju šloga, dijabetesa i/ili kongestivne srčane insuficijencije (CHF). Ovaj pronalazak se dalje odnosi na postupak prevencije i/ili lečenje šloga, dijabetesa i/ili CHF, uključujući davanje terapeutski efektivne količine nekog inhibitora RAS ili njegovog farmaceutski prihvatljivog derivata pacijentima kod kojih je potrebna takva prevencija i/ili lečenje.
POREKLO PRONALASKA
Jedinjenja koja deluju na RAS su dobro poznata u praksi i koriste se za lečenje kardiovaskularnih poremećaja, posebno arterijske hipertenzije i srčane insuficijencije. Načelno, na RAS se može delovati inhibicijom enzimske sinteze angiotenzina ili blokiranjem odgovarajućih receptora na mestu delovanja. Danas su raspoloživi inhibitori angiotenzin konvertujućeg enzima (ACE) i antagonisti angiotenzin II tip 1 receptora (AT II).
ACE inhibitori su jedinjenja koja inhibiraju konverziju angiotenzina I u aktivni angiotenzin II i istovremeno prekidaju delovanje vazodilatatora bradikinina. Oba ova mehanizma dovode do vazodilatacije. Takva jedinjenja su opisana u, na primer, EP 158927, EP 317878, US 4, 743, 450 i US 4, 857, 520.
Ramipril (otkriven u EP-A-079022) je ACE inhibitor sa dugim delovanjem. Njegov aktivni metabolit je slobodni diacid ramiprilat, koji je dobijen in vivo posle uzimanja ramiprila. Poznato je da kod pacijenata sa hipertenzijom koji uzimaju ramipril dolazi do redukcije otpora u perifernim arterijama i time do redukcije krvnog pritiska bez kompenzovanja u porastu brzine rada srca. Koristi se u lečenju hipertenzije i CHF.
Isto tako, ramipril smanjuje smrtnost kod pacijenata sa kliničkim znacima kongestivne srčane insuficijencije posle preživljavanja akutnog infarkta miokarda. Sugerisano je da ramipril ima dodatne prednosti u odnosu na mnoge druge ACE inhibitore zbog svoje jako izražene inhibicije ACE u tkivima, što dovodi do zaštitnih efekata u organima, na primer, u srcu, bubregu i krvnim sudovima.
Jedinjenja koja deluju na RAS, uključujući ACE inhibitore i AT II antagoniste, se sada koriste u lečenju različitih kardiovaskularnih oboljenja, posebno kod pacijenata koji imaju visok krvni pritisak. Upotreba ovih jedinjenja u prevenciji kardiovaskularnih oboljenja je mnogo manja i upotreba ovih jedinjenja u prevenciji šloga, dijabetesa i/ili CHF je manje-više nepoznata.
KRATAK SADRŽAJ PRONALASKA
Ovaj pronalazak se odnosi na upotrebu nekog inhibitora RAS ili njegovog farmaceutski prihvatljivog derivata u proizvodnji medikamenta za prevenciju šloga, posebno kod pacijenata koji imaju normalan ili nizak krvni pritisak.
Ovaj pronalazak se dalje odnosi na upotrebu nekog inhibitora RAS ili njegovog farmaceutski prihvatljivog derivata u proizvodnji medikamenta za prevenciju dijabetesa.
Ovaj pronalazak se takođe odnosi na upotrebu nekog inhibitora RAS ili njegovog farmaceutski prihvatljivog derivata u proizvodnji medikamenta za prevenciju razvoja CHF kod pacijenata koji ranije nisu imali CHF, to jest, nisu imali znake ili simptome CHF.
Drugi aspekt ovog pronalaska je postupak za prevenciju šloga, dijabetesa i/ili CHF, uključujući davanje terapeutski efektivne količine nekog inhibitora RAS ili njegovog farmaceutski prihvatljivog derivata pacijentima kojima je potrebna takva prevencija.
Još jedan aspekt ovog pronalaka je farmaceutska formulacija za upotrebu u prevenciji šloga, dijabetesa i/ili CHF, koja uključuje terapeutski efektivnu količinu nekog inhibitora RAS ili njegovog farmaceutski prihvatljivog derivata.
Dalji aspekt ovog pronalaska je upotreba nekog inhibitora RAS ili njegovog farmaceutski prihvatljivog derivata u prevenciji šloga, dijabetesa i/ili CHF davanjem inhibitora RAS ili njegovog farmaceutski prihvatljivog drivata pacijentima kojima je potrebna takva prevencija.
DETALJAN OPIS PRONALASKA
Bilo je iznenađujuće kada je otkriveno da kardiovaskularna i metabolička oboljenja, kao što su šlog, dijabetes i CHF, mogu biti predupređena upotrebom nekog inhibitora RAS, posebno nekog ACE inhibitora koji deluje na sintezu angiotenzina II. Ovaj pronalazak je posebno iznenađenje za takve posebne pacijente sa sačuvanom osnovnom srčanom funkcijom i/ili koji pokazuju normalan ili nizak krvni pritisak koji je najviše prouzrokovan preventivnim delovanjem inhibitora RAS. Pronalazak opisuje novi postupak za prevenciju oboljenja kao što su šlog, dijabetes i/ili CHF, uzimanjem nekog inhibitora RAS.
Pacijenti koji imaju normalan ili nizak krvni pritisak su poznati kao normotenzivni pacijenti. Primeri graničnih vrednosti koje definišu nivo krvnog pritiska za različite grupe pacijenta uključujući različite godine, obuhvata granične vrednosti koje su dale WHO i JNC (USA). U ovom pronalasku, odgovarajuća definicija za normalan ili nizak krvni pritisak je uzeta iz JNC VI, koji je ovim uključen u reference.
U ovom pronalasku, pod nazivom "šlog" podrazumeva se i fatalni i ne-fatalni šlog.
U ovom pronalaku, pod nazivom "dijabetes" se podrazumevaju oba tipa I dijabetesa poznat kao insulin-zavisni dijabetes melitus (IDMM), i tip II dijabetes, poznat kao insulin-nezavisni dijabetes melitus (NIDDM).
U ovom pronalasku, naziv "inhibitor renin-angiotenzin sistema (RAS) ili njegov farmaceutski prihvatljiv derivat" obuhvata bilo koje jedinjenje koje samo po sebi ili posle davanja blokira negativne efekte angiotenzina II na krvne sudove ili redukcijom sinteze angiotenzina II ili blokiranjem njegovog delovanja na receptor.
U ovom pronalasku, naziv "inhibitor angiotenzin konvertujućeg enzima (ACE) ili njegov farmaceutski prihvatljiv derivat" obuhvata bilo koje jedinjenje koje samo po sebi ili posle davanja deluje na sintezu angiotenzina II.
Kada inhibitor RAS, koji se koristi u ovom pronalasku, ima nekoliko asimetričnih atoma ugljenika, on istovremeno može da egzistira u nekoliko stereohemijskih oblika. Ovaj pronalazak uključuje mešavinu izomera kao i pojedinačne stereoizomere. Ovaj pronalazak dalje uključuje geometrijske izomere, rotacione izomere, enantiomere, racemate i dijastereomere.
Gde se može primeniti, inhibitori RAS se upotrebljavaju u neutralnom obliku, to jest, u obliku karboksilne kiseline ili u obliku soli, posebno u obliku farmaceutski prihvatljive soli, kao što su natrijum, kalijum, amonijum, kalcijum ili magnezijumova so jedinjenja, po izboru. Jedinjenja koja su prethodno navedena se koriste u obliku hidrolizirajućeg estra, kada se to može primeniti.
U ovom pronalasku, u inhibitore RAS spadaju i svi njihovi prolekovi, bilo da su aktivni ili inaktivni in vitro. Prema tome, i u slučaju da takvi zaštićeni derivati ne poseduju farmakološku aktivnost sami po sebi, mogu se davati, na primer, parenteralno ili oralno i posle metabolizma in vivo nastaju farmakološki aktivni RAS. Preferirani primeri su ramipril, koji se metaboliše u ramiprilat i kandestran cileksetil, koji se metaboliše u kandesartan.
U inhibitore RAS spadaju ACE inhibitori, antagonisti AT II koji su takođe poznati kao blokatori angiotenzin receptora (ARBs), antagonisti renina i inhibitori vazopeptidaze (VPIs).
Izraz "inhibitori vazopeptidaze" obuhvata takozvane NEP/ACE inhibitore (takođe se odnosi kako na selektivne tako i na dvostruko aktivne inhibitore neutralne endopeptidaze) koji poseduju inhibitomu aktivnost na neutralne endopeptidaze (NEP) i inhibitomu aktivnost na angiotenzin konvertujući enzim (ACE).
Izraz "antagonisti renina" obuhvata inhibitore renina.
U ovom pronalasku inhibitori RAS mogu da pokazuju dugotrajno dejstvo, srednje dugo dejstvo ili kratkotrajno dejstvo.
ACE inhibitori ili njihovi farmaceutski prihvatljivi derivati, uključujući aktivne metabolite, koji se mogu koristiti u prevenciji šloga, dijabetesa i/ili CHF, obuhvataju, ali se ne ograničavaju samo na, sledeća jedinjenja: alacepril, alatriopril, altiopril kalcijum, ankovenin, benazepril, benazepril hidrohlorid, benazeprilat, benzoilkaptopril, kaptopril, kaptopril-cistein, kaptopril-glutanat, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid, enalapril, enalaprilat, enapril, epikaptopril, foroksimitin, fosfenopril, fosenopril, fosenopril natrijum, fozinopril, fozinopril natrijum, fozinoprilat, fozinoprilska kiselina, glikopril, hemorfm-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, quinapril, quinapril hidrohlorid, quinaprilat, ramipril, ramiprilat, spirapril, spirapril hidrohlorid, spiraprilat, spiropril, spiropril hidrohlorid, temokapril, temokapril hidrohlorid, temartid, trandolapril, trandolaprilat, utibapril, zabicipril, zabiciprilat, zofenopril i zofenoprilat.
Preferirani ACE inhibitori za upotrebu u ovom pronalasku su ramipril, ramiprilat, lizinopril, enalapril i enalaprilat. Još više preferirani ACE inhibitori za upotrebu u ovom pronalasku su ramipril i ramiprilat. Informacija o ramiprilu i ramiprilatu se može dobiti, na primer, i Merck Index., 12-to izdanje, 1996, strane 1394-1395.
AT II antagonisti ili njihovi farmaceutski prihvatljivi derivati, uključujući i aktivne metabolite, koji se mogu koristiti za prevenciju šloga, dijabetesa i/ili CHF, obuhvataju, ali se ne ograničavaju samo na one koji su opisani u Evropskim patentnim prijavama, broj objavljivanja 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.
Ostali A II antagonisti obuhvataju one koji su otkriveni u Međunarodnoj patentnoj prijavi, broj objavljivanja WO 91/00277, WO 91/00281, WO 91/11909, WO 91/11999,
WO 91/12001, WO 91/12002, WO 91/13063, WO 91/15209, WO 91/15479,
WO 91/16313, WO 91/17148, WO 91/18888, WO 91/19697, WO 91/19715,
WO 92/00067, WO 92/00068, WO 92/00977, WO 92/02510, WO 92/04335,
WO 92/04343, WO 92/05161, 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 navedenih Evropskih i Međunarodnih patentnih prijava su na ovaj način inkorporirani u referencama.
Preferirani antagonisti AT II ili njihovi farmaceutski prihvatljivi derivati za upotrebu u ovom pronalasku, obuhvataju, ali se ne ograničavaju samo na, jedinjenja sa sledećim generičkim nazivima: kandesartan, kandesartan cileksetil, losartan, valsartan, irbesartan, tasosartan, telmisartan i eprosartan.
Posebno preferirani antagonisti AT II ili njihovi farmaceutski prihvatljivi derivati za upotrebu u ovom pronalasku su kandesartan i kandesartan cileksetil. Kandesartan i kandesartan cileksetil su poznati iz Evropskog patenta broj 459136 BI, US 5, 196, 444 i US 5, 703, 110 Takeda Chemical Industries. Kandesartan cileksetil proizvode i prodaju širom sveta AstraZeneca i Takeda, pod zaštićenim trgovačkim nazivima Atacand®, Amias® i Blopress®.
NEP/ACE-inhibitori ili njihovi farmaceutski prihvatljivi derivati, uključujući aktivne metabolite, koji se mogu koristiti u prevenciji šloga, dijabetesa i/ili CHF, obuhvataju ali se ne ograničavaju samo na jedinjenja koja su otkrivena u US Patentima broj
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 Evropskim patentnim prijavama 0481522, 0534263, 0534396, 0534492 i 0671172.
Preferirani NEP/ACE-inhibitori za upotrebu u ovom pronalasku su oni koji su navedeni kao preferirani u gore pomenutim US patentima i Evropskim patentnim prijavama i ovde su inkorporirani u referencama. Posebno je preferiran NEP/ACE-inhibitor omapatrilat (otkriven u US patentu broj 5. 508. 272), ili MDL100240 (otkriven u US patentu broj 5. 430. 145).
Renin-inhibitori ili njihovi farmaceutski prihvatljivi derivati, uključujući aktivne metabolite, koji se mogu koristiti za prevenciju šloga, dijabetesa i/ili CHF, obuhvataju, ali se ne ograničavaju samo na, sledeća jedinjenja: enalkrein; RO 425892; A 65317; CP 80794; ES 1005; ES 8891; SQ 34017; CGP 29287; CGP 38560; SR 43845; U-71038; A 62198 i A 64662.
Farmaceutske formulacije
Po jednom aspektu, ovaj pronalazak se odnosi na farmaceutske formulacije koje uključuju kao aktivni sastojak neki RAS inhibitor ili njegov farmaceutski prihvatljiv derivat ili prolek, uključujući metabolite, za upotrebu u prevenciji šloga, dijabetesa i/ili kongestivne srčane insuficijencije (CHF).
Za kliničku upotrebu, RAS inhibitor je formulisan u farmaceutsku formulaciju za oralni, intravenozni, subkutani, trahealni, bronhijalni, intranazalni, pulmonami, transdermalni, bukalni, rektalni, parenteralni ili neki drugi način davanja. Farmaceutska kompozicija može da sadrži i inhibitor u mešavini sa farmaceutski prihvatljivim pomoćnim sredstvom, razblaživačem i/ili nosačem.
U izradi farmaceutskih formulacija ovog pronalaska, aktivni sastojak može biti u mešavini sa čvrstim praškastim sastojcima, kao što su laktoza, saharoza, sorbitol, manitol, škrob, amilopektin, derivati celuloze, želatin ili neki drugi pogodan sastojak, kao i sa dezintegracionim sredstvima i lubrikantnim sredstvima, kao što su magnezijum stearat, kalcijum stearat, natrijum stearli fumarat i polietilen glikolni voskovi. Mešavine se zatim mogu prevesti u granule ili presovati u tablete.
Aktivni sastojak se može prethodno odvojeno izmešati sa drugim, neaktivnim sastojcima, pre mešanja da nagradi formulaciju.
Meke želatinske kapsule se mogu dobiti od kapsula koje sadrže mešavinu aktivnog sastojka iz pronalaska, biljno ulje, mast ili neki drugi pogodan vehikulum za mekane želatinske kapsule. Čvrste želatinske kapsule mogu da sadrže granule aktivnih sastojaka. Čvrste želatinske kapsule mogu, takođe, da sadrže aktivne sastojke u kombinaciji sa čvrstim praškastim sastojcima, kao što su laktoza, saharoza, sorbitol, manitol, krompirov škrob, kukuruzni škrob, amilopektin, derivati celuloze ili želatin.
Pojedinačne doze za rektalnu upotrebu mogu se dobiti (i) u obliku supozitorija koje sadrže aktivnu supstancu u mešavini sa neutralnom masnom podlogom; (ii) u obliku želatinske rektalne kapsule koja sadrži aktivnu supstancu u mešavini sa biljnim uljem, parafinskim uljem ili nekim drugim pogodnim vehikulumom za rektalne želatinske kapsule; (iii) u obliku gotovih mikroklizmi; ili (iv) u obliku suvih mikroklizmi koje su formulisane tako da se rekonstituišu u pogodnom rastvaraču neposredno pre davanja.
Tečni preparati se mogu dobiti u obliku sirupa ili suspenzija, to jest, rastvora ili suspenzija koje sadrže aktivne sastojke i druge sastojke, na primer, šećer ili šećerne alkohole i mešavinu etanola, vode, glicerola, propilen glikola i polietilen glikola. Ukoliko se želi, takvi tečni preparati mogu da sadrže sredstva za bojenje, sredstva za korigovanaje ukusa, konzervanse, saharin i karboksimetil celulozu ili neko drugo sredstvo za zgušnjavanje. Tečni preparati se takođe mogu dobiti u obliku suvog praha koji se rekonstituiše u odgovarajućem rastvaraču, neposredno pre upotrebe.
Rastvori za parenteralno davanje mogu se pripremiti kao rastvor formulacije iz pronalaska u farmaceutski prihvatljivom rastvaraču. Ovi rastvori mogu takođe da sadrže sredstva za stabilizaciju, konzervanse i/ili sredstva za puferovanje. Rastvori za parenteralno davanje mogu se takođe pripremiti u obliku suvog preparata koji se rekonstituiše sa pogodnim rastvaračem pre upotrebe.
Pogodna ukupna količina aktivnog sastojka je u rasponu od približno 0. 1% (w/w) do približno 95% (w/w) formulacije, pogodno je od 0. 5% do 50% (w/w) i poželjno je od 1% do 25% (w/w).
Farmaceutske kompozicije mogu da sadrže između približno 0. 1 mg do približno 1000 mg aktivnog sastojka, poželjno je između 1 mg i 100 mg aktivnog sastojka.
Doza aktivnog sastojka koja će se davati zavisi od relevantnih indikacija, godina, težine i pola pacijenta i može se odrediti od strane lekara. Pogodna doza je u rasponu od približno 0. 01 mg/kg do približno 20 mg/kg, poželjno je između 0. 1 mg/kg i 10 mg/kg.
Uobičajena dnevna doza aktivnih sastojaka varira u širokom rasponu i zavisi od različitih faktora, kao što su relevantna indikacija, način davanja, godine, težina i pol pacijenta i određuje je lekar. Generalno, doze, posebno oralne i parenteralne doze, su u rasponu od približno 0. 1 do približno 100 mg dnevno aktivnog sastojka, poželjno je između 1 i 50 mg dnevno aktivnog sastojka.
Naredni Primer treba da ilustruje, ali ni na koji način da ograniči polje pronalaska.
PRIMER
Veliki broj kliničkih ispitivanja je sproveden da bi se ispitalo dejstvo ACE inhibitora ramiprila u odnosu na placebo uzorak u smanjenju broja kardiovaskularnih slučajeva.
Ispitivanja su sprovedena u 267 centara u 19 zemalja u toku 6 godina i uključila su 9. 541 učesnika koji su bili kardiovaskularni bolesnici visokog rizika zbog ranijih oboljenja srčane ishemije, šloga, bolesti perifernih arterija ili su imah dijabetes.
Sistolni krvni pritisak uključenih pacijenata je bio na nivou prošeka od 138 mm Hg i prema tome, pacijenti su bili normotenzivni na početku ispitivanja. Posle jednomesečne terapije ili ramiprilom ili placebom, sistolni krvni pritisak se smanjio za 5. 48 mm Hg i 1. 59 mm Hg, tim redom.
Primami cilj studije je bio ispitivanje na infarkt miokarda (MI), šlog i kardiovaskularnu (CV) smrt (smrtnost).
Ispitivanje je ranije prekinuto zbog vrlo izraženog smanjenja smrtnih slučajeva od kardiovaskularnih bolesti, srčanih napada i šloga kod pacijenata koji su uzimah ramipril kao kombinovanog cilja ispitivanja. Kao dodatak gore navedenim prednostima, došlo je takođe do smanjenja za četvrtinu do petine u potrebama za procesima revaskularizacije (kao što je operacija bajpas grafta koronarne arterije, balon angioplastika itd) i komplikacije od dijabetesa.
U grupi koja je koristila ramipril za 32% je došlo do smanjenja u broju pacijenata koji su doživeli šlog, što je iznenađujuće pošto su pacijenti bili normotenzivni na početku ispitivanja.
Broj pacijenata kod kojih se razvio CHF je značajno smanjen za 21% u grupi koja je uzimala ramipril, što je neočekivano pošto pacijenti nisu imah znake ili simptome CHF na početku ispitivanja.
Podjednako iznenađujuće je bilo i registrovano smanjenje za 36% u broju pacijenata kod kojih se razvio dijabetes, u grupi koja je dobijala ramipril.
Skraćenice
ACE = angiotenzin konvertujući enzim AT II = angiotenzin II tip 1 receptor CHF = kongestivna srčana insuficijencija IDMM = insulin zavisni, dijabetes melitus JNC = Zajednički nacionalni odbor MI = infarkt miokarda NIDDM = insulin nezavisni dijabets melitus WHO = svetska zdravstvena organizacija
Claims (28)
1. Upotreba nekog inhibitora renin-angiotenzin sistema (RAS) ili njegovog farmaceutski prihvatljivog derivata u proizvodnji medikamenta za prevenciju šloga.
2. Upotreba nekog inhibitora RAS ili njegovog farmaceutski prihvatljivog derivata u proizvodnji medikamenta za prevenciju šloga kod pacijenata koji imaju normalan ili nizak krvni pritisak.
3. Upotreba nekog inhibitora RAS ili njegovog farmaceutski prihvatljivog derivata u proizvodnji medikamenta za prevenciju dijabetesa.
4. Upotreba nekog inhibitora RAS ili njegovog farmaceutski prihvatljivog derivata u proizvodnji medikamenta za prevenciju razvoja kongestivne srčane insuficijencije (CHF) kod pacijenata kod kojih ranije nije bilo CHF.
5. Upotreba u skladu sa bilo kojim od pretnodnih zahteva, naznačena time što je inhibitor RAS-a neki inhibitor angiotenzin konvertujućeg enzima ili (ACE) ili neki antagonist angiotenzin II tip 1 receptora (AT II) ili farmaceutski prihvatljivi derivati bilo kojeg od njih.
6. Upotreba u skladu sa zahtevom 5, naznačena time što je ACE inhibitor ili njegov farmaceutski prihvatljiv derivat izabran iz grupe koja sadrži alacepril, alatriopril, altiopril kalcijum, ankovenin, benazepril, benazepril hidrohlorid, benazeprilat, benzoilkaptopril, kaptopril, kaptopril-cistein, kaptopril-glutanat, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid, enalapril, enalaprilat, enapril, epikaptopril, foroksimitin, fosfenopril, fosenopril, fosenopril natrijum, fozinopril, fozinopril natrijum, fozinoprilat, fozinoprilska 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, quinapril, quinapril hidrohlorid, quinaprilat, ramipril, ramiprilat, spirapril, spirapril hidrohlorid, spiraprilat, spiropril, spiropril hidrohlorid, temokapril, temokapril hidrohlorid, teprotid, trandolapril, trandolaprilat, utibapril, zabicipril, zabiciprilat, zofenopril i zofenoprilat.
7. Upotreba u skladu sa zahtevom 6, naznačena time što je ACE inhibitor izabran iz grupe koja sadrži ramipril, ramiprilat, lizinopril, enalapril i enalaprilat.
8. Upotreba u skladu sa zahtevom 5, naznačena time što je AT II antagonist ili njegov farmaceutski prihvatljiv derivat izabran iz grupe koja sadrži kandesartan, kandesartan cileksetil, losartan, valsartan, irbersartan, tasosartan, telmisartan i eprosartan.
9. Upotreba u skladu sa zahtevom 8, naznačena time što je AT II antagonist ili njegov farmaceutski prihvatljiv derivat izabran iz grupe koja sadrži kandesartan i kandesartan cileksetil.
10. Postupak za prevenciju šloga, naznačen time što uključuje davanje terapeutski efektivne količine nekog inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata pacijentima kojima je potrebna takva prevencija.
11. Postupak za prevenciju šloga kod pacijenata koji imaju normalan ili nizak krvni pritisak, naznačen time što uključuje davanje terapeutski efektivne količine nekog inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata pacijentima kojima je potrebna takva prevencija.
12. Postupak za prevenciju dijabetesa, naznačen time što uključuje davanje terapeutski efektivne količine nekog inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata pacijentima kojima je potrebna takva prevencija.
13. Postupak za prevenciju razvoja CHF kod pacijenata koji ranije nisu imali CHF, naznačen time što uključuje davanje terapeutski efektivne količine nekog inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata pacijentima kojima je potrebna takva prevencija.
14. Postupak za prevenciju u skladu sa bilo kojim od zahteva 10 do 13, naznačen time što je inhibitor RAS-a neki inhibitor ACE ili antagonist AT II ili farmaceutski prihvatljiv derivat bilo koga od njih.
15. Postupak za prevenciju u skladu sa zahtevom 14, naznačena time što je ACE inhibitor ili njegov farmaceutski prihvatljiv derivat izabran iz grupe koja sadrži alacepril, alatriopril, altiopril kalcijum, ankovenin, benazepril, benazepril hidrohlorid, benazeprilat, benzoilkaptopril, kaptopril, kaptopril-cistein, kaptopril-glutanata, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid, enalapril, enalaprilat, enapril, epikaptopril, foroksimitin, fosfenopril, fosenopril, fosenopril natrij um, fozinopril, fozinopril natrij um, fozinoprilat, fozinoprilska kiselina, glikopril, hemorfm-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, quinapril, quinapril hidrohlorid, quinaprilat, ramipril, ramiprilat, spirapril, spirapril hidrohlorid, spiraprilat, spiropril, spiropril hidrohlorid, temokapril, temokapril hidrohlorid, teprotid, trandolapril, trandolaprilat, utibapril, zabicipril, zabiciprilat, zofenopril i zofenoprilat.
16. Postupak za prevenciju u skladu sa zahtevom 15, naznačen time što je ACE inhibitor izabran iz grupe koja sadrži ramipril, ramiprilat, lizinopril, enalapril i enalaprilat.
17. Postupak za prevenciju u skladu sa zahtevom 14, naznačen time što je AT II antagonist ili njegov farmaceutski prihvatljiv derivat izabran iz grupe koja sadrži kandesartan, kandesartan cileksetil, losartan, valsartan, irbersartan, tasosartan, telmisartan i eprosartan.
18. Postupak za prevenciju u skladu sa zahtevom 17, naznačen time što je AT II antagonist ili njegov farmaceutski prihvatljiv derivat izabran iz grupe koja sadrži kandesartan i kandesartan cileksetil.
19. Farmaceutska formulacija za upotrebu u prevenciji šloga, dijabetesa i/ili CHF, naznačena time što uključuje terapeutski efektivnu količinu nekog inhibitora RAS-a ili njegov farmaceutski prihvatljiv derivat.
20. Farmaceutska formulacija u skladu sa zahtevom 19, naznačena time što je inhibitor RAS-a neki inhibitor ACE ili antagonist AT II ili farmaceutski prihvatljiv derivat bilo koga od njih.
21. Farmaceutska formulacija u skladu sa zahtevom 20, naznačena time što je ACE inhibitor izabran iz grupe koja sadrži ramipril, ramiprilat, lizinopril, enalapril i enalaprilat.
22. Farmaceutska formulacija u skladu sa zahtevom 20, naznačena time što je AT II antagonist ili njegov farmaceutski prihvatljiv derivat izabran iz grupe koja sadrži kandesartan, kandesartan cileksetil, losartan, valsartan, irbersartan, tasosartan, telmisartan i eprosartan.
23. Farmaceutska formulacija u skladu sa bilo kojim od zahteva 19 do 22, naznačena time što je to mešavina sa farmaceutski prihvatljivim pomoćnim sredstvom, razblaživačem i/ili nosačem.
24. Farmaceutska formulacija u skladu sa bilo kojim od zahteva 19 do 23, naznačena time što je u pojedinačnom doziranom obliku.
25. Upotreba nekog inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata u prevenciji šloga, dijabetesa i/ili CHF davanjem inhibitora RAS-a ili njegovog farmaceutski prihvatljivog derivata pacijentima kojima je takva prevencija potrebna.
26. Upotreba u skladu sa zahtevom 25, naznačena time što je inhibitor RAS-a neki inhibitor ACE ili antagonist AT II ili farmaceutski prihvatljiv derivat bilo koga od njih.
27. Upotreba u skladu sa zahtevom 26, naznačena time što je ACE inhibitor izabran iz grupe koja sadrži ramipril, ramiprilat, lizinopril, enalapril i enalaprilat.
28. Upotreba u skladu sa zahtevom 26, naznačena time što je AT II antagonist ili njegov farmaceutski prihvatljiv derivat izabran iz grupe koja sadrži kandesartan, kandesartan cileksetil, losartan, valsartan, irbersartan, tasosartan, telmisartan i eprosartan.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| 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 |
| YU3602A YU3602A (sh) | 1999-08-27 | 2002-01-16 | Farmaceutske formulacije inhibitora renin-angiotenzin sistema (ras) i njihova primena |
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| AU (3) | AU7648400A (me) |
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| HU (1) | HU229107B1 (me) |
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| PT (2) | PT1437131E (me) |
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| RU (2) | RU2272651C2 (me) |
| SE (1) | SE9903028D0 (me) |
| SI (3) | SI1437131T1 (me) |
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| UA (2) | UA76702C2 (me) |
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1999
- 1999-08-27 SE SE9903028A patent/SE9903028D0/xx unknown
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2000
- 2000-08-25 KR KR1020087007837A patent/KR20080035703A/ko not_active Ceased
- 2000-08-25 ES ES08004265.8T patent/ES2525699T3/es not_active Expired - Lifetime
- 2000-08-25 HR HR20020169A patent/HRP20020169A2/hr not_active Application Discontinuation
- 2000-08-25 SI SI200031069T patent/SI1437131T1/sl unknown
- 2000-08-25 ME MEP-282/08A patent/MEP28208A/xx unknown
- 2000-08-25 IL IL148126A patent/IL148126A/en not_active IP Right Cessation
- 2000-08-25 SI SI200030766T patent/SI1212081T2/sl unknown
- 2000-08-25 AT AT04006330T patent/ATE554761T1/de active
- 2000-08-25 PL PL00353066A patent/PL353066A1/xx not_active IP Right Cessation
- 2000-08-25 WO PCT/EP2000/008341 patent/WO2001015673A2/en not_active Ceased
- 2000-08-25 ES ES00965898.0T patent/ES2250192T5/es not_active Expired - Lifetime
- 2000-08-25 NZ NZ571901A patent/NZ571901A/en not_active IP Right Cessation
- 2000-08-25 HU HU0202461A patent/HU229107B1/hu not_active IP Right Cessation
- 2000-08-25 PT PT04006330T patent/PT1437131E/pt unknown
- 2000-08-25 SI SI200031084T patent/SI1925303T1/sl unknown
- 2000-08-25 DE DE60023518.1T patent/DE60023518T3/de not_active Expired - Lifetime
- 2000-08-25 DK DK08004265.8T patent/DK1925303T3/en active
- 2000-08-25 KR KR1020027002521A patent/KR20020060167A/ko not_active Ceased
- 2000-08-25 EP EP10010670A patent/EP2277519A3/en not_active Withdrawn
- 2000-08-25 DK DK00965898.0T patent/DK1212081T4/da active
- 2000-08-25 RS RS3602A patent/RS52907B/sr unknown
- 2000-08-25 TR TR2002/00518T patent/TR200200518T2/xx unknown
- 2000-08-25 TR TR2002/02464T patent/TR200202464T2/xx unknown
- 2000-08-25 CZ CZ20020644A patent/CZ303433B6/cs not_active IP Right Cessation
- 2000-08-25 CN CNB008110700A patent/CN100408093C/zh not_active Expired - Fee Related
- 2000-08-25 AT AT00965898T patent/ATE307604T1/de active
- 2000-08-25 AU AU76484/00A patent/AU7648400A/en not_active Abandoned
- 2000-08-25 SK SK270-2002A patent/SK288239B6/sk not_active IP Right Cessation
- 2000-08-25 MX MXPA02001633A patent/MXPA02001633A/es active IP Right Grant
- 2000-08-25 CN CNA2008101259535A patent/CN101537181A/zh active Pending
- 2000-08-25 EE EEP200200085A patent/EE05130B1/xx not_active IP Right Cessation
- 2000-08-25 EP EP04006330A patent/EP1437131B1/en not_active Expired - Lifetime
- 2000-08-25 TR TR2002/02467T patent/TR200202467T2/xx unknown
- 2000-08-25 CA CA002382387A patent/CA2382387C/en not_active Expired - Fee Related
- 2000-08-25 ES ES04006330T patent/ES2386141T3/es not_active Expired - Lifetime
- 2000-08-25 TR TR2002/02463T patent/TR200202463T2/xx unknown
- 2000-08-25 RU RU2002107673/15A patent/RU2272651C2/ru not_active IP Right Cessation
- 2000-08-25 EP EP00965898.0A patent/EP1212081B2/en not_active Expired - Lifetime
- 2000-08-25 PT PT80042658T patent/PT1925303E/pt unknown
- 2000-08-25 JP JP2001519887A patent/JP4843172B2/ja not_active Expired - Fee Related
- 2000-08-25 TR TR2002/02466T patent/TR200202466T2/xx unknown
- 2000-08-25 BR BR0013540-2A patent/BR0013540A/pt not_active Application Discontinuation
- 2000-08-25 EP EP08004265.8A patent/EP1925303B1/en not_active Expired - Lifetime
- 2000-08-25 UA UA2002032397A patent/UA76702C2/uk unknown
- 2000-08-25 DK DK04006330.7T patent/DK1437131T3/da active
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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 NO NO20020850A patent/NO329245B1/no not_active IP Right Cessation
- 2002-02-21 ZA ZA200201471A patent/ZA200201471B/xx unknown
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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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