CZ303433B6 - Použití ramiprilu, ramiprilátu nebo jejich farmaceuticky prijatelných derivátu - Google Patents
Použití ramiprilu, ramiprilátu nebo jejich farmaceuticky prijatelných derivátu Download PDFInfo
- Publication number
- CZ303433B6 CZ303433B6 CZ20020644A CZ2002644A CZ303433B6 CZ 303433 B6 CZ303433 B6 CZ 303433B6 CZ 20020644 A CZ20020644 A CZ 20020644A CZ 2002644 A CZ2002644 A CZ 2002644A CZ 303433 B6 CZ303433 B6 CZ 303433B6
- Authority
- CZ
- Czechia
- Prior art keywords
- ramipril
- patients
- pharmaceutically acceptable
- ramiprilat
- heart failure
- Prior art date
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- 229960003401 ramipril Drugs 0.000 title claims abstract description 21
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Classifications
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Abstract
Rešení se týká použití ramiprilu, ramiprilátu nebo jejich farmaceuticky prijatelných derivátu k príprave léciva pro prevenci vývoje mestnavého srdecního selhání u pacientu, u kterých nebylo mestnavé srdecní selhání diagnostikováno.
Description
Oblast techniky
Vynález se týká použití ramiprilu, ramiprilátu nebo jejich farmaceuticky přijatelných derivátů.
Dosavadní stav techniky
Sloučeniny, které zasahují do RAS jsou v oboru dobře známé, a používají se k léčení kardiovaskulárních onemocnění, zejména arteriální hypertense a srdečního selhávání. V principu lze RAS ovlivňovat pomocí inhibice enzymů, které syntetizují angiotensiny, nebo pomocí blokování odpovídajících míst na receptorech či efektorech. Dnes jsou dostupné inhibitory angiotensin kon15 vertujícího enzymu (ACE) a antagonisté receptoru pro angiotensin 11 typu 1 (AT II).
ACE inhibitory jsou sloučeniny, které inhibují konversi angiotensinu I na aktivní angiotensin II, jakož i rozpad aktivního vasodilatátoru bradikyninu. Oba tyto mechanismy vedou k vasodilataci. Tyto sloučeniny jsou popsány například v EP 158927, EP 317878, US 4,743,450, a
US 4,857,520.
Ramipril (zveřejněny v EP-A-079022) je dlouho působící ACE inhibitor. Jeho účinným metabolitem je volny ramipralát se dvěma karboxylovými skupinami, který se získá při podávání ramiprilu in vivo. Je známo, že u pacientů s hypertensí působí podávání ramiprilu snížení periferního arteriálního odporu, a tím snížení krevního tlaku, bez kompenzačního zvýšení srdeční frekvence. V současné době se ramipril používá k léčení hypertense a městnavého srdečního selhávání. Dále se ukázalo, že ramipril snižuje úmrtnost u pacientů s klinickými známkami městnavého srdečního selhávání po přežití akutního infarktu myokardu. Předpokládá se, že ramipril má další výhody oproti mnohým jiným ACE inhibitorům, díky jeho zřetelné inhibici ACE ve tkáních, vedoucí v orgán-protektivní účinky např. u srdce, ledvin, a krevních cév.
Sloučeniny, které ovlivňují RAS, zahrnující ACE inhibitory a AT II antagonisty, se v současné době používají k léčení rozličných kardiovaskulárních onemocnění, zejména u pacientů s vysokým krevním tlakem. Použití uvedených sloučenin k prevenci kardiovaskulárních onemocnění je o mnoho méně obvyklé, a použití uvedených sloučenin k prevenci mrtvice, diabetů a/nebo městnavého srdečního selhávání je doposud neznámé.
Podstata vynálezu
Předmětem vynálezu je použití ramiprilu, ramiprilátu nebo jejich farmaceuticky přijatelných derivátů k přípravě léčiva pro prevenci vývoje městnavého srdečního selhání u pacientů, u kterých nebylo městnavé srdeční selhání diagnostikováno. Výhodné je použití, při kterém má pacient normální nebo nízký krevní tlak. Výhodné je použití, při kterém je pacient diabetikem.
S překvapením bylo zjištěno, že k prevenci městnavého srdečního selhání lze použít ramipril, ramiprilát nebo jejich farmaceuticky přijatelné deriváty. Překvapivost tohoto vynálezu spočívá zejména v tom, že z preventivního účinku uvedených účinných látek mají užitek obzvláště pacienti s v podstatě udržovanou funkcí srdce a/nebo s normálním nebo nízkým tlakem. Pacienti s normálním nebo nízkým tlakem jsou známí jako normotensivní pacienti. Mezi příklady směrnic, které definují hodnoty krevního tlaku pro různé skupiny pacientů, zahrnující různá stáří, patří směrnice vydaná WHO a JNC (USA). Pro účely tohoto vynálezu lze vhodné definice normálního nebo nízkého krevního tlaku nalézt v JNC VI, jejíž obsah je zde zahrnut formou odkazu.
- 1 CZ 303433 B6
Termín diabetik používaný v rámci tohoto vynálezu zahrnuje pacienty trpící diabetem typu I, který je rovněž nám jako insulin-dependentní diabetes mellitus, tak i pacienty trpící diabetem typu II, který je rovněž znám jako, insulinnedependentní diabetes mellitus.
Pokud má účinná látka podle vynálezu několik asymetrických uhlíkových atomů, potom se může vyskytovat v několika stereochemických formách. Vynález zahrnuje směs izomerů, tak také i jednotlivé stereo izomeiy. Vynález dále zahrnuje geometrické izomery, rotační izomery, enantiomery, racemáty a diastereomery.
Pokud jsou účinné, lze účinné látky použít v neutrální formě, například jako karboxylovou kyselinu, nebo ve formě soli, výhodně ve formě farmaceuticky přijatelné soli, jako jsou sodné, draselné, amonné, vápenaté a horečnaté soli dané účinné látky. Pokud jsou použitelné, lze uvedené účinné látky použít ve formě hydrolyzovatelného esteru. Vynález rovněž zahrnuje profarmaka účinných látek, ať již jsou účinná nebo neúčinná in vitro. Proto, ačkoliv tyto chráněné deriváty nevykazují farmakoligickou účinnost samy o sobě, lze je podávat parenterálně nebo orálně, načež jsou potom in vivo metabolizovány na farmakologicky účinné inhibitory. Vhodným příkladem je právě ramipril, který je metabolizován na ramiprilát. Informace o ramiprilu a ramiprilátu lze například získat z Merck Index., 12. ed,, 1996, str, 1394-1395.
Pro klinické použití jsou ramipril, ramiprilát nebo jejich farmaceuticky přijatelné deriváty zabudovány do farmaceutického prostředku pro orální, intravenózní, tracheální, bronchiální, intranasální, pulmonámí, transdermální, bukální, rektální, parenterální nebo některý jiný způsob podávání. Tento farmaceuticky prostředek může uvedený inhibitor obsahovat ve směsi s farmaceuticky přijatelnou pomocnou látkou, ředidlem a/nebo nosičem.
Během přípravy farmaceutického prostředku lze účinnou složku smíchat s pevnými, práškovými složkami, jako jsou laktóza, sacharóza, sorbitol, mannitol, škrob, amylopektin, deriváty celulózy, želatina, a nebo jinou vhodnou složkou, tak jako i s desintegračními činidly a lubrikaěními činidly, jako jsou stearát horečnatý, stearát vápenatý, natři um stearylfumarát a polyethylenglykolové vosky. Směs lze poté zpracovat do podoby granulí nebo stlačit do podoby tablet.
Účinnou složku lze předtím, než se smíchá do určité podoby prostředku, předmísit s další, neúčinnou složkou.
Měkké želatinové kapsle lze připravit jako kapsle obsahující směs účinné látky podle vynálezu, rostlinného oleje, tuku, nebo jiné vhodné pomocné látky pro měkké želatinové kapsle. Tvrdé želatinové kapsle mohou obsahovat granule z účinných látek. Tvrdé želatinové kapsle mohou též obsahovat účinné látky ve směsi s pevnými práškovými složkami, jako jsou laktóza, sacharóza, sorbitol, mannitol, bramborový škrob, kukuřičný škrob, amylopektin, deriváty celulózy nebo želatina.
Dávkovači jednotky k rektálnímu podávání lze připravit (i) ve formě čípků obsahujících účinnou látku smíchanou s neutrálním tukovým základem;
(ii) ve formě želatinové rektální kapsle obsahující účinnou látku ve směsi s rostlinným olejem, parafínovým olejem nebo jinou vhodnou pomocnou látkou pro želatinové rektální kapsle;
(iii) ve formě již připraveného mikroklyzmatu; nebo (iv) ve formě suchého mikroklyzmatu, které se pomocí vhodného rozpouštědla připraví k podání až před použitím.
Tekuté prostředky lze připravit ve formě sirupů nebo suspenzí, např. roztoků nebo suspenzí obsahujících účinné látky a zbytek, jenž se například skládá z cukru nebo cukerných alkoholů a směsi ethanolu, vody, glycerolu, propylenglykolu a polyethylenglykolu. Pokud je to žádoucí,
-2CZ 303433 B6 mohou tyto tekuté prostředky obsahovat barviva, aromatická činidla, konzervační prostředky, sacharin a karboxymethylcelulózu či jiná zahušťovadla. Tekuté prostředky lze také připravit ve formě suchého prášku, který se pomocí vhodného rozpouštědla připraví k podání až před použitím.
Roztoky k parenterálnímu podávání lze připravit jako roztoky přípravků podle vynálezu ve farmaceuticky přijatelném rozpouštědle. Tyto roztoky mohou také obsahovat stabilizační činidla, konzervační prostředky a/nebo pufrovací složky. Roztoky k parenterálnímu podávání lze připravit také jako suché přípravky, které se před podáním připraví pomocí vhodného rozpouštědla k podání.
Celkové množství účinné látky se vhodně pohybuje přibližně v rozmezí od 0,1 % (hmotn./hmotn.) do 95 % (hmotn. /hmotn.) prostředku, vhodně od 0,5 % do 50 % (hmotn. /hmotn.), a výhodně od 1 % do 25 % (hmotn. /hmotn.).
Farmaceutické prostředky mohou obsahovat přibližně 0,1 mg až 1000 mg účinné látky, výhodně 1 mg až 100 mg účinné látky.
Dávka účinné látky pro podávání závisí na konkrétní indikaci, věku, hmotnosti a pohlaví pacien20 ta, a může ji stanovit ošetřující lékař. Dávkování se bude vhodně pohybovat přibližně v rozmezí od 0,01 mg/kg do 20 mg/kg, výhodně od 0,1 mg/kg do 10 mg/kg.
Obvyklá denní dávka účinných látek se pohybuje v širokém rozmezí a závisí na rozličných faktorech, jako jsou konkrétní indikace, způsob podávání, věk, hmotnost a pohlaví pacienta, a může ji stanovit ošetřující lékař. Obecně se mohou dávky, a zejména orální a parenterální dávky, pohybovat přibližně v rozmezí od 0,1 do 100 mg účinné látky na den, výhodně od 1 do 50 mg účinné látky na den.
Následující příklad provedení vynálezu slouží k ilustraci předkládaného vynálezu, avšak nikterak neomezuje rozsah předkládaného vynálezu.
Příklad provedení vynálezu
Byla provedena rozsáhlá klinická studie k prokázání účinku ACE inhibitoru ramiprilu, oproti placebu, na snížení kardiovaskulárních příhod
Studie byla prováděna ve 267 centrech v 19 zemích po dobu 6 let a zahrnovala 9541 účastníků, u nichž bylo vysoké riziko pro kardiovaskulární příhody, kvůli anamnéze předcházející ischemické choroby srdeční, mrtvice, periferních arteriálních poruch, nebo jednotlivců s diabetem.
Systolický krevní tlak při přijetí pacientů činil průměrně 138 mm rtuťového sloupce, a proto byli tito pacienti na počátku studie normotenzivní. Po jednom měsíci léčby buď pomocí ramiprilu, nebo placeba, došlo ke snížení systolického krevního tlaku o 5,48 mm rtuťového sloupce resp.
1,59 mm rtuťového sloupce.
V rámci studie byly posuzovány infarkt myokardu (MI), mrtvice a kardiovaskulární (CV) úmrtí (úmrtnost).
K ukončení studie došlo dříve, neboť u pacientů užívajících ramipril došlo k velmi zřetelnému snížení, pokud se týká kardiovaskulárních úmrtí, srdečních příhod a mrtvic. Kromě výše uvedených prospěšných účinku, bylo pozorováno také snížení o čtvrtinu až pětinu, pokud se týká potřeby revaskularizačních postupů (jako jsou transplantační chirurgie koronárního arteriálního bypassu, balónková angioplastika, atd.) a diabetických komplikací.
-3CZ 303433 B6
U skupiny užívající ramipril bylo pozorováno zřetelné 32 % snížení počtu pacientů, u nichž se vyskytla mrtvice, a to je, vzhledem k tomu, že pacienti byli na počátku studie normotenzivní, překvapivé.
Počet pacientů, u nichž se vyskytlo městnavé srdeční selhávání, se u skupiny užívající ramipril značně snížil, a to o 21 %, cožje vzhledem k tomu, že pacienti na počátku studie nevykazovali žádné známky nebo příznaky městnavého srdečního selhávání, neočekávané.
io Stejně překvapivé je značné, 36 % snížení v počtu pacientů skupiny užívající ramipril, u nichž se vyvinul diabetes.
Přehled zkratek | |
ACE | angiotensin konvertuj ící enzym |
AT II | receptor pro angiotensin II typu 1 |
CHF | městnavé srdeční selhávání |
IDMM | insulin-dependentní diabetes mellitus |
JNC | Společná národní komise (Joint National Committee) |
MI | infarkt myokardu |
NIDMM | non-insulin-dependentní diabetes mellitus |
WHO | Světová zdravotnická organizace |
Claims (2)
- PATENTOVÉ NÁROKY1. Použití ramiprilu, ramiprilátu nebo jejich farmaceuticky přijatelných derivátů k přípravě 30 léčiva pro prevenci vývoje městnavého srdečního selhání u pacientů, u kterých nebylo městnavé srdeční selhání diagnostikováno.
- 2. Použití podle nároku 1, při kterém má pacient normální nebo nízký krevní tlak.35 3. Použití podle nároku 1 nebo 2, při kterém je pacient diabetikem.
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WO1999020260A2 (en) * | 1997-10-17 | 1999-04-29 | Eurogene Limited | The use of inhibitors of the renin-angiotensin system for the treatment of hypoxia or impaired metabolic function |
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