RS50269B - NOVE VRSTE LEKOVITIH KOMPOZICIJA NA BAZI JEDINJENJA KOJA DELUJU ANTIHOLINERGIJSKI I β-MIMETIKA - Google Patents

NOVE VRSTE LEKOVITIH KOMPOZICIJA NA BAZI JEDINJENJA KOJA DELUJU ANTIHOLINERGIJSKI I β-MIMETIKA

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Publication number
RS50269B
RS50269B YU71901A YUP71901A RS50269B RS 50269 B RS50269 B RS 50269B YU 71901 A YU71901 A YU 71901A YU P71901 A YUP71901 A YU P71901A RS 50269 B RS50269 B RS 50269B
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Serbia
Prior art keywords
pharmaceutical preparation
preparation
salmeterol
acid
tiotropium bromide
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YU71901A
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English (en)
Inventor
Karl-Heinz Bozung
Michel Pairet
Richard Reichl
Alexander Walland
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Boehringer Ingelheim Pharma Gmbh. & Co.Kg.,
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Publication date
Application filed by Boehringer Ingelheim Pharma Gmbh. & Co.Kg., filed Critical Boehringer Ingelheim Pharma Gmbh. & Co.Kg.,
Priority to MEP-366/08A priority Critical patent/MEP36608A/xx
Publication of YU71901A publication Critical patent/YU71901A/sh
Publication of RS50269B publication Critical patent/RS50269B/sr

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Abstract

Farmaceutski preparat, koji sadrži antiholinergik tiotropijum bromid, sa produženim dejstvom i β-mimetik salmeterol, sa produženim dejstvom, opciono u obliku svojih racemata, enantiomera i smeša, i opciono u obliku svojih farmakološki prihvatljivih adicionih soli sa kiselinom. Prijava sadrži još 8 patentnih zahteva.

Description

OPIS PRONALASKA
Ovaj pronalazak se odnosi na nove vrste lekovitih kompozicija na bazi tiotropijum bromida i salmeterola i na njihovu primenu u terapiji oboljenja disajnih puteva.
Stanje tehnike
Na osnovu stanja tehnike poznato je da se p-mimetici kao i antiholinergici uspešno mogu koristiti kao bronhijalni spazmolitici za lečenje opstruktivnih oboljenja disajnih puteva, kao npr. astme. Supstance sa p-simpatomimetskim dejstvom, kao npr. takođe, na osnovu stanja tehnike, poznata delotvorna supstanca formoterol, mogu prilikom primene kod ljudi ipak da budu skopčane sa neželjenim dejstvima.
Kao glavni simptomi mogu da se jave opšta uznemirenost, razdraženost, pospanost, strah, treptanje prstiju, napadi znojenja i bolovi glave. Pritom, inhalativna primena ne isključuje ove sporedne simptome, mada su ona uglavnom ipak nešto manja nego kod peroralne ili parenteralne primene.
Sporedni efekti p-simpatomimetika pri primeni kao sredstava za astmu, zasnivaju
se pre svega na više ili manje izraženim pl-stimulišućim dejstvima na srcu. Oni izazivaju tahikardiju, lupanje srca, tegobe nalik na anginu pektoris kao i aritmije.
[P.T. Ammon (izd.), Arzneimittelnebemvirkungen und - wechselwirkungen, Wis-senschaftliche Verlagsgesellschaft, Stutgart 1986, str. 584].
Opis pronalaska
Iznenada je otkriveno da se gore navedeni sporedni simptomi mogu znatno umanjiti kombinacijom titropijum bromida i salmeterola.
Pritom je potpuno neočekivano takođe utvrđeno, da se bronhospazmolitičko delovanje antiholinergetika titropijum bromida sa produženim dejstvom i p-mimetika salmeterola sa produženim dejstvom, pojačava više nego što je njihovo zbirno delovanje.
Sa kombinacijom delotvornih supstanci, na osnovu pronalaska, može se dakle očekivati znatno poboljšano delovanje, u odnosu na osnovu stanja tehnike poznatih pojedinačnih supstanci i kombinacija, kako kod COPD tako i kod astme. Salmeterolom, u datom slučaju, može biti upotrebljen u obliku racemata, enantiomera, dijastereomera i smeša, kao i, u datom slučaju, farmakološki neškodljivih adicionih soli sa kiselinom.
Kao što je prethodno pomenuto, salmeterol može da se prevede i upotrebi u oblik svojih fiziološki i farmakološki podnošljivih soli. Za pripremanje adicionih soli sa kiselinom u obzir dolaze, na primer, sona kiselina, bromovodonična kiselina, sumporna kiselina, fosforna kiselina, metansulfonska kiselina, sirćetna kiselina, fumarna kiselina, ćilibarna kiselina, mlečna kiselina, limunska kiselina, vinska kiselina ili maleinska kiselina. Osim toga mogu da se upotrebe smeše pomenutih kiselina.
Na osnovu pronalaska, salmeterol, u datom slučaju, je u obliku svojih enantiomera, od kojih najveću prednost ima (R)-enantiomer, kao i, u datom slučaju, njegove farmakološki neškodljive soli.
Prema pronalasku, kompozicije sa delotvornim komponentama, prvenstveno se pripremaju u obliku dozirnog aerosola, ali je takođe moguć i bilo koji drugi oblik za parenteralno ili oralno davanje. Pritom, primena dozirnih aerosolova predstavlja oblik primene koji ima prednost, naročito u terapiji opstruktivnih plućnih oboljenja ili u lečenju astme.
Pored primene u dozirnim aerosolovima, koji rade na bazi potisnih gasova, mogu kombinacije delotvornih supstanci, na osnovu pronalaska, da se primene pomoću tzv. raspršivača za stvaranje magle (nebulajzera), pomoću kojih se rastvori farmakološki aktivnih supstanci pod povišenim pritiskom tako raspršuju, da dolazi do stvaranja magle čestica koje se inhaliraju. Prednost takvih raspršivača za stvaranje magle je u tome što se unošenje potisnih gasova može potpuno izbeći.
Obično su određeni lekovi za inhaliranje rastvoreni u vodenom ili etanolskom rastvoru, pri čemu su, već prema karakteristikama rastvora delotvorne supstance, pogodne takođe i smeše rastvarača, sa vodom i etanolom.
Vrste takvih raspršivača za stvaranje magle su, na primer, opisane u PCT-patentnoj prijavi WO 91/14468 i u internacionalnoj patentnoj prijavi pod oznakom predmeta PCT/EP96/04351, koje se ovim u celini uzimaju u obzir. Kod tamo opisanih ras-pršivača za stvaranje magle, koji su takođe poznati pod oznakom Respimat<®>, raspr-šuju se, kroz male dizne, određene zapremine rastvora koji sadrže delotvornu supstancu, pod dejstvom povišenog pritiska, tako da se aerosol koji se inhalira stvara sa najpovoljnijom veličinom čestica između 1 i 10, prvenstveno između 2 i 5 mikrometara.
Kao rastvarači za lekovite preparate pogodne su, između ostalog, smeše, koje na primer sadrže etanol kao rastvarač.
Dalji sastojci rastvarača su pored vode, u datom slučaju, drugi kosolventi, a lekoviti preparat može takođe da sadrži, supstance koje daju ukus kao i druga farmaceut-ska pomoćna sredstva. Primeri kosolvenata su oni koji sadrže hidroksilne grupe ili druge polarne grupe, na primer alkohole, naročito izopropilalkohol, glikole, naro-čito propilenglikol, polietilenglikol, polipropilenglikol, glikoletar, glicerol, polioksi-etilenalkohole i polioksietilen estre masnih kiselina. Kosolventi su pogodni za to da povećaju rastvorljivost pomoćnih supstanci a, u datom slučaju, i delotvornih supstanci.
Druga farmakološka pomoćna sredstva, kao na primer sredstva za konzerviranje, naročito benzalkonijumhlorid, mogu da budu dodata. Povoljna količina sredstva za konzerviranje, naročito benzalkonijumhlorida, nalazi se između 8 i 12 mg/100 ml rastvora.
Da bi se izbegle anomalije pri raspršivanju mogu se kombinaciji delotvornih supstanci dodati sredstva za kompleksiranje. Pogodna sredstva za kompleksiranje su ona koja su farmakološki podnošljiva, naročito ona koja su već dozvoljena za upotrebu u lekovima. Naročito su pogodni EDTA, nitrilotrisirćetna kiselina, limunska kiselina i askorbinska kiselina, kao i njihove soli. Naročito je pogodna dinatrijumova so etilendiamintetrasirćetne kiseline.
Udeo rastvorene kombinacije delotvornih supstanci u gotovom lekovitom prepa-ratu iznosi između 0,001 i 5%, prvenstveno između 0,005 i 3%, a naročito 0,01 do 2%. Maksimalna koncentracija lekovite supstance zavisi od rastvorljivosti u rastvaraču i od potrebnog doziranja radi postizanja željenog terapeutskog dejstva.
Sledeći oblici preparata navode se kao primeri formulacija:
Pored toga, kombinacije delotvornih supstanci, prema pronalasku, mogu takođe da se inhaliraju i u obliku praha. Pripremanje takvih oblika preparata poznato je na osnovu stanja tehnike. Oni sadrže pored kombinacije delotvornih supstanci koja odgovara ovom pronalasku i farmakološki neškodljive nosače ili pomoćna sredstva, kao npr. mikrokristalnu laktozu. Doza predviđena za inhaliranje može da bude u napunjenim kapsulama, i da na primer ima sledeći sadržaj:
Eksperimentalni rezultati
Bronhospazmolitičko i kardiovaskularno delovanje tiotropijumbromida, formoterolfumarata kao i njihovih kombinacija, posle inhalativne primene vodenog rastvora pomoću Respimat<®>, na narkotiziranim psima.
Materijal i postupak
18 pasa mešovite rase, telesne mase od 27 do 32 kg. Držani u pojedinačnim, odn. skupnim boksovima, peletirana standardna hrana, poslednje hranjenje ca. 15 sati pre ogleda, pijaća voda ad libitum.
Posle prethodnog tretmana sa 2 mg/kg morfinhidrohlorida i.m. polako je injicira-no intravenski 30 mg/kg pentobarbital-natrijuma (Nembutal<®>). Životinje su relaksirane sa 1,0 mg/kg i.v. suksametonijuma.
Životinjama je posle intubiranja, pomoću Servo-Ventilator-a 900 C (firma Siemens) omogućeno disanje uduvavanjem sobnog vazduha i kiseonika (4:1), frekvenca 15/min, udahnuta zapremina 6 - 8 lit./min. Za registrovanje mehanike disanja odre-đivan je protok disanja, pomoću cevi za dinamički pritisak (Fleisch Nr. 1), koja je postavljena neposredno pre orotrahejnog tubusa, registratora diferencijalnog pritiska i pojačivača DCB-4C. Jedan kateter je postavljen u traheju a drugi (balon-)kateter u deo pluća ezofagusa. Obadva su povezana sa registratorom i pojačivačem diferencijanog pritiska, radi određivanja transpulmonalnog pritiska. Računar za praćenje mehanike disanja (IFD-Miihlheim) davao je plućni otpor (R) na osnovu registrovanih vrednosti pritiska. Na osnovu toga je kompjuterski program VAS-1 LA (IFD-Miihlheim) određivao:
Registrovanje srčane frekvence vršeno je preko EKG (ekstremitetni odvod II) i kardiotahometra.
Posle perioda ekvilibrisanja od 30 min, izazivani su kratkotrajni bronhospazmi pomoću i.v. injekcije od 10 ug/kg acetilholinhlorida, koji su ponavljani 2 - 3 x u razmaku od ca. 10 min. Test-supstance, tiotropijumbromid, formoterolfumarat, kao i kombinacija obeju supstanci, davani su kao vodeni rastvori pomoću BINEB-ras-pršivača (Respimat<®>). Aplikacija kombinacije vršena je sa pojedinačnim komponentama u razmaku od ca. 1 min. Sa BINEB-sistemom mehanizam oslobađanja se odigravao na kraju faze izdisanja a raspršeni rastvor je u sledećoj fazi udisanja potiskivan pomoću pumpe za disanje u traheobronhijalno stablo.
Doziranja
Tabele 1 - 6 prikazuju, u toku 180 min, polazne vrednosti i vrednosti posle davanja supstanci. Na slikama 1 - 2 prikazana su procentualno, u toku 180 min, inhibiranja povećanih plućnih otpora izavanih pomoću ACh
Rezultati
Rezultati su prikazani ua tabelama kao i na slikama. 3 i 10 ug tiotropijumbromida, odn. formoterolfumarata znatno inhibiraju bronhijani otpor, srazmerno povećavan dozom intravenskim injiciranjem ACh. Maksimalno bronhospazmolitičko dejstvo formoterol-a FU brzo nastupa sa oba doziranja, a sa tiotropijum-om BR je odložena za. oko 60 min. Trajanje delovanja formoterol-a FU pre svega je pri manjim doziranjima srazmerno kratko, a ono sa tiotropijum BR, prema očekivanju, održava se do kraja opita (180 min).
Sa kombinacijom od 3 ug tiotropijum bromida + 3 ug formoterol-a FU, vrlo brzo se postiže izražena bronhospazmoliza od 90%, koja se do kraja opita skoro neprome-njeno održava. Zaštitno dejstvo kombinacije veoma značajno nadmašuje dejstvo pojedinačnih komponenti, ali takođe prevazilazi i zbir pojedinačnih efekata, 3 ug tiotropijim bromida i 3 ug formoterol-a FU. Ono prevazilazi efekat koji ima 10 ug tiotropijum bromida, odn. 10 ug formoterol fumarata (v. sliku 2).
Sam tiotropijum bromid nema bilo kakav uticaj na srčanu frekvencu, kako ni sa 3 ug tako ni sa 10 ug. Nasuprot tome, formoterol FU je povećava, srazmerno dozi, a pre svega pri visokim dozama, maksimalno za preko 90%. Čak i na kraju ogleda izmerene su još vrednosti od preko 80%. Sa kombinacijama 3 + 3 ug, a takođe i sa 10 + 10 u.g tiotropijum bromida i formoterol fumarata, frekvencni efekti su primetno oslabljeni i leže ispod 30%.
Procena
Sa kombinacijom antiholinergika sa (3-mimetikom, nasuprot pojedinačnim supstan-cama, utvrđeni su potpuno neočekivani rezultati:
1. brzo otpočinjanje dejstva
2. dugotrajno delovanje
a pre svega
3. bronhospazmolitičko dejstvo koje prevazilazi zbirna dejstva i
4. znatno manji porast frekvence, pre svega sa većom dozom formoterola.
. Sa kombinacionim preparatom može da se očekuje znatno poboljšanje terapeutskog delovanja, kako kod COPD tako i kod astme, povezano sa prednošću uma-njenih kardijalnih pratećih dej stava.
Slike
51.1 prikazuje uticaj 3 ug formoterol fumarata, 3 ug tiotropijum bromida, kao i kombinacije, 3ugtiotropijum bromida + 3 ug formoterol fumarata, na bronhijalni otpor narkotiziranih pasa, n = 6.
51.2 prikazuje uticaj 10 ug formoterol fumarata, 10 ug tiotropijum bromida, kao i kombinacije, 3 ug tiotropijum bromida + 3 ug formoterol fumarata, na bronhijalni otpor narkotiziranih pasa, n = 6.

Claims (9)

1) Farmaceutski preparat, koji sadrži antiholinergik tiotropijum bromid, sa produženim dejstvom i (3-mimetik salmeterol, sa produženim dejstvom, opđono u obliku svojih racemata, enantiomera i smeša, i opciono u obliku svojih farmakološki prihvatljivih adicionih soli sa kiselinom.
2) Farmaceutski preparat prema zahtevu 1, naznačen time, što je salmeterol prisutan u obliku njegovog R-enantiomera.
3) Farmaceutski preparat, prema jednom od zahteva 1 ili 2, naznačen time, što je salmeterol prisutan u obliku soli ksinafoata.
4) Farmaceutski preparat, prema jednom od zahteva 1 do 3, naznačen time, što je to farmaceutski preparat koje se primenjuje inhalativno.
5) Farmaceutski preparat, prema jednom od zahteva 1 do 4, dalje sadrži farmakološki prihvatljive nosače ili pomoćne supstance.
6) Farmaceutski preparat, prema zahtevu 4 ili 5, naznačen time, što je prah.
7) Farmaceutski preparat, prema zahtevu 6, naznačen time, što sadrži laktozu kao farmakološki prihvatljiv nosač ili pomoćnu supstancu.
8) Upotreba preparate, prema jednom od zahteva 1 do 7, za pripremanje leka za lečenje oboljenja disajnih puteva.
9) Upotreba, prema zahtevu 8, za pripremanje leka za lečenje astme ili COPD.
YU71901A 1999-05-12 2000-05-03 NOVE VRSTE LEKOVITIH KOMPOZICIJA NA BAZI JEDINJENJA KOJA DELUJU ANTIHOLINERGIJSKI I β-MIMETIKA RS50269B (sr)

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