HRP20041211A2 - Topikalno primjenjivi farmaceutski pripravak - Google Patents
Topikalno primjenjivi farmaceutski pripravak Download PDFInfo
- Publication number
- HRP20041211A2 HRP20041211A2 HR20041211A HRP20041211A HRP20041211A2 HR P20041211 A2 HRP20041211 A2 HR P20041211A2 HR 20041211 A HR20041211 A HR 20041211A HR P20041211 A HRP20041211 A HR P20041211A HR P20041211 A2 HRP20041211 A2 HR P20041211A2
- Authority
- HR
- Croatia
- Prior art keywords
- roflumilast
- salts
- pharmaceutical preparation
- active substance
- diseases
- Prior art date
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Abstract
Opisan je topikalno primjenjivi farmaceutski pripravak za administraciju slabo topljivog PDE 4 inhibitora. Opažena je iznenađujuće dobra bioraspoloživost kod ovog dozirnog oblika.
Description
Tehničko područje
Naznačeni izum odnosi se na područje farmaceutske tehnologije i opisuje topikalno primjenjivi farmaceutski pripravak koji kao aktivnu supstancu sadrži slabo topljivi PDE 4 inhibitor. Dodatno se izum odnosi na postupke za pripravu topikalno primjenjivog farmaceutskog pripravka i na njegovu upotrebu u liječenju bolesti kože, očiju i dišnih putova.
Prethodni radovi
Ciklički nukleotidni fosfodiesteraza (PDE) inhibitori (posebno tipa 4) su trenutno od posebnog interesa kao nova generacija aktivnih supstanci za liječenje upalnih bolesti, osobito bolesti dišnih putova kao što je astma ili začepljenje dišnih kanala (kao »primjerice, COPD = kronična opstruktivna bolest pluća). Nekoliko PDE 4 inhibitora je trenutno na kliničkim ispitivanjima, uključujući i lijek za oralnu administraciju koji sadrži aktivnu supstancu N-(3,5-dikloropirid-4-il)-3-ciklopropilmetoksi-4-difluorometoksi-benzamid (INN: roflumilast). Taj i drugi spojevi s benzamidnom strukturom i njihova upotreba kao cikličkih nukleotidnih fosfodiesteraza (PDE) inhibitora opisani su u WO 95/01338. Te su aktivne supstance u WO 95/01338 predložene također za liječenje nekih bolesti kože (kao, primjerice, dermatoza). WO 00/53182 predlaže upotrebu roflumilasta ili njegovog N-oksida u liječenju multipla skleroze.
Za liječenje bolesti kože poželjno je pripraviti aktivnu supstancu u farmaceutskom pripravku pogodnom za topikalnu primjenu. Međutim, kao što je stručna osoba svjesna, to se može pokazati ekstremno teškim ili nemogućim, ako se namjerava administrirati aktivna supstanca koja ima vrlo malu topljivost. Tako je primjerice nađeno da je topljivost u vodi N-(3,5-dikloropirid-4-il)-3-ciklopropilmetoksi-4-difluorometoksi-benzamida (INN: roflumilast), koji je opisan u WO 95/01338, samo 0.53 mg/l na 21°C.
Opis izuma
Iznenađujuće je nađeno da topikalno primjenjivi farmaceutski pripravak koji sadrži slabo topljivi PDE 4 inhibitor roflumilast pokazuje vrlo dobar učinak u liječenju dermatoza lokalnom, dermalnom primjenom. Također je nađeno, potpuno iznenađujuće, da taj pripravak, pored lokalnog učinka, pokazuje i odličan sistemski učinak koji je usporediv s onim kod oralnih oblika.
Stoga je prvi aspekt ovog izuma farmaceutski pripravak koji se može administrirati topikalno i sadrži aktivnu supstancu, zajedno s jednim ili više farmaceutskih nosača i/ili pomoćnih tvari pogodnih za topikalnu administraciju, gdje je ta aktivna supstanca izabrana iz grupe koja se sastoji od roflumilasta, soli roflumilasta, N-oksida roflumilasta ili njegovih soli.
Roflumilast je INN naziv za spoj formule I
[image]
u kojoj je
R1 difluorometoksi,
R2 ciklopropilmetoksi i
R3 3,5-dikloropirid-4-il.
Taj spoj ima kemijsko ime N-(3,5-dikloropirid-4-il)-3-ciklopropilmetoksi-4-difluorometoksibenzamid (INN: roflumilast). N-oksid roflumilasta ima kemijsko ime 3-ciklo propilmetoksi-4-difluorometoksi-N-(3, 5-dikloropirid-4-il 1 oksid)benzamid.
Spoj formule I, njegove soli, N-oksid, njegove soli i upotreba tih spojeva kao fosfodiesteraza (PDE) 4 inhibitora opisani su u internacionalnoj patentnoj prijavi WO 95/01338.
Soli pogodne za spojeve formule I - ovisno o supstituciji - su sve soli nastale dodatkom kiseline, ali, posebno, sve soli s bazama. Posebice se mogu naglasiti farmakološki prihvatljive soli anorganskih i organskih kiselina i baza koje se uobičajeno koriste u farmaceutskoj tehnologiji. Farmakološki neprihvatljive soli koje, na primjer, mogu biti polazni proizvodi u postupku priprave spojeve ovog izuma u industrijskom mjerilu konvertiraju se u farmakološki prihvatljive soli postupcima znanim osobama od struke. Pogodne s jedne strane su one soli topljive u vodi te u vodi netopljive soli nastale dodatkom kiselina kao npr. klorovodične kiseline, bromovodične kiseline, fosforne kiseline, dušične kiseline, sumporne kiseline, octene kiseline, limunske kiseline, D-glukonske kiseline, benzoične kiseline, 2-(4-hidroksibenzoil)benzoične kiseline, maslačne kiseline, sulfosalicilne kiseline, maleične kiseline, laurinske kiseline, malične kiseline, fumarne kiseline, sukcinske kiseline, oksalne kiseline, tartarne kiseline, embonične kiseline, stearinske kiseline, toluensulfonske kiseline, metansulfonske kiseline, ili 3-hidroksi-2-naftoične kiseline, gdje se kiseline koriste za pripravu soli u ekvimolarnim omjerima količina, ili jednoj koja se razlikuje od njih- ovisno da li je kiselina monobazična ili polibazična i ovisno o tome koja sol se želi dobiti.
S druge strane, soli s bazama su također posebno pogodne. Primjeri bazičnih soli koji se mogu spomenuti su litijeva, natrijeva, kalijeva, aluminijeva, magnezijeva, titanova, amonijeva, megluminska ili gvanidinska sol, gdje se baze koriste za pripravu soli u ekvimolarnim omjerima količina, ili jednoj koja se razlikuje od njih.
Udio (u postotcima težine bazirano na težini gotovog farmaceutskog pripravka; w/w) aktivne farmaceutske supstance u farmaceutskom pripravku ovog izuma je uobičajeno od 0.001 do 50% težine. Udio aktivne farmaceutske supstance je poželjno do 1% težine.
Farmaceutski nosači i/ili pomoćne tvari pogodne za topikalnu administraciju su prema ovom izumu preferirano konvencionalni nosači i/ili pomoćne tvari poznate osobi od struke, a vezano uz farmaceutske pripravke za dermalnu administraciju (=dermatici). Primjeri koji se mogu spomenuti su nosači i/ili pomoćne tvari koje su pogodne za pripravu sitnih praškova, emulzija, suspenzija, sprejeva, ulja, masti, krema, pasta, gelova, pjena ili otopina, i transdermalnih terapeutskih sustava.
Topikalni farmaceutski pripravak ovog izuma može se pripraviti postupcima koji su poznati osobi od struke.
Konvencionalni dermatici i njihova priprava te preferirani nosači i/ili pomoćne tvari za pojedine farmaceutske pripravke su opisani, primjerice, u priručniku "Pharmazeutische Technologie" (Sucker, Fuchs, Speiser, Georg Thieme Verlag, 1978, od stranice 629).
U prvom primjeru ovog izuma, topikalni farmaceutski pripravak izuma je polučvrsti dozirni oblik. Primjeri koji se mogu spomenuti su posebno masti (npr. otopinska mast, suspenzijska mast), kreme, gelovi ili paste.
Emulzije ulje-u-vodi ili voda-u-ulju se uobičajeno odnose na kreme. Za uljnu fazu se uglavnom koriste masni alkoholi, npr. lauril, cetil ili stearil alkohol; masne kiseline, npr. palmitinska ili stearinska kiselina; tekući ili čvrsti parafini ili ozokerit; tekući ili čvrsti voskovi, npr. izopropil miristat; prirodna ili djelomično sintetska mast, npr. triglicerid kokosove masne kiseline; čvrsta ulja, npr. hidrogenirano ulje kikirikija ili ricinusovo ulje; ili djelomični esteri masnih kiselina i glicerola, npr. glicerol monostearat ili glicerol distearat. Pogodni emulgatori su površinski aktivne tvari, primjerice neionski surfaktanti, npr. esteri masnih kiselina i polialkohola ili njihovi etilen oksid adukti, kao što su esteri masnih kiselina i poliglicerola ili polioksietilen sorbitan esteri masnih kiselina (Tween®: ICI), sorbitan esteri masnih kiselina (Span®: ICI), kao primjerice sorbitan oleat i/ili sorbitan izostearat, steroli, također i polioksietilen eteri masnih alkohola ili esteri masnih kiselina, ili anionski surfaktanti kao što su soli alkalnih metala ili sulfati masnih alkohola, npr. natrij lauril sulfat, natrij cetil sulfat ili natrij stearil sulfat, koji se uobičajeno koriste u prisustvu spomenutih masnih alkohola, npr. cetil ili stearil alkohola. Moguće je u vođenu fazu dodati inter alia sredstva koja sprječavaju isušivanje kreme, npr. polialkohole kao što su glicerol, sorbitol, propilen glikol i/ili polietilen glikol, a također i konzervanse, mirise itd.
Masti mogu biti bezvodne i sadržavati kao bazu parafine koji su pogodni za topikalnu primjenu i u tekućem su obliku na temperaturi tijela, posebno niskoviskozni parafin, a također i spomenute prirodne ili djelomično sintetske masti, npr. triglicerid kokosove masne kiseline; čvrsta ulja, npr. hidrogenirano ulje kikirikija ili ricinusovo ulje; ili djelomični esteri masnih kiselina i glicerola, npr. glicerol monostearat ili glicerol distearat; silikoni, npr. polidimetilsiloksani, primjerice heksametildisiloksan ili oktametiltrisiloksan, i npr. masni alkoholi spomenuti vezano uz hidratantne kreme i povećanje kapaciteta upijanja vode; i steroli, ovčji vosak, drugi emulgatori i/ili ostali aditivi.
U slučaju gelova, mora se praviti razlika između vodenih gelova, bezvodnih gelova i gelova s niskim sadržajem vode, koji se sastoje od nabubrenog, gel-formirajućeg materijala. Najpogodniji su transparentni vodeni gelovi bazirani na anorganskim ili organskim makromolekulama. Makromolekulski anorganski dijelovi s gel-formirajućim svojstvima su pretežno vodeni silikati ili silikati koji apsorbiraju vodu kao što su aluminijevi silikati, npr. bentonit; magnezij-aluminij silikati, npr. Veegum® - Vanderbilt Exp. Corp., ili koloidalni silikati, npr. Aerosil® - Degussa. Primjeri makromolekula koje se koriste su prirodni, semisintetski ili sintetski polimeri. Prirodni i semisintetski polimeri nastaju npr. iz polisaharida s različitim ugljikohidratnim jedinicama, kao primjerice celuloza, škrob, tragakant, guma arabika, agar-agar, želatina, alginska kiselina i njihovih soli, npr. natrij alginat i njegovi derivati, celuloze nižih alkila npr. metil- ili etilceluloza, karboksi- ili hidroksi-celuloze nižih alkila, npr. karboksimetil- ili hidroksipropil-celuloza. Jedinice sintetskih gel-formirajućih polimera su primjerice nezasićeni, supstituirani alifatski spojevi kao što su vinil alkohol, vinilpirolidon, akrilna ili metakrilna kiselina. Primjeri takvih polimera koji se mogu spomenuti su derivati polivinil alkohola kao npr. Polyviol8 - Wacker, polivinil-pirolidoni kao npr. Kollidon® - BASF ili Poyplasdon® -General Aniline, poliakrilati i polimetakrilati, npr. Rohagit® - Rohm und Haas. Moguće je gelovima dodati konvencionalne aditive kao što su konzervansi ili mirisi.
Paste su kreme ili masti sa prethodno spomenutim konstituentima te sitno-praškastim konstituentima koji apsorbiraju sekreciju, kao što su metalni oksidi, npr. titan oksid ili cink oksid, a također i talk i/ili aluminijevi silikati, koji imaju ulogu vezanja vlage ili sekrecije.
U preferiranom primjeru ovog izuma, topikalni farmaceutski pripravak izuma je polučvrsti farmaceutski pripravak, gdje je jedna od pomoćnih tvari polietilen glikol, posebno polietilen glikol 400.
U sljedećem primjeru ovog izuma, topikalni farmaceutski pripravak izuma je transdermalni terapeutski sustav (TTS), na primjer sustav kao što je opisan u Pharmazeutische Technologie: Moderne Arzneiformen, Wissenschaftlische Verlagsgesellschaft mbH Stuttgart 1997, stranica 81 i dalje. TTS-ove karakterizira definirano nanošenje ljekovite supstance na kožu, ukupna doza ljekovite supstance u TTS-u, ukupna površina i površina koja je moguće različita od ukupne za otpuštanje ljekovite supstance, pokrovni sloj koji je nepropustan za ljekovitu supstancu, spremnik ljekovite supstance, element za kontrolu nanošenja ljekovite supstance na kožu, adhezijski sloj (osjetljiv na tlak) i odjeljivi zaštitni sloj. U nekim slučajevima moguće je da jedan element ispunjava nekoliko funkcija, npr. pogodan adhezijski matriks može imati funkciju spremnika, kontrole i adhezijsku funkciju. Sa stajališta farmaceutske tehnologije, TTS-i se kategoriziraju prema načinu na koji se postiže funkcija kontrole, tj. kako kontroliraju nanošenje ljekovite supstance na kožu. Primjeri koji će se ovdje spomenuti su TTS-i s kontroliranim membransko-permeabilnim otpuštanjem (umjereno membransko otpuštanje lijeka), TTS-i s kontroliranim otpuštanjem difuzijom kroz matriks i TTS-i s kontroliranim otpuštanjem otopine iz mikrospremnika.
TTS-e s kontroliranim membransko-permeabilnim otpuštanjem karakterizira polimerna membrana koja se sastoji od PVA-VA kopolimera (Chronomer®) koji kontrolira permeaciju ljekovite supstance iz spremnika na kožu. Ljekovita supstanca je inicijalno u obliku krutih čestica ili kao disperzija ili otopina u spremniku. Polimerna membrana može biti pričvršćena na spremnik na različite načine (ekstruzijom, kapsulacijom, mikrokapsulacijom). TTS-i s kontroliranim otpuštanjem difuzijom kroz matriks su jednostavnije strukture. Oni ne sadrže odvojeni element za kontrolu. Otpuštanje ljekovite supstance se kontrolira matriksom koji se sastoji od lipofilnog ili hidrofilnog polimera i/ili adhezijskog sloja. S obzirom na karakteristike matriksa, mogu se razlikovati TTS-i s matriksom u gel formi i TTS-i koje čine čvrsti polimerni laminati. Spremnik ljekovite supstance čini ljekovita supstanca otopljena u matriksu (monolitski sustav) ili homogena disperzija čvrstih čestica ljekovite supstance. Matriks se može pripraviti miješanjem čestica ljekovite supstance s viskoznom tekućinom ili polučvrstim polimerom na sobnoj temperaturi, nakon čega slijedi unakrsno povezivanje polimernih lanaca. Daljnja mogućnost je da se ljekovita supstanca miješa na povišenoj temperaturi s razmekšanim polimerom (tehnika vrućeg taljenja), ili se te dvije komponente (otopljene u organskom otapalu) pomiješaju a otapalo se zatim otpari u vakuumu (evaporacija otapala). Oblikovanje je moguće stavljanjem u odgovarajuće kalupe, raspršivanjem s posebnim uređajima (noževima) ili ekstruzijom. Kod TTS-a s kontroliranim otpuštanjem otopine iz mikrospremnika (MDD princip), brojni mikro-dijelovi koji sadrže aktivnu supstancu i koji su veličine 10-200 μm ugrađeni su u matriks koji predstavlja i spremnik i element za kontrolu otpuštanja. Zbog matriksa, ovi TTS-i zapravo pripadaju matriks sustavima. Za proizvodnju, ljekovita supstanca se inicijalno dispregira zajedno s vodom i 40%-tnim etilen glikolom 400 u izopropil palmitatu, koji ima ulogu permeacijskog promotora. Koristeći specijalnu visokoenergijsku disperzijsku tehniku rezultirajuća disperzija se uvede u viskozni silikonski elastomer koji se simultano podvrgne katalitičkoj polimerizaciji. Ljekovita supstanca koja sadrži matriks može se specifično oblikovati tehnikama taljenja ili ekstruzije prije nego se poveže s nosačem, na već opisani način. Ovisno o fizikalno-kemijskim svojstvima ljekovite supstance i željenom otpuštanju, moguće je zaštititi matriks sa slojem biokompatibilnog polimera kako bi se modificirao mehanizam i brzina otpuštanja.
U sljedećem primjeru izuma, topikalni farmaceutski pripravak izuma je dozirni oblik koji se koristi za oči (oftalmologik). Primjeri koji se mogu spomenuti s time u vezi su očne kupke ili očni losioni, očni umetci, očne masti, očni sprejevi, očne kapi, preparati za intraokularne injekcije masti za očne kapke. U preferiranom primjeru, lijek izuma je očna mast ili očne kapi. Očne kapi se prema izumu preferirano sastoje od vodenih ili uljastih suspenzija aktivne supstance. S time u vezi je poželjno da veličina čestica za 90% upotrijebljene aktivne supstance bude manja od 10 μm.
U slučaju vodenih suspenzija preferirano se koriste stabilizatori suspenzija, kao primjerice supstituirane celuloze (npr. metilceluloza, hidroksipropilmetilceluloza), polivinil alkohol, polivinil pirolidon, s dodatkom konzervansa (npr. klorokrezol, fenil-živa spojevi, feniletanol, benzalkonij klorid ili smjesa individualnih komponenti) i, gdje je pogodno, natrijev klorid za podešavanje izotoničnosti. U slučaju uljastih očnih kapi, preferirano se prema izumu koriste ricinusovo ulje, ulje kikirikija ili trigliceridi srednje dugih lanaca. U slučaju očnih masti moguće je prema izumu koristiti baze masti sljedećih svojstava: sterilnost ili ekstremno niski sadržaj mikroba, ne-iritantnost, dobra aktivnost, dobra raspodjela aktivne supstance ili njene otopine u masti, gipkost, brza disperzija kao tankog filma preko očnih jabučica, dobro prijanjanje na oko, dobra stabilnost i mala mogućnost oštećenja vida. Baze koje sadrže ugljikohidrate ili kolesterol će se stoga prema naznačenom izumu preferirano koristiti za očne masti. U slučaju petrolata, za konzistentnost je preferirano korištenje tekućeg parafina. Da bi se osigurala dobra raspodjela, prema izumu je preferirano prirediti sastav ograničene viskoznosti. Viskoznost na 32°C je poželjno ispod 1000 mPa, i točka iskorištenja je poželjno ispod 300 mPa. Kod suspenzijskih masti preferirano je prema izumu da 90% aktivne supstance ima veličinu čestica ispod 10 μm, i ne smije biti čestica iznad 90 μm. Kod vodenih/uljnih emulzijskih masti, prema izumu je preferirano dodati konzervanse kao što je benzalkonij klorid, tiomersal ili feniletil alkohol.
PRIMJERI
Priprava đozirnih oblika naznačenog izuma
Primjer 1
550 grama sadrži
Polietilen glikol 400 440.00 g
Carbopol 934®8.25 g
Roflumilast 1.375 g
Natrij hidroksid, otopina q.s.
Pročišćena voda do 550.00 g
Priprava se odvija tako da se aktivna supstanca otopi u danoj količini polietilen glikola na oko 60-70°C. Doda se oko 90 grama pročišćene vode i homogeno izmiješa te se u to homogeno dispergira Carbopol 934 brzom miješalicom. Uz miješanje polagano se doda otopina natrij hidroksida dok se ne postigne pH od 6.5-7.5. Doda se preostala voda do konačne težine te se homogeno izmiješa.
Primjer 2
550 grama sadrži
Roflumilast 1.65 g
Polietilen glikol 400 440.00 g
Polietilen glikol 4000 do 550.0 g
Priprava se odvija tako da se tretiraju dva polietilen glikola do 70°C tako da se dobije čista talina. Doda se aktivna supstanca kako bi se dobila bistra otopina.
Pripravak se ohladi na sobnu temperaturu uz polagano miješanje.
Primjer 3
550 grama sadrži
Roflumilast 1.10 g
Tego Care 150® 27.50 g
(Th. Goldschmidt)
Neutralno ulje (Miglyol 812®) 137.50 g
Polietilen glikol 400 275.00 g
Cetostearil alkohol 11.00 g
Pročišćena voda do 550 g
Priprava se odvija tako da se priredi bistra otopina neutralnog ulja, cetostearil alkohola i Tego Care 150 na oko 70°C. Polietilen glikol, u kojem se otopi roflumilast, miješa se koristeći brzu miješalicu. Voda zagrijana na 70°C doda se lipidnoj fazi. Za homogenizaciju se koristi Turrax. Pripravak se miješa dok se ne ohladi (na sobnu temperaturu).
Primjer 4
100 grama sadrži
Roflumilast 0.25 g
Neutralno ulje (Miglyol 812®) 16.00 g
Glicerol monostearat 8.00 g
Cremophor A6® (BASF) 4.00 g
Polietilen glikol 400 62.50 g
Pročišćena voda do 100.00 g
Priprava se odvija tako da se zagriju sve komponente (osim vode) na oko 70-80°C kako bi se dobila bistra otopina. Zatim se doda voda uz miješanje, te se pripravak dobiven na taj način ohladi na sobnu temperaturu uz miješanje.
Primjer 5
100 grama sadrži
Roflumilast 0.25 g
Tekući parafin 15.00 g
Ovčji vosak 5.00 g
Bijeli petrolat do 100 g
Priprava se odvija tako da se priredi čista talina tekućeg parafina, ovčjeg voska i bijelog petrolatuma na oko 80°C. Doda se mikronizirana aktivna supstanca, te se pripravak miješa dok se ne ohladi na sobnu temperaturu.
Primjer 6
Roflumilast 0.10 g
Tekući parafin 10.00 g
Ovčji vosak 5.00 g
Bijeli petrolat do 100 g
Priprava se odvija analogno Primjeru 5.
Primjer 7
Roflumilast 0.10 g
Neutralno ulje (Miglyol 812®) 16.00 g
Glicerol monostearat 8.00 g
Cremophor A6® (BASF) 2.00 g
Polietilen glikol 400 62.50 g
Pročišćena voda do 100.00 g
Priprava se odvija analogno Primjeru 4.
Primjer 8
Roflumilast 0.10 g
Neutralno ulje (Miglyol 812®) 16.00 g
Glicerol monostearat 8.00 g
Cremophor A6® (BASF) 4.00 g
Polietilen glikol 400 62.50 g
Pročišćena voda do 100.00 g
Priprava se odvija analogno Primjeru 4.
Primjer 9
Sastav masti za oči (količina za 1000 grama)
Roflumilast 1 g
Cetil alkohol 4 g
Visokoviskozni parafin 200 g
Bijeli petrolat 795 g
Priprava: čista talina cetil alkohola, visokoviskoznog parafina i bijelog petrolata priredi se na oko 70°C. Umiješa se mikronizirani roflumilast (sa 90% čestica ispod 10 μm), i priredi se homogena disperzija pomoću Ultra-Turrax-a. Suspenzija se ohladi na sobnu temperaturu uz miješanje, te se koristi za punjenje pogodnih tuba.
Primjer 10
Sastav otopina za kapljice u obliku emulzije (količina za 1000 mililitara)
Roflumilast 1.5 g
Trigliceridi srednje dugačkih lanaca 100.0 g
Lecitin 12.0 g
Glicerol 25.0 g
Tiomersal 0.1g
Pročišćena voda do 1000 ml
Priprava: Prvo se otopi roflumilast, a potom i lecitin u trigliceridima srednje dugačkih lanaca i glicerolu na 30°C-40°C. Uz snažno miješanje doda se voda i homogenizira dok veličina kapljica u disperznoj fazi ne bude manja od 500 nm. Uz miješanje se otopi tiomersal. Emulzija se filtrira kroz filter od 0.45 μm i razdijeli u pogodne spremnike.
Primjer 11
Sastav masti za nos (količina za 1000 grama)
Roflumilast 1 g
Cetil alkohol 4 g
Ovčji vosak 50 g
Visokoviskozni parafin 2 00 g
Bijeli petrolat 745 g
Priprava: čista talina cetil alkohola, visokoviskoznog parafina, ovčjeg voska i bijelog petrolata priredi se na oko 70°C. Umiješa se mikronizirani roflumilast (sa 90% čestica ispod 10 μm), i priredi se homogena disperzija pomoću Ultra-Turrax-a. Suspenzija se ohladi na sobnu temperaturu uz miješanje, te se koristi za punjenje pogodnih tuba.
Ispitivanja farmakokinetike topikalnih farmaceutskih pripravaka
Usporedba farmakokinetičkih parametara topikalnih farmaceutskih pripravaka izuma s oralnim oblicima
Primjer A
Pripravak koji odgovara Primjeru 7 i pripravak koji odgovara Primjeru 8 koji sadrže [14C]roflumilast primijenjeni su na obrijane dijelove kože štakora (5 štakora mužjaka vrste Wistar) površine 4 cm2. Mjerene su koncentracije radioaktivnosti u plazmi nakon 1h, 4h, 8h, 24h i u urinu (0-24h) (n = 5). Doza je bila 1.7 mg/kg.
Rezultati:
Pripravak iz Primjera 7: Cmax: 0.214 mg ekv./I, AUC (0-24h):
4.13 (mg ekv./I x h)
Pripravak iz Primjera 8: Cmax: 0.214 mg ekv./I, AUC (0-24h):
3.99 (mg ekv./I x h)
Rezultati standardizirani na 1 mg/kg su:
Pripravak iz Primjera 7: Cmax: 0.12 6, AUC: 2.43
Pripravak iz Primjera 8: Cmax: 0.12 6, AUC: 2.35
Usporedba s kinetičkim parametrima nakon oralne administracije 1 mg/kg:
Cmax: 0.225 mg ekv./I, AUC (0-24h): 3.10 (mg ekv./I x h)
Omjer AUC (pripravak iz Primjera 7) i AUC (oralni) je 78%, a AUC (pripravak iz Primjera 8) i AUC (oralni) je 76%.
Rezultati usporedbe izlučivanjem iz urina:
Pripravak iz Primjera 7: 19.4% doze
Pripravak iz Primjera 8: 18.0% doze
Oralna administracija: 18.4% doze
Zaključak:
Nakon perkutane administracije 1.7 mg/kg [14C] roflumilasta štakorima, ukupna radioaktivnost je dobro prenesena kroz kožu i dostiže maksimalnu razinu u plazmi od 0.214 mg ekv./I nakon 4h, neovisno i upotrijebljenom pripravku. Na temelju ukupne radioaktivnosti, vrijednosti AUC i izlučivanja iz urina nakon perkutane administracije su zanemarivo različite od onih kod oralne administracije.
Primjer B
Pripravak koji odgovara Primjeru 5 i koji sadrži [14C] roflumilast primijenjen je na obrijane dijelove kože štakora (štakor mužjak vrste Wistar) površine 4 cm2. Mjerene su koncentracije radioaktivnosti u plazmi nakon 1h, 4h, 8h, 24h i u urinu (0-24h) (n = 5). Doza je bila 1.77 mg/kg.
Pripravak iz Primjera 5: Cmax: 0.331 mg ekv./I, AUC (0-24h): 4.99 (mg ekv./I x h)
Rezultati standardizirani na 1 mg/kg su:
Pripravak iz Primjera 5: Cmax: 0.187, AUC: 2.82
Usporedba s kinetičkim parametrima nakon oralne administracije 1 mg/kg:
Cmax: 0.225 mg ekv./I, AUC (0-24h): 3.10 (mg ekv./I x h)
Rezultati usporedbe izlučivanjem iz urina: Pripravak iz Primjera 5: 22.0% doze Oralna administracija: 18.4% doze
Zaključak:
Ovi podaci pokazuju da se roflumilast apsorbira iz pripravka Primjera 5 čak i nešto bolje od pripravaka iz Primjera 7 i 8. Izlučivanje iz urina 24 sata nakon administracije je 22%, što je također unutar područja izlučivanja iz urina nakon dermalne administracije pripravaka iz Primjera 7 i 8. Usporedba s oralnom administracijom pokazuje da se, neovisno o sastavu topikalnog pripravka, postižu slične vrijednosti Cmax i AUC i slična izlučivanja iz urina.
Industrijska primjenjivost
Dozirni oblici izuma mogu se primijeniti za liječenje i prevenciju svih bolesti za koje se smatra da se mogu liječiti ili spriječiti korištenjem PDE 4 inhibitora. Selektivni ciklički nukleotidni fosfodiesteraza (PDE) inhibitori (posebno tipa 4) su s jedne strane pogodni kao bronhijalna terapeutska sredstva (za liječenje začepljenja dišnih putova zahvaljujući svojem učinku dilatacije, ali također i učinku povećanja respiratorne brzine i respiratornog poticanja) te za uklanjanje erekcijske disfunkcije zbog svog vazodilatacijskog učinka, dok su s druge strane pogodni posebno za liječenje bolesti inflamatorne prirode, primjerice upale dišnih putova (profilaksa astme), kože, centralnog živčanog sustava, unutrašnjih organa, očiju i zglobova, koje su potaknute posrednicima kao što je histamin, PAF (čimbenik aktivacije trombocita), derivati arahidonske kiseline kao primjerice leukotrieni i prostaglandini, citokini, interleukini, kemokini, alfa-, beta- i gama-interferon, TNF (faktor nekroze tumora) ili slobodni radikali kisika i proteaze. Farmaceutski pripravci izuma se stoga mogu koristiti kao humani ili veterinarski lijekovi za primjerice liječenje i profilaksu sljedećih bolesti: akutne i kronične (osobito upalne i one izazvane alergenima) bolesti dišnih putova različitih uzroka (bronhitis, alergijski bronhitis, bronhijalna astma, COPD); dermatoze (posebice proliferacijske, upalne i alergijske prirode) kao npr. psorijaza (vulgaris), toksični i alergijski kontaktni ekcemi, atopijski ekcemi, seborejični ekcemi, jednostavni lišaji, sunčeve opekotine, svrbež u genitalno-analnom području, alopecia areata, hipertrofni ožiljci, diskoidni lupus erythematosus, folikularne i ekstenzivne pioderme, endogene i egzogene akne, akne rosacea i druga proliferacijska, upalna i alergijska oboljenja kože; oboljenja zbog prekomjernog oslobađanja TNF i leukotriena, npr. oboljenja artritičnog tipa (reumatoidni artritis, reumatoidni spondilitis, osteoartritis i druga artritična stanja), oboljenja imunološkog sustava (AIDS, multipla skleroza), tipova šoka [septički šok, endotoksinski šok, gram-negativna sepsa, sindrom toksičnog šoka i ARDS (respiratorni stres sindrom odraslih)] i općenitih upala u gastrointestinalnom području (Kronova bolest i ulcerativni kolitis); bolesti nastale zbog alergijskih i/ili kroničnih abnormalnih imunoloških reakcija u području gornjih dišnih putova (područje ždrijela, nos) i obližnjih područja (paranazalni sinusi, oči) kao primjerice alergijski rinitis/sinusitis, kronični rinitis/sinusitis, alergijski konjuktivitis, konjuktivitis uzrokovan bakterijama, virusima ili gljivicama, upalna stanja nakon implantacije intraokularnih leća, upala očnog živca (neuritis nervi optici), keratitis, sindrom suhih očiju (keratitis sicca), uveitis, glaukom, retinalni edem, retinitis pigmentosa, dijabetička retinopatija, i nazalni polipi; ali također i srčana oboljenja koja se mogu liječiti PDE inhibitorima, kao npr. srčani udar, ili oboljenja koja se mogu liječiti zahvaljujući tkivno-opuštajućem učinku PDE inhibitora,kao primjerice erekcijska disfunkcija ili kolika bubrega i mokraćnih kanala povezano s bubrežnim kamencima; ili druga oboljenja CNS-a, kao primjerice depresija ili arteriosklerotična demencija.
Farmaceutski pripravci izuma su posebno pogodni za liječenje oboljenja kože kao što su dermatoze (posebice proliferacijske, upalne i alergijske prirode) kao npr. psorijaza (vulgaris), toksični i alergijski kontaktni ekcemi, atopijski ekcemi, seborejični ekcemi, jednostavni lišaji, sunčeve opekotine, svrbež u genitalno-analnom području, alopecia areata, hipertrofni ožiljci, diskoidni lupus erythematosus, folikularne i ekstenzivne pioderme, endogene i egzogene akne, akne rosacea i druga proliferacijska, upalna i alergijska oboljenja kože. Posebno se može spomenuti upotreba farmaceutskih pripravaka ovog izuma u liječenju psorijaze i atopijskog ekcema.
Izum se stoga također odnosi na daljnju upotrebu roflumilasta, soli roflumilasta, N-oksida roflumilasta ili njegovih soli za pripravu topikalnog farmaceutskog pripravka za dermalnu administraciju, za liječenje oboljenja kože za koje se smatra da se mogu liječiti ili spriječiti primjenom PDE 4 inhibitora. Posebno se mogu s tim u vezi spomenuti dermatoze (posebice proliferacijske, upalne i alergijske prirode) kao npr. psorijaza (vulgaris), toksični i alergijski kontaktni ekcemi, atopijski ekcemi, seborejični ekcemi, jednostavni lišaji, sunčeve opekotine, svrbež u genitalno-analnom području, alopecia areata, hipertrofni ožiljci, diskoidni lupus erythematosus, folikularne i ekstenzivne pioderme, endogene i egzogene akne, akne rosacea i druga proliferacijska, upalna i alergijska oboljenja kože.
Izum se nadalje odnosi na postupak za liječenje sisavaca, uključujući ljude, koji boluju od jedne od gore navedenih bolesti. Postupak je naznačen time da se terapeutski učinkovita i farmakološki pogodna količina aktivne supstance, izabrane iz grupe spojeva roflumilasta, soli roflumilasta, N-oksida roflumilasta ili njegovih soli, administrira oboljelom sisavcu, gdje se aktivna supstanca administrira u topikalnom farmaceutskom pripravku izuma.
Posebno se to odnosi na oboljenja kože kao što su đermatoze (posebice proliferacijske, upalne i alergijske prirode) kao npr. psorijaza (vulgaris), toksični i alergijski kontaktni ekcemi, atopijski ekcemi, seborejični ekcemi, jednostavni lišaji, sunčeve opekotine, svrbež u genitalno-analnom području, alopecia areata, hipertrofni ožiljci, diskoidni lupus erythematosus, folikularne i ekstenzivne pioderme, endogene i egzogene akne, akne rosacea i druga proliferacijska, upalna i alergijska oboljenja kože. Postupak je karakteriziran time da se administracija odvija dermalno, primjenom topikalnog farmaceutskog pripravka izuma na kožu ili sluznicu.
U sljedećem preferiranom primjeru, izum se odnosi na liječenje sisavaca, uključujući ljude, koji boluju od očnih oboljenja za koje se smatra da se mogu liječiti ili spriječiti primjenom PDE 4 inhibitora. Ta očna oboljenja su preferirano iz skupine alergijskih konjuktivitisa, konjuktivitisa uzrokovanih bakterijama, virusima ili gljivicama, upalna stanja nakon implantacije intraokularnih leća, upala očnog živca (neuritis nervi optici), keratitis, sindrom suhih očiju (keratitis sicca), uveitis, glaukom, retinalni edem, retinitis pigmentosa i dijabetička retinopatija. Posebno se to odnosi na alergijski konjuktivitis, konjuktivitis uzrokovan bakterijama, virusima ili gljivicama, upalna stanja nakon implantacije intraokularnih leća ili uveitis. Postupak je karakteriziran time da se administracija odvija primjenom topikalnog farmaceutskog pripravka izuma na oči.
Dobra sistemska raspoloživost, iznenađujuće nađena kod topikalnih administracija, čini farmaceutske pripravke ovog izuma posebno pogodnima sa sistemsko liječenje, a tako i liječenje svih drugih bolesti za koje se smatra da se mogu liječiti ili spriječiti primjenom PDE 4 inhibitora, posebno gore navedenih bolesti.
Izum se stoga također odnosi na daljnju upotrebu roflumilasta, soli roflumilasta, N-oksida roflumilasta ili njegovih soli za pripravu topikalnog farmaceutskog pripravka za dermalnu administraciju te za sistemsko liječenje bolesti za koje se smatra da se mogu liječiti ili spriječiti primjenom PDE 4 inhibitora. Posebno se mogu s tim u vezi spomenuti akutne i kronične (osobito upalne i one izazvane alergenima) bolesti dišnih putova različitih uzroka (bronhitis, alergijski bronhitis, bronhijalna astma, COPD) i bolesti artritičnog tipa (reumatoidni artritis, reumatoidni spondilitis, osteoartritis i druga artritična stanja).
Farmaceutski pripravci izuma su uz to posebno pogodni za administraciju grupi pacijenata koji boluju od gore navedenih bolesti i imaju problem uzimanja farmaceutskih pripravaka oralno, kao primjerice pacijenti vezani za krevet, pacijenti pod intenzivnom njegom, pacijenti koji imaju problema s gutanjem i djeca.
Izum sa nadalje odnosi na postupak za liječenje sisavaca, uključujući ljude, koji boluju od gore navedenih bolesti. Postupak je naznačen time da se terapeutski učinkovita i farmakološki pogodna količina aktivne supstance, izabrane iz grupe spojeva roflumilasta, soli roflumilasta, N-oksida roflumilasta ili njegovih soli, administrira oboljelom sisavcu, gdje se aktivna supstanca administrira u topikalnom farmaceutskom pripravku izuma. To se odnosi posebno na akutne i kronične (osobito upalne i one izazvane alergenima) bolesti dišnih putova različitih uzroka (bronhitis, alergijski bronhitis, bronhijalna astma, COPD) i bolesti artritičnog tipa (reumatoidni artritis, reumatoidni spondilitis, osteoartritis i druga artritična stanja). Postupak je karakteriziran time da se administracija odvija dermalno, primjenom topikalnog farmaceutskog pripravka izuma na kožu ili sluznicu.
Dozirni oblici izuma sastoje se od aktivne supstance u dozi uobičajenoj za liječenje dotične bolesti. Količina aktivne supstance je reda veličine uobičajenog za PDE inhibitore, uz mogućnost da se administrira dnevna doza u jednoj ili više dozirnih jedinica. Uobičajene doze su navedene kao primjer u WO 95/01338. Normalna doza u sistemskoj terapiji (oralno) je između 0.001 i 3 mg po kilogramu i danu. Dozirni oblici preferirani prema ovom izumu za topikalnu administraciju sadrže od 0.005 mg do 5 mg roflumilasta, poželjno od 0.01 mg do 2.5 mg, a još poželjnije od 0.1 mg do 0.5 mg roflumilasta po dozirnoj jedinici. Primjeri farmaceutskih pripravaka izuma sadrže 0.01 mg, 0.1 mg, 0.125 mg, 0.25 mg i 0.5 mg roflumilasta po dozirnoj jedinici.
Claims (17)
1. Topikalno primjenjivi farmaceutski pripravak, naznačen time, da se sastoji od aktivne supstance, zajedno s jednim ili više farmaceutskih nosača i/ili pomoćnih tvari pogodnih za topikalnu administraciju, gdje je aktivna supstanca spoj izabran iz grupe koja se sastoji od roflumilasta, soli roflumilasta, N-oksida piridinskog ostatka roflumilasta ili njegovih soli.
2. Topikalno primjenjivi farmaceutski pripravak prema zahtjevu 1, naznačen time, da je roflumilast spoj formule I
[image]
u kojoj je
R1 difluorometoksi,
R2 ciklopropilmetoksi i
R3 3,5-dikloropirid-4-il.
3. Topikalno primjenjivi farmaceutski pripravak prema zahtjevu 1, naznačen time, da je to polučvrsti dozirni oblik izabran iz grupe masti (npr. otopinska mast, suspenzijska mast), krema, gelova ili pasta.
4. Topikalno primjenjivi farmaceutski pripravak prema zahtjevu 1, naznačen time, da je to transdermalni terapeutski sustav (TTS).
5. Upotreba roflumilasta, soli roflumilasta, N-oksida roflumilasta ili njegovih soli, naznačena time, da služi za pripravu topikalnog farmaceutskog pripravka za dermalnu administraciju za sistemsko liječenje oboljenja, za koje se smatra da se mogu liječiti ili spriječiti korištenjem PDE 4 inhibitora.
6. Upotreba roflumilasta, soli roflumilasta, N-oksida roflumilasta ili njegovih soli, naznačena time, da služi za pripravu topikalnog farmaceutskog pripravka za dermalnu administraciju za liječenje oboljenja kože, za koje se smatra da se mogu liječiti ili spriječiti korištenjem PDE 4 inhibitora.
7. Postupak za liječenje sisavaca, uključujući ljude, koji boluju od dermatoza, za koje se smatra da se mogu liječiti ili spriječiti primjenom PDE 4 inhibitora, naznačen time, da se terapeutski učinkovita i farmakološki pogodna količina aktivne supstance, izabrane iz grupe spojeva roflumilasta, soli roflumilasta, N-oksida roflumilasta ili njegovih soli, administrira oboljelom sisavcu, gdje se aktivna supstanca administrira u topikalnom farmaceutskom pripravku izuma prema zahtjevu 1, i gdje se administracija odvija dermalno.
8. Postupak prema zahtjevu 7, naznačen time, da je dermatoza psorijaza (vulgaris), toksični i alergijski kontaktni ekcem, atopijski ekcem, seborejični ekcem, jednostavni lišaj, sunčeve opekotine, svrbež u genitalno-analnom području, alopecia areata, hipertrofni ožiljak, diskoidni lupus erythematosus, folikularne i ekstenzivne pioderme, endogene i egzogene akne, akne rosacea i druga proliferacijska, upalna i alergijska oboljenja kože.
9. Postupak za liječenje sisavaca, uključujući ljude, koji boluju od bolesti za koje se smatra da se mogu liječiti ili spriječiti primjenom PDE 4 inhibitora, naznačen time, da se terapeutski učinkovita i farmakološki pogodna količina aktivne supstance, izabrane iz grupe spojeva roflumilasta, soli roflumilasta, N-oksida roflumilasta ili njegovih soli, administrira oboljelom sisavcu, gdje se aktivna supstanca administrira u topikalnom farmaceutskom pripravku izuma prema zahtjevu 1, i gdje se administracija odvija dermalno.
10. Postupak prema zahtjevu 9, naznačen time, da su bolesti akutne i kronične (osobito upalne i one izazvane alergenima) bolesti dišnih putova različitih uzroka (bronhitis, alergijski bronhitis, bronhijalna astma, COPD) ili bolesti artritičnog tipa (reumatoidni artritis, reumatoidni spondilitis, osteoartritis i druga artritična stanja).
11. Topikalno primjenjivi farmaceutski pripravak prema zahtjevu 1, naznačen time, da je to dozirni oblik koji se upotrebljava za oči.
12. Topikalno primjenjivi farmaceutski pripravak prema zahtjevu 11, naznačen time, da obuhvaća kapi za oči.
13. Topikalno primjenjivi farmaceutski pripravak prema zahtjevu 11, naznačen time, da obuhvaća suspenziju aktivne supstance u nosačima i/ili pomoćnim tvarima.
14. Topikalno primjenjivi farmaceutski pripravak prema zahtjevu 11, naznačen time, da obuhvaća mast za oči.
15. Postupak za liječenje sisavaca, uključujući ljude, koji imaju očno oboljenje za koje se smatra da se može liječiti ili spriječiti primjenom PDE 4 inhibitora, naznačen time, da se terapeutski učinkovita i farmakološki pogodna količina aktivne supstance, izabrane iz grupe spojeva roflumilasta, soli roflumilasta, N-oksida roflumilasta ili njegovih soli, administrira oboljelom sisavcu, gdje se aktivna supstanca administrira u topikalnom farmaceutskom pripravku izuma prema zahtjevu 11.
16. Postupak prema zahtjevu 15, naznačen time, da je bolest alergijski konjuktivitis, konjuktivitis uzrokovan bakterijama, virusima ili gljivicama, upalna stanja nakon implantacije intraokularnih leća, upala očnog živca (neuritis nervi optici), keratitis, sindrom suhih očiju (keratitis sicca), uveitis, glaukom, retinalni edem, retinitis pigmentosa i dijabetička retinopatija.
17. Postupak prema zahtjevu 16, naznačen time, da obuhvaća alergijski konjuktivitis, konjuktivitis uzrokovan bakterijama, virusima ili gljivicama, upalna stanja nakon implantacije intraokularnih leća ili uveitis.
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