HRP20010582A2 - Valdecoxib compositions - Google Patents
Valdecoxib compositions Download PDFInfo
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- HRP20010582A2 HRP20010582A2 HR20010582A HRP20010582A HRP20010582A2 HR P20010582 A2 HRP20010582 A2 HR P20010582A2 HR 20010582 A HR20010582 A HR 20010582A HR P20010582 A HRP20010582 A HR P20010582A HR P20010582 A2 HRP20010582 A2 HR P20010582A2
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Description
Područje izuma
Ovaj izum odnosi se na farmaceutske pripravke koji se daju oralno a koji sadrže valdekoksib kao aktivnu komponentu, postupak priprave takvih pripravaka, metode tretmana ciklooksigenazom-2 posredovanih poremećaja, a koja se sastoji od oralnog davanja takvih pripravaka osobi i na upotrebu takvih pripravaka u proizvodnji lijekova.
Dosadašnje spoznaje
Spoj 4-(5-metil-3-fenil-4-izoksazolil)benzensulfonamid, ovdje naveden kao valdekoksib je prikazan u U.S. Patentu br. 5,633,272 od Talley et al. skupa s postupcima priprave tog i odgovarajućih spojeva. Valdekoksib ima sljedeću strukturu:
[image]
Spojevi prikazani u gore navedenom U. S. Patentu br. 5,633,272 uključujući valdekoksib, prikazani su ovdje kao korisna antiinflamatorna sredstva, analgenlici i antipiruvetici koji imaju visoki stupanj selektivnosti u inhibiciji ciklooksigenaze-2 (COX-2) u usporedbi s ciklooksigenazom-1 (COX-1). Gore navedeni U. S. Patent br. 5,633,272 također sadrži opće referencije formulacija takvih spojeva za davanje, uključujući oblike doza koji se mogu dati oralno kao što su tablete i kapsule.
Europska Patentna aplikacija br. O 863 134 prikazuje spojeve koji se mogu dati oralno, a koji sadrže lijek koji je selektivni inhibitor ciklooksigenaze-2, specifičnije 2-(2,5-difluorfenil)-3-(4-metilsulfonil)fenil)-2-ciklopenten-1-on u kombinaciji s ekcipijensima uključujući mikrokristalnu celulozu, laktozu monohidrat, hidroksipriopilnu celulozu, natrijevu kroskarmelozu i magenzijev stearat.
Međunarodna Patentna publikacija br. WO 00/32189 prikazuje pripravke koji se mogu dati oralno, a koji sadrže lijek koji je selektivni inhibitor ciklokksigenaze-2, specifičnije celekoksib u kombinaciji s ekcipijensima koji su odabrani od velike liste pogodnih razrjeđivača, dezintegrirajućih sredstava, veziva, ovlaživača, lubrikanata itd.
Valdekoksib ima izuzetno malu topljivost u vodi i zbog tog razloga je predloženo da se daje parenteralno u obliku mnogo topljivije prolijeka, parekoksiba koji cijepanjem tvori valdekoksib. Vidi primjerice Dionne (1999) "COX-2 inhibitore - IBC konferencija, 12-13 travnja 1999. Coronado, CA, U. S. A.", IDrugs. 2(7), 664-666.
Međutim, bit će dobro imati oblik doze valdekoksiba koja se može dati oralno i koji pokazuje dobru bioraspoloživost i svojstvo brzog oslobađanja.
Kao što je dolje pokazano, davanje valdekoksiba je indicirano ili je potencijalno indicirano širokim rasponom stanja i poremećaja posredovanim ciklooksigenazom-2. Bilo bi stoga vrlo povoljno da se prikaže formulacije koja se može dati oralno koja ima bioraspoloživost podređenu takvoj indikaciji. Bilo si posebno povoljno da se dobije oralna formulacija s brzim oslobađanjem koja ima farmakokinetički učinak u skladu s brzim početnim efektom.
Takve formulacije bi dovele do značajnog napretka u tretmanu uvjeta i poremećaja posredovanim ciklooksigenazom-2.
Sažetak izuma
Ovdje je prikazan farmaceutski pripravak koji sadrži usitnjeni valdekoksib u količini od oko 1 mg do oko 100 mg po dozi i jedan ili više farmaceutski prihvatljivih ekscijpijenasa.
U jednoj cjelini, jedinica doze nakon oralnog davanja osobi koja posti, dovodi do vremenski ovisne koncentracije valdekoksiba u serumu koja zadovoljava barem jedno od sljedećih:
(a) vrijeme postizanja koncentracije preko praga terapijskog efekta nije veće od oko 0.5 h nakon davanja;
(b) vrijeme postizanja maksimalne koncentracije (Tmax) nije veće od oko 0.5 h nakon davanja; te
(c) maksimalna koncentracija (Cmax) nije manja od oko 100 ng/mL.
"Koncentracija preko praga terapijskog efekta" znači minimalnu koncentraciju valdekoksiba u serumu koja dovodi do terapijskog poboljšanja određene indikacije zbog kojeg je valdekoksib dan. Tipična granična koncentracija je barem oko 20 ng/mL, primjerice oko 25 do oko 75 ng/ml.
Pripravak može biti u obliku pojedinačnih čvrstih oblika kao što su tablete, pilule, tvrde ili meke kapsule, lonzete, vrećice ili pastile, jedna veličine koja tvori jediničnu dozu; alternativno pripravak može biti u obliku homogene tekuće mase kao što je granulirana krutina ili tekuća suspenzija iz koje jediničnu dozu treba odmjeriti.
Ovdje je u preferiranoj cjelini pripravak u obliku tableta u kojima ekscipijent uključuje u vodi topljivi razrjeđivač, dezintegrirajuće sredstvo, vezivo i lubrikant. Najpreferiranije je da vezivo sadrži preželatinizirani kukuruzni škrob.
Također je prikazana metoda tretmana medicinskih uvjeta ili poremećaja u osobi kojoj je indiciran tretman s inhibitorom ciklooksigenaze-2, a sadrži oralno davanje pripravka iz izuma od jedanput do približno četiri puta dnevno.
Ostale karakteristike izuma će biti očite u dijelu koji slijedi.
Kratki opis slika
Slika 1 prikazuje dijagram koji ilustrira predstavnika metoda za pripravu tableta valdekoksiba iz izuma.
Slika 2 prikazuje dijagram koji ilustrira alternativnu metodu za pripravu tableta valdekoksiba iz izuma.
Slika 3 prikazuje koncentraciju valdekoksiba u plazmi pasa nakon oralnog davanja tableta valdekoksiba iz izuma.
Slika 4 prikazuje koncentraciju valdekoksiba u humanoj plazmi nakon oralnog davanja tableta valdekoksiba iz izuma.
Detaljni opis izuma
Pripravak iz izuma sadrži valekoksib u česticama u količini doze od oko 1 mg do oko 100 mg. Takav pripravak je dobar oblik doze s brzim oslobađanjem koji može dovesti do brzog poboljšanja poremećaja posredovanim ciklooksigenazom-2, a kada se daje oralno osobi, određenije čovjeku koji pati od takvih poremećaja.
Vjeruje se, a bez vezivanja na teoriju, da velika klinička korist od tih pripravaka dolazi od poboljšane bioraspoloživosti valdekoksiba, posebice zbog iznenađujuće učinkovite apsorpcije valdekoksiba u gastrointestinalnom traktu kada se takav pripravak daje oralno. Stručnjaci mogu takvu učinkovitu apsorpciju verificirati praćenjem koncentracije valdekoksiba u serumu kod osobe koja je pod tretmanom u periodu nakon davanja. Poželjno je graničnu koncentraciju valdekoksiba u serumu koja inhibira ciklooksigenazu-2 dostići u najkraćem mogućem vremenu.
Kao stoje gore naznačeno, jedna cjelina je jedinična doza koja nakon oralnog davanja osobi koja posti, dovodi do vremenski ovisne koncentracije valdekoksiba u serumu koja ima barem jedno od sljedećih:
(a) vrijeme postizanja koncentracija preko praga terapijskog efekta nije veće od oko 0.5 h nakon davanja;
(b) vrijeme postizanja maksimalna koncentracija (Tmax) nije veće od oko 0.5 h nakon davanja; te
(c) maksimalna koncentracija (Cmax) nije manja od oko 100 ng/mL.
Bit će razumljivo da količina valdekoksiba u jediničnoj dozi učinkovitoj da dovede do koncentracije u serumu koja zadovoljava kriterije (a) do (c) samo granično, ovisi o tjelesnoj težini osobe koja je pod tretmanom. Kada je primjerice tretirana osoba dijete ili mala životinja (npr. pas), količina valdekoksiba koja dovedi do koncentracije u serumu koja je u skladu s barem jednom od kriterija (a) do (c) je relativno mala u navedenom rasponu od 1 mg do oko 100 mg. Kad je osoba odrasli čovjek ili velika životinja (npr. konj), vjerojatno je da potrebna koncentracija valdekoksiba zahtjeva relativno veće količine doze valdekoksiba. Za odraslog čovjeka, pogodna količina valdekoksiba po dozi u pripravku po ovom izumu je da dovede do potrebne koncentracije u serumu koja je tipično o, onda:
(a) je koncentracija valdekoksiba u serumu 20 ng/mL, preferiranije 50 ng/mL je dostignuta ne kasnije oko 0.5 h nakon davanja;
(b) Tmax nije veće od oko 3 h nakon davanja; te
(c) Cmax nije manja od oko 100 ng/mL
Pripravci iz izuma sadrže valdekoksib u usitnjenom obliku. Primarne čestice valdekoksiba, pripravljene primjerice mljevenjam ili taloženjem iz otopine, mogu tvoriti aglomerate pri čemu nastaju čestice sekundarne agregacije. Termin "veličina čestice" se ovdje odnosi na veličinu u najduljoj dimenziji primarnih čestica, osim kad kontekst podrazumijeva drugačije. Vjeruje se da veličina čestica važan parametar koji djeluje na kliničku učinkovitost valdekoksiba. Stoga u jednoj cjelini pripravak ima raspodjelu veličine čestica valdekoksiba takvu da je D90 veličine čestica manja od 75 μm.
"D90 veličine čestica" definiran je ovdje kao takva veličina čestice da je 90% čestica po masi manje u njihovoj najvećoj dimenziji od te veličina čestice.
Dodatno ili alternativno, čestice valdekoksiba u pripravku preferirano imaju prosječnu masu čestice oko oko 1 μm do oko 10 μm, najpreferiranije oko 5 μm do oko 7 μm.
U daljnjoj cjelini, čestice valdekoksiba u pripravku iz izuma imaju prosječnu masu od oko 10 nm do oko 1000 nm (1 tim), primjerice oko 100 nm do oko 400 nm ili oko 500 nm do oko 800 nm.
Pripravci iz izuma sadrže valdekoksib skupa s jednim ili više ekscipijensom koji su odabrani od razrjeđivača, dezintegrirajućih sredstava, veziva, ovlaživača i lubrikanata. U jednoj preferiranoj cjelini najmanje jedan ekscipijens je u vodi topljiv razrjeđivač ili ovlaživač. Vjeruje se da takav u vodi topljiv razrjeđivač ili ovlaživač pomaže u disperziji i raspadanju valdekoksiba u gastointestilnalnom traktu. Preferirano je prisutan barem u vodi topljivi razrjeđivač. U sljedećoj preferiranoj cjelini barem jedan ekscipijens je dezintegrirajuće sredstvo. U sljedećoj preferiranoj cjelini barem jedan ekscipijens je vezivo; kao što je gore pokazano, posebno je preferirano da je preželatinizirani kukuruzni škrob prisutan kao vezivo. U sljedećoj preferiranoj cjelini barem jedan ekscipijens je lubrikant. Posebno je preferirano da pripravak uz valdekoksib sadrži u vodi topljivi razrjeđivač, dezintegrirajuće sredstvo, vezivo, klizno sredstvo i lubrikant.
Pripravak iz izuma može biti dovoljno homogena masa koja teče kao što je čestice ili granule krutine ili tekućine ili može biti u pojedinačnim oblicima kao što su kapsule ili tablete.
U pripravku koji je dovoljno homogena masa koja teče, jedinica doze se može dobiti korištenjem pogodne naprave za volumetrijsko mjerenje kao što je žlica ili šalica. Pogodne mase koje mogu teći uključuju, ali nisu na njih ograničene, praške i granule. Alternativni masa koja može teći može biti suspenzija koja ima valdekoksib kao čvrste čestice koje su dispergirane u tekućoj fazi, preferirano u vodenoj fazi. U pripravi takvih suspenzija pogodno je korištenje ovlaživača kao što je polisorbat 80 ili slično. Suspenzija može biti pripravljena dispergiranjem samljevenog valdekoksiba u tekućoj fazi; alternativno se valdekoksib može taložiti iz otopine u otapalu kao što je alkohol, preferirano etanol. Vodena faza preferirano sadrži vehikule s okusom kao što je voda, sirup ili voćni sok, primjerice sok od jabuke.
Pripravci iz izuma su korisni u tretmanu u prevenciji vrlo širokog raspona poremećaja posredovanih COX-2, uključujući, ali ne ograničavajući se na njih, poremećaje karakterizirane upalom, boli i/ili temperaturom. Takvi pripravci su posebice korisni kao antiupalna sredstva, kao što je tretman artritisa s tim da je značajno manji broj nuspojava nego kod uobičajenih pripravaka uobičajenih nesteroidnih antiupalnih lijekova (NSAID), a koji ne pokazuju selektivnost između COX-2 i COX-1. Pripravci iz izuma imaju smanjeni potencijal za gastrointestinalne toksičnosti i gastrointestinalne iritacije, uključujući ulceraciju i krvarenje gornjeg gastointestinalnog trakta, smanjeni potencijal za renalne nuspojave kao što je smanjivanje renalne funkcije koja vodi zadržavanju tekućine i pogoršavanje povišenog krvnog tlaka, smanjen efekt vremena krvarenja uključujući inhibiciju funkcija plateleta i moguće smanjenu mogućnost indukcije napada astme kod pacijenata s astmom koji su osjetljivi na aspirin, a u usporedbi s pripravcima uobičajenih NS AID. Stoga su pripravci iz izuma posebno korisni kao alternativa uobičajenim NSAID kada su NSAID kontraindicirani, primjerice kod pacijenata s peptičnim ulcerom, gastririsom, regionalnim enteritisom, uleraticvnim kolitisom, divertikulitisom ili s nedavnom povijesti gastrointestinalnih lezija; kod gastrointestnalnih krvarenja, poremećajima koagulacije uključujući anemiju kao što je hipoprotrombinemija, hemofilija ili kod ostalih problema krvarenja bolesti bubrega ili pacijenata prethodno podvrgnutih operaciji ili kod pacijenata koji uzimaju antikoagulanse.
Razmatranim pripravcima je korisno tretirati različite artritične poremećaje, uključujući ali ne ograničavajući se na njih, reumatoidni artritis, spondiloartritis, giht, osteoartritis, sistemsku erithematozu lupusa, te juvenilni artritis.
Takvi pripravci su korisni u tretmanu astme, bromhitisa, menstrualnih tegoba, prijevremenih trudova, tenditisa, bursitisa, alergijskog neuritisa, infekcija citomegalovirusom, apoptoze uključujući apoptozu induciranu HIV, lumbaga, bolesti jetre uključujući hepatitis, stanja kože kao što je psorijaza, ekcem, akne, opekline, dermatitis i oštećenje ultraljubičastom radijacijom uključujući opekline od sunca, postoperativnih upala uklje leće.
Takvi pripravci su korisni u tretmanu gastointestilnanih uvjeta kao što je upalna bolest crijeva, Crohnova bolest, gastritis, sindrom iritabilnih crijeva i ulcerativni kolitis.
Takvi pripravci su korisni u tretmanu upala u bolestima kao što je migrena, periarteritis nodosa, tiroiditis, aplatična anemija, Hodgkinova bolest, skerodoma, reumatična groznica, dijabetes tipa I, bolest neuromuskulrna bolest zglobova uključujući miasteniju gravis, bolest bijele tvari mozga uključujući multipla sklerozu, sarkoidoza, nefrotični sindrom, Behcetov sindrom, polimiozitis, gingivitis, nefritis, hiperosjetljivost, naticanje nakon povrede uključujući edem mozga, miokardialnu ishemiju i slično.
Takvi pripravci su korisni u tretmanu bolesti oka kao što je retinitis, konjunktivitis, retinopatije, uveitis, okularna fotofobija i akutna ozljeda tkiva oka.
Takvi pripravci su korisni u tretmanu plućnih upala kao što su one povezane s virusnim infekcijama i cističnom fibrozom, resorpcije kostiju kao one povezane s osteoporozom.
Takvi pripravci su korisni u tretmanu nekih poremećaja centralnog nervnog sustava kao što je kortikalna demencija uključujući Alzheimerovu bolest, neurodegeneracija i ozljedu centralnog nervnog sustava nastalu zbog udara, ishemije i traume. Termin "tretman" u ovom kontekstu uključuje djelomičnu ili potpunu inhibiciju demencija, uključujući Alzheimerocu bolest, vaskularnu demenciju, multiinfarktnu demenciju, presenilnu demenciju, alkoholnu demenciju i senilnu demenciju.
Takvi pripravci su korisni u tretmanu alergijskog rinitisa, sindroma respiratornog distresa, sindroma endotoksičnog šoka i bolesti jetre.
Takvi pripravci su korisni u tretmanu bolesti uključujući ali ne ograničavajući se na njih, postoperativnu bol, bol zuba, bol mišića, bol uzrokovan karcinomom. Primjerice, takvi pripravci su korisni za otklanjanje boli, groznice i upale u raznim uvjetima uključujući reumatoidnu groznicu, influencu i stale virusne infekcije koje uključuju običnu prehladu, bol u leđima i vratu, dismenoreu, glavobolju, zubobolju, iščašenje, miozitis, neuralgiju, sinovitis, artritis uključujući reumatoidni artritis, degenerativne bolesti zglobova (osteoartritis), giht i ankilozni spondilitis, bursitis, opekline i trauma nakon operacije ili zahvata na zubu.
Takvi pripravci su korisni za tretman i prevenciju upala povezanih s kardiovaskularnim poremećajima uključujući vaskularne bolesti, bolesti koronarne arterije, aneuriznu, vaskularno odbijanje, arteriosklerozu, aterosklerozu uključujući aterosklerozu srčanog transplanta, miokardijalnu infrakciju, emboliju, udar, tromboze uključujući vensku trombozu, angine uključujući nestabilnu angimu, upalu koronarnog plaka, bakterijom izazvane upale uključujući Chalmydiom izazvanu upalu, virusom izazvanu upalu, upalu povezanu operativnim zahvatom kao što je presađivanje žila uključujući operaciju prijenosnice srčane arterije, postupak revaskularizacije uključujući angioplastiju, enadrektomiju ili ostale invazivne postupke koji obuhvaćaju arterije vene i kapilare.
Takvi pripravci su korisni u tretmanu poremećaja povezanih s angiogenezom u osobi, primjerice s inhibicijom tumorne angiogeneze. Takvi pripravci su korisni u tretmanu neoplazija, uključujući metastaze; oftalmoloških stanja kao što je odbijanje korenalnog transplanta, okularna neurovaskularizacija, retinalna neurovaskularizacija uključujući neurovaskularizaciju koju slijedi ozljeda ili infekcija, dijabetičnu retinopatiju, degeneraciju mišića, retrolentalnu fibroblastiju i neurovaskularnu glaukomu; ulcerativne bolesti kao stoje ulcer gastirtisa patološke ali nemaligne uvjete kao što su hemangiome uključujući infantilne hemanginome, angiofibrome nazofarinksa i avaskularne nekroze kostiju te poremećaje ženskog reproduktivnog sustava kao što je endometrioza.
Takvi pripravci su korisni u prevenciji i tretmanu početka malignih tumora i neoplazni uključujući karcinom, kao što je karcinom kolorektuma, karcinom mozga, karcinom kosti, neoplazija vođena epitelnim stanicama (karcinom epitela) kao što je karcinom bazalnih stanica, adenokarcinom, karcinom gasointestiinalnog trakta kao što je karcinom usne, karcinom usta, karcinom jednjaka, karcinom tanko crijeva, karcinom stomaka, karcinom debelog crijeva, karcinom jetre, karcinom bubrega, karcinom pankreasa, karcinom jajnika, karcinom cerviksa, karcinom pluća, karcinom dojke, karcinom kože, kao što su bubrega i ostali poznati karcinomi koji djeluju na epitelne stanice u tijelu. Za neoplazne, za koje se smatra da je pripravaka iz izuma posebno koristan su karcinom gastointestinalnog trakta, Barretov ezofagus, karcinom jetre, karcinom mjehura, karcinom pankreasa, karcinom jajnika, karcinom prostate, karcinom cerviksa, karcinom pluća, karcinom dojke i karcinom kože. Takvi pripravci se također mogu koristiti za tretman fibrioza koja se javljaju pri radijacijskoj terapiji. Takvi pripravci se mogu koristiti u tretmanu osoba koji imaju adenomatni polip uključujući one s familijarnim adenomatnom polipozom (FAP). Uz to, takvi pripravci se mogu koristiti u prevenciji stvaranja polipa kod pacijenata koji imaju rizik na FAP.
Takvi pripravci inhibiraju prostanoidom induciranu kontrakciju glatkih mišića inhibicijom sinteze kontraktivnih prostanoida i stoga mogu biti korisni u tretmanu dismenoreje, prijevremenih trudova, astme i poremećaja vezanih na eozinofil. Također se mogu koristiti za smanjivanje gubitka kosti, posebno kod postmenopauzlnih žena (i.a u tretmanu osteoporoze) i za tretman glaukoma.
Preferirana upotreba pripravaka iz izuma je za tretman reumatoidnog artritisa i osteoartritisa, općenito za bol (posebice za bol nakon operacije usta, općenito za bol nakon operacije, za bol nakon ortopedske operacije i akutni širenje asteoartritisa), za tretman Alzheimerove bolesti i za kemoprevenciju karcinoma debelog crijeva.
Pored toga što su korisni u tretmanu ljudi, pripravci iz izuma su korisni u veterinarskom tretmanu domaćih životinja, egzotičnih životinja, s slično, posebice sisavaca. Određenije, pripravci iz izuma su korisni u tretmanu poremećaja posredovanih COX-2 u konjima, psima i mačkama.
Ovaj izum je nadalje upućen na metode terapije uvjeta stanja ili poremećaja kod kojih je tretman s inhibitorima COX-2 indiciran, a metoda sadrži oralno davanje pripravka iz izuma osobi koja za tim ima potrebu. Potrebna doza za prevenciju ili otklanjanje ili poboljšanje uvjeta ili poremećaja preferirano odgovara jedanput na dan i dva puta na dan tretmanu, ali može biti modificiran prema različitim faktorima. Oni uključuju tip, starost, težinu, spol, dijetu i medicinske uvjete osobe i prirodu i ozbiljnost poremećaja. Stoga se potrebna doza može široko mijenjati i stoga može odstupati od gore navedene preferirane doze.
Početni tretman može biti s dozom kao što je gore pokazano. Tretman se općenito produljuje ako je neophodno u periodu od nekoliko tjedana do nekoliko mjeseci ili godina, a dok je stanje ili poremećaj pod kontrolom ili eliminiran. Osobe koje podliježu tretmanu s pripravkom iz izuma se mogu rutinski pratiti bilo kojom metodom poznatom u struci za određivanje učinkovitosti terapije. Kontinuirana analiza podataka takvog praćenja dozvoljava modifikaciju potreba tretmana tako da se dade optimalno učinkovita doza u bilo kojem trenutku, tako da trajanje tretmana može biti određeno. Na ovaj način, potrebe tretmana i vrijeme uzimanja se mogu racionalno modificirati tijekom terapije tako da bude dana najmanja količina koja pokazuje zadovoljavajući učinak, te se takvo davanje nastavlja samo toliko dugo dok je neophodno za uspješni tretman uvjeta i poremećaja.
Ovi pripravci se mogu koristiti u kombinacijskoj terapiji s, među ostalim, opoidima i ostalim analgeticima, uključujući narkotične analgetike, antagoniste Mi receptora, antagoniste Kapa receptora, nenarkotične (i.e. neadiktive) analgentike, inhibitore vezanja monoamina, sredstva za reguliranje adenozina, derivate kanabiona, antagoniste tvari P, antagoniste receptora neurokinin-1 i blokatore natrijevog kanala. Preferirane kombinacijske terapije sadrže upotrebu pripravka iz izuma s jednim ili više spojeva koji su odabrani od sljedećih: aceklofenak, acemetacin,e-acetamidokapronska kiselina, acetaminofen, acetaminosalol, acetanilid, acetilsalicilna kiselina (aspirin), S-adenozilmetionin, aklofenak, alfentanil, alilprodin, aminoprofen, alioksipirin, alfaprodin, aluminijev bis(acetilsalicinat), amfenak, aminoklortenoksazin, 3-amino-4-hidrokismaslačna kiselina, 2-amino-4-pikolin, aminopropilon, aminopirin, amikestrin, amonijev salicilat, ampiroksikam, altolmetin guacil, anileridin, antipirin, antipirin-salicilat, antrafenin, apazon, bendazak.benorilat, benoksaprofen,benzpiperilon, benzidamin, benzilmorfin, bermoprofen, benzitramid, a-bisabolol,, bromfenak, p-bromacetanilid, 5-bromsalicilna kiselina acetat, bromsaligenin, bucetin, bikloksilna kiselina, bukolom, bifeksamak, bumadizon, burenorfin, butacetin, butibufen, butofanol, kalcijev acetilsalicilat, karbamazepin, karbifen, karprofen, karsalam, klorbutanol.klortenoksazin, kolin-salicilat, cinkofen, cinmetacin, ciramadol, klidanak, klormetacin, klonitazen, kloniksin, klopirak, klov, kodein, kodein metilni bromid, kodein fosfat, kodein sulfat, kropromamid, krotetamid, dezomorfin, deksoksadrol, dekstromoramid, dimpromid, natrijev diklofenak, difenamizol, difenpiramid, difunisal, dihidrokodein, dihidrokodein enol acetat, dihidromorfin, dihidroaluminijev acetilsalicilat, dimenoksadol, dimefeptanol, dimetiltiambuten, dioksafenilbutirat, dipipanon, diprocetil, dipiron, ditazol, droksikam, emorfazon, enfenaminska kiselina, epirizol, eptazocin, etersalat, etenzamid, etoheptazin, etoksazen, etilmetiltiambuten, etilmorfin, etodolak, etofenamat, etonitazen, eugenol, felbinak, fenbufen, fenklozikna kiselina, fendosal, fenopropen, fentanil, fentiazak, fepradinol, feprazon, floktafenin, flufenaminska kiselina, flunoksaprofen, fluoreson, flupirtin, fluprokvazon, flubiprofen, fosfosal, gentiska kiselina, galfenin, glukametacin, glikol salicilat, gvaiazulen, hidrokodon, hidromorfon, hidroksipeptidin, ibufenak, ibuprofen, ibuproksam, imidazol salicilat, imdometacin, imdoprofen, izofezolak, izoladol, izometadon, izoniksim, izoksepak, izoksikam, ketobemidon, ketoprofen, ketorolak, p-laktofenetid, lafetamin, levorganol, lofentranil, lonazolak, lornoksikam, loksoprofen, lizin acetilsalicilat, magnezijev acetilsalicilat, meklofenaminska kiselina, mefenaminska kiselina, meperidin, meptazinol, mezalamin, metozocin, metadon hidroklorid, metotrimeprazin, metiazinska kiselina, metofolin, metopon,mofebutazon, mofezolak, morazon, mrofin, morfin hidroklorid, morfn sulfat, mofin salicilat, mirofin, nabumeton, nalbufin, 1-naftil salicilat, naproksen, narcein, nefopam, nikomorfin, nifenazon, nifluminska kiselina, nimezulid, 5'-nitro2'-propilacetanilid, norlevorfanol, normetadon, normorfin, norpipanon, olsalazin, opij, oksaceprol, oksametacvin, oksaprozin, oksikodon, oksimorfon, oksihenbutazon, papaveretum, paranilin, parsalmid, pentazocin, perisoksal, fenacetin, fenadokson, fenazocin, fenazopiridin hidroklorid, feenokol, fenoperidin, fenopirazon, fenil-acetilsalicilat, fenbutazon, fenilni salicilat, fenilramidol, piketopren, piminodin, pipebuzon, piperilon, piprofen, pirazolak, piritramid, piroksikam, pranoprofen, proglumetacin, proheptazin, promedol, propacetamol, propiram, propoksifen, propilbenz-anon, prokvazon, protizinska kiselina, ramifenazon, remifentanil, riazolijev metilsulfat, alacetamid, salicin, salicilamid, salicilamid o-octena kiselina, salicilsumoprna kiselina, salsalat, salverin, simterid, natrijev salicilat, sufentanil, sulfasalazin, sulindak, superoksid dismutaza, suprofen, suksibuzon, talniflumat, tenidap, tenoksikam, terofenamat, tetrandrin, tiazolinobutazon, tiaprofenska kiselina, tiaramid, tilidin, tinoridin, tolfenamiska kiselina, tolmetin, tramadol, tropepsin, viminol, ksenbucin, ksimoprofen, zaltoprofen, i zomepirak (vidi Merk lndex 12. izd, Therapeutic Category and Biological Activitz lndex, ed. S. Budavari (1996) str. Thre-2 do Thre-3 i Ther-12 (Analgesic Dental), Anagelsic (Narcotic), Anagelsic (Non-narcotic), Anti-inflammatorz (Nonsteroidal)).
Posebne preferirane kombinacijske terapije obuhvaćaju upotrebu pripravka iz izuma s opoidnim spojem, određenije, u kojem je opoidni spoj kodein, meperidin, morfin ili njihov derivat.
Pripravak s valdekoksibom iz izuma se također može dati u kombinaciji s drugim selektivnim inhibitorom COX-2, primjerice s celekoksibom rofekoksibom itd.
Spoj koji će se dati u kombinaciji s valdekoksibom može biti formuliran posebno od valdekoksiba ili zajedno formuliran s valdekoksibom u pripravku iz izuma. Tamo gdje je valdkoksib formuliran zajedno s drugim lijekom, primjerice s opoidom, drugi lijek može biti formuliran za brzo otpuštanje, za odgođenje otpuštanja ili za dvostruko otpuštanje.
Pripravci iz izuma su općenito pogodni za davanje valdekoksiba u dnevnoj količini od oko 1 mg do oko 100 mg. Svaka jedinica doze pripravka iz izuma tipično sadrži količinu valdekoksiba od oko desetine dnevne doze do oko cijele dnevne doze. Preferirane dnevne doze su od oko 5 mg do oko 40 mg. Gdje je jedinica doze u obliku diskretnih oblika pogodnih za oralno davanje kao što su kapsule i tablete, svaki od tih oblika sadrži od oko 1 do oko 100 mg, preferirano od oko 5 mg do oko 60 mg, još preferiranije od oko 10 mg do oko 50 mg, primjerice od oko 10 mg, oko 20 mg ili oko 40 mg valdekoksiba.
Valdekoksib korišten u pripravcima iz izuma se može pripraviti prema bilo kojem poznatom postupku per se, uključujući način prikazan u gore navedenom U. S. Patentu br. 5,633,272.
Uz valdekoksib, pripravci iz izuma sadrže jedan ili više ekscipijenasa pogodnih za oralno davanje. Ekscipijensi moraju biti farmaceutski prihvatljivi tako da budu kompatibilni s ostalim sastojcima pripravka i ne smiju biti štetni za primatelja. Korišteni ekscipijensi mogu biti krutine, tekućine i obje vrste.
Pripravak iz izuma sadrži željenu količinu valdekoksiba po dozi i može biti u obliku primjerice tablete, pilule, tvrde ili meke želatinske kapzule, lozete, vrećice, dispergivnog praška, granula, suspenzije ili bilo kojeg drugog oblika koji je prilagođen oralnom davanju. Tablete, pilule i slično mogu biti pripravljene sa ili bez presvlačenja.
Pripravci iz izuma pogodni za buklano ili sublingvalno davanje uključuju primjerice lozete koje sadrže valdekoksib u bazi s dodatkom okusa, kaso stoje saharoza i akacija ili tragakant, te pastile koje sadrže valdekoksib u inertnoj bazi kao što je želatina i glicerin ili saharoza i akacija.
Tekući oblici doze uključuju suspenzije valdekoksiba u tekućim razrjeđivačima koji je tipično voda. Takve suspenzije mogu sadržavati dodatni ekscipijens, primjerice klizno sredstvo, emulgator ili sredstvo za tvorbu suspenzije, stabilizator, ugušćivač, zaslađivač, sredstvo za poboljšanje okusa i sredstvo za poboljšanje mirisa.
Pripravci iz izuma se mogu pripraviti pogodnim metodama u farmaciji koje uključuju dovođenje u kontakt valdekoksiba s ekscipijensom (ekscipijensima). Općenito, pripravci se priređuju miješanjem do jednolične smjese valdekoksiba s tekućinom ili fino usitnjenim čvrstim razrjeđivačem, a zatim ako je neophodno kapsuliranjem ili oblikovanjem nastale smjese. Primjerice, tableta se može pripraviti prešanjem ili kalupljenjem praška ili granula takve smjese koja može biti s jednim ili više dodatnih ekscipijenasa. Prešane tablete se mogu pripraviti kompresijom u pogodnom stroju mase pripravka u obliku praška ili granula koji sadrži valdekoksib, a koji može biti miješan s jednim ili više razrjeđivača, dezintegrirajućih sredstava, veziva i lubrikanata. Tablete u kalupu se mogu pripraviti kalupljenjem praškastog valdekoksiba koji može imati jedan ili više ekscipijenasa u pogodnom stroju, a koji je navlažen tekućim razrjeđivačem.
Preko odabira kombinacije ekscipijenasa pripravcima se može poboljšati djelovanje s aspekta učinkovitosti, bioraspoloživosti, vremena čišćenja, stabilnosti, kompatibilnosti valdekoksiba i ekscipijenasa, sigurnosti, profilu raspadanja i/ili farmakokinetici, kemijskim i/ili fizičkim svojstvima. Ekscipijensi preferirano uključuju jedno ili više ovlaživača koja nadoknađuju slabu topljivost i hidrofobnost valdekoksiba. Gdje je pripravak formuliran kao tablete, kombinacija odabranih ekscipijenasa može dovesti do poboljšanja među inim svojstvima profila raspadanja, čvrstoće, otpora na usitnjavanje i/ili zdrobljivosti.
Pripravci iz izuma mogu sadržavati jedan ili više farmaceutski prihvatljivih razrjeđivača ili ekscipijenasa. Pogodni razrjeđivači kao ilustraciju uključuju svaki sljedeći, pojedinačno ili u kombinaciji: laktoza uključujući bezvodnu laktozu i laktozu monohidrat; kukuruzni škrob uključujući škrob koji se izravno može komprimirati i hidrolizirani škrob (npr. Celutab™ i Emedex™); manitol; sorbitol; ksilitol; dekstroze (npr. Celeroze™ 2000) i dektrozu monohidrat; dibazni kalcijev fosfat dihidrat; razrjeđivače zasnovane na saharozi; šećer; monobazni kalcijev sulfat monohidrat; kalcijev sulfat dihidrat; kalcijev laktat trihidrat u granulama; dekstrate; inozitol; hidrolizirane žitarice; amilozu; celuloze uključujući mikrokristalnu celulozu; α- i amorfnu celulozu čistoće za ishranu (npr. Rexcel™) i praškastu celulozu; kalcijev karbonat; glicin; bentonit; polivinilpirolidon; i slično. Takvi razrjeđivači, ako su prisutni čine ukupno od oko 5% do oko 99%, preferirano od oko 10% do oko 85%, a još preferiranije od oko 20% do oko 80% ukupne mase pripravka.
Odabrani razrjeđivač ili razrjeđivači pokazuju pogodno svojstvo točnosti, a kad je poželjnija tableta, mogućnosti kompresije.
Laktoza i mikrokristalna celuloza pojedinačno ili u kombinaciji su preferirani razrjeđivači. Oba razrjeđivača su kemijski kompatibilna s valdekoksibom. Upotreba ekstragranularne mikrokristalne celuloze (to je mikrokristalna celuloza dodana u vlažni granulirani pripravak nakon koraka sušenja) se može koristiti za poboljšanje tvrdoće (za tablete) i/ili vremena raspadanja. Izuzetno je preferirana laktoza, a posebice laktoza monohidrat. S laktozom tipično nastaju pripravci koji imaju pogodnu brzinu oslobađanja valdekoksiba, stabilnost, tečnost prije kompresije, i/ili svojstva sušenja uz reaktivno jeftini razrjeđivač. To dovodi do velike gustoće supstrata i doprinosi dezinfekciji tijekom granuliranja (gdje se koristi vlažno granuliranje) i stoga poboljšava svojstva tečnosti smjese.
Pripravci iz izuma mogu sadržavati jedan ili više farmaceutski prihvatljivih dezintegrirajućih sredstava kao ekscipijenasa, posebno za formulaciju tablete. Pogodna dezintegrirajuća sredstva uključuju, pojedinačno ili u kombinaciji, razne vrste škroba, uključujući natrijev glikolat škroba (npr. Expotab™ od Pen West), te preželatinizirani kukuruzni škrob (npr. National™ 1551, National™ 1550, te Colocorn™ 1500), gline (npr. Veegum™ HV), celuloze kao što je pročišćena celuloza, mikrokristalna celuloza, metilceluloza, karboksimetilceluloza i natrijeva karboksimetilceluloza, kroskarmeloza i natrijeva karboksimetil celuloza, natrijeva kroskarmeloza (npr. Ac-Di-Sol™ od FMC), alginati, krospovidon i gume kao što je agar, guar, karaja, pektin i tragakant Dezintegrirajuća sredstva mogu biti dodana u bilo kojem pogodnom koraku, posebno prije granuliranja ili tijekom koraka s lubrikantom, a prije prešanja. Takva dezintegriajuća sredstva, ako su prisutna tvore ukupno oko 0.2% do oko 30%, preferirano od oko 0.2% do oko 10%, a još preferiranije od oko 0.2% do oko 5% ukupne mase pripravka.
Natrijeva kroskarmeloza je preferirano dezintegrirajuće sredstvo za tablete ili kapsule, te ako je prisutna tvori oko 0.2% do oko 10%, preferirano od oko 0.2% do oko 7%, a još preferiranije od oko 0.2% do oko 5% ukupne mase pripravka. Natrijeva kroskarmeloza dovodi do izvrsnih dezintegrirajućih svojstava za granulirane pripravke ovog izuma.
Pripavci iz izuma mogu sadržavati jedan ili više od farmaceutski prihvatljivih veziva ili adheziva kao ekscipijensa, posebno za formulaciju tablete. Takva veziva i adhezivi preferirano doprinose koheziji praška koji je tabletiran i dozvoljavaju normalno procesuiranje kao što je usitnjavanje, lubrikacija, prešanje i pakiranje, ali još uvijek dozvoljavaju dezintegraciju tablete i pripravka da se apsorbira tijekom varenja. Pogodna veziva i adhezivi uključuju, pojedinačno ili u kombinaciji, akaciju, tragakant, saharozu, želatinu, glukozu, razne vrste škroba kao što je, ali bez ograničenja na njih, preželatinizirani kukuruzni škrob (npr. National™ 1551, National™ 1550), celuloze kao što je, ali bez ograničenja na njih, metilceluloza i natrijeva karboksimetil celuloza (npr. Tylose™), alginska kiselina i soli alginske kiseline, magnezijev auminijev silikat, polietilenglikol (PEG), guma guar, polisaharidne kiseline, bentoniti, polivinilpirolidon (povidon ili PVP), primjerice povidon K-15, K-30 i K-29/32, polimetilakrilati, hidroksipropilmetilceluloza (HPMC), hidroksipropil celuloza (npr. Klucel™), te etilceluloza (npr. Etocel™). Takva veziva i/ili adhezivi, ako su prisutni, tvore ukupno oko 0.2% do oko 25%, preferirano od oko 0.75% do oko 15%, a još preferiranije od oko 1% do oko 10% ukupne mase pripravka.
Preželatinizirani kukuruzni škrob je preferirano vezivo koje se koristi za dovede do ahezivnih svojstava praškastoj smjesi valdekoksiba i ostalih ekscipijenasa za granuliranje formulacije valdekoksiba. Preželatinizirani kukuruzni škrob ako je prisutan, tvori ukupno od oko 0.5% do oko 20%, preferirano od oko 5% do oko 15% ukupne mase pripravka, te olakšava vezanje čestica u smjesi za tvorbu granule tijekom granuliranja.
Pripravci iz izuma mogu sadržavati jedno ili više farmaceutski prihvatljivih ovlaživača kao ekscipijensa. Takvi ovlaživači su preferirano odabrani tako da održavaju valdekoksib asociran s vodom, za koji uvjet se vjeruje da poboljšava bioraspoloživost pripravka.
Neograničavajući primjeri površinski aktivnih tvari koji se mogu koristiti kao ovlaživači u ovom izumu uključuju kvaterne amonijeve spojeve, primjerice benzalkonijev klorid, benzetionijev klorid i cetilpiridinijev klorid, dioktilni natrijev sulfosukcinat, polioksietil gliceridi masnih kiselina i ulja, primjerice polietilen (8) kaprilska/kaprilna mono i dikliceridi (npr.Labrasol™ ili Gattefossé), polioksietilen (35) ulje kikirikija i polietilen (40) hidrogenirano ulje kikirijkija; polioksietilenski esteri masnih kiselina, primjerice polietilen (40) sterarat, polioksietilnski esteri sorbitana, primjerice polisorbat 20 i polisorbat 80 (npr. Tvveen™ 80 od IĆI), propilenglikoni esteri masnih kiselina, primjerice propilenglikol laurat (npr Lauroglikol™ od Gattefosse), natrijev lauril sulfat, masne kiseline i njihove soli, primjerice oleinska kiselina, natrijev oleat i trietanolamin oleat, glicerilni esteri masnih kiselina, primjerice glicerilni monostearat, esteri sorbitana, primjerice sorbitan monolaureat, sorbitan monooleat, Takvi ovlaživači, ako su prisutni tvore ukupno od oko 0.25% do oko 15%, preferirano od oko 0.4% do oko 10%, a još preferiranije od oko 0.5% do oko 5% ukupne mase pripravka.
Preferirani su ovlaživači sredstva koja su anionska površinski aktivna sredstva. Natrijev lauril sulfat, ako je prisutan tvori oko 0.25% do oko 7%, preferirano od oko 0.4% do oko 4%, a još preferiranije od oko 0.5% do oko 2% ukupne mase pripravka.
Pripravci iz izuma mogu sadržavati jedan ili više od farmaceutski prihvatljivih lubrikanata (uključujući sredstva protiv adhezije i/ili klizna sredstva) kao ekscipijenasa. Pogodni lubrikanti uključuju, pojedinačno ili u kombinaciji, gliceril behapat (npr. Conprito™ 888), stearinsku kiselinu i njene soli, uključujući magnezijev, kalcijev i natrijev stearat, hidrirana biljna ulja (npr. Sterotex™), koloidni silikagel, talk, voskove, bornu kiselinu, natrijev benzoat, natrijev acetat, natrijev fumarat, natrijev korid, DL-leucin, polietilen glikole (npr. Carbowax™4000 i Carbowax™6000), natrijev oleat, natrijev lauril sulfat, te magnezijev lauril sulfat. Takvi lubrikanti ako su prisutni, tvore ukupno od oko 0.1 do 0.251% do oko 5% ukupne mase pripravka.
Magnezijev stearat je preferirani lubrikant, primjerice da smanji mrvljenje uzrokovano strojem, te mrvljenje granulirane smjese tijekom kompresije formulacije za tablete.
Pogodna sredstva protiv adhezije uključuju talk, kukuruzni škrob, DL-leucin, natrijev lauril sulfat i metalne stearate. Talk je preferirano sredstvo protiv adhezije, primjerice da smanji ljepljenje formulacije na površinu opreme i također da smanji statični elektricitet u smjesi. Talk, ako je prisutan tvori oko 0.1% do oko 10%, preferirano od oko 0.25% do oko 5%, a još preferiranije od oko 0.5% do oko 2% ukupne mase pripravka.
Ostali ekscipijensi su boje, okusi i zaslađivači poznati u farmaceutskoj struci i mogu se koristiti u pripravcima iz ovog izuma. Tablete mogu biti presvučana, primjerice presvlakom ili mogu biti nepresvučene. Pripravci iz izuma mogu također sadržavati, sredstva za puferiranje.
Smanjivanje veličine čestica valdekoksiba može dovesti do poboljšane bioraspoloživosti kada se lijek formulira kao pripravak za oralno davanje, a u skladu s ovim izumom. Prema tome, D90 veličine čestica valdekoksiba je manji od 75 μm, preferiranije manji od 40 μm, a najpreferiranije manji od 25 μm. Nadalje ili alternativno, valdekoksib preferirano ima masu prosječne čestice u rasponu od oko 1 μm do oko 10 μm, preferiranije od oko 5 μm do oko7jim. Bilo koje pogodno mljevenje, usitnjavanje ili metoda prevođenja u mikročestice se može koristiti za smanjivanje veličine čestica.
Kapsule i tablete pripravaka iz izuma za trenutačno oslobađanje koje oslobađaju najmanje oko 50%, preferiranije najmanje oko 60%, a najpreferiranije najmanje oko 75% valdekoksiba, mjereni in vitro u standardnom testu raspadanja, a unutar 45 minuta.
Posebno se preferirane kapsule i tablete pripravaka iz izuma koje oslobađaju in vitro najmanje oko 50% valdekoksiba unutar oko 15 minuta, i/ili najmanje 60% valdekoksiba unutar oko 30 minuta.
Mada se pripravci iz izuma mogu prirediti primjerice izravnim kapsuliranjem ili izravnim prešanjem, preferirano se podvrgavaju vlažnom granuliranju prije kapsuliranja ili prešanja. Vlažno granuliranje, među ostalim efektima dezinficira samljeveni pripravak što rezultira u poboljšanim svojstvu vezanom za tečenje, poboljšanoj mogućnosti prešanja i lakšem mjerenju ili disperziji mase pripravka, ta kapsuliranju ili tabletiranju. Sekundarna veličina čestica nastala granuliranjem (npr. veličina granula) je vrlo kritična pa je važno da je prosječna veličina granule takva da dozvoljava konvencionano rukovanje i procesuiranje u slučaju tablete, te da dozvoljava tvorbu smjese koja se lako komprimira i tvori farmaceutski prihvatljive tablete.
Željena gustoća granula, a kad se izlijevaju ili odmjeravaju je normalno od oko 0.3 do oko 1.0 g/mL, primjerice oko 0.6 do oko 0.9 g/mL.
Da bi se tablete pripravile prešanje, granulirana smjesa u količini dovoljnoj da se pripravi jednolična šarža tablete se može podvrći uobičajenom postupku u stroju za tabletiranje pri normalnom tlaku za prešanje (primjerice primjenom sile od oko 1 do oko 50 kN pri tipičnom tabletiranju). Tvrdoća nastale tablete trebala bi biti pogodna za rukovanje, pripravu i skladištenje te se može doprinijeti lakšem gutanju; međutim, minimalna tvrdoća od oko 4 kP, preferirano oko 5 kP, a još preferiranije od 6 kP je poželjna da se izbjegne mrvljenje, a maksimalna tvrdoća od oko 18 kP, preferirano oko 15 kP, a još preferiranije oko 12 kP je poželjna da se izbjegne poteškoća u hidrataciji tablete pri izlaganju želučanim tekućinama. Kada je tvrdoća u prihvatljivom rasponu, mrvljivost tablete je tipično manja od oko 1.0%, preferirano manja od oko 0.8%, a još preferiranije manja od oko 0.5% u standardnom testu.
Ekscipijensi, posebno dezintegrirajuća sredstva za trenutačno oslobađanje pripravaka kapsula i tableta su preferirano odabrani tako da je vrijeme dezintegracije u standardnom in vitro testu manje od oko 30 minuta, preferirano manje od oko 20 minuta, a još preferiranije manja od oko 15 minuta.
Izum je, nadalje, upućen na metode priprave pripravaka koji sadrže usitnjeni valdekoksib. U posebnoj cjelini, izum je upućen na metode priprave takvih pripravaka u obliku tableta. Mada se mogu koristiti metode suhog granuliranja ili izravnog prešanja, ovdje je preferirano vlažno granuliranje. Dvije ilustrativne cjeline vlažnog granuliranja se izvode pri niskoj, odnosno visokoj razini usitnjavanja.
Postupak s niskom razinom usitnjavanja je prikazan na dijagramu na Slici 1. U tom ilustrativnom primjeru usitnjeni valdekoksib je miješan, primjerice mikserom s jednim ili više čvrstih razrjeđivača, npr. laktoza monohidratom (primarni razrjeđivač) i mikrokristalnom celulozom (sekundarni razrjeđivač) i vezivom, preferirano preželatiniziranim kukuruznim škrobom, čime se stvara početna smjesa. Zatim je dodana voda uz kontinuirano miješanje u količini koja potiče stvaranje granula. Granule su zatim sušene, primjerice u sušioniku, te su usitnjene u mlinu uz odgovarajuće praćenje veličine zrna, a da se dobiju dovoljno jednolične granule. One su zatim pomiješane s dezintegrirajućim sredstvom, npr. natrijevom kroskarmelozom i konačno s lubrikantom, npr. magnezijevim stearatom, a čine se dobiva smjesa za tabletiranje. Valja naznačiti da je u tom ilustrativnom postupku, mikrokristalna celuloza dodana intragranularno, a natrijeva kroskarmeloza ekstragranularno. Konačno, smjesa je tabletiranje je prešana, primjerice u rotirajućoj preši čime nastaju tablete. Tablete mogu biti presvučene korištenjem bilo kojeg u struci poznatog pogodnog postupka za presvlačenje.
Postupak s visokom razinom usitnjavanja je prikazan na dijagramu na Slici 2. U tom ilustrativnom procesu je usitnjeni valdekoksib miješan u mikseru s velikom razinom usitnjavanja s primarnim razrjeđivačem, npr. laktoza monohidratom, prvim obrokom sekundarnog razrjeđivača, npr. mikrokristalnom celulozom i vezivom, preferirano preželatiniziranim kukuruznim škrobom, prvim obrokom sredstva za dezintegraciju, npr. natrijevom kroskarmelozom, čime se stvara početna smjesa. Zatim je dodana voda uz kontinuirano miješanje s visokom razinom usitnjavanja, a u količini koja potiče stvaranje granula. Granule se mogu vlažne usitniti, a zatim sušiti, primjerice u fluidnom sušilu. Zatim se može provesti suho usitnjavanjem primjerice u Flitzovom mlinu. Nastale granule se zatim miješaju s drugim obrokom sekundarnog razrjeđivača i drugim obrokom sredstva za dezintegraciju, te konačno s lubrikantom, npr. magnezijevim stearatom, a čine se dobiva smjesa za tabletiranje. Valja naznačiti da su u tom ilustrativnom postupku mikrokristalna celuloza i natrijeva kroskarmeloza dodani intragranularno i ekstragranularno. Konačno, smjesa za tabletiranje je prešana, a tablete se mogu presvući kao i u postupku s niskom razinom usitnjavanja.
Ovaj izum je također upućen na upotrebu pripravaka u ovom izumu za pripravu lijekova korisnih u tretmanu i/ili profilaksi stanja i poremećaja posredovanih COX-2.
PRIMJERI
Sljedeći primjeri ilustriraju aspekte ovo izuma, ali nisu načinjeni kao ograničenja. Osim kad je drugačije napomenuto, svi navedeni postoci u ovim primjerima su maseni zasnovani na masi pripravka.
Primjer 1: Tablete valdekoksiba pripravljene pri niskoj raži n i usitnjavanja Pripravljene tablete imaju sastav prikazan u Tablici 1.
Tablica 1
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Odgovarajuća količina usitnjenog valdekoksiba za šaržu je miješana s istom količinom laktoza monohidrata, prosijano je kroz sito veličine 20 mesh, te je dodano u mikser po Hobartu. U mikser je dodana laktoza monohidrat i mikrokristalna celuloza, koji je zatim radio pri maloj brzini tijekom 10 minuta. Nastala početna smjesa je zatim granulirana u mikseru nakon ručnog dodatka pročišćene vode kroz 12-15 minuta, dok se miješanje nastavljeno pri maloj i srednjoj brzini. Nastale vlažne granule su zatiom sušene u posudama u sušioniku po Gruenbrgu pri temperaturi od 60±5 °C do sadržaja vlage od 2.0±1.0%, mjereno gubitkom pri sušenju. Nastale suhe granule su zatim usitnjene kroz sito 14 korištenjem Quadro mlina pri srednjoj brzini, te su smještene u V-miješalici po Patterson Kelley skupa s natrijevom kroskarmelozom. V-miješalica je radi oko 5 minuta, a do potpunog miješanja natrijeve kroskarmeoze i granula; zatim je dodan magnezijev stearat i miješano je još oko 3 minute, pri čemu je pripravljena smjesa s lubrikantom. Ona je prešana na Manesty DB16 rotacionoj preši korištenjem 7.5 mm standardnog konkavnog kalupa da se postigne masa tablete od 200±10 mg tvrdoće od 10±4kP.
Primjer 2: Tablete valdekoksiba prioravjene ori visokoj razini usitnjavanja
Pripravljene tablete imaju sastav prikazan u Tablici 2.
Tablica 2
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Usitnjenog valdekoksiba, laktoza monohidrat, intragranularna mikrokristalna celuloza, preželatinizirani kukuruzni škrob i intragranularna kroskarmeloza su miješani u mikseru po Baker Perkinsu pri visokoj razini usitnjavanja i pri velikoj brzini noža, a oko 3 minuta da bi se stvorila početna smjesa. Dodana je pročišćena voda u početnu smjesu putem Watson Marlovove peristaltičke pumpe u periodu od oko 3 minuta i miješanje je nastavljeno daljnjih 45 sekundi. Našale vlažne granule su sušene u fluidnom sušilu Aeromatic pri ulaznoj temperaturi od 60±5 °C do sadržaja vlage od 2.0±1.0%, mjereno gubitkom pri sušenju, pri čemu nastaju suhe granule. Suhe granule su zatim prosijane preko sita od 20 mesh korištenjem mlina po Fitzu koji ima noževe prema naprijed, pri 1800 rpm, te su smještene u V-miješalicu po Patterson Kelleyu. Ovdje su granule miješane s ekstragranularnom mikrokristalnom celulozom i ekstragranularnom natrijevom kroskarmelozom kroz 5 minuta, a zatim s magnezijevim stearatom daljnjih 3 minute, da se dobije smjesa s lubrikantom. Ona je prešana pomoću Korsch pH-230 rotacione preše korištenjem 7.5 mm standardnog konkavnog kalupa da se postigne masa tablete od 200±10 mg. Pripravljene su tablete tvrdoće 6, 8, 10i12kP.
Primjer 3: Presvučene tablete valdekoksiba od 5. 10. 20 i 40 mg
Koristeći postupak iz Primjera 2, pripravljene tablete imaju sastav prikazan u Tablici 3. Tablete su film presvučene s Opadry Yellow YS-1-12525A ili Opadry White YS-1-18027A s 3% mase presvučene tablete, korištenjem vodene suspenzije materijala za presvlačenje.
Tablica 3
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Svojstva tableta iz Primjera 3 su prikazana u Tablici 4. Dezintegracija je procijenjena sljedećim postupkom. Šest identičnih tableta je zasebno smješteno u jedan od šest cijevi koji imaju metalno sito na dnu u posudi za dezintegraciju. Vodena kupelj je prethodno ugrijana na 37±2 °C i održavana je pri toj temperaturi tijekom trajanja testa. Čaša od 1000 mL je smještena u kupelj. Čaša je napunjena dovoljnom količinom vode da se osigura da cijev sa sitom na kraju ostane barem 2.5 cm ispod površine vode tijekom testa. Posuda za dezintegraciju je smještena u vodu i spuštana je i podizana tijekom testa tako da je cijev sa sitom barem 2.5 cm ispod površine vode. Vrijeme dezintegracije svake tablete je vrijeme, a mjereno od spuštanja posude u vodu, do vremena u kojem je zadnja porcija tablete prošla kroz sito na kraju cijevi.
Tablica 4
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Primjer 4: Farmakokinetička svojstva tableta valdekoksiba u psima
Istraživanje je provedeno da se odrede farmakokinetička svojstva pripravka valdekoksiba iz Primjera 2, u 23 pasa brakiraca. Valdekoksib je dan pri dozama od 20 mg (2 tablete). Venska krv je sakupljena prije doze, te 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 i 24 sata nakon oralnog davanja. Plazma je odvojena od krvi centrifugiranjem pri 3000 i uzorci su čuvani pri -20 °C do analize.
Koncentracija valdekoksiba u plazmi je određena korištenjem HPLC. Rezultati su prikazani na Slici 3.
Primjer 5: Farmakokinetička svojstva tableta valdekoksiba u ljudima
Istraživanje je provedeno da se odrede farmakokinetička svojstva pripravka valdekoksiba iz Primjera 2, u 24 zdravih ljudi. Valdekoksib je dan pri dozama od 20 mg (2 tablete). Venska krv je sakupljena prije doze, te 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 i 24 sata nakon oralno davanja. Plazma je odvojena od krvi centrifugiranjem pri 3000 i uzorci su čuvano pri -20°C do analize.
Koncentracija valdekoksiba u plazmi je određena korištenjem HPLC. Rezultati su prikazani na Slici 4.
Izračunati Cmax je 303±93 ng/mL. Izračunati Tmax je 2.97±0.73 h.
Claims (14)
1. Farmaceutski pripravak koji sadrži usitnjeni valdekoksib u količini od oko 1 mg do oko 100 mg po dozi i jedan ili više farmaceutski prihvatljivih ekscipijenasa, naznačeno time da je jedinica doze nakon oralnog davanja pacijentu koji posti, dovodi do vremenski ovisne koncentracije valdekoksiba u serumu koja zadovoljava barem jedno od sljedećih:
(a) vrijeme postizanja koncentracije preko praga terapijskog efekta nije veće od oko 0.5 h nakon davanja;
(b) vrijeme postizanja maksimalne koncentracije (Tmax) nije veće od oko 0.5 h nakon davanja; te
(c) maksimalna koncentracija (Cmax) nije manja od oko 100 ng/mL
2. Pripravak iz patentnog zahtjeva 1, naznačeno time da je granična koncentracija za terapijski učinak oko 20 ng/mL.
3. Farmaceutski pripravak iz patentnog zahtjeva 2, naznačeno time da nakon oralnog davanja pacijentu koji posti dovodi do vremenski ovisne koncentracije valdekoksiba u serumu koja zadovoljava barem jedno od sljedećih:
(a) vrijeme postizanja koncentracije preko praga terapijskog efekta nije veće od oko 0.5 h nakon davanja;
(b) vrijeme postizanja maksimalna koncentracija (Tmax) koncentracija nije veće od oko 0.5 h nakon davanja; te
(c) maksimalna koncentracija (Cmax) nije manja od oko 100 ng/mL.
4. Pripravak iz patentnog zahtjeva 1, naznačeno time da je valdekoksib u količini od oko 5 mg do oko 40 mg po dozi.
5. Pripravak iz bilo kojeg patentnog zahtjeva od 1 do 4 koji je tableta, naznačeno time da ekscipijens sadrži jedan ili više razrjeđivača u količini od oko 5% do oko 99%, jedno ili više dezintegrarajućeg sredstva u količini od oko 0.2% do oko30%, jedno ili više veziva u količini od oko 0.5% do oko 25%, te jedan ili više lubrikanata u količini od oko 0.1% do oko 10% mase pripravka.
6. Pripravak iz patentnog zahtjeva 5, naznačeno time da je vezivo preželatinizirani kukuruzni škrob.
7. Pripravak iz bilo kojeg patentnog zahtjeva od 1 do 4 koji je tableta, naznačeno time da ekscipijens jeste laktoza monohidrat, mikrokristalna celuloza, natrijeva kroskarmeloza, preželatinizirani kukuruzni škrob i magnezijev stearat.
8. Pripravak iz patentnog zahtjeva 1, naznačeno time da sadrži jedan ili više opoida ili analgetika.
9. Pripravak iz bilo kojeg patentnog zahtjeva od 1 do 8, naznačeno time da je D90 čestica valdekoksiba manji od oko 75 μm.
10. Pripravak iz bilo kojeg patentnog zahtjeva od 1 do 8, naznačeno time da čestice valdekoksiba prosječne mase imaju veličinu čestice od oko 1 μm do oko 10 μm.
11. Pripravak iz bilo kojeg patentnog zahtjeva od 1 do 8, naznačeno time da čestice valdekoksiba prosječne mase imaju veličinu čestice od oko 10 nm do oko 1000 nm.
12. Metoda priprave pripravka iz bilo kojeg patentnog zahtjeva od 5 do 7, naznačeno time da sadrži korak vlažnog granuliranja valdekoksiba skupa s jednim ili više razrjeđivača i veziva, sušenje nastanih granula i prešanje nastalog granulata u oblik tablete.
13. Metoda tretmana medicinskih stanja ili poremećaja u osobi kojoj je tretman s inhibitorom ciklooksigenaze-2 indiciran, naznačeno time da sadrži oralno davanje osobi pripravka iz bilo kojeg od Patentnih zahtjeva 1 do 12 jedanput ili dvaput na dan.
14. Metoda upotrebe pripravka iz bilo kojeg od Patentnih zahtjeva 1 do 12 naznačeno time da je za proizvodnju lijeka za tretman ili profilaksu poremećaja posredovanih cikooksigenazom-2 kod osobe koja za tim ima potrebu.
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CO (1) | CO5261582A1 (hr) |
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EA (1) | EA003639B1 (hr) |
EE (1) | EE200100414A (hr) |
HK (1) | HK1041637A1 (hr) |
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