Polimerne mješavine obložene Eudragitom: Potencijalni sustav za kontroliranu peroralnu isporuku teofilina

Abstract

Sustained release (SR) dosage forms enable prolonged and continuous deposition of the drug in the gastrointestinal (GI) tract and improve the bioavailability of medications characterized by a narrow absorption window. In this study, a new strategy is proposed for the development of SR dosage forms for theophylline (TPH). Design of the delivery system was based on a sustained release formulation, with a modified coating technique and swelling features aimed to extend the release time of the drug. Different polymers, such as Carbopol 71G (CP), sodium carboxymethylcellulose (SCMC), ethylcellulose (EC) and their combinations were tried. Prepared matrix tablets were coated with a 5 % (m/m) dispersion of Eudragit (EUD) in order to get the desired sustained release profile over a period of 24 h. Various formulations were evaluated for drug concentration and in vitro drug release. It was found that the in vitro drug release rate decreased with increasing the amount of polymer. Coating with EUD resulted in a significant lag phase in the first two hours of dissolution in the acidic pH of simulated gastric fluid (SGF) due to decreased water uptake, and hence decreased driving force for drug release. Release became faster in the alkaline pH of simulated intestinal fluid (SIF) owing to increased solubility of both the coating and matrixing agents. The optimized formulation was subjected to in vivo studies in rabbits and the pharmacokinetic parameters of developed formulations were compared with the commercial (Asmanyl®) formulation. Asmanyl® tablets showed faster absorption (tmax 4.0 h) compared to the TPH formulation, showing a tmax value of 8.0 h. The cmax and AUC values of TPH formulation were significantly (p < 0.05) higher than those for Asmanyl®, revealing relative bioavailability of about 136.93 %. Our study demonstrated the potential usefulness of eudraginated polymers for the oral delivery of the sparingly soluble drug theophylline.Pripravci za produljeno oslobađanje (SR) omogućavaju produljeno i kontinuirano oslobađanje lijeka u gastrointestinalnom (GI) traktu i poboljšavaju bioraspoloživost lijekova s uskim apsorpcijskim prozorom. U radu se predlaže nova strategija za razvoj formulacija s produljenim oslobađanjem teofilina (TPH), koja se temelji na sustavu za produljeno oslobađanje, kojem je u svrhu produljenja vremena oslobađanja modificiran način oblaganja i bubrenja. Korišteni su različiti polimeri, kao što su Carbopol 71G (CP), natrijeva karboksimetilceluloza (SCMC), etilceluloza (EC) i njihove kombinacije. Pripravljene matriks tablete obložene su 5-postotnom (m/m) disperzijom Eudragita (EUD) kako bi se postiglo produljeno oslobađanje tijekom 24 h. U pripravljenim formulacijama određena je koncentracija lijeka i in vitro oslobađanje. Rezultati pokazuju da se povećanjem udjela polimera smanjuje brzina oslobađanja in vitro. Oblaganje s EUD značajno je produljilo lag fazu tijekom prva 2 sata otapanja u kiselom pH simuliranog želučanog soka (SGF). Naime, oblaganje usporava ulazak vode i tako smanjuje pogonsku silu za oslobađanje lijeka. Zbog povećane topljivosti obložnog sloja i matriksa u lužnatom mediju, oslobađanje u simuliranoj intestinalnoj tekućini (SIF) je brže. Optimizirana formulacija ispitana je in vivo na zečevima. Farmakokinetički parametri novih formulacija uspoređivani su s komercijalnim pripravkom Asmanyl®. Asmanyl® tablete pokazuju bržu apsorpciju (tmax 4,0 h) u odnosu na TPH formulaciju (tmax 8,0 h). cmax i AUC vrijednosti TPH formulacije bile su značajno (p < 0,05) više od onih za Asmanyl®, što ukazuje na relativnu bioraspoloživost od oko 136,93 %. Stoga smatramo da su polimeri obloženi eudragitom potencijalno korisni za oralnu upotrebu teško topljivog lijeka teofilina