Investigation the influence of formulation factors on the carbamazepine released rate and swelling and erosion kinetics of hydrophilic extrudates

Abstract

Hot-melt extrusion has been widely used during last decade in the development formulation with poorly soluble drugs, as well as, modified released formulation. Numerous factors can influence on the drug released rate from prepared extrudates. The aim of this study is to investigate the influence of the polyethylene oxide (PEO) polymers molecular weight and proportion, proportion of carbamazepine and extrudates length on carbamazepine dissolution rate and extrudates swelling and erosion kinetics. Extrudates contained carbamazepine (5-25%), Poloxamer 407 (15-25%) and 50-80% of one of the different polyethylene oxide polymers PEO WSR (N60K, Coagulant, 301 i 303). Polymers of molecular mass 2-7x106 were used. Dissolution testing for the hot-melt extrudates was performed during 8 hours. Carbamazepine released rate is decreased with increasing molecular weight and proportion of polymer and increasing proportion of carbamazepine. Extrudates length doesn't affect carbamazepine dissolution rate significantly. Analyzing the processes of swelling and erosion it was concluded that formulations with PEO of higher molecular weight exhibit slower swelling swell and lower degree of erosion, that all cause decrease of carbamazepine dissolution rate. Carbamazepine is released from hydrophilic matrix systems by the combination of diffusion and erosion processes, with higher contribution of the diffusion process.

Primena ekstruzije topljenjem u farmaceutskoj industriji je u poslednjoj deceniji usmerena na razvoj formulacija sa teško rastvorljivim lekovitim supstancama, kao i na razvoj formulacija sa modifikovanim oslobađanjem lekovite supstance. Veliki broj faktora može uticati na brzinu oslobađanja leka iz dobijenih ekstrudata. Cilj rada predstavlja ispitivanje uticaja molekulske mase i udela polietilenoksidnih polimera (PEO), udela lekovite supstance i dužine ekstrudata na brzinu rastvaranja karbamazepina, kinetiku bubrenja i erozije ekstrudata, izrađenih postupkom ekstruzije topljenjem. Ekstrudati su sadržali karbamazepin (5-25%), Poloxamer 407 (15-25%) i 50-80% jednog od različitih polietilen oksidnih polimera PEO WSR (N60K, Coagulant, 301 i 303). Korišćeni su polimeri molekulskih masa 2-7x106. Brzina rastvaranja karbamazepina iz pripremljenih ekstrudata praćena je u toku 8 h. Brzina oslobađanja karbamazepina se smanjuje sa povećanjem molekulske mase polimera, i udela polimera, kao i povećanjem udela karbamazepina. Dužina ekstrudata ne utiče značajno na brzinu rastvaranja karbamazepina. Analizom procesa bubrenja i erozije utvrđeno je da formulacije sa polimerima veće molekulske mase sporije bubre i pokazuju manji stepen erozije, što sve zajedno dovodi do smanjenja brzine rastvaranja karbamazepina. Karbamazepin se iz hidrofilnog matriksa oslobađa kombinacijom procesa difuzije i erozije, pri čemu je doprinos procesa difuzije značajniji.