Abstract
Poly (?-caprolactone), PCL, is an aliphatic polyester suitable for controlled drug release due to its biodegradability, biocompatibility, non-toxicity and high permeability to many therapeutic drugs. This study investigates the effect of the preparation parameters on the size and the morphology of the PCL microspheres and on the release profile of carbamazepine from these microspheres. The PCL microspheres were prepared using oil-in-water (o/w) emulsion solvent evaporation method with the poly(vinyl alcohol), PVA, as the emulsion stabilizer. The influence of the stirring rate applied during the emulsion formation, the homogenization time and the emulsifier concentration on diameter and size distribution of the microspheres was analyzed by scanning electron microscope (SEM). The initial emulsion was formed applying high stirring rates of 10000, 18000 and 23000 rpm, for homogenization times: 5, 10 and 15 min. The diameter was strongly influenced by the stirring rate, and the average particle size decreased from 9.2 to 2.8 ?m with the increase of the stirring rate. Increasing the amount of PVA in the water phase from 0.2 to 1 mass% improved stabilization of the oil droplets and led to a slight decrease of the average particle diameter. Drug-loaded microspheres were prepared by the same technique using different amounts of carbamazepine (10 and 15 mass%), under given conditions (1 mass% PVA, stirring rate of 18000 rpm for a period of 5 min of emulsion formation). Additionally, microspheres were prepared by applying low stirring rate of 1000 rpm with 10 and 15 mass% of the drug. The SEM analysis showed that microspheres created with 18000 rpm stirring rate, had average diameters of 3-4 ?m, and the microspheres prepared with 1000 rpm stirring rate were larger than 100 ?m. It was also observed that, in the case of the large microspheres, carbamazepine was deposited on their surfaces, while the small microspheres had smooth surfaces without observable drug crystals. The encapsulation efficiency and the release behavior of the carbamazepine were examined using high performance liquid chromatography-ultraviolet spectroscopy (HPLC-UV). The drug encapsulation efficiencies were in the range from 69 to 81%, and were increasing with the increase of the amount of carbamazepine in both series. In vitro release experiments were carried out in the phosphate buffer solution (pH 7) at 37?C. The release rate was influenced by the microspheres size and morphology. The larger microspheres released more carbamazepine (85-95%) compared to the small ones (50-65%) for the same period. This behavior was attributed to the different drug distribution in the PCL matrix. Different mathematical models were used to describe drug release kinetics. It was concluded that the mechanism of the carbamazepine release from the microspheres was diffusion-controlled, independent on the type of microspheres. The kinetic parameters showed that the release of carbamazepine was slower from the smaller microspheres, probably as a result of more even distribution of the drug in the polymer matrix.
Highlights
Eksperiment kontrolisanog otpuštanja leka je rađen na svim uzorcima inkapsuliranih mikrosfera, a da bi se simulirali in vivo uslovi korišćen je neutralni fosfatni pufer na 37 °C
Pri odabranim uslovima (1,0 mas.% PVA, brzina mešanja 18000 o min–1 tokom formiranja emulzije u trajanju od 5 min) izrađene su mikrosfere sa 10 i 15 mas.% leka računato na masu polimera
SEM photographs of PCL microspheres with different drug amount prepared with different stirring rates: a) PCL-10, b) PCL-15, c) PCL-H-10 i d) PCL-H-15
Summary
OPTIMIZACIJA USLOVA DOBIJANJA MIKROSFERA NA BAZI BIODEGRADABILNOG POLI(ε-KAPROLAKTONA) ZA KONTROLISANO OTPUŠTANJE KARBAMAZEPINA. Na veličinu i raspodelu veličina sfera dobijenih metodom otparavanja rastvarača iz emulzije utiču vrsta i koncentracija emulgatora, zapremina i koncentracija rastvora polimera, brzina mešanja i dužina homogenizovanja tokom formiranja emulzije [16,17,18,19,20]. Uticaj dužine trajanja homogenizovanja, pri formiranju emulzije u homogenizatoru pod pritiskom, na veličinu i raspodelu veličina nanosfera izrađenih korišćenjem dva biorazgradiva polimera poli(D,L-laktid-co-glikolne kiseline) 50/50 i poli(ε-kaprolaktona). Mikrosfere su dobijene emulzionim postupkom uz otparavanje rastvarača, pri čemu je u koraku dobijanja emulzije korišćen homogenizator velike snage koji može razviti brzine mešanja u opsegu od 10000 do 23000 o min–1. Ispitivano je kako brzina mešanja tokom formiranja emulzije homogenizatorom velike snage, dužina trajanja mešanja velikim brzinama pri formiranju emulzije i koncentracija emulgatora, PVA, utiču na veličinu i raspodelu veličina čestica. Za odabrane procesne parametre u mikrosfere je inkapsuliran karbamazepin i određivana je efikasnost inkapsulacije, kao i profil otpuštanja leka
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