Optimization of preparation conditions of poly(ε-caprolactone) microspheres for controlled release of carbamazepine
Authors: Pepic Dragana , Andjelkovic Darinka , Nikolic Marija , Grujic Svetlana , Djonlagic Jasna 
Published: November 2010

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.