Drug distribution within poly(ɛ-caprolactone) microspheres and in vitro release

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Abstract

Poly(ɛ-caprolactone) (PCL) microspheres loaded two model compounds (p-nitroaniline and rhodamine B) with different water solubilities were prepared by an s/o/w single emulsion solvent evaporation method. The microspheres morphology was investigated by scanning electron microscopy, drug loading and encapsulation efficiency were calculated. Drug distribution within microsphere matrix was studied by confocal laser scanning microscopy. p-Nitroaniline, as a more hydrophobic compound, distributed more evenly in the matrix, while the more hydrophilic compound rhodamine distributed close to the surfaces of microspheres. The in vitro release profiles therefore were different. This study helps to further understand the drug release mechanism from microsphere matrix, and design effective long-term drug delivery system.

Introduction

Biodegradable polymer microspheres are widely studied because of their nontoxic property and biodegradability. Among these polymers, poly(lactic acid), poly(glycolic acid), especially their copolymer—poly(lactic-co-glycolic acid) (PLGA) have been investigated extensively as drug delivery system (Chandy et al., 2002, Shi et al., 2003, Fu et al., 2005), But their acidic degradation products and possibility of initiating inflammatory limit their developments.

Poly(ɛ-caprolactone) (PCL), as one of the most popular synthetic polymers, has been researched as biodegradable carrier for controlled drug release (Dhanaraju et al., 2006, Lim et al., 1998, Barbato et al., 2001). PCL is suitable for controlled drug release because of its high permeability to many drugs and biocompatibility in physiological environments (Murthy, 1997). Preparation methods of microspheres were primarily determined by the solubility of the drug and the polymer in various solvent systems, such as: single emulsion solvent evaporation (Perez et al., 2000), double emulsion solvent evaporation (Dhanaraju et al., 2006, Cleek et al., 1997) or spray drying technique (Chu et al., 2006) and so on. Among these techniques, s/o/w emulsion solvent evaporation method is a convenient and effective technique to incorporate water-soluble or water-insoluble drugs into polymer microspheres (Shi et al., 2003, Xue and Shi, 2004).

Degradation of PCL is very slow comparing many other polymers (Pitt, 1990). Mechanism of drug release from PCL microspheres is often dominated by drug diffusion from microsphere matrix, which makes PCL microspheres suitable for long-term drug release system (Sinha et al., 2004). Drug distribution within polymer microspheres has very important influence on drug diffusion rate from polymer matrix. Drug molecules close to the surface of microspheres are prone to diffuse from matrix faster. Drug distribution depends on the “compatibility” between drugs and polymers (Shi et al., 2003, Berkland et al., 2004, Pack and Pollauf, 2006). In this paper, we choose two model compounds, p-nitroaniline and rhodamine B, with varying water solubility to investigate the influences of drug contribution on drug release mechanism. These studies provide references to design long-term and sustained release drug delivery system.

Section snippets

Materials

PCL (MW 10,000) was purchased from Sigma–Aldrich. p-Nitroaniline and rhodamine B was purchase from Sigma. All other chemicals used were of analytical grade.

Preparation of microspheres

PCL microspheres were fabricated using a modified s/o/w single emulsion solvent evaporation method (Xue and Shi, 2004). Briefly, 10 ml of solutions of 20% w/v PCL in DCM containing various amounts of p-nitroaniline or rhodamine B were mixed with the aid of ball-milling. The mixtures were then pour into 300 ml of 0.2% w/v methylcellulose and

Morphology of microspheres

The microspheres prepared by a single emulsion solvent evaporation technique showed good sphericity (Fig. 2). The micrographs showed smooth surface and no pores on the surface of the microspheres with lower drug loading. While with higher drug loading, the microspheres like b and c had rougher surface morphology. The preparation condition such as drug polymer ratio, stirring speed and emulsifier concentration did not affect the surface morphology.

Although the microspheres had the same initial

Discussion

Polymer microspheres are becoming an attractive drug delivery system because of their biodegradability, facile administration and sustained release over a long-term period. For researchers, it is important to know the mechanisms affecting drug release kinetic. In this paper, we prepared model drug loaded microspheres with various drug loading and encapsulation efficiency, to learn different factors, especially drug distribution, influencing drug release kinetic.

Drug solubility in water

Conclusions

Two model drug loaded PCL microspheres with various drug loading and encapsulation efficiency were prepared. Drug solubility in water affected drug distribution within the polymer matrix. Water-insoluble drugs distribute more evenly in microspheres, while relatively higher water-soluble drugs distribution was mostly near the surface. Drugs near surface were the reason for initial burst, and led to releasing fast.

Selection of appropriate conditions can enable the preparation of a long-term drug

Acknowledgements

This work was supported by the National Nature Science Foundation of China (59932050, 50572029 and 50472054) and the Foundation of the State Key Developing Plan for Fundamental Research (973 Plan) of China (2005CB623902), Natural Science Foundation Cooperative Project Grant of Guangdong (04205786).

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