GELATIN MICROSPHERES FOR THE CONTROLLED RELEASE OF ANTICANCER DRUGS: COLCHICINE RELEASE

摘要

In recent years, there has been an increasing interest in developing drug delivery systems suitable for cancer therapy. Gelatin is a non- toxic, and biodegradable natural polymeric material with low antigenicity. It has been commonly used for microencapsulation and microspheres as a carrier matrix of drugs. In this study, gelatin microspheres (GMs) of various gelatin contents (15%, 10% and 5% (w/v) were prepared by crosslinking with glutaraldehyde (GTA) at different concentrations (5%, 0.5% and % 0.1% (v/v). Microspheres of gelatin were prepared under different conditions using (w/o) emulsion and the influence of preparation parameters on microsphere production and recovery, particle size and morphology, drug entrapment and other chemico-physical characteristics were investigated. In general, particle size analysis of microspheres showed that as the concentration of gelatin was decreased, the mean particle diameter was also decreasing. This is due to a change in the viscosity of gelatin solution. At higher viscosities, large particles with rough surfaces were formed. In fact, scanning electron photomicrographs indicated that, when the concentration of gelatin was decreased microspheres having better surface characteristics were obtained. On the other hand, increase in the GTA concentration produced the reverse effect. Since the addition of GTA to the aqueous gelatin phase produced the crosslinking between the protein chains, the matrix became stronger. Therefore, the addition of a crosslinker leads to the reduction of size of the gelatin droplets during the emulsification step. In order to find evidence of GTA mediated crosslinking, FTIR and DSC experiments were performed. In the IR spectrum of native gelatin microspheres, two main absorption bands can be considered: the N-H and the C=O stretching bands, respectively, located at 3300 and 1650 cm~(-1). Moreover, gelatin showed a multi-peak absorption pattern typical of the protein backbone between 1540 and 1650 cm~(-1). In the spectra of glutaraldehyde crosslinked GMs, an additional absorption band located at 1450 cm~(-1) was observed. This peak was characteristic of an aldimine stretching vibration which provides further evidence of crosslinking of gelatin. In addition, it was found that concentration of gelatin and GTA influenced the encapsulation efficiency and release properties of the microparticles. As the concentration of gelatin was increased, the encapsulation efficiency and loading were increased respectively. Colchicine, COLC, a model antimitotic drug which is known to be effective against many of the antineoplastic diseases, was loaded in the GM and the in vitro drug release was carried out in phosphate buffer (0.01 M, pH 7.4) at 37℃. Rapid colchicine release (about 83% of COLC release in the first 92 hrs) was observed for lightly crosslinked microspheres whereas a particular slower release profile was obtained for the highly crosslinked ones (only 38.5 % of COLC release in 92 hrs). In general, two phases of drug release from the gelatin microspheres was observed for colchicine: an initial period of rapid release (i.e reaching about 40 % in 12 hrs for lightly crosslinked GM; about 25% in 8 hrs for highly crosslinked GM) which is due to the release of drug dispersed in the peripheral domains of the microsphere matrix and a following period during which the release continued to be approximately linear with respect to time.