Synthesis and characterisation of poly(acrylic acid) microspheres containing β-cyclodextrin

xviii, 160 leaves :ill. ; 30 cm. Includes bibliographical references. "February 1999"Purpose. The therapeutic benefit of a number of drugs administered in traditional dosage forms is sometimes limited by physiological barriers, undesirable physicochemical drug properties or issues of drug toxicity. In such cases the development of drug delivery systems that produce a modified in vivo drug release is a common research aim. By manipulating the release of drug from its dosage form such restrictions may be overcome and an improvement in therapeutic effect observed. In this study a water-in-oil solvent evaporation technique for the preparation of microspheres composed of β-cyclodextrin and a hydrophilic polymer, poly(acrylic acid), was developed. Following characterisation, these microspheres were investigated for their potential to act as controlled drug delivery systems. Methods. The effect of homogenisation speed (used in the preparation of the emulsion), phase volume ratio and cyclodextrin-polymer load on particle size of microspheres produced by an emulsion solvent evaporation technique was investigated in a replicated full factorial design. Microspheres were sized by light microscopy and the volume number mean determined. Using selected conditions, a series of microspheres were prepared using poly(acrylic acid) of two different weight average molecular weights (90 000 and 450 000 M w) and a range of β-cyclodextrin concentrations. In addition, microspheres containing maltose and polymer alone were also prepared for comparison. Following synthesis microspheres were characterised for morphology, β-cyclodextrin / maltose, free carboxylic acid and residual oleic acid content. The type of matrix formed during microsphere synthesis was also investigated by a number of analytical techniques including solid state carbon NMR, in vitro release of β-cyclodextrin and swelling measurements. Two dyes, phenolphthalein and rhodamine B, were selected. as model agents for microsphere loading and in vitro release studies. Microspheres composed of the 90 000 Mw poly(acrylic acid) and containing 0, 20 or 50 % w/w maltose or β-cyclodextrin were used. Loading of microspheres was achieved by soaking each microsphere type in a saturated propan-2-o1 solution of the appropriate dye for 6 h. The in vitro release of phenolphthalein or rhodamine B from these microspheres was then determined in phosphate buffer (pH 7.4, 37°C). Results. Microspheres were smooth and spherical when viewed by light and scanning electron microscope. Particle size ranged from 16 to 150 μm, depending on the production variables employed. Using selected conditions, microspheres were produced with a particle size between 20 and 30 urn, For those microspheres prepared with β-cyclodextrin / maltose, a high efficiency of encapsulation of the carbohydrate was observed (> 80 %). All microspheres hydrated rapidly and formed aggregates when dispersed in water (in comparison with physical mixtures of the unreacted microsphere components which readily dissolved). The in vitro release of β-cyclodextrin in water over 24 h was initially rapid (70 % in 3 h) but no further release was noted thereafter, suggesting a potential covalent binding of the residual β-cyclodextrin. NMR studies showed that in the presence of β-cyclodextrin two concomitant chemical processes occurred during microsphere synthesis: i.) esterification of the hydroxyl group(s) of the β-cyclodextrin with the carboxylic acid groups of the poly(acrylic acid) and, ii.) formation of intra- / inter- polymer acid anhydrides. Total dye content following loading was less than 0.5 % w/w in all cases. For both dyes, initial release was rapid with greater than 75 % release into the buffer medium after 30 min and a near complete release of dye being observed within 1 h. No differences in the release profile of either dye was noted between the different microsphere types. That is, neither the incorporation of β-cyclodextrin nor maltose at 0, 20 or 50 % w/w concentration had any appreciable effect on dye release. Conclusions. Microspheres containing poly(acrylic acid) with and without carbohydrate (β-CD / maltose) can be prepared using an emulsion solvent evaporation technique. It appears likely that encapsulated carbohydrate is both physically mixed and covalently bound within the polymer matrix. In addition, acid anhydrides within or between the polymer chains are formed during synthesis. Post-synthesis loading of microspheres was possible using saturated organic solutions, however dye load was poor, being less than 0.5 % w/w in all cases. Microspheres containing poly(acrylic acid) and β-CD or maltose in a range of concentration failed to modify the in vitro release kinetics of two model drugs, phenolphthalein and rhodamine B, compared to microspheres synthesised from polymer alone