Modulation of rifampicin release from spray-dried microspheres using combinations of poly-(DL-lactide)

Microspheres containing 20% w/w rifampicin (RIF) with smooth morphology hav e been readily prepared from combinations of low, R104 (Mw, 2000) and moder ate, R202W (Mw, 9000), molecular weight poly(D,L-lactide) (PDLLA) as a mean s to modulate drug release from either polymer when used alone. These have been characterized with respect to their drug loading, granulometry, in vit ro drug release and thermal behaviour. Particle size distributions were Gau ssian, whereby mean microsphere diameter was found to increase from 2.11 to 2.98 mu m as the proportion of more viscous R202H increased, whilst >95% o f particles were <10 mu m, irrespective of the polymer blend used. Use of a reduced inlet temperature for spray-drying gave uncharacteristically high production yields in the range of 55.8-80.7% for the process. Encapsulation efficiencies were quantitative with the weight proportion of drug co-disso lved (p < 0.05), yielding microspheres of high and predictable RIF loading. In vitro drug release revealed a dramatic shift in release profile between 40 and 60% R104. Closer examination in this range showed the predicted pat tern of increased release rate as the fraction of more hydrophilic R104 inc reased. However, disproportionate differences a ere evident between 44 and 48% R104. From the apparent temperature dependent drug release, the critica lity of matrix composition was attributed to the coincidence of matrix soft ening with the dissolution medium temperature and consequent hydration, whi ch, at a finite composition, resulted in a controlled auto-hydration mechan ism. Dramatic dependence of release rate with dissolution methodology was a ccountable to the fact that drug release was considerably quicker where mic rospheres remained suspended and individualized with the USP paddle method as opposed to aggregated with the shaking bath methodology. In conclusion, the utility of blending racemic PDLLA to modulate drug release and the conv enience of spray-drying as a technique to produce microspheres of predictab le character have been demonstrated. The temperature-dependent release exhi bited may have application in the site-specific delivery of drugs where loc al increased biochemical activity promotes drug release in response to an i ncreased pharmacological need.