Subcutaneously injected polymeric dosage forms have been used successfully to achieve sustained release of various drugs and peptides. A complex interplay of factors affect drug release rates from such dosage forms, such as nature of dosage form, drug and polymer properties, formulation variables etc. making the prediction of release characteristics challenging. In this thesis, the effect of drug lipophilicity on absorption rates from PLGA microspheres and in situ-forming depots was investigated.
The beta-blockers were chosen as model drug compounds, being a homologous group of drugs having similar molecular weights and pKa values, yet widely differing lipophilicities. Alprenolol, metoprolol and atenolol were selected to represent the series based on their experimentally determined octanol-buffer partition coefficients.
The first part of the study focused on formulation and characterisation of beta-blocker loaded microspheres with suitable in vitro release profiles. Microspheres were prepared by spray drying, and characterised in terms of particle size, surface morphology, drug loading and release. The beta-blockers represented a considerable challenge owing to their surface-active nature and tendency to suffer a large burst release from microspheres. Efforts were therefore directed towards modifying the formulation to improve the drug release profiles, including emulsion spray drying, addition of competing surfactants and hydrophobic ion pairing. The latter was successful in reducing burst and prolonging release, and microspheres were deemed suitable for in vivo investigation. In situ-forming depot preparations were also formulated with the aim of comparing release profiles and tissue compatibility with the preformed microspheres.
Following initial experiments to ascertain intravenous clearance kinetics, the polymeric dosage forms were injected subcutaneously in rats. Drug plasma concentrations were analysed and absorption profiles were determined by deconvolution. It was found that the nature of the dosage form had a significantly greater impact on the rate and extent of absorption than the lipophilicity of the encapsulated drugs
