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This study was carried out with the aim to optimize the pharmacological profile of gliquidone (GLI)--a poorly bioavailable hypoglycaemic agent sparingly soluble in water--through complexation with cyclodextrins. In order to increase the apparent solubility of GLI, two cyclodextrins, namely beta-cyclodextrin (betaCD) and hydroxypropyl-beta-cyclodextrin (HPbetaCD), were tested. The effect of cyclodextrin addition on the aqueous solubility of GLI was evaluated by the phase solubility method at different pH values. The amount of GLI in solution increased upon CD addition according to A type plots. The aqueous solubility of GLI was enhanced more at higher pH values and using HPbetaCD. On the basis of its performance, HPbetaCD was selected as host to prepare GLI oral formulations. GLI/HPbetaCD solid systems were prepared at 1:2 molar ratio by co-grinding, spray-drying and freeze-drying and characterized by DSC, FTIR and X-ray powder diffractometry. Powders were amorphous and showed an improved dissolution rate in comparison with GLI. GLI/HPbetaCD co-ground and freeze-dried products were the most interesting systems, since they dissolved 62 and 94% of total drug after 15 min, respectively. The hypoglycaemic effect of the most rapidly dissolving binary systems was evaluated after oral administration in fasted rats by measuring plasma glucose level in the time interval 0.5-36 h and compared to free GLI. Our findings indicate that cyclodextrin-containing formulations not only provide an onset of hypoglycaemic effect faster than GLI, but also enhance significantly the pharmacological effect due to improved biopharmaceutics. The association GLI/HPbetaCD allows a reduction of the oral dose and is expected to provide a better control over drug side effects, contributing to improve safety and efficacy of GLI.

The aim of this work was to produce insulin-loaded microspheres allowing the preservation of peptide stability during both particle processing and insulin release. Our strategy was to combine the concepts of using surfactants to improve insulin stability while optimising overall microsphere characteristics such as size, morphology, peptide loading and release. Bovine insulin was encapsulated within poly(lactide-co-glycolide) (PLGA 50:50, Resomer RG504H) microspheres by the multiple emulsion-solvent evaporation technique. Microspheres were prepared by adding to the primary emulsion three non-ionic surfactants, poloxamer 188, polysorbate 20 and sorbitan monooleate 80, at different concentrations (1.5 and 3. 0% w/v). The presence of surfactants was found to decrease the mean diameter and to affect the morphology of the microspheres. Insulin encapsulation efficiency was reduced in the presence of surfactants and especially for sorbitan monooleate 80, in a concentration-dependent mode. The influence of the surfactants on the interactions between insulin and PLGA together with the primary emulsion stability were found to be the major determinants of insulin encapsulation. The release of insulin from microspheres was biphasic, showing an initial burst effect followed by a near zero-order release for all the batches prepared. The initial burst was related to the presence of insulin molecules located onto or near to the microsphere surface. In the presence of surfactants, a faster insulin release with respect to microspheres encapsulating insulin alone was observed. Insulin stability within microspheres after processing, storage and release was evaluated by reversed phase- and size-exclusion-HPLC. The analysis of microsphere content after processing and 6 months of storage showed that insulin did not undergo any chemical modification within microspheres. On the contrary, during the period of sustained release insulin was transformed in a high-molecular weight product, the amount of which was related to the surfactant used. In conclusion, polysorbate 20 at 3% w/v concentration was the most effective in giving regular shaped particles with both good insulin loading and slow release, and limiting insulin modification within microspheres.