(139h) Study of PLA Particle Formation by Supercritical Fluid Technology for Oral Release of Active Agents

Increasing development of techniques to improve the bioavailability of various drugs and to reduce their dosage has been noticed recently, particularly approaches associating the drugs with different types of devices for controlled release. In this context, biodegradable polymers have received special attention due to their possible applications in the pharmaceutical, medical and biomedical engineering areas. Particulate systems based on PLA are already being used successfully for the release of active agents mostly intravenously, due to their high stability, which allows the release of the desired compound for extended periods. The successful use of such devices for intravenous drug delivery suggests that adopting similar strategies to administer drugs orally can be of interest, with the advantage of using a less invasive route. Among the techniques that may be employed to obtain PLA particles are the ones based on polymer precipitation through supercritical fluid technology, such as the method known as Supercritical Anti-Solvent (SAS). In the present work a statistically experimental design study was performed to analyze in detail the influence of pressure (8 to 16 MPa), concentration of PLA dissolved in dichloromethane (0.5 to 1.5 % w/v), and injection flow of polymer solution in the system (0.5 to 2.5 mL/min) on particles characteristics. It is noteworthy that the combination of flow reduction with increasing concentration of polymer solution resulted in the production of particles with smaller diameters (20 to 5um), since this condition favored increased solvent extraction combined with higher nucleation rates. The degree of crystallinity measured by X ray diffraction (XRD) and the thermal behavior evaluated by differential scanning calorimetry (DSC) of particles obtained in all tested conditions showed no change in comparison to the pure polymer. Regardless of the process operating conditions, strong tendency of particle aggregation was noticed, what was confirmed by zeta potential analysis, which showed low values (> ±5 mV) in the presence of aqueous solutions at different pH values (2.0, 4.5, 7.4 and 9.0). In general, particle morphology, size distribution, stability, thermal behavior and degree of crystallinity were not significantly affected by the distinct operational conditions tested. However, the residual amount of dichloromethane was lower (below 600 ppm) in particles prepared at high polymer concentration and low solution flow rate.