(493e) Membrane Emulsification for Polyd,L-Lactide-Co-Glycolide Acid Microparticle Production: Influencing Factors

A vibrant field in the pharmaceutical and health care industries is controlled release drug particles. Particles capable of gradually releasing the encapsulated drug are of great interest since they improve the effectiveness of the treatment and the patient compliance. One of the most suitable polymers to produce these particles is PLGA, poly(lactic-glycolic acid). PLGA is a highly biocompatible polymer, it degrades in vivo to lactic (C3H6O3) and glycolic (C2H4O3) acids which are subsequently eliminated as CO2 and H2O via the Krebs cycle. PLGA has been approved by the Food and Drug Administration and it has been used for suture, dental repairs and bone replacement surgery for a long time. It is widely commercially available and the degradation can be controlled. It can entrap the drug either by a matrix encapsulation, where the phase is dispersed through the porous inner morphology of the solid particle or, alternatively in a hollow core-shell encapsulation. In producing particles for controlled drug release, particle size and particle size distribution are a major issue. Size is important to target the desired treatment area. Manufacturing monomodal distributions avoids sieving, hence waste of valuable material, and allows a higher control of release, reducing side effects due to overdose. Membrane emulsification is known to produce very monosized droplets and it is easy to tailor the droplet size. Mild production conditions make membrane emulsification a suitable method for working with perishable drugs. In this work, the production of PLGA particles encapsulating a water-soluble model drug is presented. The particles are produced by double emulsification followed by solvent evaporation, hence the particle size and size distribution is tightly linked to the droplet size and size distribution of the second emulsification.

Emulsification and Particle Production

The emulsification method is a non-crossflow membrane emulsification. The emulsion was obtained by injecting the discontinuous phase through a plate membrane with a regular array of pores into the continuous phase, agitated by a two-bladed paddle governed by a motor in a stirred cell. Studies with a model system were previously conducted in order to study the innovative production method. The operating conditions that can be varied to customize the emulsion are many and they were all studied: injection rate of the discontinuous phase, agitation speed of the continuous phase, membrane pore size, pore spacing, membrane coatings and phase physical properties. A model was successfully developed predicting the droplet size with or without applied shear. When producing PLGA particles, a PLGA and DCM (dichloromethane) solution was the organic phase, water, salt (NaCl) and blue dextran (model drug) was the inner water phase and water saturated in DCM, PVA (polyvinyl alcohol) and salt was the outer water phase. Operating conditions were set in order to obtain final particle diameter of 50 and 100 microns (suitable size ranges for subcutaneous depot). Discontinuous phase viscosity and optimized membrane working area led to a narrow size distribution. Different solidification methods were tried in order to maintain the narrow size distribution and the spherical shape obtained during the emulsification phase. Effect of salt and PLGA concentration on inner porosity and particle shrinkage were studied. Typical span value, an index of the particle size distribution spread, are between 0.3 and 0.5 with a best result of 0.29.

Encapsulation Efficiency and Drug Release

Once the particles were obtained, they were analysed in order to obtain the encapsulation efficiency, then they went through drug release studies. Encapsulation efficiency of less than 100% may be due to two effects: disruption of the primary W/O emulsion which is being emulsified into a W/O/W emulsion, and by the leaching out of material from the inner aqueous phase after the encapsulated particles have been formed. Effect of different salt concentration in the outer water phase, particle size and PLGA concentration on the encapsulation efficiency has been studied.

Conclusions

PLGA particles for encapsulation of controlled release drug can be successfully produced by the novel membrane emulsification method presented. The size can be tailored and the particles are very monosized. The encapsulation efficiency can be as high as 100%, this means that the droplets-particles are not disrupted during the production. Operating conditions can be varied in order to obtain the desired target size and a model has been proposed to predict the droplet size.