The mechanism of PLA microparticle formation by waterin-oil-in-water solvent evaporation method

Abstract

Microparticles containing ovalbumin as a model protein drug were prepared using poly(L-lactide; PLA) with a water-in-oil-in-water emulsion/solvent evaporation technique. The dispersed phase was PLA dissolved in dichloromethane (DCM), and the continuous phase was water-containing polyvinyl pyrolidone (PVP) as stabilizer with sodium chloride. Microparticle characteristics, loading efficiencies, protein distribution in microparticles, and in-vitro release properties were investigated. The OVA leaking into the continuous phase during the formation of microparticle by DCM evaporation was also evaluated. Results show that OVA was successfully entrapped in the microparticles with trapping efficiencies up to 72%, loading level 8.7% w/v, and particle size 14 microm. The semi-solid suspension changes to a solid particle happened during a 10-min period. Total protein-leaking amount was reduced after addition of NaCl in the continuous aqueous phase, which resulted from reducing the solidification time and protein-leaking rate. Using 5% w/v NaCl in the continuous phase resulted in higher loading content (87.2 +/- 1.0 microg/mg), and loading efficiency (72.2%), which resulted from more protein in the deeper layer (50.2 +/- 2.3 microg/mg) and higher microparticle yield (75.2%) than without NaCl (loading content: 74.0 +/- 1.0 microg/mg; loading efficiency 51.8%; deeper layer content: 18.3 +/- 3.5 microg/mg; yield: 63.6%). These results constitute a step forward in the improvement of existing technology in controlling protein encapsulation and delivery from microparticles prepared by the multiple emulsion solvent evaporation method.

Critical attributes of formulation and of elaboration process of PLGA-protein microparticles

“…These results are in accordance with the literature (Chen et al, 2002;Dorati et al, 2008Dorati et al, , 2005Jiang et al, 2002) where the addition of NaCl to the aqueous phase is claimed to lead to an increase in the osmotic pressure preventing thereby protein diffusion to this external aqueous phase and consequently increasing both encapsulation efficiency and protein loading. According to Chen et al (2002), the inner structure of microparticles prepared using NaCl was very dense and compact regardless of the physical-chemical properties of the polymer used. Such structural feature limits the permeation of protein molecules across the polymeric chains during the solidification process (Dorati et al, 2008).…”

“…The microparticles were prepared by the water-in oil-in water (W/O/W) solvent evaporation technique, on the basis of the procedure described by Chen et al (2002). Briefly, a primary emulsion is obtained by adding 1 ml of ALB aqueous solution (30 mg/ml) to 5 ml of dichloromethane (DCM) containing 300 mg of PLGA.…”

“…Besides, the release of the proteins from microparticles is commonly low and non-uniform. To solve these problems, different excipients have been incorporated during microencapsulation process, as poly(ethylene glycol) (PEG) and sodium chloride (NaCl) (Bock et al, 2014;Buske et al, 2012;Chen et al, 2002;Nugraha et al, 2014;Van de Weert et al, 2000;Ye et al, 2010). These both excipients also improve proteins stability.…”

The mechanism of surface-indented protein-loaded PLGA microparticle formation: the effects of salt (NaCl) on the solidification process

“…Recently, a modified method was reported by combining NaCl in the external aqueous phase for preparing ovalbumin (OVA)-loaded PLA microparticles. The OVA content was greatly improved to achieve 96% of the theoretical content (Chen et al 2002). The OVA distribution is predominately dispersed in the inner core region of the microparticles using 3% or higher NaCl.…”

PEG–PLGA based large porous particles for pulmonary delivery of a highly soluble drug, low molecular weight heparin

“…Poor entrapment of hydrophilic drugs in PLGA particles prepared by double emulsion-solvent evaporation method results from the positive osmotic gradient produced by the drugs that pushes a fraction of the entrapped drug from the core to the external aqueous phase (EAP) during the solidification phase of the particles [22,23]. Based on this observation and above described features of LMWH and PEG-PLGA, we hypothesize that PEG-PLGA based particles prepared by conventional double-emulsion-solvent-evaporation method enhance loading of LMWH and provide favorable release of the drug upon inhalation.…”