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

This study was designed to evaluate the feasibility of PEG-PLGA copolymers as carriers for pulmonary delivery of a highly soluble drug. We attempt to address the limitations of low entrapment efficiencies and poor release profiles that are associated with the use of conventional PLGAs. We have used low molecular weight heparin (LMWH) as a model for highly soluble and ionizable drugs and a 3 × 3 full factorial design to prepare nine formulations. We considered polymer type and percent NaCl in external phase as two independent variables at three different levels; the levels for polymer type were PLGA, PEG-PLGA and PLGA-PEG-PLGA and that for percent NaCl were 0%, 5% and 8%. Formulations were characterized for various physical properties, respirability, drug release, and evaluated for in vivo absorption, alveolar uptake, and safety. Statistical analyses suggest that both polymer type and salt concentration influenced the morphology and micromeritic properties of the particles. Compared with PLGA, PEG-PLGA copolymers produced inherently larger porous particles with high drug entrapment and a greater extent of drug release. Moreover, addition of NaCl in the external phase maximized drug entrapment but minimized burst release and produced smaller and denser particles. Fluorescent PEG-PLGA particles showed reduced uptake by alveolar macrophages, and exhibited a uniform distribution in the lungs compared with PLGA particles. Further, ~85% of the particles were cleared off the lungs within 6 days. Intratracheally administered PEG-PLGA based optimized formulation exhibited a biological half-life of 18.64 h, which was ~4.5 times longer than plain LMWH. No cytotoxic effect was observed when bronchial epithelial cells were incubated with PEG-PLGA based formulations. Similarly, no increase in the injury markers was observed in the bronchoalveolar lavage fluids collected from rats treated with PEG-PLGA particles of LMWH. Overall, this study suggests that PEG-PLGA block copolymers have the potential to be developed as efficient and biocompatible carriers for pulmonary delivery of highly water-soluble drugs.