Biocompatible and biodegradable copolymer stabilizers for hydrofluoroalkane dispersions: a colloidal probe microscopy investigation

Abstract

In this work we investigate the ability of biodegradable and biocompatible lactide-based nonionic amphiphiles to stabilize a model drug (salbutamol base) dispersion in hydrofluoroalkane (HFA) propellant. A series of triblock copolymers of the type poly(lactide)-poly(ethylene glycol)-poly(lactide) (LA(m)EO(n)LA(m)) with varying molecular weight (MW) and % EO were synthesized. The cohesive forces between drug particles in liquid HFA in the presence of the amphiphiles were quantitatively determined by colloidal probe microscopy (CPM). The effect of cosolvent, oleic acid, and a nonionic triblock copolymer with the propylene oxide moiety as the HFA-phile was also investigated. CPM results show that the overall concentration, MW, surfactant tail (LA) length, and the ratio between the stabilizing LA moiety and the anchor EO group have a great impact on the drug cohesive forces. The CPM results in liquid HFA were correlated to the bulk physical stability of the drug suspensions in the propellant 1,1,1,2,3,3,3-heptafluoropropane (HFA227). The dispersions in HFA227 were significantly improved in the presence of LA(m)EO(n)LA(m), correlating well with the low cohesive forces determined by CPM. The applicability of LA-based amphiphiles might be extended to other suspension-based formulations provided a suitable headgroup is found. This study is relevant for the development of HFA-based dispersion pressurized metered-dose inhaler formulations.