PLGA and PEG based porous microparticles as vehicles for pulmonary somatropin delivery

Abstract

Breakthrough advances in protein therapeutics and sustained release systems continue to fuel innovation in novel, non-invasive polymeric platforms for delivery of biologicals. Despite the bench potential and proof-of-concept work, market analysis still shows biologicals to be predominantly injections. Characterized by insufficient secretion of growth hormone by the pituitary gland, growth hormone deficiency (GHD) is a rare disorder. Currently, chronic somatropin (r-hGH) replacement therapy is only available as subcutaneous injections administered several times a week. We aim to prepare large, porous, biodegradable and aerodynamically light microparticles as tunable carriers for pulmonary r-hGH delivery. We developed a range of microparticles using PLGA 5050 1Awith sizes between 5 μm and 13 μm, densities lower than 0.4 g/cc and aerodynamic diameters lower than 6 μm. Polyethylene glycol’s multitude of advantages – plasticizing PLGA, improving the biocompatibility of the system and preventing protein burst release – have been extensively studied, making it our excipient (pore-former) of choice. Drug loading was characterized at pH 4.0 (acidic), 5.3 (pI) and pH 7.2 (neutral) and was a result of an interplay of electrostatic and hydrophobic interactions between the polymer and somatropin. Considering the physicochemical interactions, we observed some pH dependent protein unfolding characterized by reduction in intrinsic fluorescence of the Tryptophan 86 residue at 331 nm. The secondary ⍺-helix structure characterized by 2 negative minima at 209 nm and 222 nm in the circular dichroism spectra, was intact at all pH values. R-hGH was released over a period of seven days, and the release profile was a function of the microparticle porosity.