Sustained release of human growth hormone from PLGA solution depots

Purpose. The effects of altering the dynamics of phase inversion of a polyl actic glycolic acid (PLGA) solution depot on the sustained-release delivery profile of human growth hormone (hGH) were evaluated. The impact of adjust ing the protein particle composition was also studied in a slow phase-inver ting formulation. Methods. Protein release profiles of depots prepared from four model solven ts were generated by injecting formulations into the subcutaneous space of normal rots and monitoring hGH serum levels over the course of 1 month. Sca nning electron microscopy, Coulometric Karl Fischer titration, size-exclusi on liquid chromatography, and reversed-phase liquid chromatography were use d to observe depot morphologies, bulk water absorption, PLGA degradation, a nd protein particle dissolution rates, respectively. Results. An extended-release profile and significantly reduced burst effect resulted when the aqueous affinity of the depot solvent was reduced. As se en earlier in in vitro experiments, lowering the solvent's aqueous affinity slows the phase inversion rate, which in turn produces depot morphologies favorable to prolonged release. Protein burst on injection was entirely eli minated in a slow phase-inverting formulation by densifying the lyophilized protein particles. Unlike the use of metal cations to prolong release of s ome proteins in PLGA microsphere depots, this technique is more universal, and thus is potentially usable with any protein or highly soluble drug agen t. The onset of biodegradation was observed to occur at 14 days for all dep ot formulations, however the bulk biodegradation rate slowed as the aqueous affinity of the depot solvent decreased. This result supports the hypothes is that, in a slow phase-inverting system, drug release over the first few weeks is governed by the diffusion rate of drug through the polymer solutio n. Conclusions. By taking advantage of the effects of low aqueous affinity and protein particle densification, a PLGA solution depot was produced with th e capability of sustaining hGH levels in normal rats at a serum level of ID to 200 ng/ml for 28 days.