PURPOSE: The effects of altering the dynamics of phase inversion of a polylactic glycolic acid (PLGA) solution depot on the sustained-release delivery profile of human growth hormone (hGH) were evaluated. The impact of adjusting the protein particle composition was also studied in a slow phase-inverting formulation. METHODS: Protein release profiles of depots prepared from four model solvents were generated by injecting formulations into the subcutaneous space of normal rats and monitoring hGH serum levels over the course of 1 month. Scanning electron microscopy, Coulometric Karl Fischer titration, size-exclusion liquid chromatography, and reversed-phase liquid chromatography were used to observe depot morphologies, bulk water absorption, PLGA degradation, and 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 seen 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 eliminated in a slow phase-inverting formulation by densifying the lyophilized protein particles. Unlike the use of metal cations to prolong release of some proteins in PLGA microsphere depots, this technique is more universal, and thus is potentially usable with any protein or highly soluble drug agent. The onset of biodegradation was observed to occur at 14 days for all depot formulations, however the bulk biodegradation rate slowed as the aqueous affinity of the depot solvent decreased. This result supports the hypothesis 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 solution. CONCLUSIONS: By taking advantage of the effects of low aqueous affinity and protein particle densification, a PLGA solution depot was produced with the capability of sustaining hGH levels in normal rats at a serum level of 10 to 200 ng/ml for 28 days.
PURPOSE: The effects of altering the dynamics of phase inversion of a polylactic glycolic acid (PLGA) solution depot on the sustained-release delivery profile of humangrowth hormone (hGH) were evaluated. The impact of adjusting the protein particle composition was also studied in a slow phase-inverting formulation. METHODS: Protein release profiles of depots prepared from four model solvents were generated by injecting formulations into the subcutaneous space of normal rats and monitoring hGH serum levels over the course of 1 month. Scanning electron microscopy, Coulometric Karl Fischer titration, size-exclusion liquid chromatography, and reversed-phase liquid chromatography were used to observe depot morphologies, bulk water absorption, PLGA degradation, and 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 seen 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 eliminated in a slow phase-inverting formulation by densifying the lyophilized protein particles. Unlike the use of metal cations to prolong release of some proteins in PLGA microsphere depots, this technique is more universal, and thus is potentially usable with any protein or highly soluble drug agent. The onset of biodegradation was observed to occur at 14 days for all depot formulations, however the bulk biodegradation rate slowed as the aqueous affinity of the depot solvent decreased. This result supports the hypothesis 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 solution. CONCLUSIONS: By taking advantage of the effects of low aqueous affinity and protein particle densification, a PLGA solution depot was produced with the capability of sustaining hGH levels in normal rats at a serum level of 10 to 200 ng/ml for 28 days.
Authors: O L Johnson; W Jaworowicz; J L Cleland; L Bailey; M Charnis; E Duenas; C Wu; D Shepard; S Magil; T Last; A J Jones; S D Putney Journal: Pharm Res Date: 1997-06 Impact factor: 4.200
Authors: Luis Solorio; Alexander M Olear; Haoyan Zhou; Ashlei C Beiswenger; Agata A Exner Journal: Drug Deliv Transl Res Date: 2012-02-01 Impact factor: 4.617