The effect of Pluronic on the protein release kinetics of an injectable drug delivery system.

A new class of injectable controlled release depots has been prepared by incorporating materials that preferentially segregate during phase inversion. These consist of blends of poly(ethylene oxide) (PEO)/poly(propylene oxide) (PPO)/poly(ethylene oxide) (PEO) triblock copolymers (Pluronics) with poly(D,L-lactide) (PDLA)/1-methyl-2-pyrrolidinone (NMP) solutions. The effects of preferential segregation on the phase inversion dynamics and in vitro protein release kinetics were examined using dark ground imaging, high performance liquid chromatography (HPLC), scanning electron microscopy (SEM), and confocal microscopy. Variations in Pluronic concentration and molecular weight had an insignificant effect on the internal depot morphologies, however, increasing the concentration and molecular weight did result in increased phase separation rates and, surprisingly, a decrease in the magnitude of the protein burst, though the release profiles still retained a typical burst-type shape. Additionally, increasing the Pluronic concentration beyond a critical point resulted in a transition from a burst-type profile to an extended-release profile. An interpretation of these results in terms of a qualitative model for the protein release mechanism is also given.

Role of crystallization in the phase inversion dynamics and protein release kinetics of injectable drug delivery systems.

The role of polymer crystallization in the phase inversion dynamics and in vitro protein release kinetics of semi-crystalline poly (epsilon-caprolactone) and amorphous poly (D,L-lactide) (PDLA) blend solutions has been examined using high performance liquid chromatography (HPLC), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC) techniques. Varying the degree of crystallizability of the solutions led to the emergence of two general classes of depots. Depots with a high degree of crystallinity are characterized by porous morphologies indicative of solid-liquid (s--l) de-mixing and delayed burst release profiles. Alternatively, depots with a low degree of crystallinity are characterized by dense morphologies formed by mild liquid-liquid (l--l) phase separation and slow, uniform protein release rates. An interpretation of these results in terms of a qualitative model for the protein release mechanism is also given.

Phase inversion dynamics of PLGA solutions related to drug delivery. Part II. The role of solution thermodynamics and bath-side mass transfer.

The role of solvent properties and bath-side composition on the phase inversion dynamics and in vitro protein release kinetics of polylactic-co-glycolic acid (PLGA) solutions has been examined using dark ground imaging, in vitro release rate, and SEM techniques. Thermodynamic phase diagrams for three model systems (PLGA in 1-methyl-2-pyrrolidinone (NMP), triacetin, and ethyl benzoate) suggest two general classes of precipitation behavior, depending on the relative solvent strength and water miscibility. Drug release from the NMP-based system is primarily governed by the dynamics of phase inversion and exhibits a distinct burst region followed by a much slower release. Alternatively, depots with low solvent/water affinity (PLGA in triacetin or ethyl benzoate) undergo much slower phase inversion, resulting in a less porous, more fluid, two-phase structure that also releases protein more uniformly. Addition of a small chain triglyceride or organic salt to the aqueous receptor bath also evokes a significant increase in the mass transfer rate of protein from the low solvent/non-solvent affinity depots. An interpretation of these results in terms of a qualitative model for the protein release mechanism is also given.