Effect of Manufacturing Variables and Raw Materials on the Composition-Equivalent PLGA Microspheres for 1-Month Controlled Release of Leuprolide

Abstract

The 1-month Lupron Depot (LD) is a 75/25 acidcapped poly(lactic-co-glycolic acid) (PLGA) microsphere product encapsulating water-soluble leuprolide acetate with no generic products available in the U.S. Composition-equivalent PLGA microsphere formulations to the LD as a function of raw material and manufacturing variables were developed by using the solvent evaporation encapsulation method. The following variables were adjusted: polymer supplier/polymerization type, gelatin supplier/ bloom number, polymer concentration, first homogenization speed and time, volume of primary water phase, second homogenization time, volume of secondary water phase, and stirring rate. The loading and encapsulation efficiency (EE) of leuprolide and gelatin were determined to identify a large number of compositionequivalent formulations within a ±10% specification of the LD. Key physical−chemical properties of the formulations (e.g., morphology, particle size distribution, glass transition temperature (T g ), residual moisture and solvent, and porosity) were characterized to determine the effect of manufacturing variables on the product attributes. The EE of gelatin across all formulations prepared (101 ± 1%) was observed to be much higher than the EE of leuprolide (57 ± 1%). Judicious adjustment of polymer concentration, second homogenization time, and volume of second water phase was key to achieving high EE of leuprolide, although EE higher than 70% was not easily achievable owing to the difficulty of emulsifying highly viscous primary emulsion into homogeneous small droplets that could prevent peptide loss during the second homogenization under the conditions and equipment used. The in vitro release kinetics of the formulations was highly similar to the LD in a zero-order manner after ∼20% initial burst release, indicating a critical role of the composition on peptide release in this formulation. The characterization of compositionequivalent formulations described here could be useful for further development of generic leuprolide PLGA microspheres and for guiding decisions on the influence of process variables on product physicochemical attributes and release performance.

A review of existing strategies for designing long-acting parenteral formulations: Focus on underlying mechanisms, and future perspectives

“…The process of micro-encapsulation is that solid or liquid drug substances are dispersed or dissolved in polymeric materials to form microspheres, or as a core surrounded by a polymeric shell to form a microcapsule 89 , 90 . The first sustained-release injectable microsphere (Lupron Depot®) based on biodegradable poly(lactic -co- glycolic acid) (PLGA) was approved by FDA in 1986 for the treatment of prostatic cancer 91 , 92 . The latest approved microsphere-based product (Zilretta®) is used for the therapy of osteoarthritis (OA) pain of the knee.…”

Key Factor Study for Generic Long-Acting PLGA Microspheres Based on a Reverse Engineering of Vivitrol®

“…The detected water contact angle of the GNM was lower than that of Vivitrol ® . The larger the water contact angle, the more hydrophobic the microsphere will be, which indicates that the polymer chain may be a hydrophobic diffusion barrier [37]. The contact angles of the GNM and Vivitrol ® are somewhat different.…”

Micro-imaging and Microanalysis of PLGA Complex Drug Products by Scanning Electron Microscopy (SEM)

“…Both room temperature SEM and cryogenic -SEM (cryo-SEM) coupled with energy dispersive X-ray spectrometer (EDS) were used to characterize commercially available brand name product, Lupron Depot® microspheres, together with in-house PLGA microsphere formulations. The leuprolide acetate encapsulated PLGA microspheres were prepared as described before [2]. To study their external structures, Lupron Depot® microspheres and in-house PLGA microspheres were placed on conductive tape while their internal structures were exposed after cutting using a razor blade.…”