Abstract
Over the past few decades, long acting injectable (LAI) depots of polylactide-co-glycolide (PLGA) or polylactic acid (PLA) based microspheres have been developed for controlled drug delivery to reduce dosing frequency and to improve the therapeutic effects. Biopharmaceuticals such as proteins and peptides are encapsulated in the microspheres to increase their bioavailability and provide a long release period (days or months) with constant drug plasma concentration. The biodegradable and biocompatible properties of PLGA/PLA polymers, including but not limited to molecular weight, end group, lactide to glycolide ratio, and minor manufacturing changes, could greatly affect the quality attributes of microsphere formulations such as release profile, size, encapsulation efficiency, and bioactivity of biopharmaceuticals. Besides, the encapsulated proteins/peptides are susceptible to harsh processing conditions associated with microsphere fabrication methods, including exposure to organic solvent, shear stress, and temperature fluctuations. The protein/peptide containing LAI microspheres in clinical use is typically prepared by double emulsion, coacervation, and spray drying techniques. The purpose of this review is to provide an overview of the formulation attributes and conventional manufacturing techniques of LAI microspheres that are currently in clinical use for protein/peptides. Furthermore, the physicochemical characteristics of the microsphere formulations are deliberated.
Highlights
Protein and peptide drugs are known to be some of the most effective therapies to elicit a desired therapeutic activity due to their specific interactions with biological targets [1]
The selection of the PLGA/polylactic acid (PLA) polymer for the development of microspheres depends on the route of administration, which is specific for a particular drug, the amount of microspheres administered per unit dose, rate of drug release from the microspheres in a day to meet the therapeutic concentration of the specific drug, and the degradation time of the polymer
During the in vitro release of PLGA-based long acting injectable (LAI) microspheres, water is absorbed by PLGA upon immersion in aqueous media or administration in vivo, and the volume occupied by the water inside the PLGA matrix creates pores
Summary
Protein and peptide drugs are known to be some of the most effective therapies to elicit a desired therapeutic activity due to their specific interactions with biological targets [1]. Understanding and managing drug release kinetics from PLGA-based microspheres requires a thorough analysis of PLGA, such as the lactic acid (LA)/glycolic acid ratio (GA) (LA/GA), molecular weight and distribution, and polymer end group [23,24]. The present review discusses the key formulation attributes, and the manufacturing techniques employed for the development of PLGA/PLA-based LAI microspheres for protein/peptide delivery. The selection of the PLGA/PLA polymer for the development of microspheres depends on the route of administration, which is specific for a particular drug, the amount of microspheres administered per unit dose, rate of drug release from the microspheres in a day to meet the therapeutic concentration of the specific drug, and the degradation time of the polymer. Glu-PLGA polymer exhibits a faster mass loss and degradation rate than the linear PLGA of similar molecular weight. [36]
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