Poly(lactic-co-glycolic acid) (PLGA) is one of the preferred polymeric inactive ingredients for long-acting parenteral drug products that are constituted of complex formulations. Despite over 30 years of use, there are still many challenges faced by researchers in formulation-related aspects pertaining to drug loading and release. Until now, PLGA-based complex generic drug products have not been successfully developed. The complexity in developing these generic drug products is not just due to their complex formulation, but also to the manufacturing process of the listed reference drugs that involve PLGA. The composition and product attributes of commercial PLGA formulations vary with the drugs and their intended applications. The lack of standard compendial methods for in vitro release studies hinders generic pharmaceutical companies in their efforts to develop PLGA-based complex generic drug products. In this review, we discuss the challenges faced in developing PLGA-based long-acting injectable/implantable (LAI) drug products; hurdles that are associated with drug loading and release that are dictated by the physicochemical properties of PLGA and product manufacturing processes. Approaches to overcome these challenges and hurdles are highlighted specifically with respect to drug encapsulation and release.

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Subcutaneous and pulmonary insulin is associated with medical and pharmaceutical complications. Oral insulin mimics physiological glucose regulation with reduced hypoglycemia and coma risks. Nanoparticles are advocated as oral insulin carrier to overcome intestinal absorption barrier. Their insulin bioavailability and blood glucose lowering performances are hampered by inefficient mucus and mucosa transport of nanoparticles. This review discusses critical materials used in oral insulin nanoparticle design to address mucus and mucosa penetrating hurdles. It highlights intestinal receptor targeting, biomimetic virus mimicking, particulate surface charge switching, coat-core detachment, and combination approaches developed through material sciences. Mucus penetration favors particles with hydrophilic/amphiphilic surfaces with no net charges. Mucosa penetration shows a preponderance for hydrophobic or positively charged surfaces with intestinal receptor binding affinity. Materials with switchable physicochemical properties along with mucus-mucosa transit require research exploration, with consideration of their influences on endocytosis, lysosomal escape, exocytosis, and intestinal receptor upregulation.