PHARMACOLOGICAL CHALLENGES AND ADVANCES IN CONTROLLED RELEASE DELIVERY OF PEPTIDE THERAPEUTICS

Sneha S. Pawar, Isha C. Bachhav, Nandini A. Panda, Lina B. Bhoi, Bhavana B. Ahire, Nikhil M. Patil*, Ghanshyam M. Chavan

Background: Peptide therapeutics have emerged as a significant class of modern pharmacological agents owing to their high target specificity, potent biological activity, and favorable safety profiles. However, their clinical application is substantially limited by inherent pharmacokinetic and pharmacodynamic challenges, including poor oral bioavailability, rapid enzymatic degradation, short plasma half-life, limited membrane permeability, and dependence on parenteral administration. Objective: This review aims to critically analyze the pharmacological challenges associated with peptide therapeutics and to highlight the role of controlled-release drug delivery systems in overcoming these limitations to improve therapeutic efficacy and patient compliance. Methods: A comprehensive literature-based analysis was conducted focusing on the physicochemical, pharmacokinetic, and pharmacodynamic barriers of peptide drugs. Various controlled-release delivery platforms, including polymeric microspheres, nanoparticles, hydrogels, lipid-based carriers, and depot systems, were systematically evaluated along with recent advances such as chemical modification strategies, stimuli-responsive systems, and nanotechnology-based approaches. Results: Controlled-release delivery systems significantly enhance peptide stability, prolong systemic circulation, and enable sustained and site-specific drug release, thereby improving bioavailability and reducing dosing frequency. Advanced delivery technologies demonstrate promising outcomes in overcoming enzymatic degradation, rapid clearance, and distribution limitations. However, challenges such as maintaining peptide bioactivity, controlling release kinetics, preventing burst release, immunogenicity concerns, and large-scale manufacturing complexities remain critical barriers to clinical translation. Conclusion: Controlled-release systems represent a pivotal strategy in optimizing peptide drug delivery and bridging the gap between preclinical potential and clinical application. Future advancements integrating nanotechnology, artificial intelligence, and personalized medicine approaches are expected to further enhance the therapeutic performance of peptide-based drugs and expand their clinical utility.