BIORELEVANT RELEASE TESTING OF LONG-ACTING INJECTABLES INTENDED FOR PARENTERAL ADMINISTRATION

In vitro release testing is pivotal in supporting various stages of pharmaceutical development, from formulation design to routine quality control. Its implementation ensures the consistent quality, performance, and regulatory compliance of medicinal products. For orally administered small-molecule drugs, in vitro testing has been extensively studied to establish a quantitative relationship between the dissolution data and plasma drug concentration-time profiles (in vitro-in vivo correlation (IVIVC)). However, the applicability of IVIVC models is limited when interactions of complex drug product (complex in the characteristics of the drug substance, the formulation and/or the route of administration) with the physiological environment occur. These limitations are particularly evident for parenteral administration routes, such as subcutaneous and intradermal delivery, where the structural and compositional complexity of the injection site can markedly influence drug release, diffusion, and bioavailability. Consequently, there is a growing need of reliable dissolution methods that mimic key aspects of human physiology, both in terms of the composition and physicochemical properties of bodily fluids and hydrodynamics at the specific site of drug administration. This PhD project aimed to advance the development of biorelevant in vitro testing strategies for complex drug delivery systems intended for parenteral administration, as well as for innovative oral formulations. The first part of the work focused on the subcutaneous tissue, evaluating current methodologies for assessing drug release following subcutaneous administration. Poly(lactide-co-glycolide) microspheres loaded with naltrexone or flurbiprofen were used as model delivery systems to investigate the impact of interstitial fluid and extracellular matrix components on release behavior under different hydrodynamic conditions. Biorelevant media were developed based on an extensive analysis of subcutaneous tissue characteristics, and human tissue samples were analyzed to clarify discrepancies in reported glycosaminoglycan content. The second part of the project addressed intradermal administration by developing a synthetic model that reproduces the key mechanical properties of the dermis, enabling a more reproducible assessment of drug diffusion compared with conventional ex vivo approaches. Finally, the performance of orodispersible dosage forms containing β-galactosidase was investigated in simulated gastric conditions to evaluate the influence of variability in gastric fluid volumes on in vitro lactose hydrolysis. Overall, this work contributes to a deeper understanding of the role of biorelevant testing in predicting drug release and performance for complex drug products, supporting more reliable formulation development and regulatory assessment.