Thermosensitive polymers such poly(N-isopropylacrylamide) (PNIPAM) and poly(2-alkyl-2-oxazoline)s (PAOxs) have been under investigation as drug delivery systems for over three decades but did not reach clinical phases. The challenges impeding their regulatory approval include difficulties in translating experimental research into pharmaceutical development, vague regulatory guidelines, incomplete biocompatibility studies, and the absence of defined critical quality attributes (CQAs) outlined for parenteral administration. In our dissertation, we defined that as in situ forming depot PNIPAM- and PAOx-based drug delivery systems classify as implantable medical devices. When coupled with biotherapeutics, they can stabilize the active pharmaceutical ingredient and supply extended-release features. Generally, this combination needs a type 5 new drug application, and specific subset studies are needed depending on the physical and chemical nature of the polymer-protein loading. The scientific literature highlights thermosensitive PAOx as favored compared to PNIPAM for biomedical applications. This due to the antifouling properties, synthetic options, and the wide range of chemical designs which distinct PAOx from PNIPAM. Nonetheless, until differently proven, both express good biocompatibility and excretion by renal pathway for polymers below 50 kDa.
To evaluate the developability of thermosensitive injectables, it is essential to precisely determine their lower critical solution temperatures (LCSTs). We established a standardized threshold for LCST detection by harmonizing and cross-validating orthogonal methods, employing techniques such as nuclear magnetic resonance spectroscopy, light scattering, turbidimetry, background membrane imaging, and rheology. These techniques aligned and revealed unique features and potential biases in the characterization of thermosensitive polymers. Hyaluronic acid-poly(N-isopropylacrylamide) copolymers were synthesized using strain-promoted azide-alkyne cycloaddition (SPAAC) to clarify their critical material attributes and set the fundaments for a modulable drug product design. We assessed the structure-function relationships and behaviors of these copolymers under in vitro conditions simulating in vivo environments.
We later tested the universal applicability of the developed analytical workflow with an optimized subset of techniques. Also, the developed modular drug product approach was evaluated as a platform technology strategy. The aim was to guide the chemical design of thermosensitive, in situ forming injectables according to the intended target product profile. Self-assembly, mechanical properties, physical state, and thermal transition behavior were evaluated using nuclear magnetic resonance, oscillatory rheology, turbidimetry, and visual inspection. Both PNIPAM and PAOxs with LCSTs below body temperature were studied, both before and after grafting onto azido-substituted hyaluronic acid (HA) via SPAAC. We identified critical material attributes crucial for advancing the pharmaceutical development of in situ gelling thermosensitive polymers.
Our final investigation assessed the use of PNIPAM and PAOx derivatives, conjugated to azido-substituted hyaluronic acid copolymers (HA) through SPAAC, as thermosensitive, in situ form.
