Gels without Vapor Pressure: Soft, Nonaqueous, and Solvent‐Free Supramolecular Biomaterials for Prospective Parenteral Drug Delivery Applications

Abstract

now making up 90% of the drugs in development. [9] Since hydrogel matrices are predominantly hydrophilic with high water content, there may be limits in loading clinically relevant concentrations of poorly water-soluble APIs and achieving bolus-free, prolonged, zero or first-order release kinetics of these drugs over several weeks. [11] Further challenges include the mechanical fragility of many biodegradable hydrogels, dehydration over time, and nonideal drug release due to leakage or phase separation. [12] Although mechanical weaknesses of hydrogels may be overcome by several approaches such as introducing a second interpenetrating supramolecular or covalent network within the primary hydrogel matrix, [13] other problems due to the inherent presence of water have no straightforward remedy.Given these current limitations in hydrogel technology, in particular those associated with the incompatibility of aqueous matrices with controlled release of poorly soluble drugs, some groups have explored whether nonaqueous matrices can overcome these challenges. [14,15] One alternative class of materials to hydrogels is organogels. A typical organogel is composed of a hydrophobic or amphiphilic gelator and an organic solvent, such as N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO). [3] A common strategy for the use of organogels in parenteral drug delivery is direct injection of polymer mixed with drug and added organic solvent for solubilization and viscosity reduction. Subsequent solvent leeching results in the formation of an implant in situ to release the drug over time. [14] However, compelling reasons against the clinical adoption of such materials exist, including the concern over safety of injecting organic-solvent loaded materials into patients with potentially harmful or unknown biological consequences. [3,16] A highly promising subset of organogels that has seen limited adoption into drug delivery is called oleogels, which do not contain organic solvents, such as NMP, and consist of oligomers or polymer oils/melts. [8] These materials are supramolecular analogues to soft, covalent elastomers. A key advantage of such polymer melt-based gels is their lack of any appreciable vapor pressure. [17] Such stability and lack of evaporation over time makes these materials quite distinct from hydrogels or organic solvent-based organogels. Whereas hydrogels can be left sealed on the benchtop or in the fridge and remain unaltered due to evaporation on the order of days, solvent-free gels are potentially stable for months to years. While the application of these The engineering advantages of soft, nonaqueous, solvent-free supramolecular materials have resulted in their emerging transition and adoption from a predominantly food, cosmetics, and paint industry-driven technology to biocompatible matrices for parenteral drug delivery. Factors that have contributed to this trend are the drastic increase of hydrophobic and combination drugs in the pharmaceutical pipeline and the limitations of hydrated drug delivery materia...

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