Innovative Strategies in the Design of in situ Forming Implants: Optimizing Workflow and Sustained Release for the Treatment of Neglected Tropical Diseases

The first part of this research project focused on a comprehensive preformulation study using levonorgestrel (LNG) as a model drug to evaluate the impact of the supplier variation on the solidstate properties of LNG raw materials. High consistency across suppliers was confirmed using multiple analytical techniques, source variability does not significantly impact the manufacturing of novel long-acting injectable (LAI) formulations containing LNG. Subsequently, the research shifted focus towards optimizing development workflows by examining the impact of implementing focused ultrasonication to accelerate the attainment of thermodynamic equilibrium in polar aprotic solvents, such as N-methyl-2-pyrrolidone (NMP). This innovative approach significantly reduced the incubation periods for the model drugs atovaquone (ATQ), praziquantel (PZQ), and proguanil (PRG),thereby enhancing laboratory throughput. Subsequent investigations were conducted to assess the influence of amphiphilic additives on drug solubilization and, consequently, on the drug loading capacity of in situ forming implants (ISFIs). The findings indicated that when dissolved in pure NMP, poloxamers predominantly exist as unimers or large aggregates, thereby inhibiting micelle formation. Furthermore, an antagonistic effect was observed, i.e., a reduction in the apparent solubility of themodel drugs, regardless of the surfactant type and concentration.

The second part focused on investigating the impact of incorporating hydrophobic ion pairing(HIP) complexes within ISFIs on the co-delivery of drugs with distinct physicochemical properties. Solid-state characterization (i.e., X-ray powder diffraction and infrared spectroscopy) of the dualdrug ISFIs confirmed the formation of HIP complexes between ATQ and PRG base. Furthermore, it was observed that formulation parameters, including the choice of solvent, polymer concentration, and polymer molecular weight (Mw), substantially influence the dynamics of phase inversion and implant microstructure, thereby affecting the in vivo drug release. The formation of HIP complexes markedly enhanced ATQ exposure by inhibiting premature recrystallization, which would otherwise result in a very slow dissolution-limited absorption. Moreover, pharmacokinetic studies conducted on Sprague-Dawley rats demonstrated sustained therapeutic plasma concentrations of both ATQ and PRG for at least six weeks following a single subcutaneous administration.

In conclusion, the findings of this research project demonstrate the potential of HIP-loaded ISFIs for the sustained co-delivery of antimalarials, highlighting the fundamental role of preformulation studies in the rational design of novel long-acting injectable (LAI) formulations.