Enabling oral drug formulations: mechanistic studies and modeling

Abstract The current drug discovery pipeline is flooded with challenging molecules, characterized by poor aqueous solubility and/or low permeability. This necessitates the use of “enabling” formulation strategies, which are specifically designed formulations to overcome the drug’s challenging properties, reducing attrition and enabling

the successful drug development and commercialization. However, the present formulation development process is through trial-and-error and relies heavily on costly animal experiments. Consequently, the capacity of the drug development process is highly limited, leading to early elimination of numerous otherwise promising

drug candidates. The ability to design formulations rationally and predict bioavailability accurately will greatly save time and resource in drug development. This will allow more potent drug candidates to succeed through development. Such advancements will not only enable more life-saving drugs to reach the market, but also

alleviate the financial burden on patients due to reduced drug development cost. Nonetheless, two main processes involved in drug absorption remain poorly understood: the particle drifting effect, which determines the extent to which submicron and micron sized drug particles and complexes facilitate absorption, and de-

supersaturation kinetics, which governs the rate at which the drug precipitates from solution, rendering it unavailable for absorption. Several key unanswered questions are: 1. What are the key factors affecting these two processes in vivo? 2. How can these processes be accurately predicted? 3. To what extent do these

processes influence drug absorption from different formulations, such as amorphous solid dispersions (ASDs) and lipid-based formulations (LBFs)? Over the past few years, my group has systematically investigated the particle drifting effect and de-supersaturation kinetics in vitro. I also have extensive expertise in ASDs, an

enabling formulation where the particle drifting effect and/or de-supersaturation dominate drug absorption. These endeavors have positioned me well to provide mechanistic and quantitative insights of the complex drug absorption process. To solve these unanswered questions, three research areas are proposed: 1. Systematically

evaluate the particle drifting effect in vitro and in vivo, develop mass transport models, and utilize physiologically- based pharmacokinetic (PBPK) models to predict drug absorption from ASDs; 2. Examine key factors affecting de-supersaturation kinetics in vivo, develop suitable in vitro surrogate tests and kinetic models to predict de-

supersaturation in vivo; 3. Evaluate the particle drifting effect and de-supersaturation kinetics in LBFs, and promote permeation enhancement and lymphatic uptake using suitable lipid excipients. Successful completion of this proposal will contribute to model-based oral formulation development and more accurate bioavailability

prediction. These outcomes will enable more drug candidates to proceed through the development process, reduce the need of animal pharmacokinetic studies, lower drug development cost, and ultimately save more patients’ lives.