(T1530-12-80) Elucidating the Mechanisms Underlying Enhanced Absorption in Rapidly Dissolving Amorphous Solid Dispersions

Purpose: A major hurdle in the pharmaceutical industry is the formulation of new active pharmaceutical ingredients due to their poor water solubility which can subsequently result in limited bioavailability. Amorphous Solid Dispersion (ASD), in which a drug and a polymer are mixed at a molecular level presents a feasible method to accomplish systemic exposure that surpasses the aqueous solubility of the drug. The dissolution of a fast-releasing ASD leads to the spontaneous generation of amorphous drug nanoparticles when the concentration of the dissolved drug exceeds its amorphous solubility. The formation of these nanoparticles is believed to significantly contribute to improved absorption, facilitated by the particle drifting effect, thereby augmenting the concentration of the drug in the mucosal tissue. However, such absorption advantage does not always extend to other drug nanoparticle systems such as nanocrystals. Therefore, the objective of this study is to investigate the membrane permeability of different types of drug nanoparticles as well as underlying mechanisms.

Methods: Clotrimazole was chosen as a model compound where redispersable amorphous nanoparticles can be prepared at normal experimental conditions. A polymeric stabilizer Eudragit^® L100 was used to inhibit recrystallization of amorphous drug amorphous nanoparticles. Using the solvent-shift method, amorphous drug nanoparticles were generated in situ, mirroring those produced during rapid ASD dissolution. Dried amorphous nanoparticles that are redispersable were also prepared from these in situ particles. The in situ particles were dried at 65 °C and 150 mbar using a BUCHI Rotavapor® R-300 rotary evaporator. The resulting dried film was then re-dispersed in pH 6.5 phosphate buffer, vortexed, and analyzed for redispersibility using dynamic light scattering (DLS). Nanocrystals were prepared via wet media milling. Flux measurements were conducted using diffusion cells combined with lipophilic membranes. The dissolution of amorphous drug nanoparticles was conducted by diluting them to the drug's amorphous solubility using pH 6.5 phosphate buffer. At specified time intervals, triplicate samples were filtered using 0.22 μm PVDF syringe filters, and the resulting filtrate was diluted with 1:1 water: acetonitrile solvent (to prevent crystallization) and subsequently analyzed using HPLC. The size of drug particles in solution was measured using dynamic light scattering (DLS). Lack of crystallinity was confirmed using polarized light microscopy (PLM).

Results: As shown in Figure 1, for in situ amorphous nanoparticles, increased membrane flux was observed at drug concentrations beyond the drug's amorphous solubility. A flux plateau was reached at high particle concentrations, confirming that enhanced membrane flux by drug particles occurs only through the dissolved drug. Conversely, a minimal increase in flux was demonstrated by dried amorphous particles and nanocrystals at similar donor concentrations (50-100 µg/mL) and particle sizes. To gain insight into the variations observed in flux measurements between in situ and dried amorphous particles, particle dissolution studies were conducted, as illustrated in Figure 2. In situ amorphous particles quickly dissolved, with the aqueous solution achieving amorphous solubility within 5 minutes. Extremely slow dissolution rate was observed for dried amorphous particles, which failed to attain amorphous solubility even after 5 hours. Additionally, the nanocrystals exhibited a even lower dissolution rate owing to their crystalline nature. Since particle dissolution is a prerequisite for the particle drifting effect, the observed high membrane flux by in situ particles is primarily attributed to rapid particle dissolution as compared to dried amorphous particles. Particle concentration, sink condition and drug solubility were found to play important roles in particle dissolution rate.

Conclusion: This research investigated the membrane permeability of various drug nanoparticles, highlighting the superior performance of in situ amorphous nanoparticles. These particles demonstrated quick dissolution, resulting in enhanced membrane flux. Conversely, dried amorphous nanoparticles and nanocrystals had slower dissolution rates, indicating minimal flux increase. It was suggested that particle dissolution was key to the enhanced absorption facilitated by the particle drifting effect. These findings provide mechanistic insights behind the enhanced absorption observed with fast-releasing ASDs and will contribute to the improvement of developing strategies to design ASDs with optimal release performance and aid in bioavailability prediction.

Flux measurements of different particle type showing minimal flux enhancement was for both dried amorphous particles and nanocrystals in comparison to in situ amorphous particles

Impact of dissolution rate of different particle type suggesting rapid dissolution of in situ amorphous particles as key to enhanced membrane flux