(T1430-12-79) Improving Oral Absorption of Rapidly Crystallizing Parent API Using Prodrug Strategy: Comparison of Phosphate Versus Glycine Based Prodrugs

Purpose: With an increasing number of Biopharmaceutical Classification System (BCS) II/IV candidate molecules, solubilizing and supersaturating formulation strategies are becoming prevalent. Beyond formulation and solid form strategies, prodrugs are also investigated to overcome solubility limited absorption of poorly water soluble compounds. Prodrugs can potentially yield supersaturated systems due to conversion to their parent intraluminally and thus enhance, absorption. However, high supersaturation level also increases the driving force for crystallization resulting in low solution concentrations; thus, negating the advantage of prodrugs. In this work, two unique solubility enhancing prodrugs, phosphate and glycine, were investigated for a rapidly crystallizing parent.

Methods: In this work we compared a highly soluble phosphate prodrug of a rapidly crystallizing parent with a moderately soluble glycine prodrug using ex vivo Ussing (permeability) and dog studies. Ussing studies were used to derive flux and conversion kinetics of prodrug to parent. Physicochemical properties such as crystalline and amorphous solubility and crystallization propensity from supersaturated systems was measured.

Results: We observed that the conversion kinetics of phosphate prodrug to parent were highly dependent on the media used. Conversion rate increased ~14-fold in presence of intestinal contents and ~24-fold in the presence of tissue compared to neat buffer. In contrast conversion of the glycine prodrug was minimal on the donor side suggesting conversion after absorption into the enterocytes. Phosphate prodrug showed non-linear increase in absorptive flux with concentration (low to high supersaturation based on parent solubility) when intestinal contents were used as donor media. This was attributed to rapid conversion and high supersaturation of the parent which subsequently resulted in crystallization at high doses in the donor chamber. Glycine prodrug did not undergo complete conversion at high doses and was absorbed unchanged on the basolateral side, suggesting saturation of the enzymes in the enterocytes. However, combined flux (parent and glycine) showed a linear increase with dose and crystallization was not observed. In vivo glycine prodrug can undergo complete conversion in hepatocytes or in blood. Thus, glycine prodrug provided overall higher absorption compared to phosphate prodrug. Oral dosing in dog study revealed that bioavailability with the phosphate prodrug was ~50% whereas, it was ~100% with glycine prodrug, thus, supporting in vitro observations.

Conclusion: Conversion to parent from a phosphate prodrug occurs intraluminally before absorption due to abundance of alkaline phosphatase enzyme in the lumen and at the brush border. Therefore, phosphate prodrug can generate high supersaturation levels in intestinal fluids. For rapidly crystallizing parent molecules, especially when doses are high, phosphate prodrugs may pose a risk of crystallization and ultimately, non-linear absorption. Glycine prodrug is expected to convert after uptake into the enterocytes, by esterases present in enterocytes or hepatocytes. Thus, no crystallization in the donor was observed using glycine prodrug strategy and the overall absorption as seen in in vitro and in vivo studies was linear and complete. Thus, for rapidly crystallizing parent molecules, especially when doses are high, phosphate prodrugs may pose a risk of crystallization and ultimately, non-linear absorption. For such molecules, amino acid based prodrug strategy may serve as a better alternate. For such molecules, amino acid (gycine) based prodrug strategy may serve as a better alternate.