Supersaturated formulations of poorly soluble weak acid drugs evaluated in rodents; a case study

In the present study we describe a way of working to overcome oral administration challenges in an early preclinical project. As candidate drugs were obtained, the preclinical delivery route was replaced by the intended route of the product and resources were allocated to optimize the oral absorption. Two main approaches were followed in order to formulate a selected weak acid, AZ'403, for oral administration in large scale toxicological studies and the early clinical phases. Both approaches relies on the suppression of precipitation from obtained supersaturated solutions achieved either by amorphous solid dispersions (using hydroxypropyl methylcellulose acetate succinate, HPMC-AS) or crystalline salts (sodium and potassium salts). In vivo studies in rodents were performed to evaluate oral AZ'403 absorption from amorphous and crystalline formulations, using nano- and micro crystalline particles of the neutral form, as references. The oral absorption of AZ'403 formulated using both approaches was significantly higher compared with the references. The improvements in overall exposures were 7-100 times during the investigated conditions. The pharmacokinetic profiles implied that both solid dispersions and crystalline salts of AZ'403 generated supersaturation in the small intestine in rodents and indicated that both approaches may be ways forward for subsequent late stage product development.

Automated summary

This study describes a way to overcome oral administration challenges in early preclinical projects. Two main approaches were used to formulate a weak acid, AZ'403, for oral administration, resulting in significantly higher oral absorption compared to references. The findings suggest that both solid dispersions and crystalline salts may be promising for late stage product development.