Developing a Parenteral Formulation ofMetolazone

Project Summary AbstractMetolazone is a quinazoline sulfonamide with potent thiazide like diuretic activity on the cortical diluting segmentas well as diuretic action on the proximal tubuleMetolazoneorallyis often employed in patients with severe congestive heart failureCHFas a supplement to a loop diureticas well as in patients with diuretic resistance to loop diureticsHowevermetolazone has not been available for IV administration due to its very poor solubilityAn IV formulation would be useful in heart failure patients who invariably have poor oral absorptionin patients unable to take oral medications and in patients with loop diuretic resistance when rapid IV administration is difficult to coordinate with peak loop diuretic actionWe have developed a new formulation of metolazone for IV administration at a neutral pHthat we believe is not be phlebitic and is effective in diuretic resistant statesStudies proposed in this grant aim to characterize the new formulation and establish its diuretic action in an animal modelinitial steps in obtaining an IND to initiate clinical studies Project NarrativeMetolazone orally is an effective diuretic in patients with severe edemacongestive heart failure and diuretic resistance to loop diureticsDiuretic resistance to loop diuretics occurs frequently with large doses administered to patients with severe HFAn IV formulation of metolazone would be useful to treat patients with severe heart failureand patients with loop diuretic resistanceWe had previously developed an IV formulation at pHtobut the formulation was venous irritatinglimiting its utilityA newly developed lipid emulsion formulation at pHwe believewill be less phlebitic and effective in diuretic resistant statesThe studies proposed aim to characterize the formulation and evaluate the diuretic effectsas well as demonstrating the lack of venous irritationphlebitisall requisite steps in the development of a viable product for both adult and pediatric populations