DEVELOPMENT OF AN ORAL-DRUG FORMULATION FOR DICHLOROACETATE AND THIAMINE

Dichloroacetate (DCA) is an investigational drug for the treatment of several metabolic and cardiovascular disorders. Hitherto, it has been used mostly in intravenous, short term treatment regimens. Chronic administration of the drug may be toxic, due in part to the depletion of tissue thiamine stores. We therefore developed a stable liquid preparation of the sodium salt of DCA and thiamine.HC1 suitable for chronic oral administration. The DCA-thiamine mixture is formulated as a palatable solution containing glycerol, sodium benzoate and aspartame in phosphate buffer at pH 3.5. A thermally accelerated decomposition study of the oral DCA formulation revealed a shelf-life of about 5 years at 4 degrees C and about 156 days at 25 degrees C. The stability was also followed for 1 year at its storage condition of 4 degrees C and it was found to be stable at least for 1 year, which is its current recommended storage time. A new high performance liquid chromatographic method was developed to quantitate DCA, thiamine, aspartame and sodium benzoate in the formulation. The DCA-thiamine formulation is palatable and well tolerated by children, some of whom have received it continuously for over three years. Under chronic treatment, at a dose of 12.5 mg/Kg or 25 mg/Kg, DCA has a mean plasma half life of 7.9 hrs in children with congenital lactic acidosis.