SBIR-STTR Award

The favorable efficacy, toxicity and adverse side-effect profiles of carbamazepine (CBZ) contribute to its widespread and increasing use to control seizure in the epileptic patient. However, in cases when oral drug treatment is not feasible, no parenteral formulation is available for CBZ. Currently epileptic patients who are unable to maintain oral CBZ must be treated with other anticonvulsants formulated for parenteral administration. This multiple drug approach often leads to unpredictable seizure control and increased drug toxicity in chronically CBZ treated patients. Our preliminary studies showed first that aqueous solutions of CBZ can be given intravenously (i.v.). Second, anticonvulsant activity of CBZ is unaltered in the mouse MES (maximal electroconvulsant shock) model when given in the aqueous formulation. Third, the i.v. total daily dose of CBZ projected to maintain seizure control can be formulated in a reasonable volume. This approach to parenteral formulation of CBZ is based on using a water soluble excipient which is known to form an inclusion complex with lipophilic drugs. The excipient has a favorable toxicity profile for i.v. dosing and the solutions are stable to heat sterilization. The studies examine the feasibility of developing a parenteral formulation of CBZ based on this patented inclusion complex technology. Studies will explore: formulation stability, compatibility with other i.v. fluids, venous irritation, toxicity profiles and manufacturing reproducability. Successful development of a CBZ formulation for i.v. administration would benefit the epileptic patient who is unable to maintain oral CBZ therapy.Awardee's statement of the potential commercial applications of the research:Successful development of this drug product will provide an important therapeutic advantage for controlling seizures in epileptic patients temporarily unable to tolerate oral carbamazepine.National Institute of Neurological Disorders and Stroke (NINDS)

The favorable therapeutic profile of carbamazepine (CBZ) explains its widespread use in epileptic patients. However, no parenteral formulation is available for CBZ. Epileptic patients unable to maintain oral CBZ must be treated parenterally with other anticonvulsants. This multiple drug approach often leads to unpredictable seizure control and increased drug toxicity. Results of Phase I studies showed that developing an aqueous parenteral formulation for CBZ is feasible. The formulation uses a water soluble modified cyclodextrin excipient which forms inclusion complexes with lipophilic drugs. Phase I results convincingly demonstrated (i) the anticonvulsant activity of CBZ is maintained (ii) the laboratory scale production of the CBZ complex is feasible, (iii) toxicity profiles are acceptable with no evidence of venous irritation and (iv) stability profiles indicate the bulk material and prototype formulation are stable. The currently proposed studies are designed to develop a prototype formulation for clinical investigation. Specific studies (i) define the manufacturing conditions for the bulk pharmaceutical material, (ii) define and pharmaceutically characterize the prototype clinical product, including the effects of antimicrobials buffers and specifications for the excipient, (iii) evaluate the pharmacokinetic profile f the prototype formulation in brain tissue using microdialysis techniques and peripheral compartments using more traditional sampling methods, and (iv) characterize the safety profile of the prototype formulation. Successful completion of these studies will support the clinical development of an intravenous CBZ formulation able to benefit the epileptic patient who is temporarily unable to tolerate oral CBZ