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
| Brewster, M E; Anderson, W R; Meinsma, D et al. (1997) Intravenous and oral pharmacokinetic evaluation of a 2-hydroxypropyl-beta-cyclodextrin-based formulation of carbamazepine in the dog: comparison with commercially available tablets and suspensions. J Pharm Sci 86:335-9 |
