New Injectable Aqueous Carbamazepine Solution Through Complexing with 2‐Hydroxypropyl‐β‐Cyclodextrin: Tolerability and Pharmacokinetics After Intravenous Injection in Comparison to a Glycofurol‐Based Formulation

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Abstract
Summary: The poor water solubility of the antiepileptic drug (AED) carbamazepine (CBZ) is generally considered an absolute contraindication to parenteral administration in epileptic patients. However, the water solubility of CBZ can be largely enhanced through formation of an inclusion complex with an amorphous cyclodextrin derivative, 2-hydroxypropyl-β-cyclodextrin(HPβCD). We studied tolerability and pharmacokinetics of an aqueous CBZ:HPβCD solution after intravenous (i.v.) administration in dogs. For comparison, a conventional glycofurol-based solution of CBZ was used. We also administered a commercial liquid formulation of CBZ orally Infusion of CBZ:HPβCD solutions or HPbCD “placebo” formulations i.v. was well tolerated by the animals. In contrast, infusion of CBZ: glycofurol solutions and glycofurol placebo solutions induced marked behavioral and cardio-vascular adverse effects. Pharmacokinetic studies indicated that glycofurol inhibited CBZ metabolism by de-creasing formation of the major CBZ metabolite CBZ-10,11-epoxide (CBZ-E). With infusion of CBZ:HPβCD 10 ml/min for 12–15 min, resulting in a CBZ dose of CBZ 5 mg/kg body weight, peak CBZ plasma levels of −3.6 pgl μmCl were obtained. This relatively low peak concentration is primarily due to the rapid elimination of CBZ in dogs [half-life (t/2) <1 h]. Comparison of peak plasma levels determined after p.0. administration of CBZ to dogs with peak CBZ levels previously determined after p.0. administration in humans indicated that about four times higher doses are needed in dogs to attain the same peak plasma levels as in humans. In view of previous experimental data showing rapid penetration of CBZ into brain, our results indicate that aqueous CBZ:HPPCD solutions might be ideally suited for parenteral use in acute clinical conditions such as status epilepticus (SE), particularly because CBZ is a drug with only minor respiratory or cardiovascular effects.