One Ring to Dissolve Them All

Many commonly used antiepileptic drugs (AEDs) are not available in intravenous (IV) formulations, including lamotrigine, topiramate, and carbamazepine. This is not surprising considering that more than 40% of the new chemical entities developed in the pharmaceutical industry are practically insoluble in water (1). Improving drug solubility remains one of the most challenging aspects of drug development, though progress is being made in developing IV formulations of these drugs.

Numerous approaches to enhance the solubility of drugs that are poorly soluble in water have been reported in the literature (1). Particle size can be decreased by milling to increase the surface area available to the solvent. Solid dispersions can be used to mix a poorly soluble drug with a carrier that is highly water soluble to create small crystals that enable the poorly soluble drug to dissolve more easily. Nanosuspensions of a poorly soluble drug can be created by breaking the drug into small nanoparticles by milling or by dissolving the drug in a surfactant and forcing it through a nano-size aperture. Cryogenic techniques can also be used to create nanoparticles of the drug to facilitate solubilization. And, most useful, inclusion complex formation can be used to insert a poorly soluble molecule into a hole in a larger water-soluble molecule. Using these methods, most poorly soluble drugs can now be dissolved.

Inclusion complex formulations are most commonly formed using cyclodextrins (CDs), which are a family of ring-shaped oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. CDs are made up of sugar molecules bound together in a cyclic structure and are hydrophilic on the outside and lipophilic on the inside. Poorly soluble drugs fit into the lipophilic central cavity and can thereby be carried into solution. CDs are widely used as “molecular cages” in the pharmaceutical, agrochemical, food and cosmetic industries (2) and are used by the pharmaceutical industry not only to increase aqueous solubility but also to increase bioavailability, improve stability, reduce gastrointestinal drug irritation, convert liquid drugs into microcrystalline or amorphous powder, and prevent drug–drug and drug–excipient interactions. CDs are created in three forms—alpha, beta, and gamma—which the beta form is most commonly used to improve solubility (Figure 1).

FIGURE 1.

Chemical structure of the three main types of cyclodextrins (8).

Several recent studies (3, 4, 6) have demonstrated inclusion complex formulation methods using cyclodextrins to create IV formulations of several AEDs that have not been previously available in IV forms: lamotrigine, topiramate and carbamazepine. Lamotrigine is available in tablet form and is approved for use in adult and pediatric epilepsy and in bipolar disorder. Conway et al. (3) recently reported administration of an IV preparation of lamotrigine dissolved using beta 2-hydroxypropyl-ß-cyclodextrin to 20 patients with epilepsy. A single 50-mg dose was given to inpatients to replace 50 mg of the patient's oral dose. The patients' total lamotrigine doses ranged from 200 to 800 mg/day, so they were given only a fraction of their dose IV. The only adverse events were one subject who reported irritation at the IV site and one subject who reported chest tightness. Because this was a small study that used a small dose of lamotrigine, additional studies are needed to determine the utility of this formulation as a full-dose replacement for bridge therapy.

Topiramate is available as tablets and sprinkle capsules and is approved for use in adults and children for epilepsy and in adults for migraine prophylaxis. Clark et al. (4) recently reported the results of an open-label crossover study of oral and IV topiramate in 12 healthy adult subjects. The IV topiramate was formulated as a 10 mg/ml solution dissolved using 10% sulfobutylether ß-cyclodextrin (Captisol, Ligan Technologies, La Jolla, CA). Subjects were given 100-mg doses of IV and oral topiramate 2 weeks apart. The study found that the IV infusion was bioequivalent to the oral route. Some side effects were noted, including ataxia and lightheadedness. No injection-site reactions were reported. Additional studies are needed to demonstrate tolerability of this formulation in patients with epilepsy who are already taking topiramate.

Carbamazepine is a widely used AED that has been effective in the treatment of focal-onset seizures and trigeminal neuralgia for 40 years. A problem facing the delivery of carbamazepine is its poor water solubility (<200 μg/mL), which generally results in a slow and irregular absorption (5). A phase I bioequivalence study of a 10 mg/mL solution dissolved using 10% sulfobutylether ß-cyclodextrin (Captisol, Ligan Technologies) showed that this formulation provided comparable exposure to oral carbamazepine when adults with epilepsy were administered IV carbamazepine at a 70% dosage conversion (6). A second and larger phase III open-label study to assess the safety and tolerability of this IV formulation was recently completed (7). This study included a 1-month lead-in period in which subjects were treated with oral carbamazepine, a 7-day confinement period during which IV administration occurred, and a 1-month follow-up period during which oral carbamazepine was resumed. Infusions were given every 6 hours over 15 or 5 minutes. All study subjects were adults with epilepsy. A total of 105 subjects were given IV carbamazepine infusions, and 101 subjects completed the study (96%). During the infusion period, the most commonly reported adverse events were dizziness (19%), somnolence (6%), and headache (8%). No notable differences were observed between the 15- and 5-minute groups for any specific adverse event. Although there were three serious adverse events (cerebral hemorrhage, convulsion, and bacteremia), none were deemed related to the study drug. No clinically relevant findings were observed from the physical exam or laboratory parameters. Overall, it appeared that this IV carbamazepine formulation was well tolerated as short-term replacement therapy for oral carbamazepine. The formulation is currently under review by the Food and Drug Administration, and a decision is anticipated 2015.

The IV formulations of all commonly used AEDs are needed to provide bridge therapy for patients in the intensive care unit or in the preoperative period when oral therapy is not possible. Switching patients to a different AED in these circumstances puts patients at risk for medication side effects and fluctuations in therapy, which could lead to potentially life-threatening seizures. As with IV carbamazepine, it is hoped that safety trials will be conducted with cytodextran-based IV formulations of many other AEDs so that they can become clinically available.