Abstracts

Rationale: Benzodiazepines, including diazepam, are the cornerstone for out-of-hospital treatment of episodes of increased seizure activity. For more than 20 years, diazepam rectal gel (RG) was the only US Food and Drug Administration (FDA) approved option for this condition. Alternative routes of administration are needed due to the unpredictability of absorption and social acceptability of RG administration. Other benzodiazepine formulations are sometimes prescribed for seizure rescue, but these off-label uses have not been specifically formulated nor adequately studied to gain FDA approval. The intranasal (IN) route offers theoretical advantages over other routes of administration, including more convenient and timely access than RG administration. Even with the recent approval of IN midazolam, formulation challenges related to inadequate solubility, intermediate and inconsistent bioavailability, and safety and tolerability issues continue to hamper the development of IN benzodiazepines. To address this unmet need, Neurelis undertook development of a new diazepam formulation that overcomes these challenges while delivering a therapeutic dose in an acceptable spray volume of ≤100 µL. Methods: Formulations were investigated for IN use to optimize diazepam solubility, achieve high and consistent bioavailability, and exhibit good tolerability. Results: Tolerability and absorption are two major reasons why IN formulations have not moved forward. Several excipients have been explored to overcome the challenges of solubility, bioavailability, and tolerability of IN formulations. A solution with 0.25% Intravail A3 has favorable results as a mucosal permeation enhancer (Figure 1). Intravail enables the noninvasive delivery of a broad range of proteins, peptides (up to 30,000 Daltons in size), and nonpeptide drugs, including treatments for neurologic conditions such as migraine. Further, Intravail is “Generally Recognized as Safe” by the FDA for oral administration and is included in the FDA-approved IN formulation of sumatriptan for acute migraine in adults. NRL-1 (Valtoco™) is formulated with a proprietary combination of a vitamin E-based solvent system and Intravail A3. Absolute bioavailability of the IN formulation was 97% of intravenous diazepam and was generally well tolerated (Agarwal S, et al. Epilepsy Research 2013;105:362–367). In healthy volunteers, mean plasma concentration-time profiles comparable to RG and oral diazepam have been reported, with a majority of adverse events (>90%) reported as mild (Poster #1.301 Hogan et al. 72nd Annual Meeting of the American Epilepsy Society, November 30–December 4, 2018, New Orleans, LA). Further investigations of the long-term tolerability and safety of NRL-1, with particular emphasis on local nasal adverse events, are underway. Conclusions: A number of technologies for overcoming challenges of IN delivery of benzodiazepines have been investigated. The use of Intravail, which has a proven tolerability and safety profile in animal models and humans, improves IN absorption. NRL-1 has the potential to be an effective rescue therapy with a more reliable and socially appropriate diazepam formulation. Funding: Neurelis, Inc.