Children experiencing a seizure of series of seizures cannot be given oral medication, intravenous delivery is difficult, and intramuscular injection is ineffective. Infusion of a rectal diazepam solution provides a good solution. Rectal diazepam gel is now available in the US, but rectal use of IV diazepam solution is common practice. Diazepam causes side effects such as respiratory depression. Lorazepam does not cause respiratory depression and requires a lower does. While rectal solutions act rapidly, they are difficult for patients to keep close at hand and to administer quickly, especially to deal with an unexpected seizure outside the home. Solutions also have a tendency to leak out from the rectum. During Phase I, BIOTEK formulated and tested several rectal lorazepam gels. Using the rabbit model we demonstrated that a properly formulated gel can raise the blood level of lorazepam to therapeutic levels of 10-30 ng/ml within 15 minutes after rectal administration. From these studies, two formulations were selected for optimization in Phase II. After optimization, one formulation will be selected and will be prepared under GMP and its stability tested. An IND application will be submitted to the FDA and a Phase I clinical trial will be conducted in 12 normal healthy volunteers at two dose levels. The purpose of the clinical study will be to evaluate the safety and rectal irritation of the gel, to quantitate the achieved serum concentration, to establish dose proportionality, and to determine bioavailability of rectal lorazepam compared to intravenous lorazepam.
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