RAPID ACTING LORAZEPAM GEL FOR EPILEPTIC SEIZURES

经历一系列癫痫发作的儿童不能口服药物，静脉注射很困难，肌肉注射无效。直肠注射安定溶液是一种很好的解决方法。直肠地西泮凝胶现在在美国可用，但直肠使用IV地西泮溶液是常见的做法。安定会引起呼吸抑制等副作用。 劳拉西泮不会引起呼吸抑制，需要较低的剂量。 虽然直肠溶液作用迅速，但患者很难将其保持在手边并快速给药，特别是在处理家庭以外的意外癫痫发作时。溶液也有从直肠漏出的趋势。 在第一阶段，BIOTEK配制并测试了几种直肠劳拉西泮凝胶。使用兔模型，我们证明了适当配制的凝胶可以在直肠给药后15分钟内将劳拉西泮的血液水平提高到10-30 ng/ml的治疗水平。从这些研究中，选择了两种制剂用于II期优化。优化后，将选择一种处方，按照GMP进行制备，并进行稳定性试验。 将向FDA提交IND申请，并在12名正常健康志愿者中以两个剂量水平进行I期临床试验。 临床研究的目的是评价凝胶的安全性和直肠刺激性，定量达到的血清浓度，确定剂量比例，并确定直肠劳拉西泮与静脉劳拉西泮相比的生物利用度。

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.