RAPID ACTING LORAZEPAM GEL FOR EPILEPTIC SEIZURES

有一系列癫痫发作的儿童不能口服药物，静脉给药困难，肌肉注射无效。直肠输注安定溶液提供了一个很好的解决方案。直肠安定凝胶现在在美国可以买到，但直肠使用静脉安定溶液是常见的做法。安定会引起呼吸抑制等副作用。劳拉西潘不会引起呼吸抑制，需要较低的呼吸抑制。虽然直肠溶液起效很快，但患者很难随手拿着它们，也很难快速给药，特别是在处理家庭外意外的癫痫发作时。溶液也有从直肠渗出的趋势。 在第一阶段，Biotek配制并测试了几种直肠劳拉西潘凝胶。在兔模型上，我们证明了适当配方的凝胶可以在直肠给药后15分钟内将劳拉西潘的血药浓度提高到10-30 ng/ml的治疗性水平。在这些研究中，选择了两个处方进行第二阶段的优化。优化后，将选择一个处方并在GMP下制备并进行稳定性测试。IND申请将提交给FDA，并将在12名正常健康志愿者中进行两种剂量水平的I期临床试验。临床研究的目的将是评估该凝胶的安全性和直肠刺激性，定量获得的血药浓度，建立剂量比例，并确定直肠劳拉西潘与静脉注射劳拉西潘的生物利用度。

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.