A NOVEL METHOD TO TREAT CHRONIC PAIN

SRI Ganeshaya Namaha 摘要 齐康肽是一种治疗慢性疼痛的强效药物，大小约3 kDa。它目前是 由于生物利用度低和严重的副作用，只能使用鞘内泵给药 有系统的管理。然而，由于并发症，能够从中受益的人并不多 与鞘内分娩有关。因此，存在一种迫切的、尚未得到满足的需求，即开发一种替代方案， 非侵入性、患者依从性和有效的脑脊液(CSF)给药方法。在……里面 此外，需要开发能够维持药物在脑脊液中的滞留的药物输送系统以 延长其药理活性。我们推测齐康肽可以通过鼻腔给脑脊液。 给药和使用适当的屏障调节剂将显著改善其 脑脊液的生物利用度。此外，我们还假设纳米共胶束系统将显著改善 其生物利用度及在脑脊液中的滞留时间延长。我们提出了四个具体目标 评估我们的假设。在目标1中，我们建议开发新的鼻腔给药系统， 加入适当的屏障调节剂(BMA)以将齐康肽输送到 脑脊液。药物及药物-TPGS纳米复合胶束对嗅黏膜的渗透作用 将在体外进行研究，在有无BMA的情况下进行。三种铅(原位胶凝液)配方 将使用合适的聚合物进行开发，以促进长时间保留和药物输送。在目标2中，我们 建议研究齐康肽鼻腔给药后在脑脊液中的药代动力学 铅配方。铅制剂将在SpragueDawley大鼠鼻内给药，该药物 将在不同的时间点采集脊髓液中的药物，并用放射免疫法测定药物的含量。 该制剂的组成将被修改，以达到脑脊液中药物的有效水平。在目标3中，我们 计划在大鼠模型中研究含铅鼻腔制剂的安全性/毒性。随之而来的是频繁和长期的 给药后，鼻粘膜、嗅黏膜、嗅球、脑和脊髓将被分离并 接受组织学检查。此外，免疫组织化学研究将有助于我们了解 利康宁的吸收。在目标4中，我们建议研究鼻用制剂在大鼠身上的药效学效果。 选定的铅制剂将在大鼠模型上进行后爪和口腔福尔马林试验。福尔马林引起的退缩 爪部的反应将使用自动痛觉分析仪记录，并在面部福尔马林测试中手动记录。要加入的组 鞘内给药将作为阳性对照。 拟议项目的成功完成将产生一种新的给药方式，用于快速和长期地向脑脊液中注射齐可肽 在治疗慢性疼痛中的作用。我们坚信，齐康肽鼻腔制剂的开发将 显著提高慢性疼痛患者的生活质量，并增加患者数量，这将 从这种药物中受益。

Sri Ganeshaya namaha ABSTRACT Ziconotide (¿-conotoxin of size ~3kDa) is a potent drug used for the treatment of chronic pain. It is currently administered only using intrathecal pump owing to the poor bioavailability and profound side effects associated with systemic administration. However, not many people are able to derive its benefit due to complications associated with the intrathecal delivery. Therefore, there is an urgent, unmet need to develop an alternative, noninvasive, patient compliant and effective method of delivering ziconotide to cerebrospinal fluid (CSF). In addition, there is need to develop drug delivery systems which can sustain the retention of drug in CSF to prolong its pharmacological activity. We hypothesize that ziconotide could be delivered to CSF via intranasal administration and the use of appropriate barrier modulating agents would significantly improve its bioavailability to CSF. Further, we also hypothesize that nano co-micellar systems would significantly improve the bioavailability and prolong the retention time of ziconotide in the CSF. We propose four specific aims to assess our hypotheses. In aim 1, we propose to develop novel intranasal drug delivery systems, incorporated with appropriate barrier modulating agents (BMAs) to deliver ziconotide to the cerebrospinal fluid. The permeation of drug and drug-TPGS nano co-micelles across the olfactory mucosa will be investigated in vitro, in presence and absence of BMAs. Three lead (in situ gelling solution) formulations will be developed using suitable polymers to facilitate prolonged retention and drug delivery. In aim 2, we propose to investigate the pharmacokinetics of ziconotide in CSF, following intranasal administration of lead formulations. The lead formulations will be administered intranasally in sprague dawley rats, the drug in the spinal fluid will be sampled at different time points and the drug will be measured by radioimmunoassay. The composition of the formulation will be modified to achieve effective levels of drug in the CSF. In aim 3, we plan to investigate the safety/toxicity of the lead intranasal formulations in rat model. Following frequent and prolonged administration of the formulation, the nasal mucosa, olfactory mucosa, olfactory bulb, brain and spinal cord will be isolated and subjected to histological investigations. In addition, the immunohistochemistry studies would help us understand the pathways of absorption of ziconotide. In aim 4, we propose to investigate the pharmacodynamic efficacy of intranasal formulations in rats. The selected lead formulations will be subjected to hind paw and orofacial formalin tests in rat model. The formalin induced flinch response in the paw will be recorded using automated nociception analyzer and manually in facial formalin test. The group to which ziconotide is administered intrathecally will serve as positive control. The successful completion of the proposed project will result in a novel mode of delivery of ziconotide to CSF for rapid and prolonged effect in the treatment of chronic pain. We strongly believe that development of an intranasal formulation of ziconotide would significantly improve the quality of life of patients suffering from chronic pain and increase the size of the patient population that would benefit from this drug.