A NOVEL METHOD TO TREAT CHRONIC PAIN

描述（由申请人提供）：齐iconotide (？- concontoxin大小约3kDa)是一种治疗慢性疼痛的强效药物。由于生物利用度差和与全身给药相关的严重副作用，目前仅使用鞘内泵给药。然而，由于与鞘内分娩相关的并发症，并不是很多人能够从中获益。因此，迫切需要开发一种替代的、无创的、患者适应的、有效的将齐iconotide输送到脑脊液（CSF）的方法。此外，还需要开发能够维持药物在脑脊液中滞留的药物传递系统，以延长其药理活性。我们假设齐iconotide可以通过鼻内给药进入脑脊液，使用适当的屏障调节剂可以显著提高其对脑脊液的生物利用度。此外，我们还假设纳米共胶束系统可以显著提高齐iconotide在脑脊液中的生物利用度并延长其保留时间。我们提出了四个具体目标来评估我们的假设。在目标1中，我们建议开发新的鼻内给药系统，与适当的屏障调节剂（bma）结合，将齐iconotide输送到脑脊液。我们将在体外研究BMAs存在和不存在的情况下，药物和药物- tpgs纳米共胶束在嗅粘膜上的渗透。将使用合适的聚合物开发三种铅（原位胶凝溶液）配方，以促进延长保留和药物递送。在目的2中，我们建议研究鼻内给药铅制剂后齐iconotide在脑脊液中的药代动力学。先导制剂将在斯普拉格道利大鼠中经鼻给药，在脊髓液中给药

DESCRIPTION (provided by applicant): 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 ra 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. PUBLIC HEALTH RELEVANCE: Ziconotide, an effective drug used in the treatment of chronic pain, is currently administered only by intrathecal route. Systemic delivery of ziconotide is associated with profound side effects. Therefore, we propose to investigate the plausibility of delivering drugs to the cerebrospinal fluid via intranasal route, which is likely to be more patien compliant than the current modes of administration.