Delivery of ziconotide to cerebrospinal fluid via intranasal pathway for the treatment of chronic pain.
Delivery of ziconotide to cerebrospinal fluid via intranasal pathway for the treatment of chronic pain.
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DOI：
10.1016/j.jconrel.2015.12.044
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发表时间：
2016-02-28
期刊：
影响因子：
--
通讯作者：
Murthy SN
中科院分区：
文献类型：
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作者：
Manda P;Kushwaha AS;Kundu S;Shivakumar HN;Jo SB;Murthy SN
本研究的目的是研究通过鼻内给药将齐考诺肽递送至脑脊液（CSF）的可行性。以溶液或Kolliphor P 407凝胶（KP 407）的形式对Sprague-Dawley大鼠鼻内给予齐考诺肽。还研究了在制剂中掺入壳聚糖的效果。通过从枕大池收集CSF来研究CSF中药物的时间过程。研究了鞘内和静脉内（i.v）给予齐考诺肽后CSF中齐考诺肽的药代动力学。鞘内给药后，齐考诺肽在CSF中的消除速率常数为1.01 ± 0.34 h−1。静脉给药后，齐考诺肽在CSF中的Cmax和Tmax分别为37.78 ± 6.8 ng/mL和约2 h。与静脉给药（120 min）相比，鼻内给药（15 min）达到CSF中最大浓度所需的时间（Tmax）更短。壳聚糖的存在增强了齐考诺肽鼻内溶液和凝胶制剂的总体生物利用度。齐考诺肽溶液鼻内和静脉给药后，CSF中齐考诺肽的消除速率常数分别为0.54 ± 0.08 h-1和0.42 ± 0.10 h-1。然而，以原位形成凝胶的形式鼻内施用齐考诺肽显著降低消除速率。这些结果表明，鼻内给药可能是一种潜在的无创性和患者依从性的方法，将齐考诺肽递送至CSF以治疗慢性疼痛。
The purpose of the current study was to investigate the plausibility of delivery of ziconotide to the cerebrospinal fluid (CSF) via intranasal administration. Ziconotide was administered either in the form of solution or Kolliphor P 407 gels (KP 407) intranasally in Sprague-Dawley rats. The effect of incorporation of chitosan in the formulation was also investigated. Time course of drug in the CSF was investigated by collecting CSF from cisterna magna. Pharmacokinetics of ziconotide in CSF following intrathecal and intravenous (i.v) administration of ziconotide was investigated. Upon intrathecal administration the elimination rate constant of ziconotide in CSF was found to be 1.01 ± 0.34 h−1. The Cmax and Tmax of ziconotide in CSF following intravenous administration were found to be 37.78 ± 6.8 ng/mL and ~2 h respectively. The time required to attain maximum concentration (Tmax) in CSF was less upon intranasal administration (15 min) compared to i.v administration (120 min). Presence of chitosan enhanced the overall bioavailability of ziconotide from intranasal solution and gel formulations. The elimination rate constant of ziconotide in CSF following intranasal and intravenous administration of ziconotide solution was found to be 0.54 ± 0.08 h−1 and 0.42 ± 0.10 h−1 respectively. Whereas, intranasal administration of ziconotide in the form of in situ forming gel lowered the elimination rate significantly. These results suggest that intranasal administration could be a potential noninvasive and patient compliant method of delivering ziconotide to CSF to treat chronic pain.