title: Delivery of ziconotide to cerebrospinal fluid via intranasal pathway for the treatment of chronic pain.
abstract: 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±0.34h(-1). The Cmax and Tmax of ziconotide in CSF following intravenous administration were found to be 37.78±6.8ng/mL and ~2h respectively. The time required to attain maximum concentration (Tmax) in CSF was less upon intranasal administration (15min) compared to i.v. administration (120min). 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±0.08h(-1) and 0.42±0.10h(-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.
authors.affiliation: Department of Pharmaceutics and Drug Delivery, The University of Mississippi, University, MS 38677, USA.
authors.forename: Prashanth
authors.initials: P
authors.lastname: Manda
authors.affiliation: Department of Pharmaceutics and Drug Delivery, The University of Mississippi, University, MS 38677, USA.
authors.forename: Avadhesh Singh
authors.initials: AS
authors.lastname: Kushwaha
authors.affiliation: Dave C. Swalm School of Chemical Engineering, Mississippi State University, MS 39762, USA.
authors.forename: Santanu
authors.initials: S
authors.lastname: Kundu
authors.affiliation: Institute for Drug Delivery & Biomedical Research, Bangalore, Karnataka, India; KLE's University College of Pharmacy, Bangalore, Karnataka, India.
authors.forename: H N
authors.initials: HN
authors.lastname: Shivakumar
authors.affiliation: Department of Pharmaceutics and Drug Delivery, The University of Mississippi, University, MS 38677, USA.
authors.forename: Seong Bong
authors.initials: SB
authors.lastname: Jo
authors.affiliation: Department of Pharmaceutics and Drug Delivery, The University of Mississippi, University, MS 38677, USA; Institute for Drug Delivery & Biomedical Research, Bangalore, Karnataka, India.
authors.forename: S Narasimha
authors.initials: SN
authors.lastname: Murthy
mesh_terms: D000281:Administration, Intranasal; D061605:Administration, Intravenous; D000700:Analgesics / Q000008:administration & dosage / Q000134:cerebrospinal fluid* / Q000627:therapeutic use*; D000818:Animals; D001682:Biological Availability; D059350:Chronic Pain / Q000188:drug therapy*; D016503:Drug Delivery Systems; D005782:Gels; D007278:Injections, Spinal; D008297:Male; D009831:Olfactory Mucosa / Q000378:metabolism; D019999:Pharmaceutical Solutions; D051381:Rats; D017207:Rats, Sprague-Dawley; D014783:Viscosity; D020960:omega-Conotoxins / Q000008:administration & dosage / Q000134:cerebrospinal fluid* / Q000627:therapeutic use*
chemical_list: D000700:Analgesics; D005782:Gels; D019999:Pharmaceutical Solutions; D020960:omega-Conotoxins; C078452:ziconotide
keywords: Cerebrospinal fluid; In situ gels; Intranasal; Ziconotide