Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Feb 28:224:69-76.
doi: 10.1016/j.jconrel.2015.12.044. Epub 2015 Dec 28.

Delivery of ziconotide to cerebrospinal fluid via intranasal pathway for the treatment of chronic pain

Prashanth Manda  1 , Avadhesh Singh Kushwaha  1 , Santanu Kundu  2 , H N Shivakumar  3 , Seong Bong Jo  1 , S Narasimha Murthy  4
Affiliations

Delivery of ziconotide to cerebrospinal fluid via intranasal pathway for the treatment of chronic pain

Prashanth Manda et al. J Control Release. .

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.

Keywords: Cerebrospinal fluid; In situ gels; Intranasal; Ziconotide.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Chromatogram representing 125I and 125I ziconotide.
Figure 2
Figure 2
Negative mode ESI-MS spectra of free Iodine acquired on a Waters synapt HDMS.
Figure 3
Figure 3
Pharmacokinetics of ziconotide in the CSF following intrathecal (●) and intravenous (▲) administration.
Figure 4
Figure 4
In vitro permeation of ziconotide across the bovine olfactory mucosa in presence of control (◆), 0.1% chitosan (■), 0.25% chitosan (▲) and 0.5% chitosan (●).
Figure 5
Figure 5
Pharmacokinetic profile of ziconotide in CSF following intranasal administration of ziconotide with chitosan (■), without chitosan (◆) and intravenous (▲) administration of ziconotide.
Figure 6
Figure 6
Determination of gelation temperature, storage and loss modulus of 18% (■,□), 20% (●,○) and 22% (▲,△) KP 407. Filled symbols represent storage modulus and empty symbols represent loss modulus.
Figure 7
Figure 7
Pharmacokinetic profile of ziconotide in CSF following intranasal administration of ziconotide KP 407 without chitosan (▲), with chitosan (◆) and ziconotide solution with chitosan (■).
Figure 8
Figure 8
Pharmacokinetic profile of ziconotide in plasma following intranasal administration of ziconotide KP 407 without chitosan (X), with chitosan (+), ziconotide solution with chitosan (■) without chitosan (◆), i.v (▲) and intrathecal (●) administration of ziconotide solution.
See this image and copyright information in PMC

References

    1. Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. European journal of pain. 2006;10:287–287. - PubMed
    1. Scholz J, Woolf CJ. Can we conquer pain? Nature neuroscience. 2002;5:1062–1067. - PubMed
    1. Staats PS, Yearwood T, Charapata SG, Presley RW, Wallace MS, Byas-Smith M, Fisher R, Bryce DA, Mangieri EA, Luther RR. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. Jama. 2004;291:63–70. - PubMed
    1. Vlieghe P, Lisowski V, Martinez J, Khrestchatisky M. Synthetic therapeutic peptides: science and market. Drug discovery today. 2010;15:40–56. - PubMed
    1. Diao L, Meibohm B. Pharmacokinetics and pharmacokinetic–pharmacodynamic correlations of therapeutic peptides. Clinical pharmacokinetics. 2013;52:855–868. - PubMed

Publication types

MeSH terms