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Vaginal rings with exposed cores for sustained delivery of the HIV CCR5 inhibitor 5P12-RANTES.

Authors
  • McBride, John W1
  • Boyd, Peter1
  • Dias, Nicola2
  • Cameron, David2
  • Offord, Robin E3
  • Hartley, Oliver4
  • Kett, Vicky L1
  • Malcolm, R Karl5
  • 1 School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.
  • 2 Envigo, Huntingdon, Cambridgeshire, UK.
  • 3 Mintaka Foundation for Medical Research, Geneva, Switzerland. , (Switzerland)
  • 4 Mintaka Foundation for Medical Research, Geneva, Switzerland; Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. , (Switzerland)
  • 5 School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK. Electronic address: [email protected]
Type
Published Article
Journal
Journal of controlled release : official journal of the Controlled Release Society
Publication Date
Mar 28, 2019
Volume
298
Pages
1–11
Identifiers
DOI: 10.1016/j.jconrel.2019.02.003
PMID: 30731150
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Antiretroviral-releasing vaginal rings are at the forefront of ongoing efforts to develop microbicide-based strategies for prevention of heterosexual transmission of the human immunodeficiency virus (HIV). However, traditional ring designs are generally only useful for vaginal administration of relatively potent, lipophilic, and small molecular weight drug molecules that have sufficient permeability in the non-biodegradable silicone elastomer or thermoplastic polymers. Here, we report a novel, easy-to-manufacture 'exposed-core' vaginal ring that provides sustained release of the protein microbicide candidate 5P12-RANTES, an experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. In vitro release, mechanical, and stability testing demonstrated the utility and practicality of this novel ring design. In a sheep pharmacokinetic model, a ring containing two ¼-length excipient-modified silicone elastomer cores - each containing lyophilised 5P12-RANTES and exposed to the external environment by two large windows - provided sustained concentrations of 5P12-RANTES in vaginal fluid and vaginal tissue between 10 and 10,000 ng/g over 28days, at least 50 and up to 50,000 times the reported in vitro IC50 value. Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.

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