An evaluation of polycaprolactone matrices for vaginal delivery of the antiviral, tenofovir, in preventing heterosexual transmission of HIV

Dang, Nhung T. T., Sivakumaran, Haran, Harrich, David and Coombes, Allan G. A. (2013) An evaluation of polycaprolactone matrices for vaginal delivery of the antiviral, tenofovir, in preventing heterosexual transmission of HIV. Journal of Pharmaceutical Sciences, 102 10: 3725-3735. doi:10.1002/jps.23684

Author Dang, Nhung T. T.
Sivakumaran, Haran
Harrich, David
Coombes, Allan G. A.
Title An evaluation of polycaprolactone matrices for vaginal delivery of the antiviral, tenofovir, in preventing heterosexual transmission of HIV
Journal name Journal of Pharmaceutical Sciences   Check publisher's open access policy
ISSN 0022-3549
Publication date 2013-10-01
Sub-type Article (original research)
DOI 10.1002/jps.23684
Open Access Status Not Open Access
Volume 102
Issue 10
Start page 3725
End page 3735
Total pages 11
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Language eng
Abstract Nevirapine (NVP) was loaded in polycaprolactone (PCL) matrices to produce vaginal inserts with the aim of preventing HIV transmission. NVP dispersions in PCL were prepared, at 10% (w/w) theoretical loading, measured with respect to the PCL content of the matrices, in the form of (1) NVP only, (2) a physical mixture of NVP with polyethylene glycol (PEG) 6000 or (c) a solid dispersion (SD) with PEG produced by co-dissolution in ethanol. Characterisation of SD by differential scanning calorimetry and attenuated total reflectance-Fourier transform infrared spectroscopy suggested transformation of the crystalline structure of NVP to an amorphous form which consequently increased the dissolution rate of drug. A low-loading efficiency of 13% was obtained for NVP-loaded matrices and less than 20% for matrices prepared using physical mixtures of drug and PEG. The loading efficiency was improved significantly to around 40% when a 1:4 NVP-PEG SD was used for matrix production. After 30 days, 40% of the drug content was released from NVP-loaded matrices, 55% from matrices containing 1:4 NVP-PEG physical mixtures and 60% from matrices loaded with 1:4 NVP-PEG SDs. The in vitro anti-viral activity of released NVP was assessed using a luciferase reporter gene assay following the infection of HeLa cells with pseudo-typed HIV-1. NVP released from PCL matrices in simulated vaginal fluid retained over 75% anti-HIV activity compared with the non-formulated NVP control. In conclusion, 1:4 NVP-PEG SDs when loaded in PCL matrices increase drug loading efficiency and improve release behaviour.
Formatted abstract
Tenofovir was incorporated in controlled-release polycaprolactone (PCL) matrices designed for production of vaginal inserts for prevention of HIV transmission. Rapid cooling of suspensions of the drug powder in PCL solution resulted in micro-porous matrices with tenofovir loadings up to 12% (w/w) and high incorporation efficiencies in excess of 90%. The release behaviour of tenofovir in simulated vaginal fluid (SVF) demonstrated high delivery efficiency of 85%–99% over 30 days and could be described effectively by a first-order kinetics model giving a mean value of 0.126 day-1 for the release constant (k1). Tenofovir released from PCL matrices into SVF exhibited high relative activity ranging from 70 to 90%, against pseudo-typed HIV-1-infected HeLa cells. The inhibitory activity of tenofovir standard solutions in SVF provided an IC50 value of 2.38 μM. Besides confirming high levels of in vitro antiviral activity, the predicted concentrations of tenofovir, which would be released from a PCL intra-vaginal ring in vivo, exceeded the IC50 value for HIV-1 by a factor of 35–200 and clinically protective concentrations by a factor of 50. These findings recommend further investigations of antiviral-loaded PCL matrices for controlling heterosexual transmission of HIV.
Keyword Intra-vaginal inserts
Polycaprolactone matrices
Drug release
Drug delivery system
Mathematical model
In vitro model
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Pharmacy Publications
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Citation counts: TR Web of Science Citation Count  Cited 5 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 10 Sep 2013, 08:52:39 EST by Nhung Dang on behalf of School of Pharmacy