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Formulation of the microbicide INP0341 for in vivo protection against a vaginal challenge by Chlamydia trachomatis.

Pedersen C, Slepenkin A, Andersson SB, Fagerberg JH, Bergström CA, Peterson EM - PLoS ONE (2014)

Bottom Line: Gelling agents (polymers) with inherent antimicrobial properties were chosen to maximize the total antimicrobial effect of the gel.Formulations with and without INP0341 afforded protection, but the inclusion of INP0341 increased the protection.The lack of toxicity was confirmed by in vitro assays using EpiVaginal tissues, which showed that a 24 h exposure to the gel formulation did not decrease the cell viability or the barrier function of the tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Uppsala University, Biomedical Center, Uppsala, Sweden.

ABSTRACT
The salicylidene acylhydrazide (SA) compounds have exhibited promising microbicidal properties. Previous reports have shown the SA compounds, using cell cultures, to exhibit activity against Chlamydia trachomatis, herpes simplex virus and HIV-1. In addition, using an animal model of a vaginal infection the SA compound INP0341, when dissolved in a liquid, was able to significantly protect mice from a vaginal infection with C. trachomatis. To expand upon this finding, in this report INP0341 was formulated as a vaginal gel, suitable for use in humans. Gelling agents (polymers) with inherent antimicrobial properties were chosen to maximize the total antimicrobial effect of the gel. In vitro formulation work generated a gel with suitable rheology and sustained drug release. A formulation containing 1 mM INP0341, 1.6 wt% Cremophor ELP (solubility enhancer) and 1.5 wt% poly(acrylic acid) (gelling and antimicrobial agent), was chosen for studies of efficacy and toxicity using a mouse model of a vaginal infection. The gel formulation was able to attenuate a vaginal challenge with C. trachomatis, serovar D. Formulations with and without INP0341 afforded protection, but the inclusion of INP0341 increased the protection. Mouse vaginal tissue treated with the formulation showed no indication of gel toxicity. The lack of toxicity was confirmed by in vitro assays using EpiVaginal tissues, which showed that a 24 h exposure to the gel formulation did not decrease the cell viability or the barrier function of the tissue. Therefore, the gel formulation described here appears to be a promising vaginal microbicide to prevent a C. trachomatis infection with the potential to be expanded to other sexually transmitted diseases.

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In vitro drug release.Comparison of in vitro INP0341 release from the gel formulation and from a 50% DMSO solution. A sustained release is observed from the gel, when INP0341 is solubilized in Cremophor ELP micelles.
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pone-0110918-g003: In vitro drug release.Comparison of in vitro INP0341 release from the gel formulation and from a 50% DMSO solution. A sustained release is observed from the gel, when INP0341 is solubilized in Cremophor ELP micelles.

Mentions: The release of INP0341 from the gel formulation was studied in vitro using Franz cells, to confirm that the gel formulation yields slow drug release. SVF without albumin was used as receptor liquid. The drug release was expected to be governed by Cremophor ELP diffusion, since INP0341 is solubilized in Cremophor ELP micelles in the gel. For comparison, INP0341 release was also studied in the absence of micelles, using 50 wt% DMSO in 25 mM acetate buffer (pH 5.2) as both dissolution media and receptor liquid. Figure 3 shows that the drug release is considerably slower from the gel, as compared to the DMSO solution. After 2 h, 56% of the dose has been released from the DMSO solution while only 2.7% has been released from the gel formulation. The Cremophor ELP-containing gel formulation therefore contributes to a sustained drug release (roughly 20 times slower) which corresponds well with the expected; the theoretical diffusion coefficient of INP0341 is 8.6×10−6 cm2/s (calculated using ADMET predictor 5.5), while the diffusion coefficient of a drug-containing Cremophor ELP micelle is around 0.4×10−6 cm2/s [20].


Formulation of the microbicide INP0341 for in vivo protection against a vaginal challenge by Chlamydia trachomatis.

Pedersen C, Slepenkin A, Andersson SB, Fagerberg JH, Bergström CA, Peterson EM - PLoS ONE (2014)

In vitro drug release.Comparison of in vitro INP0341 release from the gel formulation and from a 50% DMSO solution. A sustained release is observed from the gel, when INP0341 is solubilized in Cremophor ELP micelles.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214720&req=5

pone-0110918-g003: In vitro drug release.Comparison of in vitro INP0341 release from the gel formulation and from a 50% DMSO solution. A sustained release is observed from the gel, when INP0341 is solubilized in Cremophor ELP micelles.
Mentions: The release of INP0341 from the gel formulation was studied in vitro using Franz cells, to confirm that the gel formulation yields slow drug release. SVF without albumin was used as receptor liquid. The drug release was expected to be governed by Cremophor ELP diffusion, since INP0341 is solubilized in Cremophor ELP micelles in the gel. For comparison, INP0341 release was also studied in the absence of micelles, using 50 wt% DMSO in 25 mM acetate buffer (pH 5.2) as both dissolution media and receptor liquid. Figure 3 shows that the drug release is considerably slower from the gel, as compared to the DMSO solution. After 2 h, 56% of the dose has been released from the DMSO solution while only 2.7% has been released from the gel formulation. The Cremophor ELP-containing gel formulation therefore contributes to a sustained drug release (roughly 20 times slower) which corresponds well with the expected; the theoretical diffusion coefficient of INP0341 is 8.6×10−6 cm2/s (calculated using ADMET predictor 5.5), while the diffusion coefficient of a drug-containing Cremophor ELP micelle is around 0.4×10−6 cm2/s [20].

Bottom Line: Gelling agents (polymers) with inherent antimicrobial properties were chosen to maximize the total antimicrobial effect of the gel.Formulations with and without INP0341 afforded protection, but the inclusion of INP0341 increased the protection.The lack of toxicity was confirmed by in vitro assays using EpiVaginal tissues, which showed that a 24 h exposure to the gel formulation did not decrease the cell viability or the barrier function of the tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Uppsala University, Biomedical Center, Uppsala, Sweden.

ABSTRACT
The salicylidene acylhydrazide (SA) compounds have exhibited promising microbicidal properties. Previous reports have shown the SA compounds, using cell cultures, to exhibit activity against Chlamydia trachomatis, herpes simplex virus and HIV-1. In addition, using an animal model of a vaginal infection the SA compound INP0341, when dissolved in a liquid, was able to significantly protect mice from a vaginal infection with C. trachomatis. To expand upon this finding, in this report INP0341 was formulated as a vaginal gel, suitable for use in humans. Gelling agents (polymers) with inherent antimicrobial properties were chosen to maximize the total antimicrobial effect of the gel. In vitro formulation work generated a gel with suitable rheology and sustained drug release. A formulation containing 1 mM INP0341, 1.6 wt% Cremophor ELP (solubility enhancer) and 1.5 wt% poly(acrylic acid) (gelling and antimicrobial agent), was chosen for studies of efficacy and toxicity using a mouse model of a vaginal infection. The gel formulation was able to attenuate a vaginal challenge with C. trachomatis, serovar D. Formulations with and without INP0341 afforded protection, but the inclusion of INP0341 increased the protection. Mouse vaginal tissue treated with the formulation showed no indication of gel toxicity. The lack of toxicity was confirmed by in vitro assays using EpiVaginal tissues, which showed that a 24 h exposure to the gel formulation did not decrease the cell viability or the barrier function of the tissue. Therefore, the gel formulation described here appears to be a promising vaginal microbicide to prevent a C. trachomatis infection with the potential to be expanded to other sexually transmitted diseases.

Show MeSH
Related in: MedlinePlus