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Sustained local delivery of structurally diverse HIV-1 microbicides released from sublimation enthalpy controlled matrices.

Gunaseelan S, Gallay PA, Bobardt MD, Dezzutti CS, Esch T, Maskiewicz R - Pharm. Res. (2012)

Bottom Line: Differences in matrix material sublimation enthalpies determined drug release and matrix erosion rates in a thermodynamically definable manner, in vitro and in vivo.Durations of release ranging from several days to several months were readily achieved.Subliming solid matrices show promise as a delivery system providing multi month intravaginal release of a wide range of HIV-1 microbicides.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, School of Pharmacy Loma Linda University, 11175 Campus Street, Chan Shun Pavilion 21018, Loma Linda, California 92350, USA.

ABSTRACT

Purpose: Use of coital-dependent products to prevent HIV-1 transmission has resulted in mixed success. We hypothesize that incorporation of antiviral drug candidates into a novel controlled delivery system will prolong their activity, making their use coital independent, thus increasing their chance of prophylactic success.

Methods: Tenofovir, emtricitabine, and C5A peptide HIV microbicides were mechanically incorporated into matrices comprising a series of subliming solids. Matrix sublimation rates and drug release rates were measured in three in vitro and one in vivo environments intended to model human vaginal interior. Antiviral activity studies evaluating matrix incorporated microbicides were performed using in vitro cell cultures and human ectocervical explants.

Results: Drug release rates were identical to matrix sublimation rates, and were zero order. Differences in matrix material sublimation enthalpies determined drug release and matrix erosion rates in a thermodynamically definable manner, in vitro and in vivo. Durations of release ranging from several days to several months were readily achieved. Prolonged duration of anti HIV-1 activity was shown for matrix incorporated microbicides, using ectocervical explant and cell culture models of HIV-1 infection.

Conclusion: Subliming solid matrices show promise as a delivery system providing multi month intravaginal release of a wide range of HIV-1 microbicides.

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Related in: MedlinePlus

Comparison of intravaginal sublimation rates in ewes for (a) NOR and (b) HMCS matrices relative to “accelerated” rates obtained in vitro under controlled convection conditions. Each plotted point represents a mean ± SEM (N = 4).
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Fig4: Comparison of intravaginal sublimation rates in ewes for (a) NOR and (b) HMCS matrices relative to “accelerated” rates obtained in vitro under controlled convection conditions. Each plotted point represents a mean ± SEM (N = 4).

Mentions: For NOR and HMCS matrices, intravaginal sublimation occurred (similar to in vitro measurements) at zero-order (constant) rates (Fig. 4a and b), with the 4.5 fold in vivo difference in erosion rates between the two materials being similar if not equivalent to the 6.3 fold difference in rates measured using the “accelerated” in vitro model. The fact that the thermodynamically expected differences in sublimation rates between NOR and HMCS were measured both in vitro and in vivo, suggests that even for the most volatile of the evaluated matrices the thermodynamically controlled surface sublimation step remains rate limiting.Fig. 4


Sustained local delivery of structurally diverse HIV-1 microbicides released from sublimation enthalpy controlled matrices.

Gunaseelan S, Gallay PA, Bobardt MD, Dezzutti CS, Esch T, Maskiewicz R - Pharm. Res. (2012)

Comparison of intravaginal sublimation rates in ewes for (a) NOR and (b) HMCS matrices relative to “accelerated” rates obtained in vitro under controlled convection conditions. Each plotted point represents a mean ± SEM (N = 4).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3473190&req=5

Fig4: Comparison of intravaginal sublimation rates in ewes for (a) NOR and (b) HMCS matrices relative to “accelerated” rates obtained in vitro under controlled convection conditions. Each plotted point represents a mean ± SEM (N = 4).
Mentions: For NOR and HMCS matrices, intravaginal sublimation occurred (similar to in vitro measurements) at zero-order (constant) rates (Fig. 4a and b), with the 4.5 fold in vivo difference in erosion rates between the two materials being similar if not equivalent to the 6.3 fold difference in rates measured using the “accelerated” in vitro model. The fact that the thermodynamically expected differences in sublimation rates between NOR and HMCS were measured both in vitro and in vivo, suggests that even for the most volatile of the evaluated matrices the thermodynamically controlled surface sublimation step remains rate limiting.Fig. 4

Bottom Line: Differences in matrix material sublimation enthalpies determined drug release and matrix erosion rates in a thermodynamically definable manner, in vitro and in vivo.Durations of release ranging from several days to several months were readily achieved.Subliming solid matrices show promise as a delivery system providing multi month intravaginal release of a wide range of HIV-1 microbicides.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, School of Pharmacy Loma Linda University, 11175 Campus Street, Chan Shun Pavilion 21018, Loma Linda, California 92350, USA.

ABSTRACT

Purpose: Use of coital-dependent products to prevent HIV-1 transmission has resulted in mixed success. We hypothesize that incorporation of antiviral drug candidates into a novel controlled delivery system will prolong their activity, making their use coital independent, thus increasing their chance of prophylactic success.

Methods: Tenofovir, emtricitabine, and C5A peptide HIV microbicides were mechanically incorporated into matrices comprising a series of subliming solids. Matrix sublimation rates and drug release rates were measured in three in vitro and one in vivo environments intended to model human vaginal interior. Antiviral activity studies evaluating matrix incorporated microbicides were performed using in vitro cell cultures and human ectocervical explants.

Results: Drug release rates were identical to matrix sublimation rates, and were zero order. Differences in matrix material sublimation enthalpies determined drug release and matrix erosion rates in a thermodynamically definable manner, in vitro and in vivo. Durations of release ranging from several days to several months were readily achieved. Prolonged duration of anti HIV-1 activity was shown for matrix incorporated microbicides, using ectocervical explant and cell culture models of HIV-1 infection.

Conclusion: Subliming solid matrices show promise as a delivery system providing multi month intravaginal release of a wide range of HIV-1 microbicides.

Show MeSH
Related in: MedlinePlus