Limits...
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.

Show MeSH

Related in: MedlinePlus

Anti-HIV-1 activity prolongation of (a) tenofovir, (b) emtricitabine, and (c) bC5A in human macrophage cell culture during delivery from HMCS, PF-11, PF-12, and CDD matrices. Antiviral activity prolongation in TZM reporter cells due to release of (d) tenofovir, (e) emtricitabine, and (f) bC5A from HMCS, PF-11, PF-12, and CDD matrices. The error bars represent standard errors of triplicates.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3473190&req=5

Fig7: Anti-HIV-1 activity prolongation of (a) tenofovir, (b) emtricitabine, and (c) bC5A in human macrophage cell culture during delivery from HMCS, PF-11, PF-12, and CDD matrices. Antiviral activity prolongation in TZM reporter cells due to release of (d) tenofovir, (e) emtricitabine, and (f) bC5A from HMCS, PF-11, PF-12, and CDD matrices. The error bars represent standard errors of triplicates.

Mentions: To further demonstrate the ability of subliming solid based delivery to enhance and prolong antiviral activity of TDF, bC5A, and FTC, durations of protection against HIV-1 challenge were determined using human macrophages and TZM reporter cell cultures (40), maintained in a low convection environment to provide an alternate approximation of the vaginal interior. The panels in Fig. 7a-c show that for macrophages infected with HIV-1 (GFP), complete protection by all three microbicides was maintained for at least 3 weeks, regardless of whether the drug incorporating matrix material was HMCS, PF-11, PF-12, or CDD. However, by the fourth week only the microbicides incorporated into slowest subliming matrix (CDD) were still providing complete protection, with durations of residual protection provided by the other matrices being inversely proportional to their intrinsic rates of sublimation (Fig. 2a and b). In comparison, unformulated microbicides (aqueous solutions in culture medium) in all cases provided fewer than 2 weeks of complete protection. Anti-HIV-1 activity prolongation experiments employing TZM reporter cells (Fig. 7d-f), cultured under the same low convection conditions, appeared to show complete elimination of viral infection (at least out to 30 days) regardless of whether the microbicide was TDF, FTC or bC5A, when released from any of the four matrix materials. Aqueous solutions of the microbicides on the other hand could not prevent re-establishment of infections, which in all cases occurred after only 7–12 days of continuous incubation.Fig. 7


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)

Anti-HIV-1 activity prolongation of (a) tenofovir, (b) emtricitabine, and (c) bC5A in human macrophage cell culture during delivery from HMCS, PF-11, PF-12, and CDD matrices. Antiviral activity prolongation in TZM reporter cells due to release of (d) tenofovir, (e) emtricitabine, and (f) bC5A from HMCS, PF-11, PF-12, and CDD matrices. The error bars represent standard errors of triplicates.
© Copyright Policy
Related In: Results  -  Collection

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

Fig7: Anti-HIV-1 activity prolongation of (a) tenofovir, (b) emtricitabine, and (c) bC5A in human macrophage cell culture during delivery from HMCS, PF-11, PF-12, and CDD matrices. Antiviral activity prolongation in TZM reporter cells due to release of (d) tenofovir, (e) emtricitabine, and (f) bC5A from HMCS, PF-11, PF-12, and CDD matrices. The error bars represent standard errors of triplicates.
Mentions: To further demonstrate the ability of subliming solid based delivery to enhance and prolong antiviral activity of TDF, bC5A, and FTC, durations of protection against HIV-1 challenge were determined using human macrophages and TZM reporter cell cultures (40), maintained in a low convection environment to provide an alternate approximation of the vaginal interior. The panels in Fig. 7a-c show that for macrophages infected with HIV-1 (GFP), complete protection by all three microbicides was maintained for at least 3 weeks, regardless of whether the drug incorporating matrix material was HMCS, PF-11, PF-12, or CDD. However, by the fourth week only the microbicides incorporated into slowest subliming matrix (CDD) were still providing complete protection, with durations of residual protection provided by the other matrices being inversely proportional to their intrinsic rates of sublimation (Fig. 2a and b). In comparison, unformulated microbicides (aqueous solutions in culture medium) in all cases provided fewer than 2 weeks of complete protection. Anti-HIV-1 activity prolongation experiments employing TZM reporter cells (Fig. 7d-f), cultured under the same low convection conditions, appeared to show complete elimination of viral infection (at least out to 30 days) regardless of whether the microbicide was TDF, FTC or bC5A, when released from any of the four matrix materials. Aqueous solutions of the microbicides on the other hand could not prevent re-establishment of infections, which in all cases occurred after only 7–12 days of continuous incubation.Fig. 7

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