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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

Natural log of matrix surface erosion rate constant (37°C, controlled convection) as a function of matrix material sublimation enthalpy. Each plotted point represents a mean value (N = 4).
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Fig3: Natural log of matrix surface erosion rate constant (37°C, controlled convection) as a function of matrix material sublimation enthalpy. Each plotted point represents a mean value (N = 4).

Mentions: The unprecedented range of release rates can be correlated to enthalpies of sublimation specific to each employed matrix material (Fig. 3), and allows a sublimation/release rate range of more than 6 (base e) log units. This correlation also suggests that the microbicide release mechanism is different from currently employed diffusion, dissolution, or hydrolytically mediated erosion processes for drug delivery. Sustained release of powdered drug substances through their incorporation into hydrophobic matrix monoliths where liberation of active agent occurs through sublimation driven surface erosion of matrix material, has therefore not previously been employed for drug delivery (26,27). Since the range of available sublimation rates is broad, the potential for short-term but continuous and controlled rectal delivery of HIV-1 microbicides also exists.Fig. 3


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)

Natural log of matrix surface erosion rate constant (37°C, controlled convection) as a function of matrix material sublimation enthalpy. Each plotted point represents a mean value (N = 4).
© Copyright Policy
Related In: Results  -  Collection

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

Fig3: Natural log of matrix surface erosion rate constant (37°C, controlled convection) as a function of matrix material sublimation enthalpy. Each plotted point represents a mean value (N = 4).
Mentions: The unprecedented range of release rates can be correlated to enthalpies of sublimation specific to each employed matrix material (Fig. 3), and allows a sublimation/release rate range of more than 6 (base e) log units. This correlation also suggests that the microbicide release mechanism is different from currently employed diffusion, dissolution, or hydrolytically mediated erosion processes for drug delivery. Sustained release of powdered drug substances through their incorporation into hydrophobic matrix monoliths where liberation of active agent occurs through sublimation driven surface erosion of matrix material, has therefore not previously been employed for drug delivery (26,27). Since the range of available sublimation rates is broad, the potential for short-term but continuous and controlled rectal delivery of HIV-1 microbicides also exists.Fig. 3

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