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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

(a) Viability of human PBMC cells during 10 days exposure to HMCS, PF-12, ADM and CDD matrices. (b) Viability of cultured T-lymphocytes and (c) macrophages during 12 and 20 days exposures to HMCS, PF-11, PF-12, and CDD matrices. Data presented in (a), (b) and (c) are expressed in percentage of viable cells. The error bars in (a), (b) and (c) represent standard errors of duplicates. Data shown in panels (a), (b) and (c) are each representative of two independent experiments. (d) Ex vivo viability of human ectocervical tissue during 5 days exposure to CDD, PF-11, and HMCS matrices. The data represent the mean ± SD of three independent tissues performed in duplicate. The viability of the N9-treated tissues were significantly reduced from control (untreated) tissues (P < 0.05) (Wilcoxon T-test).
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Fig5: (a) Viability of human PBMC cells during 10 days exposure to HMCS, PF-12, ADM and CDD matrices. (b) Viability of cultured T-lymphocytes and (c) macrophages during 12 and 20 days exposures to HMCS, PF-11, PF-12, and CDD matrices. Data presented in (a), (b) and (c) are expressed in percentage of viable cells. The error bars in (a), (b) and (c) represent standard errors of duplicates. Data shown in panels (a), (b) and (c) are each representative of two independent experiments. (d) Ex vivo viability of human ectocervical tissue during 5 days exposure to CDD, PF-11, and HMCS matrices. The data represent the mean ± SD of three independent tissues performed in duplicate. The viability of the N9-treated tissues were significantly reduced from control (untreated) tissues (P < 0.05) (Wilcoxon T-test).

Mentions: Subliming solid matrix materials under investigation appear to have low toxicity and acceptable biocompatibility. Human PBMC cell culture remained 100% viable after 10 days exposure to partially immersed HMCS, PF-12, ADM, and CDD matrix discs (Fig. 5a). Other intravaginal HIV-1 target cells such as human T-lymphocytes (Fig. 5b) and macrophages (Fig. 5c) exhibited full viabilities over 12 and 20 day periods of continuous exposure to HMCS, PF-11, PF-12, and CDD pellets. A saponin control demonstrated intrinsic sensitivity of each cell type to toxic substances. Viability of ectocervical tissue after 5 days continuous exposure to the different subliming matrix discs did not differ from control tissue cultured in parallel (Fig. 5d). Nonoxonyl-9 (N9) served as a toxic substance control. In summary, no evidence of sub-acute toxicity was observed with any of the matrix materials, whether evaluated in ectocervical tissue, macrophages, T-lymphocytes, or PBMC. This very preliminary indication of low toxicity for our delivery system provides the basis for more extensive future studies evaluating local irritation potential, and chronic toxicology assessment intravaginally and systemically. The ultimate clinical viability of sustained intravaginal microbicide release in general, and the potentially long-term intravaginal exposure to vaporized subliming solids, will require demonstration of acceptable drug product toxicology on a case by case basis for each particular microbicide plus subliming matrix combination.Fig. 5


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)

(a) Viability of human PBMC cells during 10 days exposure to HMCS, PF-12, ADM and CDD matrices. (b) Viability of cultured T-lymphocytes and (c) macrophages during 12 and 20 days exposures to HMCS, PF-11, PF-12, and CDD matrices. Data presented in (a), (b) and (c) are expressed in percentage of viable cells. The error bars in (a), (b) and (c) represent standard errors of duplicates. Data shown in panels (a), (b) and (c) are each representative of two independent experiments. (d) Ex vivo viability of human ectocervical tissue during 5 days exposure to CDD, PF-11, and HMCS matrices. The data represent the mean ± SD of three independent tissues performed in duplicate. The viability of the N9-treated tissues were significantly reduced from control (untreated) tissues (P < 0.05) (Wilcoxon T-test).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3473190&req=5

Fig5: (a) Viability of human PBMC cells during 10 days exposure to HMCS, PF-12, ADM and CDD matrices. (b) Viability of cultured T-lymphocytes and (c) macrophages during 12 and 20 days exposures to HMCS, PF-11, PF-12, and CDD matrices. Data presented in (a), (b) and (c) are expressed in percentage of viable cells. The error bars in (a), (b) and (c) represent standard errors of duplicates. Data shown in panels (a), (b) and (c) are each representative of two independent experiments. (d) Ex vivo viability of human ectocervical tissue during 5 days exposure to CDD, PF-11, and HMCS matrices. The data represent the mean ± SD of three independent tissues performed in duplicate. The viability of the N9-treated tissues were significantly reduced from control (untreated) tissues (P < 0.05) (Wilcoxon T-test).
Mentions: Subliming solid matrix materials under investigation appear to have low toxicity and acceptable biocompatibility. Human PBMC cell culture remained 100% viable after 10 days exposure to partially immersed HMCS, PF-12, ADM, and CDD matrix discs (Fig. 5a). Other intravaginal HIV-1 target cells such as human T-lymphocytes (Fig. 5b) and macrophages (Fig. 5c) exhibited full viabilities over 12 and 20 day periods of continuous exposure to HMCS, PF-11, PF-12, and CDD pellets. A saponin control demonstrated intrinsic sensitivity of each cell type to toxic substances. Viability of ectocervical tissue after 5 days continuous exposure to the different subliming matrix discs did not differ from control tissue cultured in parallel (Fig. 5d). Nonoxonyl-9 (N9) served as a toxic substance control. In summary, no evidence of sub-acute toxicity was observed with any of the matrix materials, whether evaluated in ectocervical tissue, macrophages, T-lymphocytes, or PBMC. This very preliminary indication of low toxicity for our delivery system provides the basis for more extensive future studies evaluating local irritation potential, and chronic toxicology assessment intravaginally and systemically. The ultimate clinical viability of sustained intravaginal microbicide release in general, and the potentially long-term intravaginal exposure to vaporized subliming solids, will require demonstration of acceptable drug product toxicology on a case by case basis for each particular microbicide plus subliming matrix combination.Fig. 5

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