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


CONCLUSIONS
Subliming solid matrices show promise as a delivery system providing multi month intravaginal release of a wide range of HIV-1 microbicides.
Department of Pharmaceutical Sciences, School of Pharmacy Loma Linda University, 11175 Campus Street, Chan Shun Pavilion 21018, Loma Linda, California 92350, USA.
Simi
S
Gunaseelan
Philippe A
PA
Gallay
Michael D
MD
Bobardt
Charlene S
CS
Dezzutti
Timothy
T
Esch
Richard
R
Maskiewicz
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000737:chemistry*; D002478:Cells, Cultured; D003274:Contraceptive Devices, Female; D003692:Delayed-Action Preparations; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D016503:Drug Delivery Systems / Q000379:methods*; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects; D063065:Organophosphonates / Q000008:administration & dosage; D012756:Sheep; D013329:Structure-Activity Relationship; D000074706:Sublimation, Chemical; D013601:T-Lymphocytes / Q000187:drug effects; D000068698:Tenofovir
D019380:Anti-HIV Agents; D003692:Delayed-Action Preparations; D063065:Organophosphonates; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine