Sustained release of microbicides by newly engineered vaginal rings.
OBJECTIVE
An effective vaginal microbicide against sexual HIV transmission remains elusive, with requirements for adherence to appropriate application of effective, nontoxic products being a major deterrent. We explored methods to enable sustained release of combinations of antiretroviral microbicides, utilizing intravaginal rings composed of biosoluble Acacia gum or nonbiodegradable hydrogel of 2-hydroxyethyl methacrylate and sodium methacrylate, materials approved for use by the US Food and Drug Administration.


METHODS
The reverse transcriptase inhibitors TMC120, PMPA, 3'-azido-3'-deoxythymidine, and a newly characterized anti-HIV agent, Boc-lysinated betulonic acid, were incorporated into vaginal rings with different combinations. Daily and cumulative release rates of these inhibitors in ring eluates were determined by high-performance liquid chromatography, gas chromatography, or immunoassay. Anti-HIV effects were measured by assessment of p24 Gag antigen in T-cell cultures exposed to HIV-1 isolates.


RESULTS
Drug release rates were sustained at concentrations higher than the minimum effective dose for HIV inhibition. The release was maintained for no less than 15 and 28 days from the Acacia gum and 2-hydroxyethyl methacrylate and sodium methacrylate rings, respectively. Boc-lysinated betulonic acid showed more than 90% inhibition of HIV-1 infection in H9 cells, with little toxicity to normal cells.


CONCLUSIONS
The intravaginal rings described here are capable of efficacious drug delivery. Incorporation of several antiretroviral agents, including betulinol derivatives, which act at multiple levels of the HIV life cycle, may provide a synergistic effect to achieve higher efficacy on the inhibition of HIV infection.
Saxena
Brij B
BB
Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, 515 East 71st Street, Room #S-412, New York, NY 10021, USA. brs2003@med.cornell.edu
Han
Young A
YA
Fu
Dingyi
D
Rathnam
Premila
P
Singh
Mukul
M
Laurence
Jeffrey
J
Lerner
Sidney
S
D000282:Administration, Intravaginal; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D003274:Contraceptive Devices, Female; D016503:Drug Delivery Systems / Q000295:instrumentation*; D005260:Female; D015683:Gene Products, gag / Q000378:metabolism; D006170:Gum Arabic / Q000627:therapeutic use; D015658:HIV Infections / Q000517:prevention & control*; D006801:Humans; D020100:Hydrogels / Q000627:therapeutic use; D007118:Immunoassay; D008689:Methacrylates / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage*; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D015683:Gene Products, gag; D020100:Hydrogels; D008689:Methacrylates; D018894:Reverse Transcriptase Inhibitors; C005044:hydroxyethyl methacrylate; D006170:Gum Arabic