Abstract
Antiretroviral-releasing vaginal rings are at the forefront of ongoing efforts to develop microbicide-based strategies for prevention of heterosexual transmission of the human immunodeficiency virus (HIV). However, traditional ring designs are generally only useful for vaginal administration of relatively potent, lipophilic, and small molecular weight drug molecules that have sufficient permeability in the non-biodegradable silicone elastomer or thermoplastic polymers. Here, we report a novel, easy-to-manufacture ‘exposed-core’ vaginal ring that provides sustained release of the protein microbicide candidate 5P12-RANTES, an experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. In vitro release, mechanical, and stability testing demonstrated the utility and practicality of this novel ring design. In a sheep pharmacokinetic model, a ring containing two ¼-length excipient-modified silicone elastomer cores – each containing lyophilised 5P12-RANTES and exposed to the external environment by two large windows – provided sustained concentrations of 5P12-RANTES in vaginal fluid and vaginal tissue between 10 and 10,000 ng/g over 28days, at least 50 and up to 50,000 times the reported in vitro IC50 value.
Highlights
Vaginal rings for controlled release of drug substances to the human vagina were first described in 1970 [1,2,3] following earlier reports demonstrating drug permeation through polysiloxane tubes when implanted in the ventricular myocardium of dogs [4,5], subdermally in ewes [6] and subdermally in rats [7]
Much of the innovation in vaginal ring design during recent years has been driven by efforts to develop microbicidal vaginal rings for prevention of sexual transmission of the human immunodeficiency virus (HIV) and multipurpose prevention technology (MPT) rings for simultaneous prevention of HIV, pregnancy, and/or sexually transmitted infections [11,12,13]
Pharmacokinetic concentrations of 5P12-RANTES obtained with these sustained release vaginal rings were significantly lower than those reported previously for aqueous vaginal gel formulations in the sheep model, where vaginal fluid concentrations declined from a high of 106 to 107 ng/g at 1 h and 102 to 104 ng/g at 96 h post dosing and vaginal tissue concentrations ranged from 105 to 106 ng/g at 12 h post dose [41]. This new, simple to manufacture, vaginal ring design – comprising one or more drug-loaded cores exposed to the external environment via orifices or windows in the overmolded sheath – has demonstrated potential for sustained release of the model protein lysosome and the antiretroviral protein 5P12-RANTES, and presumably might be useful for release of other macromolecular drugs
Summary
Vaginal rings for controlled release of drug substances to the human vagina were first described in 1970 [1,2,3] following earlier reports demonstrating drug permeation through polysiloxane tubes when implanted in the ventricular myocardium of dogs [4,5], subdermally in ewes [6] and subdermally in rats [7]. The active pharmaceutical ingredients in these vaginal ring products are all highly potent, small molecular weight (< 540 g/mol), lipophilic (log P > 2) steroids or antiviral molecules (Table 1, Fig. 1) that can readily permeate the hydrophobic silicone elastomers and thermoplastic polymers to offer clinically significant release rates. By using more innovative vaginal ring designs and alternative polymer materials, researchers have demonstrated effective release of relatively hydrophilic small-molecule antiviral molecules (e.g. tenofovir [14,15,16,17], tenofovir disoproxil fumarate [18,19,20,21], acyclovir [17,22,23,24], emtricitabine [19,20]), peptides (e.g. leuprolide acetate [25], T-1249 [26]), proteins (e.g. HIV glycoprotein gp140 [27], antibodies [28,29,30]), Journal of Controlled Release 298 (2019) 1–11
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
