19A matrix-type silicone elastomer vaginal ring providing 28-day continuous release of dapivirine

Despite a long history of incorporating steroids into silicone elastomers for drug delivery applications, little is presently known about the propensity for irreversible drug binding in these systems. In this study, the ability of the contraceptive progestin levonorgestrel to bind chemically with hydrosilane groups in addition-cure silicone elastomers has been thoroughly investigated. Cure time, cure temperature, levonorgestrel particle size, initial levonorgestrel loading and silicone elastomer type were demonstrated to be key parameters impacting the extent of levonorgestrel binding, each through their influence on the solubility of levonorgestrel in the silicone elastomer. Understanding and overcoming this levonorgestrel binding phenomenon is critical for the ongoing development of a number of drug delivery products, including a multi-purpose technology vaginal ring device offering simultaneous release of levonorgestrel and dapivirine - a lead candidate antiretroviral microbicide - for combination HIV prevention and hormonal contraception.

Vaginal rings (VRs) are currently marketed for contraceptive or hormone regulation purposes, and investigationally, have been widely reported for delivery of antiretrovirals to reduce HIV transmission. To date, there is no national or international standard for the mechanical testing and minimum performance characteristics of any VR based products. Here, we describe a a series of mechanical tests examining the durometer hardness, static and dynamic compression response, tensile properties and twist resistance of vaginal rings. The tests were conducted on currently marketed VRs and a number of the International Partnership for Microbicides' (IPM) investigational VR formulations. With wider application in the field, the tests described herein could form the basis for a more standardised approach to the mechanical testing of VRs.

Regioregular, alkyl-substituted poly(heteroaromatics) tend to crystallize in π-stacked structures as opposed to the herringbone pattern characteristic of non-substituted, planar aromatic molecules, e.g. sexithiophene. π-Stacking, favored by the crystallization of the sidechains, induces planarity in the conjugated backbone. The increased planarity causes a large (50-100 nm) shift in λmax (abs.) compared to the solution phase in which the backbone is twisted out of coplanarity, π-Stacking is a form of ground state aggregation that causes “fine structure” on the absorption peak. Excitation into the aggregate states rapidly leads to the formation of excimers as shown by the excitation spectra. In -stacked polymers, photoluminescence is almost entirely from the excimer states.

ARV: TDF, tenofovir, maraviroc, and IQP-0528 and several macromolecules. We evaluated IQP-0528 IVR-pumps in sheep for drug release rate, and drug concentration and distribution in the vaginal canal. Results: Altering the type of swelling polymer, drug loading, orifice design and the mass of pellets can control the drug release rate and duration. Formulations for high molecular weight species like IgG and linear polymers could be obtained that were nearly zero order for a month. Less controlled release profiles were achieved with more water-soluble drugs including maraviroc, tenofovir and TDF since the drugs possess much higher diffusivity in the hydrated polymer matrix. We observed mg per day release rates in sheep with an average IQP-0528 concentration in vaginal fluid of 270 lg/mL (*10 5 x the IC 90 ). Conclusions: This device provides an adaptable platform for vaginal drug delivery. We have been able to deliver impressive quantities of hydrophobic drugs as microparticles and high molecular weight agents for a month in animal models.Background: By extending the use duration of vaginal rings (VRs), the overall production cost per patient per month can be greatly reduced. Matrix-type ring designs produce an initial burst of drug release, and concentrations during the burst must be maintained within safe limits. This constrains both the maximum drug load and, in turn, the use duration of a matrix ring. By contrast, reservoir-type VRs comprise a drug-loaded reservoir surrounded by a rate-controlling non-medicated sheath, such that initial burst release is minimised and constant daily release rates are achieved. In this way, greater drug loadings and longer use periods are possible. Here, we report the development of reservoir VRs formulations containing dapivirine (DPV) and various contraceptive steroids. Methods: Reservoir VRs were manufactured with injection molded cores containing ethinyl estradiol (EE), etonogestrel (ETO), levonorgestrel (LNG) or DPV. Addition-and condensation-cured silicone cores were tested. All cores were overmolded with a blank 1.5 mm addition-cured silicone sheath. Invitro release was assessed for up to 60 days. Results: VRs comprising addition cured silicone cores and blank addition cured silicone sheath layers provided zero order release of DPV (95 lg/day) and LNG (30 lg/day), but not EE (detectable release on days 2 to 10 only) or ETO (no detectable release at any time). Rings comprising a condensation-cured silicone core provided zero order release of DPV (119 lg/day), EE (328 lg/day, days 4 to 18), ETO (422 lg/day, days 4 to 18) and LNG (69 lg/day). Conclusions: Reservoir-type VRs offering zero order release kinetics have potential as a multipurpose prevention technology (MPT) product for contraception and HIV-prevention with use duration of several months. However, the contraceptive hormones require careful selection of the silicone polymer system to ensure adequate release, while DPV is readily released from both types tested.Background: Multipurpose drug delivery systems (MDDS) hav...