Silicones represent a category of synthetic polymers comprising a main chain of alternating silicon and oxygen atoms, and having two organic groups covalently bonded to the silicon atom ().10
The most common silicone derivative is that having two methyl groups, called polydimethylsiloxane. The linear polymeric forms of silicones are liquids at room temperature, even for large molecular weights. Elastomeric silicone materials are produced by incorporating reactive functional groups into the linear polymers that may be subsequently “cross-linked” using suitable cross-linking molecules. Silicone polymers, and particularly the elastomeric forms, have a long history of use in both medical devices and drug-delivery devices, stemming from their excellent biocompatibility and biodurability.11
Silicone elastomer rings are generally made by elevated-temperature reaction injection molding, using either condensation or addition-cure chemistries.10
Chemical structures representing (A) silicone, (B) polyurethane and (C) poly(ethylene-co-vinyl acetate) materials used in the fabrication of drug-releasing vaginal rings.
Two estrogen-releasing, reservoir-type silicone elastomer vaginal rings have been commercialized for the treatment of menopausal symptoms related to estrogen deficiency. Estring®
(Pfizer, New York, NY) contains a full-length reservoir core () and releases 7.5 μg/day of 17β-estradiol continuously over 3 months for the treatment of local symptoms. Femring®
(Warner Chilcott UK Ltd, Larne, Northern Ireland) contains a single partial-length reservoir core (single-core version of ) and releases either 50 μg/day or 100 μg/day (depending on core length) of the estradiol prodrug 17β-estradiol-3-acetate over 3 months for the treatment of both systemic and local symptoms. Both rings show a high degree of user acceptability and are preferred by women over estrogen vaginal gels.12
A 1-year combination contraceptive ring device, worn for 3 weeks per cycle and simultaneously releasing 15 mcg/day ethinyl estradiol and 150 mcg/day nestorone, is also in clinical development.16
The first report of a microbicide-releasing vaginal ring described the continuous in vitro release over 8 days of the non-ionic surfactant nonoxynol-9 from a matrix-type silicone elastomer device.20
Unlike the solid antiretroviral compounds currently being tested as HIV microbicides, nonoxynol-9 is a liquid at a room temperature, such that its release from the ring followed unconventional release kinetics. Nonoxynol-9 has since been discontinued as a microbicide candidate since studies showed that it increased the risk of HIV transmission following frequent application.21
A subsequent study showed that dapivirine (also known as TMC120) could be effectively released in vitro over 71 days from a silicone elastomer reservoir-type ring device.23
Moreover, it was calculated that the constant daily rate observed of 130 μg release could effectively be maintained for at least 1 year, and theoretically for up to 4 years.
Many of the lead-candidate antiretroviral compounds being developed as HIV microbicides (eg, dapivirine, maraviroc, UC781, and MC1220) have physicochemical properties (specifically, high hydropobicity and low molecular weight) very similar to those of steroid molecules, suggesting that silicone elastomer vaginal ring formulations may also be useful for the controlled release of microbicides. Although numerous antiretroviral compounds have been tested in rings in vitro, only the dapivirine-matrix and reservoir-type silicone elastomer rings have reached the clinical stages of development (). Two Phase I safety studies have been completed for a 200 mg dapivirine reservoir ring (study IPM 001) (),24
a 25 mg dapivirine reservoir ring (studies IPM 008 and IPM 01) (),24
and a 25 mg dapivirine matrix ring (study IPM 018) ().21
Although these rings had different designs, they were both manufactured using a condensation-cure silicone elastomer system specifically designed for the incorporation and release of drug molecules. The IPM 001 and IPM 008 studies demonstrated good safety and tolerability for both the 25 mg and 200 mg dapivirine reservoir-type rings, compared with a placebo ring, during the 7-day study period. Reported vaginal-fluid concentrations of dapivirine at various locations along the cervicovaginal tract (introitus, cervix, ring position) were in the range 0.7–7.1 μg/mL, with levels highest close to the ring and lowest at the introitus. Vaginal- and cervical-tissue concentrations on day 7 were between 0.3 μg/g and 3.5 μg/g. Plasma concentrations, which are a particularly important consideration from the perspective of the potential emergence of strains resistant to the drug in HIV-positive users, were less than 50 pg/mL. Dapivirine concentrations in vaginal fluid and tissue were more than three orders of magnitude greater than the in vitro EC50 against a wild-type HIV-1 strain.26
Dapivirine levels measured with the 25 mg continuous core device () were generally higher (but did not reach statistical significance) than those for the 200 mg two-core ring device (). This is consistent with the nature of membrane-type diffusion-controlled drug-delivery systems, where drug release kinetics are determined by the length of the reservoir and the thickness of the rate-controlling membrane, but not the drug-loading (which only influences the duration of release).28
Completed, ongoing and planned microbicide ring clinical studies
Figure 3 Schematic diagrams (to scale) describing the design and dimensions of dapivirine-releasing vaginal rings. The design in (A) was evaluated in clinical study IPM 001 () and reported in Romano et al.24 The design in (B) was evaluated in IPM 008 and (more ...)
Reservoir rings are associated with several disadvantages compared with matrix-type rings, most notably their complexity of manufacture (a multistep process) and the relatively low (but constant) release rates. In the IPM 018 study (), the pharmacokinetics of matrix and reservoir rings, each containing 25 mg dapivirine (), were compared.25
The results clearly illustrated differences in dapivirine release rates, with significantly higher plasma and vaginal-fluid levels achieved with the matrix format, owing to the presence and rapid release of the drug at the device surface (). Vaginal-fluid levels peaked at ~1000 μg/g 24 hours after placement of the matrix ring, and declined steadily to around ~10 μg/g on day 28, immediately prior to ring removal (). In general, vaginal-fluid levels for the reservoir ring were between one and two orders of magnitude lower than those for the matrix ring. Plasma levels of dapivirine ranged from 10–1000 pg/mL ().
Figure 4 Reported pharmacokinetic profiles for the 25 mg matrix and 25 mg reservoir rings tested in IPM 018. (A and B) show plasma concentrations (conc) over 24 hours and 33 days, respectively. (C and D) show vaginal-fluid concentrations over 24 hours and 33 days, (more ...)
The propanol by-product associated with condensation-type silicone elastomers can lead to a “drug burst effect,” where the incorporated solid drug is dissolved in the propanol, transported to the device surface, and subsequently deposited following evaporation of the propanol.29
This solvent-aided deposition of the drug can artificially increase its release rate during the early period of use, beyond that attributed to the normal polymer diffusion-controlled process. Subsequent studies have confirmed that a substantial drug burst occurred with the early prototype condensation-cure dapivirine-releasing silicone elastomer rings, prompting a move to addition-cure silicone elastomer systems (which produce no solvent by-product during the silicone-curing reaction) for the future clinical development of the dapivirine matrix ring. Preliminary pharmacokinetic data (unpublished) from the IPM013 and IPM024 Phase 1 studies for the addition-cure 25 mg-dapivirine ring showed detection of dapivirine in both vaginal fluid and plasma 1.5 hours after ring insertion; the maintenance of dapivirine concentrations in vaginal fluid was in the 10–50 mcg/g range over the 35-day study period. The ASPIRE Phase III study (MTN 020, ) of the addition-cure silicone elastomer 25 mg dapivirine ring will be launched at several African sites in 2012 and involve almost 3500 women. First results are anticipated in late 2014 or early 2015.
Following the success of antiretroviral combinations for the treatment of HIV infection, there is also considerable interest in combination microbicide products, including vaginal rings, that simultaneously release two or more microbicide compounds having different mechanisms of action. The first clinical trial of such a ring (IPM 026/MTN 013, ), comprising 25 mg dapivirine and 100 g maraviroc (an entry inhibitor) in an addition-cure silicone elastomer matrix format () is planned for 2012 with 48 healthy women using either the combination ring, a 25 mg dapivirine-only ring, a 100 mg maraviroc-only ring, or a placebo ring continuously for 28 days.
Microbicide-releasing silicone elastomer vaginal rings have also been designed for use in macaques, enabling important pharmacokinetic and challenge studies to be performed in a more clinically relevant nonhuman-primate model.32