The simplest vaginal ring design contains solid drug particles (usually in a micronized form) dispersed throughout the entire polymeric matrix. The drug-release yield from these so-called “homogeneous” or “matrix” rings (Figure 1B) is governed by a permeation mechanism for which the release rate is dependent upon (1) the drug’s solubility in the polymer, (2) the ability of the solvated drug to diffuse through the polymer, (3) the drug-loading within the device, and (4) the ring surface area. The drug-permeation process involves dissolution of the solid drug in the polymer, followed by diffusion of the solubilized molecules through the elastomeric polymer network. Drug near the surface of a matrix ring is released first, creating a drug-depleted layer through which solubilized molecules within the ring body must first diffuse in order to be effectively released. As time progresses the surface area of this inward-moving depletion boundary decreases, causing an increase in the thickness of the depletion layer, resulting in decreased drug-release rates over time.

The “sandwich” and “core” vaginal ring designs (also known as “shell” and “reservoir,” respectively) were developed to provide constant daily release rates throughout the period of use, conforming to “zero order” release kinetics. The sandwich design (Figure 1F) consists of a narrow drug-loaded polymer layer positioned between a nonmedicated inner central core and a nonmedicated outer membrane. The position of the drug core close to the surface ensures efficient delivery of drugs having poor polymer diffusion characteristics. Core-type rings contain the drug(s) within one or more central cores that are encapsulated by a drug-free outer polymer membrane (Figure 1C–E). Several individual drug-loaded cores of various lengths may be incorporated into the same core ring, thereby allowing delivery of multiple actives at predetermined and independent release rates. The release rates of both the core and sandwich-ring designs may be further modified by changing the thickness of the rate-controlling outer membrane.

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 (Figure 1C) 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 Figure 1D) 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.12–15 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.16–19

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.21,22 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 (Table 1). Two Phase I safety studies have been completed for a 200 mg dapivirine reservoir ring (study IPM 001) (Figure 3A),24 a 25 mg dapivirine reservoir ring (studies IPM 008 and IPM 01) (Figure 3B),24,25 and a 25 mg dapivirine matrix ring (study IPM 018) (Figure 3C).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.26,27 Dapivirine levels measured with the 25 mg continuous core device (Figure 3B) were generally higher (but did not reach statistical significance) than those for the 200 mg two-core ring device (Figure 3A). 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

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 (Table 1), the pharmacokinetics of matrix and reservoir rings, each containing 25 mg dapivirine (Figure 3B and C), 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 (Figure 4). 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 (Figure 4D). 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 4A and B).

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.29–31 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, Table 1) 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, Table 1), comprising 25 mg dapivirine and 100 g maraviroc (an entry inhibitor) in an addition-cure silicone elastomer matrix format (Figure 1B) 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.

Nuvaring^® is a nonbiodegradable, flexible, transparent, colorless, contraceptive vaginal ring (Table 1), developed by Organon Inc and first marketed in 2002. It contains two active compounds, progestin etonogestrel (11.7 mg) and estrogen ethinyl estradiol (2.7 mg), both located within a central PEVA (28% w/w vinyl acetate) core as a supersaturated eutectic mixture, and surrounded by a nonmedicated polyethylene-co-vinyl acetate (9% w/w vinyl acetate) sheath layer. The slow permeation of the steroid molecules through the low-vinyl-acetate-content nonmedicated sheath provides for controlled release, resulting in mean daily release rates of 120 μg etonogestrel and 15 μg ethinyl estradiol over the 3-week period of use. The ring is used continuously for 3 weeks, and then removed for 1 week before being replaced with a new ring. Nuvaring^® is highly efficacious, with a Pearl index of 1.18 and an efficacy of 99.1%. Off-label 28-day continuous use of Nuvaring^® is also being evaluated.35

Despite the commercial success of Nuvaring^®, there have been very few reports of the use of PEVA for microbicide-releasing vaginal rings, probably owing to ongoing difficulties in accessing clinical-grade materials for testing in humans. A comparison of the pharmacokinetics of the nonnucleoside reverse-transcriptase inhibitor UC781 in rabbits following vaginal administration of ring segments fabricated from PEVA, polyurethane, and silicone elastomer showed similar in vivo release rates and kinetics.8 Recently, a combination PEVA matrix-type ring providing simultaneous release of the microbicide candidate UC781 and the contraceptive progestin levonorgestrel has been reported.36 If the proof of concept of a microbicide vaginal ring device can be realized with the dapivirine-releasing silicone elastomer ring, then these multipurpose prevention technologies that combine HIV protection with effective contraceptive regimes will be actively pursued.

The Versaring^® technology platform (Auritec Pharmaceuticals) is based on drug-loaded pod inserts, comprising polymer-coated solid drug, incorporated into a silicone elastomer ring and exhibiting pseudo-zero order release kinetics.38–40 Drug cores are coated with layers of semipermeable poly(lactic acid) polymer. Coated drug pods are incorporated into silicone rings, and the drug is released through a delivery window in the silicone ring, with the release rate determined by the window diameter. The amount of drug released from each ring can be adjusted by changing the amount and composition of the polymer coating of the drug core, the size of the drug-delivery window, and the number of drug pods in each ring. Vaginal rings containing tenofovir provide in vitro daily release rates spanning 2.5 orders of magnitude (10–4000 mcg/day for tenofovir). The modular nature of the rings permits the release of multiple drugs having very different physicochemical characteristics. To date, in vitro release of tenofovir and acyclovir from the same ring segments has been demonstrated.40 In vivo studies have demonstrated sustained release of tenofovir in the micro-molar range over 14 days in rabbits and 28 days in macaques, with no local inflammation or altered vaginal flora.40 In rabbits, the vaginal tissue tenofovir levels at sacrifice were 3597 ± 1678 ng/g. In the macaques, vaginal biopsies proximal and distal to the inserted rings at days 7 and 21 measured tenofovir levels at 76 ± 54 mcg/g, over 100 times the IC 50 of tenofovir (2 μM). The data demonstrates the feasibility of a 1-month tenofovir microbicide ring for women.

Similar to the pod-insert vaginal ring, rod and tablet-insert vaginal rings comprise one or more polymeric solid dosage forms (lyophilized polymer gel rods and directly compressed tablets, respectively) inserted into a silicone elastomer ring.41 While the ring acts primarily as a retainer for the solid dosage inserts, it may also be used to load and deliver other microbicide candidates compatible with conventional permeation-controlled release mechanisms. Lyophilized inserts may be prepared by freeze-drying microbicide-loaded aqueous gel formulations. This technology is potentially useful for the production of solid dosage inserts containing peptide- and protein-based microbicide candidates, since it does not involve high temperatures, and the water-free insert serves to stabilize the active biomolecule. Once administered, the gel is slowly reconstituted by imbibing vaginal fluid, leading to sustained release of the active agent. Similar lyophilized tablets have recently been reported for the formulation of dapivirine.42 The compressed tablet-insert strategy makes use of traditional direct-compression tableting technology to manufacture conventional sustained-release solid dosage forms.