Drug Deliv. and Transl. Res. (2011) 1:185–193 DOI 10.1007/s13346-011-0024-4

RESEARCH ARTICLE

Intravaginal rings: controlled release systems for contraception and prevention of transmission of sexually transmitted infections David R. Friend

Published online: 9 April 2011 # Controlled Release Society 2011

Abstract Intravaginal rings (IVRs) are a dosage form used to locally or systemically deliver drugs in the vagina. They are capable of releasing one or more drugs over an extended period of time (from several weeks to a year or longer). Contraceptive IVRs are currently gaining popularity due to the success of the contraceptive product NuvaRing®. Delivery of contraceptives from IVRs should promote compliance/adherence, and they also provide effective cycle control and symptom relief (menorrhagia, dysmenorrheal, and polycystic ovarian syndrome). Vaginal delivery of proteins from IVRs was first explored in an attempt to deliver IgG2a antibody intravaginally to neutralize herpes simplex virus 2. More recently, IVRs capable of releasing antibodies and recombinant proteins potentially along with low molecular weight microbicides are under investigation for prevention of HIV-1 transmission. Vaginal delivery of microbicides has been studied with several drugs most notably the nonnucleoside reverse transcriptase inhibitor dapivirine. Another drug capable of blocking transmission of HIV-1 when released from IVRs is tenofovir. Finally, combinations of drugs with different indications (i.e., multipurpose prevention technologies) are actively being pursued. Keywords Intravaginal rings . Contraceptives . Antibodies . Microbicides . Dapivirine . Tenofovir . Dual protection

Portions of this work were funded by the US Agency for International Development under Cooperative Agreement GPO-A-00-08-00005-00. D. R. Friend (*) Department of Obstetrics and Gynecology, CONRAD, Eastern Virginia Medical School, 1911 North Fort Myer Drive Suite 900, Arlington, VA 22209, USA e-mail: [email protected]

Introduction Intravaginal rings (IVRs) are used to deliver drugs to the vagina and the systemic circulation [1]. A key advantage of IVRs over most other vaginal dosage forms is the ability to release one or more drugs over an extended period of time (e.g., months) from a single application. Development of contraceptive IVRs began in the 1960s [2, 3] but it took until the 1980s to reach clinical testing [4]. Early efforts towards the development of a contraceptive IVR releasing levonorgestrel were hindered by vaginal lesions and negative impact on lipoproteins [5]. Eventually, hormone replacement IVRs reached the market followed by a contraceptive IVR (NuvaRing®). The eventual successful development of contraceptive-based IVRs has prompted new applications in the area of vaginal protein and microbicide delivery [6]. All three types of IVR products (and combinations known as Multipurpose Technologies [7]) are discussed below. Background on IVRs IVRs are torus shaped, elastomeric or thermoplastic/thermosetting polymers devices available commercially for release of steroid hormones for 1 to 3 months. IVRs have traditionally been formulated as matrix or reservoir devices. In the matrix systems, drug is uniformly distributed throughout the polymer matrix. Release rates tend to show more rapid release followed by a period of slower release as drug is depleted from the polymer close to the IVR surface. In general, release of drugs from matrix-based IVRs follows the Higuchi equation for diffusion controlled release from a matrix IVR (amount released is linear with the t1/2) [8–10]. Reservoir devices typically demonstrate more constant release due to the presence of a rate limited membrane around a core

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containing the drug (or drugs). Since macromolecules and microbicides are composed of diverse molecules in terms of physicochemical properties, more recent approaches under development include tablets or pods incorporated into IVRs. The segregation of drugs into these elements (tablets or pods) permits controlled release independent of the polymer matrix or reservoir designs. All these approaches are discussed with examples below. The elastomer commonly used to prepare IVRs is silicone, which is well tolerated in the vagina and has a long history of safe clinical use. The influence of properties such as solubility and diffusivity on the release in vitro of various drugs in silicone has been studied [8]. This publication represents an early attempt to model drug release from IVRs. A more recent attempt to model drug release and distribution throughout the vagina has been published [11]. NuvaRing is composed of the thermoplastic ethylene-vinylacetate copolymers (EVAcs). The types of IVR products currently marketed and some of their attributes are shown in Table 1. A picture of the currently available products described in Table 1 is shown in Fig. 1. There are dimensional differences between IVRs composed of silicone elastomers and EVAc as can be seen in Fig. 1. While all IVRs have a similar outer diameter of around 55 mm, cross-sectional diameters vary considerably. In general, silicone elastomer-based IVRs have a larger cross-sectional diameter since they are more flexible than IVR prepared from thermoplastics such as EVAc. Of the IVRs used for contraception, only NuvaRing is available in North America and Europe. Progering and Fertiring are available in a few countries in South America. To date, no other IVRs have been commercialized for indications other than contraception or hormone replacement. IVRs are under active investigation for protein delivery and drugs potentially capable of preventing transmission of HIV-1 to women as discussed in detail below. Contraceptive IVRs The availability of contraceptive products has reduced maternal mortality and child mortality while reducing the number of induced abortions around the world [12]. Like all drug products, contraceptives must be used as labeled. Table 1 Commercially available IVRs for hormone replacement (Estring and Femring) and contraception (NuvaRing, Progering, and Fertiring)

Fig. 1 Commercially available IVRs for hormone replacement and contraception as listed in Table 1. IVRs shown at the top panel are available in many developed world countries for hormone replacement therapy (Femring and Estring) or contraception (NuvaRing). IVRs shown in the bottom panel are available in several South American countries for contraception

To that end, methods enhancing adherence should improve desired outcomes. The combined advantages of convenience, effectiveness, and long-acting nature of IVRs are positive attributes of contraceptive IVRs [13]. Contraceptive IVRs also provide, in addition to effective cycle control, relief of symptoms such as menorrhagia, dysmenorrheal, and polycystic ovarian syndrome. Excellent reviews of the history of contraceptive IVR development are found in two recent reviews [4, 13]. Therefore, only

Product

Active(s)

Polymer

Device/active

Estring® Femring® NuvaRing® Progering® Fertiring®

17β-Estradiol 17β-Estradiol-3-acetate Etonogestrel+ethinyl estradiol Progesterone Progesterone

Silicone Silicone EVAc Silicone Silicone

Reservoir/non-ionizable, logP=3.6 Reservoir/non-ionizable, logP=4.0 Reservoir/non-ionizable, logP=3.4, 4.3 Matrix/non-ionizable, logP=3.5 Matrix/non-ionizable, logP=3.5

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more recent advances in contraceptive IVRs are presented herein. NuvaRing represents a unique IVR design compared with earlier silicone elastomer IVRs. It has a relatively small cross-sectional diameter of 4.0 mm. It contains 2.7 mg ethinyl estradiol (EE) and 11.7 mg etonorgestrel (ENG) loaded into a core of EVAc (28% vinyl acetate content) which is surrounded by a drug free EVAc sheath (9% vinyl acetate content). This ring structure is created through coaxial extrusion [14]. The product releases 15 μg/ day EE and 120 μg ENG/day [15]. In vitro release of ENG from NuvaRing is loading-dependent as shown in Fig. 2. The clinical pharmacokinetics of EE and ENG over the intended period of release (21 days) and extended release (days 22 to 35) are shown in Fig. 3 [16]. Overall, NuvaRing is efficacious, well tolerated, and well accepted by women [17–19]. Progering is another contraceptive IVR available in Chile, Boliva, Peru, and Ecuador for use in lactating women. The ring is designed to release progesterone at a daily rate of 10 mg [20]. This rate is relatively high compared with most drugs released from IVRs. The IVR and plasma concentrations in women over a 120-day period are shown in Fig. 4. The effectiveness of Progering in users during breast feeding demonstrated the safety and efficacy of this IVR product [20, 21]. Vaginal delivery of proteins from IVRs Vaginal delivery of proteins encompasses primarily two types of molecules: antibodies and vaccines. The potential of protein delivery was first reported in 1992 [22]. This work was directed at releasing antibodies directly in the vagina in an attempt to provide immunoprotection against sexually transmitted infections. EVAc was used to control the release of IgG antibodies in vitro for 30 days. The

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Fig. 3 Serum concentration time curve (mean±SD; n=16) of ENG and EE during treatment with NuvaRing (days 1 to 21 (intended use) and days 22 to 35 (extended use)). With permission from ref. [16]

devices were also used in vivo to examine the release of bovine serum albumin (BSA) or anti-human chorionic gonadotrophin (anti-hCG) antibodies in mice. The ring devices used are shown sutured into the vagina of mice in Fig. 5. The devices were capable of releasing BSA and antihCG to the vaginal mucus for 30 days [22]. The EVAc ring technology was also examined for its ability to provide topical passive immunoprotection in female mice [23]. An antibody (IgG2a monoclonal antibody [Mab] III-174) capable of neutralizing herpes simplex virus-2 (HSV-2) [24] was loaded into EVAc disks. Relatively large amounts of III-174 (5 to 3,000 ng) were recovered from vaginal fluid over 8 days following implantation. Mice challenged with 10 or 500 times the infectious dose needed to infect half of untreated mice (10 ID50 and 500 ID50, respectively) were protected by disks releasing III-174 compared with devices releasing nonspecific IgG. Despite these early results, no further reports on vaginal delivery of proteins have appeared until recently.

Fig. 2 a In vitro release of ENG at several concentrations from EVAc reservoir IVRs and b influence of ENG concentration in the core on steadystate release. With permission from ref. [14]

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release of proteins including antibodies (2F5, b12, and 2G12) and recombinant proteins (gp160, gp140, and gp41) for HIV-1 prophylaxis [25–31]. A different approach to delivery of proteins from IVRs is based on protein-containing inserts placed into the ring. The composition of the insert is designed to prolong release of the protein. An example of the insert approach has recently been published [32]. The inserts are prepared from standard tableting excipients or lyophilized gels. These inserts are placed in small holes in rings prepared from silicone elastomers (Fig. 6). Using this technology, over 1 mg of the MAb 2F5 was released from a device prepared with lyophilized gels composed of varying molecular weights of hydroxypropylmethylcellulose. The advantage of the insert approach as compared with traditional IVR configurations is the added ability to provide simultaneous release of drugs from the silicone portion of the IVR. Thus an antiretroviral drug could be combined with an antibody or vaccine for enhanced protection against HIV-1 transmission. IVRs for microbicides

Fig. 4 Top, IVR containing progesterone (2.074 g) with an average release rate of 10 mg/day; bottom, mean daily plasma progesterone concentration attained during the third and fourth months of IVR use. With permission from ref. [20]

The HIV-1 epidemic has lead to various approaches to prevent transmission. As discussed below, microbicides are being delivered intravaginally from IVRs. The agents in development are primarily small molecule antiretroviral agents; however there is continued interest in vaginal

Fig. 5 Position of vaginal rings in the mouse’s reproductive tract. The EVAc/protein ring (~4 mm outer diameter and ~1.5 mm internal diameter) was retained in the vagina by a single suture secured to another small ring of EVAc. This diagram reflects the actual size of the rings used. With permission from ref. [22]

Microbicides are products designed to prevent the transmission of HIV-1. The early microbicides evaluated in Phase III clinical trials were non-specific polyanionic compounds. They universally were found to be ineffective. More recently, antiretroviral (ARV) drugs such as tenofovir (TFV) and dapivirine (DPV) have entered or are about to enter efficacy studies. These compounds can be administered in gels peri-coitally. From an adherence perspective, controlled release systems requiring once monthly or longer dosing should make microbicide products more attractive. To that end, IVRs are being extensively investigated as controlled release systems for microbicides. Early work on IVRs relied on the use of silicone elastomers. This was a logical starting point since nearly all commercial IVRs rely on silicone (see Table 1). The range of drug molecules that can be delivered at rates believed to be therapeutically effective from silicone is limited however. The next material to be considered based on commercial use is EVAc. However, the source of medical grade EVAc for use in IVRs is limited despite its ability to release a wider range of molecules at the desired rates. More recently, polyurethanes (PUs) have been investigated as controlled release polymers in IVRs. As noted below, PUs can be prepared in a wide range of properties making them suitable for many ARVs. A review covering use of IVRs to deliver microbicides intravaginally was published by Woolfson et al. [33] after work had already begun on DPV (TMC120) releasing IVRs [34, 35]. A recent review of microbicide IVRs was published addressing not only development of these products but scale-up and manufacturing challenges [36].

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Fig. 6 i, Silicone insert vaginal ring; ii, injection molds for insert VR manufacture; iii, directly compressed insert manufacture, iv, silicone insert; v, directly compressed tablet insert, and vi, lyophilized insert. With permission from ref. [32]

DPV is a potent non-nucleoside reverse transcriptase inhibitor [37] under development as a microbicide in both gel [38, 39] and IVR dosage forms. The IVR dosage form for DPV is composed of silicone elastomer. The device is designed to release DPV intravaginally over a 28-day period. In one study, matrix and reservoir devices were evaluated in a phase I clinical safety/pharmacokinetic study [40]. Pharmacokinetic data from this study are shown in Fig. 7. The matrix form of the DPV IVR is scheduled to be tested in a phase III efficacy study in Africa. Fig. 7 Vaginal fluid levels based on samples collected by Sno-Strips from the vagina near the IVR. m matrix IVR, r reservoir IVR. With permission from ref. [40]

The use of silicone elastomers is well established for delivery of drugs from IVRs. Thermoplastic EVAc is capable of providing desired mechanical properties and rate controlling properties at least for potent steroids (i.e., NuvaRing). Use of EVAc as a polymeric matrix microbicide IVRs is at an early stage of development. A currently unresolved issue with EVAc polymers is a commercial source of medical grade materials. Many suppliers of these polymers are reluctant to enter into new supply agreements, particularly with non-profit organizations, due to perceived litigation issues. As a result,

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development of IVRs composed of EVAc for delivery of microbicides has been hindered. A second thermoplastic material currently under investigation is based on PUs. The chemistry available using PUs to create unique IVRs capable of controlling the release of drugs with a wide range of physicochemical properties is appealing. The primary composition involves synthesis of copolymers with varying ratios of hard block (hydrophobic) and soft block (hydrophilic) segments [36]. These properties are obtained for instance by reacting hydrophilic polymeric diols such as polytetramethylene oxide (PTMO) or polyethylene oxide (PEO) with an aliphatic diisocyanate [41]. Of the two hydrophilic monomers, PTMO imparts considerably more hydrophilic properties than PEO. Aromatic diisocyanates are avoided due to potential toxicologic issues. The use of PU-based IVRs has been explored with both DPV and TFV (a nucleotide reverse transcriptase inhibitor). The latter drug was recently shown to be effective at prevention of HIV transmission in a phase IIB study [42]. TFV targets reverse transcriptase but acts at a different location on the enzyme. Combining these two agents could improve the overall effectiveness of the product compared with the single entity forms and it should help reduce the potential for development of resistant strains of HIV 1 [43–46]. As the name implies, thermoplastics require heating to effectively mix drug and other additives followed by extrusion or injection molding. PUs generally require temperatures around 150°C or higher to create sufficient flow properties. Therefore, the drug must be stable at these temperatures at least for short periods of time (minutes). DPV was found to be stable during processing and extrusion into rods using a relatively hydrophobic PU (Tecoflex® EG-80A, Lubrizol Inc.) [47]. This particular approach to IVR preparation creates a matrix (monolithic) device. Depending on drug loading, release of DPV into an isopropanol/water (25/75) dissolution medium ranged from 64±1 to 473±36 μg/day and was essentially constant over the 30-day test period. The use of PUs was extended to include release of a second agent called tenofovir (TFV) [48]. Like DPV, Combining dapivirine and TFV presents a formulation challenge due to the significantly different solubilities, as reflected in their calculated log partition coefficient (ClogP) values. DPV’s ClogP is 6.3 while that of TFV is −2.3 [48]. One approach to addressing this difference is through a segmented ring design. As mentioned above, PUs can be prepared with hydrophilic characteristics thus making them suitable for TFV; a more hydrophobic PU can be used to control the release of DPV. Thus, TFV was extruded with the water-swellable Tecophilic® HP-60D-20 while DPV was extruded with the non-water-swellable Tecoflex EG80A. The design of the segmented IVR is shown in Fig. 8. In vitro release data are shown in Fig. 9. The ring

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Fig. 8 Left, segmented IVR consisting of TFV in Tecophilic HP-60D20 (top section) and DPV in Tecoflex EG-85A) (bottom section). Right, NuvaRing. With permission from ref. [48]

Fig. 9 Top, cumulative release TFV as a function of time (30 days total expressed as normalized from 0 to 1) from Tecophilic HP-60D20 at three different drug loadings: 25.4, 50.2, and 71.8 mg/g. Release studies were conducted on extruded rods (~15 mm). The release medium was 25/75 (v/v) isopropanol/water (5 mL) at 37°C in a water bath shaker set at 64±2 rpm. The release medium was replaced with fresh fluid once every 24±0.5 h [47]. Data are means±SEM (n=4). Bottom, cumulative release of DPV as a function of time from Tecoflex EG-85A loaded with drug at 50 mg/g. Data are means±SEM (n=4). Double asterisks, wt.% cumulative release over 30. With permission from ref. [48]

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composed of the two segments had mechanical properties considered to be appropriate for maintenance of IVR location in the vagina (i.e., it will not be easily expelled or displaced) while being comfortable. Both drugs when formulated in the IVR were stable when stored at 40°C/ 75% RH and 50°C for 90 days [13]. Another approach to delivering more than one drug from a single IVR is under development by Auritec and Oak Crest Research Institute. This technology platform is based on a polymer-coated core of drug incorporated into a silicone elastomer ring. Dissolution of drugs from the cores (or pods) is controlled by varying the amount of core coating polymer (polylactic acid) applied and the dimensions of the delivery window that communicates with the coated core and vaginal fluids. Drug release typically exhibits pseudo-zero order kinetics. Examples of IVRs and a core are shown in Fig. 10. In vitro release of TFV from a ten-core IVR is also shown in Fig. 10. An advantage of this type of device is the ability to release two or more different drugs. This IVR design is most suitable for potent, water soluble compounds since dissolution of poorly was soluble compounds through the delivery window can be limited. Providing clinical supplies for phase III and commercial launch for microbicides presents some unique challenges. All IVR products need to be developed according to current FDA or EMEA drug-device guidelines. The demand for microbicide-based IVR products could be substantially greater than currently available commercial IVRs. Supplying a phase III clinical trial can be met without too much difficulty [36]; however, projecting forecast demand for IVRs following approval and launch are difficult to make due to the countries involved (developing) and the role of public sector involvement. The availability of IVR manufacturing equipment is limited currently and virtually no capabilities exist in the developing world. Meeting even limited product demand will require expansion of the current manufacturing capabilities. Manufacturing of thermoplastic IVRs prepared by injection molding will require significant investment in manufacturing capacity than what exists currently. A possible compensating factor is the ability to create IVRs by extruding rods, cutting, and sealing/welding. This manufacturing approach is less expensive than injection molding. The need for raw materials may also well exceed the amount of material currently used commercially and could present issues from a cost and supply perspective [36].

Conclusions IVRs are a proven dosage form for local administration of steroid hormones for contraception and hormone replace-

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Fig. 10 Top, various forms of the core-based IVR system; bottom, in vitro release of TFV from an IVR composed of ten ~3-mg cores per ring, 1-mm diameter delivery windows. Mean release rate over the 30 days was 385 μg/day

ment therapy. The ability to control release of peptides and proteins has been explored and appears to be feasible; however, considerably more research is required to determine if the approaches under consideration are clinically viable and cost effective. The use of IVRs for controlled release of microbicides is well advanced, as demonstrated by the evaluation of a 28-day DPV releasing IVR in an upcoming phase III efficacy trial evaluating the ability of this product to prevent transmission of HIV. Newer IVR designs are addressing the need to release more than one drug; this approach should lead to more effective microbicide products as well as multipurpose protection technologies capable of addressing two different indications (e.g., prevention of HIV transmission and contraception) [7, 49].

192 Acknowledgments The contributions of Meredith Clark and Gustavo Doncel of CONRAD are gratefully acknowledged. Karl Malcolm (Queens University Belfast) and Patrick Kiser (University of Utah) also provided considerable support. The contributions of Tom Smith (Auritec) and John Moss (Oak Crest Research Institute) are also acknowledged. Portions of this work were funded by the US Agency for International Development (USAID) through Cooperative Agreement GPO-A-00-08-00005-00. The views expressed do not necessarily reflect those of USAID.

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