Use of a hydrophilic excipient to modulate the release of dapivirine, copper ions and zinc ions from a matrix-type vaginal ring

Abstract

Two major challenges for developers of drug-releasing vaginal rings are (i) the formulation and release of hydrophilic water-soluble actives, which generally require novel ring designs, very high drug loadings, and/or inclusion of substances to modify the release mechanism and enhance release, and (ii) the incorporation and release of multiple actives, particularly when the actives have very different solubility/permeability characteristics. In this study, as part of ongoing efforts to develop inexpensive and easily-manufactured multipurpose vaginal rings for HIV prevention, non-hormonal contraception, and prevention of bacterial and viral sexually transmitted infections, we describe formulation development and testing of matrix-type silicone elastomer rings containing combinations of three actives—dapivirine (D), copper sulfate anhydrous (C), and zinc sulfate monohydrate (Z)—and the hydrophilic excipient hydroxypropyl methylcellulose (H). Inclusion of H significantly impacted in vitro release and the properties of the vaginal rings, including mechanical performance, ring dimensions, and swelling. Preliminary testing of a lead candidate triple-active DCZH ring prototype showed good stability.

Introduction

All currently or previously marketed vaginal rings (Estring®, Progering®, Fertiring®, NuvaRing®, Femring®, Ornibel®, DapiRing®, Annovera®, and generics) provide sustained or controlled release of one or two hydrophobic (log P > 3.5), low molecular weight (<400 g/mol) drug molecules (mostly steroid hormones) over extended time periods (21 days—1 year) (Boyd et al., 2019, Carson et al., 2021, Malcolm et al., 2016, McCoy et al., 2026). The focus on small hydrophobic drugs is understandable since the medical grade non-biodegradable silicone elastomers and thermoplastic polymers (e.g., low vinyl acetate content ethylene vinyl acetate copolymers) commonly used to manufacture rings are also hydrophobic. For these marketed rings, drug release is invariably achieved via a molecular permeation mechanism requiring a fraction of the incorporated drug substance to first dissolve in the polymer matrix and then passively diffuse through the polymer driven by the concentration gradient between device and release medium (Malcolm et al., 2003).

A major challenge for developers of drug-releasing vaginal rings is the formulation and release of hydrophilic/water-soluble actives (including biomacromolecules), which generally require special ring designs, very high drug loadings, and/or inclusion of hydrophilic excipients to overcome the solubility and diffusivity constraints and be released effectively. Further, since few drug classes have the nano- or sub-nanomolar potency of steroid hormones, vaginal rings releasing hydrophilic/water-soluble actives also generally require much larger doses/release rates, thereby exacerbating the problem. The challenge has not gone unnoticed or unaddressed. Various vaginal rings have been reported for enhanced release of hydrophilic/water-soluble actives, including (i) modified rod-insert rings designed to deliver hydrophilic proteins (Gorlani et al., 2012, McKay et al., 2017, Morrow et al., 2011), (ii) exposed-core rings (McBride et al., 2019a, McBride et al., 2019b, Wang et al., 2018), (iii) swellable hydrogel-based rings (Han et al., 2007, Saxena et al., 2004, Saxena et al., 2009, Sharifzadeh et al., 2020), (iv) modular pod rings (Baum et al., 2015, Gunawardana et al., 2014, Moss et al., 2014, Srinivasan et al., 2016, Vincent et al., 2018b, Vincent et al., 2018a, Zhao et al., 2017), (v) rings with hydrophilic cores and pore channels (Derby et al., 2017, Ugaonkar et al., 2015), (vi) rings fabricated, at least in part, from hydrophilic polymers (Clark et al., 2014, Clark et al., 2012, Johnson et al., 2012a, Johnson et al., 2012b, Verstraete et al., 2017), (vii) rings fabricated from biodegradable polymers (Asvadi et al., 2013, Dang et al., 2013, Pathak et al., 2018, Verstraete et al., 2017), (viii) 3D-printed rings (Chen et al., 2022, Traore et al., 2022), and (ix) rings with relatively high drug loadings such that the release mechanism is modulated beyond simple permeation (Shen et al., 2025a).

The inclusion of hydrophilic excipients in silicone elastomers has a long history. Reports from the 1980s and 1990s describe use of various water‑soluble excipients—alginate polymers, glycerol, poly(ethylene)glycol, sucrose, etc.—to modify silicone elastomer matrices and enhance drug release (Brook et al., 2008, Carelli et al., 1987, Hsieh et al., 1985a, Hsieh et al., 1985b, Hsieh and Chien, 1985a, Hsieh and Chien, 1985b, Kajihara et al., 2003, Kajihara et al., 2001, Li and Vu, 1995, Maeda et al., 2003a, Maeda et al., 2003b, Maeda et al., 2002, Shen et al., 2025b). This strategy is simple and practical to implement since pharmaceutical-grade hydrophilic excipients are widely available and extensively used in dosage forms. Despite phase immiscibility due to the hydrophobic/hydrophilic mismatch, hydrophilic excipients—particularly in micronized form—do not tend to aggregate or separate when dispersed in silicone elastomers, due to high-efficiency mixing protocols, the relatively high viscosity of the silicone elastomer systems, and the trapping of excipient particles in the silicone elastomer matrix as the system cures. However, hydrophilic excipients often act as void-formers within the silicone matrix, reducing tensile strength, increasing brittleness, or altering elasticity. Also, although the formation of aqueous channels in the silicone elastomer matrix caused by fluid uptake via the dispersed hydrophilic excipients can serve as a useful mechanism to enhance release of hydrophilic drugs, it can also cause unwanted swelling of the device. Given these limitations, incorporation of hydrophilic actives and/or excipients in matrix-type vaginal rings—in which the drug is dispersed throughout the entire volume of the ring body—for the purpose of modulating drug release is particularly challenging.

Previously, we reported a matrix-type silicone elastomer vaginal ring containing dapivirine (25 mg) combined with various copper/zinc substances (copper nanopowders, zinc nanopowders, copper sulphate pentahydrate, and zinc acetate dihydrate) as a potential new multipurpose prevention technology (MPT) formulation for non-hormonal contraception and prevention of sexually acquired infections, including human immunodeficiency virus 1 (HIV-1) (Shen et al., 2025a). The formulation strategy leverages the recent approval of a matrix-type dapivirine-releasing vaginal ring (DapiRing®) for HIV prevention coupled with recent developments and increased interest in new non-hormonal methods for contraception in women (Howard and Benhabbour, 2023, Kushiro et al., 2025, Mauck et al., 2024, Shrestha et al., 2021).

As part of efforts to optimize the release of dapivirine, Cu2+ ions and Zn2+ ions from the ring, this article describes formulation development of a complex combination matrix-type multipurpose silicone elastomer vaginal ring containing three actives—dapivirine (D), anhydrous copper sulfate (C), and zinc sulfate monohydrate (Z)—and the release modulating excipient hydroxypropyl methylcellulose (H) for HIV prevention, non-hormonal contraception, and prevention of sexually transmitted infections. D is a highly hydrophobic antiretroviral drug whereas C, Z and H are highly hydrophilic; therefore, the challenge here is combining all four substances into a single matrix-type device and achieving release rates that might provide efficacy over a 30-day use period.

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Materials

Medical grade addition-cure LSR-4350 silicone elastomer (Parts A and B) was supplied by Factor II, Inc. (Lakeside, USA). Dapivirine (micronized; lot number: 604160010) was synthesised by S.A. Ajinomoto OmniChem (Wetteren, Belgium) and supplied by the International Partnership for Microbicides (IPM; acquired by Population Council in 2022). Copper sulfate anhydrous (C; ≥98.0%) was purchased from Scientific Laboratory Supplies Ltd. Zinc sulfate monohydrate (Z), HPLC-grade acetonitrile, phosphoric acid (85% w/w in water), Kolliphor HS® 15 and acetic acid were purchased from Sigma-Aldrich (Gillingham, UK). HPMC (MW 1261.45 g/mol) was purchased from Alfa Aesar (MA, USA). D, C and H were supplied in micronized form, while Z was milled in-house using a mortar grinder (Pulverisette 2, Fritsch, Brackley, UK) and then sieved (< 100 μm). Sodium acetate and sodium hydroxide were purchased from VWR International Ltd. (Dublin, Ireland). Potassium phosphate monobasic was purchased from Fisher Scientific (Leicestershire, UK). Deionised water was obtained using a Millipore Direct-Q 3 UV Ultrapure Water System (Watford, UK).

Xin Shen, Xinyu Zhao, Peter Boyd, Yahya H. Dallal Bashi, Clare F. McCoy, Rand Z. Murtadha, R. Karl Malcolm, Use of a hydrophilic excipient to modulate the release of dapivirine, copper ions and zinc ions from a matrix-type vaginal ring, International Journal of Pharmaceutics, Volume 701, 2026, 127143, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.127143.

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