pharmaceutics Review The Vaginal Microbiota, Bacterial Biofilms and Polymeric Drug-Releasing Vaginal Rings Louise Carson 1, Ruth Merkatz 2, Elena Martinelli 2, Peter Boyd 1, Bruce Variano 2 , Teresa Sallent 2 and Robert Karl Malcolm 1,* 1 School of Pharmacy, Queen’s University Belfast, Belfast BT9 7BL, UK; [email protected] (L.C.); [email protected] (P.B.) 2 Population Council, One Dag Hammarskjold Plaza, New York, NY 10017, USA; [email protected] (R.M.); [email protected] (E.M.); [email protected] (B.V.); [email protected] (T.S.) * Correspondence: [email protected] Abstract: The diversity and dynamics of the microbial species populating the human vagina are increasingly understood to play a pivotal role in vaginal health. However, our knowledge about the potential interactions between the vaginal microbiota and vaginally administered drug delivery systems is still rather limited. Several drug-releasing vaginal ring products are currently marketed for hormonal contraception and estrogen replacement therapy, and many others are in preclinical and clinical development for these and other clinical indications. As with all implantable polymeric devices, drug-releasing vaginal rings are subject to surface bacterial adherence and biofilm formation, mostly associated with endogenous microorganisms present in the vagina. Despite more than Citation: Carson, L.; Merkatz, R.; 50 years since the vaginal ring concept was first described, there has been only limited study and Martinelli, E.; Boyd, P.; Variano, B.; reporting around bacterial adherence and biofilm formation on rings. With increasing interest in the Sallent, T.; Malcolm, R.K. The Vaginal vaginal microbiome and vaginal ring technology, this timely review article provides an overview Microbiota, Bacterial Biofilms and of: (i) the vaginal microbiota, (ii) biofilm formation in the human vagina and its potential role in Polymeric Drug-Releasing Vaginal Rings. Pharmaceutics 2021, 13, 751. vaginal dysbiosis, (iii) mechanistic aspects of biofilm formation on polymeric surfaces, (iv) polymeric https://doi.org/10.3390/ materials used in the manufacture of vaginal rings, (v) surface morphology characteristics of rings, pharmaceutics13050751 (vi) biomass accumulation and biofilm formation on vaginal rings, and (vii) regulatory considerations. Academic Editor: Keywords: controlled release; drug delivery system; silicone elastomer; ethylene vinyl acetate Natasa Skalko-Basnet copolymers; thermoplastics; polyurethanes; vaginal microbiome; lactobacillus; Gardnerella vaginalis Received: 23 April 2021 Accepted: 18 May 2021 Published: 19 May 2021 1. Introduction The human vagina is a useful and accessible route for local and systemic adminis- Publisher’s Note: MDPI stays neutral tration of drugs, and particularly for clinical indications that are directly associated with with regard to jurisdictional claims in women’s sexual and reproductive health. Spurred in part by progressive societal changes published maps and institutional affil- to attitudes, behaviors and stigmas around the human vagina, the past twenty years has iations. witnessed increased interest among users, clinicians, and the pharmaceutical industry in developing and using vaginal products for therapeutic benefit. Two different types of polymeric ring device for vaginal use are currently marketed— drug-releasing vaginal rings (VRs) for pharmacotherapy, and ring pessaries for the manage- Copyright: © 2021 by the authors. ment of pelvic organ prolapse and urinary stress incontinence. Drug-releasing VRs—the Licensee MDPI, Basel, Switzerland. focus of this review article—are torus-shaped devices designed to administer drugs over This article is an open access article extended time periods to the human vagina for therapeutic benefit [1–4]. To date, seven distributed under the terms and drug-releasing VRs—Estring®, Femring®, NuvaRing® (and generics EluRyng™, Myring™), conditions of the Creative Commons Progering®, Fertiring®, Ornibel® (also known as SyreniRing and Kirkos®) and Annovera™ Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ (Table1)—have reached market, with total estimated annual sales of $1.8 billion, and many 4.0/). others are in preclinical or clinical development [5–9]. Pharmaceutics 2021, 13, 751. https://doi.org/10.3390/pharmaceutics13050751 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2021, 13, 751 2 of 28 Table 1. Descriptions of marketed vaginal rings. Vaginal Ring Device Type Active Agent(s) Polymer(s) Indication Ring Dimensions (Company) (Duration of Release) (Loading/Release Rate) Ring OD: 55 mm reservoir 17β-estradiol silicone elastomer core and Ring CSD: 9.0 mm Estring® (Pfizer) estrogen replacementtherapy (3 months) (2 mg/7.5 µg/day) sheath (both Q7-4735, Dow) Core CSD: 2.0 mm Core length: 145 mm NuvaRing® (Merck) etonogestrel Ring OD: 54 mm EluRyng™ (Amneal) reservoir (11.7 mg/120 µg/day) 28% EVA * copolymer core combination Ring CSD: 4.0 mm Myring™ (Mithra) (21 days) ethinyl estradiol and 9% EVA * sheath contraception Membrane thickness: 110 µm Generic (TEVA) (2.7 mg/15 µg/day) Ring OD: 56 mm silicone elastomer reservoir 17β-estradiol-3-acetate Ring CSD: 7.6 mm Femring® (Millicent) core and sheath estrogen replacement therapy (3 months) (12.4, 24.8 mg/50, 100 µg/day) Core CSD: 2.0 mm (both MED-6382, NuSil) Core lengths: 8 and 16 mm Progering® (Population matrix progesterone silicone elastomer post-partum contraception in Ring OD: 56 mm Council/Silesia SA/Grupo (3 months) (2074 mg/~10 mg/day) (MED-4211, NuSil) breastfeeding women Ring CSD: 8.4 mm Grünenthal Chile) Fertiring® (Population matrix progesterone silicone elastomer IVF/hormone Ring OD: 56 mm Council/Silesia SA/Grupo (3 months) (1000 mg/~10 mg/day) (MED-4211, NuSil) supplementation Ring CSD: 8.4 mm Grünenthal Chile) etonogestrel Ornibel® (Exeltis) Ring OD: 54 mm reservoir (11.0 mg/120 µg/day) polyurethane sheath and 28% combination SyreniRing (Crescent Pharma) Ring CSD: 4.0 mm (21 days) ethinyl estradiol EVA* copolymer core contraception Kirkos® (Farmitalia) Membrane thickness: 150 µm (3.47 mg/15 µg/day) segesterone acetate silicone elastomer cores (x2, Ring OD: 56 mm Annovera™ reservoir (103 mg/150 µg/day) MED-6603 and MED-6385, combination Ring CSD: 8.4 mm (Population Council) (1 year) ethinyl estradiol NuSil) and sheath contraception Core CSD: 3.0 mm (17.4 mg/13 µg/day) (MED-4224, NuSil) Core lengths: 11 and 18 mm * EVA—ethylene vinyl acetate; # OD—overall diameter; CSD—cross-sectional diameter. Pharmaceutics 2021, 13 2 of 29 ® Pharmaceutics 2021, 13, 751 Kirkos ) and Annovera™ (Table 1)—have reached market, with total estimated annual3 of 28 sales of $1.8 billion, and many others are in preclinical or clinical development [5–9]. Each marketed ring provides either ‘sustained release’ (drug release maintained over an extendedEach marketed period ringbut not provides at a constant either ‘sustained rate) or ‘controlled release’ (drug release’ release (drug maintained release main- over antained extended over an period extended but notperiod at a at constant constant rate) or near-constant or ‘controlled rate) release’ of one (drug or more release steroidal main- taineddrugs for over hormonal an extended contraception period at constant (either prog or near-constantestin-only or rate)proges oftin one + or estrogen more steroidal combi- drugsnations), for estrogen hormonal replacement contraception therapy, (either or progestin-only luteal-phase support or progestin for assisted + estrogen reproduction. combina- tions),In estrogen recent years, replacement there has therapy, been very or luteal-phase significant supportinnovation for assistedin drug-releasing reproduction. rings, mostlyIn recentdriven years,by efforts there to has develop been very(i) antiretroviral-releasing significant innovation rings in drug-releasing for preventing rings, sex- mostlyually-acquired driven by infection efforts to of develop human (i)immunodeficiency antiretroviral-releasing virus rings(HIV) for in preventingwomen [4,7,10–12], sexually- acquired(ii) new longer-acting infection of human contraceptive immunodeficiency ring devices virus [6,13–15], (HIV) and in women (iii) new [4, 7ring,10– designs12], (ii) newthat longer-actingextend the range contraceptive of drug substances ring devices that [ca6,n13 be–15 effectively], and (iii) administered new ring designs beyond that conven- extend thetional range hydrophobic of drug substances small molecules that can (such be effectivelyas steroid molecules) administered [11,12,16–20]. beyond conventional hydrophobicBy comparison, small molecules ring pessaries (such (often as steroid simply molecules) referred [to11 as,12 ‘vaginal,16–20]. pessaries’ and not to beBy confused comparison, with ring dissolvable/meltable pessaries (often simply drug-containing referred to aspessaries/suppositories) ‘vaginal pessaries’ and notare tonon-medicated be confused withpolymeric dissolvable/meltable devices inserted drug-containing vaginally to support pessaries/suppositories) areas affected by pelvic are non-medicatedorgan prolapse, polymerica common devices condition inserted that vaginallyoccurs when to support the bladder, areas affectedrectum byor pelvicuterus organdrops or prolapse, bulges into a common the vagina condition [21–23]. thatAs wi occursth many when of the the drug-r bladder,eleasing rectum VR orproducts, uterus dropsring pessaries or bulges are into commonly the vagina fabricated [21–23]. Asfrom with silicone many ofelastomer, the drug-releasing although some VR