Dose-finding study of a 90-day contraceptive vaginal ring releasing estradiol and segesterone acetate.

ObjectiveTo evaluate serum estradiol (E2) concentrations during use of 90-day contraceptive vaginal rings releasing E2 75, 100, or 200 mcg/day and segesterone acetate (SA) 200 mcg/day to identify a dose that avoids hypoestrogenism.Study designWe conducted a multicenter dose-finding study in healthy, reproductive-aged women with regular cycles with sequential enrollment to increasing E2 dose groups. We evaluated serum E2 concentrations twice weekly for the primary outcome of median E2 concentrations throughout initial 30-day use (target ≥40 pg/mL). In an optional 2-cycle extension substudy, we randomized participants to 2- or 4-day ring-free intervals per 30-day cycle to evaluate bleeding and spotting based on daily diary information.ResultsSixty-five participants enrolled in E2 75 (n = 22), 100 (n = 21), and 200 (n = 22) mcg/day groups; 35 participated in the substudy. Median serum E2 concentrations in 75 and 100 mcg/day groups were <40 pg/mL. In the 200 mcg/day group, median E2 concentrations peaked on days 4-5 of CVR use at 194 pg/mL (range 114-312 pg/mL) and remained >40 pg/mL throughout 30 days; E2 concentrations were 37 pg/mL (range 28-62 pg/mL) on days 88-90 (n = 11). Among the E2 200 mcg/day substudy participants, all had withdrawal bleeding following ring removal. The 2-day ring-free interval group reported zero median unscheduled bleeding and two (range 0-16) and three (range 0-19) unscheduled spotting days in extension cycles 1 and 2, respectively. The 4-day ring-free interval group reported zero median unscheduled bleeding or spotting days.ConclusionsEstradiol concentrations with rings releasing E2 200 mcg/day and SA 200 mcg/day avoid hypoestrogenism over 30-day use.ImplicationsA 90-day contraceptive vaginal ring releasing estradiol 200 mcg/day and segesterone acetate 200 mcg/day achieves estradiol concentrations that should avoid hypoestrogenism and effectively suppresses ovulation

The ins and outs of drug-releasing vaginal rings: A literature review of expulsions and removals

Introduction: There is considerable interest in vaginal ring technology for sustained/controlled release of pharmaceutical drugs to the human vagina. Seven drug-releasing vaginal ring products have reached market and have many other experimental devices are in preclinical/clinical development. Although most women who have use vaginal rings are satisfied and find them acceptable, involuntary ring expulsions and voluntary ring removals are known to occur and are widely reported in the scientific literature. There have been no previous efforts to review the historical data and understand the contributing factors leading to expulsions. Areas covered: This article is intended to help researchers, clinicians and product developers understand the pertinent factors and issues around ring expulsions and removals, and to inform new research aimed at optimising the design of new ring products. The review contains four sections: (i) introduction to vaginal ring technology; (ii) a discussion of the anatomical, physiological, device, and user factors potentially affecting ring expulsion; (iii) a literature review around involuntary ring expulsions; (iv) a literature review around voluntary ring removals; and (v) concluding remarks and opinions. Expert opinion: Further research is needed to better understand the factors contributing to involuntary ring expulsions and removals so that rings can be designed from the outset to minimise rates of expulsion and to reduce removals. Determination of optimum ring dimensions and stiffness for each ring product are likely key factors, alongside better counselling around ring removal and reinsertion

Polymorphism characterization of segesterone acetate: A comprehensive study using XRPD, FT-IR and Raman spectroscopy

Segesterone acetate (SA) is a promising and recently approved drug substance used as a contraceptive. SA has two major polymorphic forms, Form I and II. We have shown through indirect analysis that Form I is the more thermodynamically stable polymorphic form at room temperature, however, during the manufacturing process of SA drug products the solid-state stability must be shown to be under control. In the present work, a systematic study has been done using X-ray powder diffraction (XRPD), Fourier Transformed Infrared spectroscopy (FT-IR), and room temperature Raman spectroscopy on both micronized and non-micronized SA powder samples. XRPD showed a crystalline structure in both powder samples with a distinct coexistence of the polymorphic Forms I and II which was confirmed by FT-IR and Raman spectroscopy. The study showed that after thermal annealing a noticeable reduction of the amount of polymorphic Form II was found in both samples. Our results suggest the possibility of reducing the amount of SA Form II by thermal treatment inducing an irreversible solid-state transition to yield the thermodynamically more stable polymorphic Form I. To quantify the ratio of polymorphs I and II we have implemented a method that can be used as a routine analysis step in the manufacturing process of SA

The vaginal microbiota, bacterial biofilms and polymeric drug-releasing vaginal rings

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 50 years since the vaginal ring concept was first described, there has been only limited study and reporting around bacterial adherence and biofilm formation on rings. With increasing interest in the vaginal microbiome and vaginal ring technology, this timely review article provides an overview of: (i) the vaginal microbiota, (ii) biofilm formation in the human vagina and its potential role in vaginal dysbiosis, (iii) mechanistic aspects of biofilm formation on polymeric surfaces, (iv) polymeric materials used in the manufacture of vaginal rings, (v) surface morphology characteristics of rings, (vi) biomass accumulation and biofilm formation on vaginal rings, and (vii) regulatory considerations

In vitro release testing methods for drug-releasing vaginal rings

Drug-releasing vaginal rings are torus-shaped devices, generally fabricated from thermoplastic polymers or silicone elastomers, used to administer pharmaceutical drugs to the human vagina for periods typically ranging from three weeks to twelve months. One of the most important product performance tests for vaginal rings is the in vitro release test. Although it has been fifty years since a vaginal ring device was first described in the scientific literature, and despite seven drug-releasing vaginal rings having been approved for market, there is no universally accepted method for testing in vitro drug release, and only one non-compendial shaking incubator method (for the estradiol-releasing ring Estring®) is described in the US Food and Drug Administration\u27s Dissolution Methods Database. Here, for the first time, we critically review the diverse range of test methods that have been described in the scientific literature for testing in vitro release of drug-releasing vaginal rings. Issues around in vitro-in vivo correlation and modelling of in vitro release data are also discussed

Solid state 13C NMR spectroscopy provides direct evidence for reaction between ethinyl estradiol and a silicone elastomer vaginal ring drug delivery system

Steroid molecules have a long history of incorporation into silicone elastomer materials for controlled release drug delivery applications. Previously, based on in vitro release testing and drug content analysis, we demonstrated indirectly that the contraceptive progestin levonorgestrel (LNG) chemically and irreversibly binds to addition cure silicone elastomers, presumably via a hydrosilylation reaction between the levonorgestrel ethynyl group and the hydrosilane groups in the poly(dimethylsiloxane-co-methylhydrosiloxane) crosslinker of the silicone elastomer. Here, for the first time, we report that solid state ^13C nuclear magnetic resonance (NMR) spectroscopy provides direct evidence for the irreversible binding of ethinyl estradiol (EE) – an estrogenic steroid molecule also containing an ethynyl functional group – to an addition cure silicone elastomer. By preparing silicone elastomer samples containing ^13C-labelled EE, signals in the NMR spectra could readily be assigned to both the free and bound EE. Additional depolymerisation studies, performed on an addition cure silicone elastomer system from which the unbound EE fraction was completely extracted, further confirmed the presence of bound EE through the formation of coloured reaction mixtures resulting from the reaction of bound EE and trifluoroacetic acid (TFA). These methods will be particularly useful in the ongoing development of new steroid-releasing silicone drug delivery devices, including various vaginal ring devices for contraception, HIV prevention and multipurpose prevention technology applications

Post-use ring weight, residual drug content and drug depletion zone thickness as objective measures of user adherence to a contraceptive progesterone vaginal ring

Objectives: The primary aim was to investigate post-use ring weight as a potential measure of cumulative adherence to a progesterone-releasing vaginal ring. Study design: We weighed and quantified residual progesterone in 115 vaginal rings following 90-day use by participants in an acceptability trial conducted in Nigeria, Senegal and Kenya. The primary objective was to correlate residual progesterone content with post-use ring weight. Secondary objectives included correlating ring weight with putative duration of ring use, and, where participants used two rings consecutively in the study, correlating residual content between these paired rings. Results: Mean ring weight and progesterone content of used rings was 8.62 ± 0.24 g and 1245 ± 245 mg respectively, versus 9.37 ± 0.02 and 2058 ± 21 mg for control rings. Most used rings (90.4%) had residual progesterone levels less than 85% of the nominal loading. Linear regression showed a strong positive linear trend between residual progesterone content and post-use ring weight for all rings (r^2 = 0.82). Duration of ring use was inversely associated (p = .00020) with ring weight. Conclusions: Post-use ring weight is highly correlated with residual progesterone content, a benchmark objective cumulative measure of adherence, and thus potentially useful as a surrogate objective measure of cumulative adherence to a progesterone-releasing vaginal ring. Implication statement: For vaginal rings containing a high initial drug loading and releasing a relatively large fraction of the initial loading during clinical use, post-use ring weight may offer a simple and inexpensive alternative to residual content testing for accurate monitoring of user adherence

Progesterone vaginal ring as a new contraceptive option for lactating mothers: Evidence from a multicenter non-randomized comparative clinical trial in India

Objectives: Evaluate and compare contraceptive efficacy, safety, continuation rates and duration of lactational amenorrhea (LA) in married lactating women (20-35 years) using the progesterone vaginal ring (PVR) or Copper-T380A intrauterine device (IUD) during the first postpartum year. Study design: We conducted a one-year multicenter, non-randomized, non-inferiority, open-label, comparative trial at 20 centers in India and compared efficacy, safety, continuation and LA plus feeding patterns and growth/well-being of participants’ infants. Women used four 3-month PVRs consecutively (lost PVRs were not replaced) and were to breastfeed at least four times/day. We used Pearl Index (PI) and Kaplan Meier (K-M) rates to analyze pregnancy and K-M for continuation. Results: We enrolled 789 women (459 PVR, 330 IUD). Neither PI nor K-M one-year pregnancy rates differed significantly between groups (PI: PVR-0.62; IUD-0.35); (K-M: PVR-0.7; IUD-0.4, p=0.58). Continuation rates at 12 months were 78.5% (IUD) vs. 56.9% (PVR) (p \u3c 0.001). Ring expulsions and menorrhagia were the most common discontinuation among PVR/ IUD users respectively. The median duration of LA among PVR vs. IUD users was 405 vs. 120 days (p \u3c 0.001). Both groups reported similar adverse events (PVR: 24.2%; IUD: 23.0%); there were no serious adverse events among PVR users. Infants from both groups fed 12-7 times/day and grew at expected rates. Conclusions: Efficacy and safety outcomes were comparable among women in both groups. Continuation rates for PVR, a woman-controlled method, were shorter than IUD rates while PVR users maintained LA significantly longer than IUD users. Infant breastfeeding and growth patterns/well-being were favorable in both groups. Implications: PVR, a user-controlled device, offers an additional contraceptive choice for lactating women for one-year postpartum use and can help to address the unmet need for contraception among postpartum women while encouraging breastfeeding to enhance infant growth and well-being