Silicone Elastomer Vaginal Ring Research Articles

Physicochemical considerations in the formulation development of silicone elastomer vaginal rings releasing 5-nitroimidazole drugs for the treatment of bacterial vaginosis

Bacterial vaginosis (BV) is a common dysbiosis of the human vaginal microbiota characterized by depletion of hydrogen peroxide and lactic acid-producing Lactobacillus bacteria and an overgrowth of certain facultative anaerobic bacteria. Although short-term cure rates following treatment with frontline antibiotics (most notably oral metronidazole (MNZ), clindamycin vaginal cream, and MNZ vaginal gel) are generally high, longer-term recurrence rates are an issue. The development of vaginal formulations offering continuous/sustained administration of antibiotic drugs over one or more weeks might prove useful in reducing recurrence. Here, we report the manufacture and preclinical testing of matrix-type vaginal rings offering sustained release of four 5-nitroimidazole antimicrobial drugs either being used clinically or having potential in treatment of BV – MNZ, tinidazole (TNZ), secnidazole (SNZ) and ornidazole (ONZ). All four drugs showed good compatibility with a medical-grade addition-cure silicone elastomer based upon thermal analysis experiments, and matrix-type rings containing 250 mg (3.125 %w/w) of each drug were successfully manufactured by reaction injection molding. 28-day in vitro drug release studies demonstrated root-time kinetics, with daily release rates of 25, 22, 9 and 6 mg/day½ for SNZ, ONZ, MNZ and TNZ, respectively. The rank order of drug release from rings correlated with the simple molecular permeability parameter S/V, where S is the measured drug solubility in silicone fluid and V is the drug molecular volume. The relative merits of SNZ and ONZ over MNZ (the current reference treatment) are discussed. The data support development of vaginal rings for sustained release of 5-nitroimidazole compounds for treatment of BV.

Vaginal formulations containing prebiotics and probiotics for treatment of bacterial vaginosis

Bacterial vaginosis (BV) is a common dysbiosis of the human vagina in which commensal vaginal lactobacilli are displaced by mixed pathogenic bacterial populations. Current treatments by antibiotics result in short- term cure but often lead to recurrence. Lactobacilli are being actively developed as a probiotic treatment option for BV, given their ability to inhibit growth of pathogenic microorganisms and to maintain the health and stability of the vaginal tract microbiota. Therefore, incorporation of freeze-dried lactobacillus and metronidazole (MET) into matrix-type silicone elastomer vaginal rings (VR) is a long-effective novel treatment of BV which can also prevent recurrence. Here, MED-4870 matrix-type VRs containing four different lyoprotectants of three concentrations were manufactured by reaction injection molding, and Shore M Hardness test, compression test and twist test were applied to determine the impact of incorporation of lyoprotectants on mechanical characteristics of VRs. Results indicated that incorporation of lyoprotectants can increase the resistance force and decrease the rotational angles of the VRs. As the category and concentration of incorporated lyoprotectant also have impact on the releasing profile of MET and protecting ability of lactobacillus during freeze-drying process, more research such as in-vitro release tests and microbiology tests will be needed.

In vitro drug release, mechanical performance and stability testing of a custom silicone elastomer vaginal ring releasing dapivirine and levonorgestrel

We have previously reported a multipurpose silicone elastomer vaginal ring providing sustained release of dapivirine (an antiretroviral) and levonorgestrel (a progestin) for HIV prevention and hormonal contraception. During initial development, issues arose due to reaction between the ethynyl group in the levonorgestrel molecule and the hydride-functionalised polydimethylsiloxane components in the silicone elastomer formulation. This unwanted reaction occurred both during and to a lesser extent after ring manufacture, impacting the curing process, the mechanical properties of the ring, and the in vitro release of levonorgestrel. Recently, we reported custom silicone elastomer grades that minimise this reaction. In this follow-on study, we describe the manufacture, in vitro drug release, mechanical, and pharmaceutical stability testing of ring formulations prepared from a custom silicone elastomer and containing 200 mg dapivirine and 80, 160, 240 or 320 mg levonorgestrel. The rings showed mechanical properties similar to marketed ring products, sustained in vitro release of both drugs over 30 days in quantities deemed clinically relevant, offered acceptable assay values, and provided good product stability over 15 weeks at 40 °C and 75% relative humidity.

Refining the in vitro release test method for a dapivirine-releasing vaginal ring to match in vivo performance

Previously reported in vitro release test methods for drug-releasing vaginal rings containing poorly water-soluble drugs have described use of water-alcohol systems or surfactant solutions in efforts to maintain sink conditions. Here, as part of efforts to more closely match in vitro and in vivo release for the 25 mg dapivirine matrix-type silicone elastomer vaginal ring for HIV prevention, we have investigated alternatives to the 1:1 v/v water/isopropanol medium described previously. Specifically, we evaluated dapivirine release from rings into (i) monophasic water/isopropanol mixtures of varying compositions and (ii) biphasic buffer/octanol systems using pH 4.2 and pH 7.0 buffers. The rate and mechanism of dapivirine release were dependent upon the isopropanol concentration in the release medium, in accordance with the observed trend in drug solubility. At 0 and 10% v/v isopropanol concentrations, dapivirine release followed a partition-controlled mechansim. For media containing ≥ 20% v/v isopropanol, in vitro release of dapivirine was significantly increased and obeyed permeation-controlled kinetics. Cumulative release of ~3.5 mg dapivirine over 28 days was obtained using a water isopropanol mixture containing 20% v/v isopropanol, similar to the ~4 mg dapivirine released in vivo. Dapivirine release into the biphasic buffer/octanol system (intended to mimic the fluid/tissue environment in vivo) was constrained by the limited solubility of dapivirine in the buffer component in which the ring resided, such that cumulative dapivirine release was consistently lower than that observed with the 20% v/v isopropanol in water medium. Release into the biphasic system was also pH dependent, in line with dapivirine’s pKa and with potential implications for in vivo release and absorption in women with elevated vaginal pH.Graphical abstract

Silicone elastomer formulations for improved performance of a multipurpose vaginal ring releasing dapivirine and levonorgestrel

A dapivirine-releasing silicone elastomer vaginal ring for reducing women's risk of HIV acquisition has recently been approved. A next-generation multipurpose vaginal ring releasing dapivirine and levonorgestrel is currently in development, offering hormonal contraception and HIV prevention from a single device. Previously, we reported challenges with incorporating levonorgestrel into rings manufactured from addition-cure silicone elastomers due to an irreversible chemical reaction between the levonorgestrel molecule and the hydride-functionalised crosslinker component of the silicone elastomer formulation, leading to low drug content assay, cure inhibition, and reduced ring mechanical properties (which may account for the increased incidence of ring expulsion in vivo). Here, we report on the development and testing of various custom silicone elastomer materials specifically formulated to circumvent these issues. After extensive testing of the custom silicones and subsequent manufacture and testing (Shore M hardness, pot life, content assay, oscillatory rheology, mechanical testing) of rings containing both dapivirine and levonorgestrel, a lead candidate formulation was selected that was amenable to practical ring manufacture via injection molding, exhibited no substantial levonorgestrel binding, and offered suitable mechanical properties.

Use of simulated vaginal and menstrual fluids to model in vivo discolouration of silicone elastomer vaginal rings

Vaginal rings releasing antiretrovirals – either alone or in combination with contraceptive progestins – are being developed for prevention of human immunodeficiency virus (HIV) transmission via vaginal sex. Following Phase I trials, significant discolouration was observed on the surface of investigational silicone elastomer antiretroviral-contraceptive matrix-type vaginal rings containing either 25 mg dapivirine or 200 mg dapivirine plus levonorgestrel. In this study, potential causes of the discolouration have been assessed in vitro using simulated vaginal and menstrual fluids (SVF and SMF, respectively) to model in vivo exposure. The fluid compositions also included hydrogen peroxide (H2O2), hydrogen peroxide plus a copper intrauterine device (IUD), or synthetic dyes (representing personal care and household cleaning products). No discolouration was observed for rings exposed to SVF + hydrogen peroxide (with or without an IUD). However, the SVF + dye compositions showed significant ring discolouration, with staining patterns similar to those observed with rings that had been exposed to highly-coloured personal care and household cleaning products during clinical trial use. Exposure of rings to SMF compositions invariably caused yellow surface discolouration, dark spotting and markings, similar to the staining patterns observed following clinical use. The darker marks on the ring surface were identified as blood debris derived from the SMF. The study indicates that surface discolouration of rings in vivo can be attributed to exposure to menstrual fluid or highly coloured personal care or household cleaning products. Discolouration of the rings was not associated with any specific safety risks for the user, though severe discolouration could potentially impact acceptability and adherence.

Towards a dapivirine and levonorgestrel multipurpose vaginal ring: Investigations into the reaction between levonorgestrel and addition-cure silicone elastomers.

With a dapivirine-releasing vaginal ring having successfully completed late-stage clinical testing for HIV prevention and currently undergoing regulatory review, there is now growing interest in next-generation multipurpose prevention technologies that seek to combine antiretroviral and contraceptive drugs within a single product. Here, we focus on ongoing efforts to develop a silicone elastomer vaginal ring releasing both dapivirine and levonorgestrel. Specifically, we evaluate various strategies aimed at both better understanding and reducing the tendency of levonorgestrel to bind with the elastomer, including: (i) formulation and post-manufacturing strategies aimed at reducing the extent of levonorgestrel reaction with addition-cure silicone elastomers; (ii) evaluation of a simple silicone system to model the complex elastomer; (iii) use of model compounds representing the enone and ethinyl moieties of levonorgestrel to probe the mode of addition of levonorgestrel to addition-cure silicone elastomers; and (iv) solution and solid-state 13C NMR analysis to probe the structural features of the levonorgestrel-silicone system. The results demonstrate that both the enone and ethinyl groups within levonorgestrel undergo hydrosilylation reactions with the hydrosiloxane groups in the silicone elastomer leading to covalent binding. The results also highlight potential strategies for further optimising the dapivirine + levonorgestrel silicone vaginal ring formulation to ensure that the levonorgestrel is available for release.

Development and pharmacokinetics of a combination vaginal ring for sustained release of dapivirine and the protein microbicide 5P12-RANTES

The past fifteen years have witnessed a resurgence of interest in vaginal ring technologies for drug delivery applications, mostly driven by the impetus for development of vaginally-administered antiretroviral microbicides to help reduce the high acquisition rates for human immunodeficiency virus (HIV) among Sub-Saharan African women. Currently, the lead candidate microbicide is a 28-day silicone elastomer vaginal ring releasing dapivirine (Ring-004), an experimental non-nucleoside reverse transcriptase inhibitor. The ring was tested in two pivotal Phase III clinical studies in 2016 and is currently undergoing review by the European Medicines Agency. Recently, we described a new type of silicone elastomer vaginal ring offering sustained release of the protein molecule 5P12-RANTES, a potent experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. Building on our previous work, here we report the preclinical development of a new combination vaginal ring that offers sustained release of both 5P12-RANTES and dapivirine, in which the 5P12-RANTES is incorporated into an exposed core within the ring body and the dapivirine in the sheath. In this way, in vitro release of dapivirine matches closely that for Ring-004. Also, we report the pharmacokinetic testing of this combination ring formulation in sheep, where vaginal concentrations of both drugs are maintained over 28 days at levels potentially useful for preventing HIV infection in women.

Impact of ring size and drug loading on the pharmacokinetics of a combination dapivirine-darunavir vaginal ring in cynomolgus macaques

This work investigates the impact of vaginal ring size and drug loading on the in vitro release, safety, ease of fit, and pharmacokinetics in cynomolgus macaques of matrix-type silicone elastomer vaginal rings containing a combination of the non-nucleoside reverse transcriptase inhibitor dapivirine and the protease inhibitor darunavir. Drug-free and drug-loaded vaginal rings having three different geometries were manufactured by reaction injection molding. In vitro drug release was assessed using both a solvent/water mixture and a vaginal fluid simulant. Macaques fitted with drug-free vaginal rings for 28 days were assessed by colposcopy, cytological evaluation of cervico-vaginal lavage and histological evaluation of tissue after ring removal. The 20 × 4.5 mm combination ring, deemed most appropriate for vaginal fit and comfort in the macaques, was evaluated for pharmacokinetics over 28 days. Substantial differences were observed in the in vitro release profiles between the three ring sizes. However, these differences were not manifest in vivo, where measured drug concentrations after 20 × 4.5 mm ring use were not significantly different from those reported previously with a 25 × 6 mm ring. These results suggest that ring placement and fit is an important species-specific study parameter that should be optimised prior to pharmacokinetic testing.

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.

Packing Polymorphism of Dapivirine and Its Impact on the Performance of a Dapivirine-Releasing Silicone Elastomer Vaginal Ring

A silicone elastomer vaginal ring providing sustained release over 28 days of the anti-retroviral microbicide dapivirine has recently completed phase III clinical testing and showed moderate protection against HIV acquisition. In support of the product licensure program, we report the impact of dapivirine packing polymorphism on the thermal and solubility characteristics of dapivirine and on the in vitro performance of the 25 mg dapivirine ring product. This is the first time that polymorphism has been reported for a drug-releasing vaginal ring product. Thermal, particle size, powder X-ray diffraction, and thermodynamic solubility analyses of dapivirine polymorphic forms I and IV, both of which are persistent at room temperature and with form I being the thermodynamically stable form, were conducted for both micronized and non-micronized materials. No significant differences in solubility between DPV forms I and IV were observed in media commonly used for in vitro release testing. Matrix-type silicone elastomer vaginal rings were manufactured and the impact of dapivirine polymorphism on key in vitro parameters (compression and tensile behavior; content assay; in vitro release; residual content assay) was investigated. The data demonstrate that dapivirine packing polymorphism has no significant impact on in vitro performance of the 25 mg dapivirine vaginal ring.

Matrix and reservoir-type multipurpose vaginal rings for controlled release of dapivirine and levonorgestrel

A matrix-type silicone elastomer vaginal ring providing 28-day continuous release of dapivirine (DPV) ⿿ a lead candidate human immunodeficiency virus type 1 (HIV-1) microbicide compound ⿿ has recently demonstrated moderate levels of protection in two Phase III clinical studies. Here, next-generation matrix and reservoir-type silicone elastomer vaginal rings are reported for the first time offering simultaneous and continuous in vitro release of DPV and the contraceptive progestin levonorgestrel (LNG) over a period of between 60 and 180days. For matrix-type vaginal rings comprising initial drug loadings of 100, 150 or 200mg DPV and 0, 16 or 32mg LNG, Day 1 daily DPV release values were between 4132 and 6113μg while Day 60 values ranged from 284 to 454μg. Daily LNG release ranged from 129 to 684μg on Day 1 and 2⿿91μg on Day 60. Core-type rings comprising one or two drug-loaded cores provided extended duration of in vitro release out to 180days, and maintained daily drug release rates within much narrower windows (either 75⿿131μg/day or 37⿿66μg/day for DPV, and either 96⿿150μg/day or 37⿿57μg/day for LNG, depending on core ring configuration and ignoring initial lag release effect for LNG) compared with matrix-type rings. The data support the continued development of these devices as multi-purpose prevention technologies (MPTs) for HIV prevention and long-acting contraception.

A Temperature-Monitoring Vaginal Ring for Measuring Adherence

BackgroundProduct adherence is a pivotal issue in the development of effective vaginal microbicides to reduce sexual transmission of HIV. To date, the six Phase III studies of vaginal gel products have relied primarily on self-reporting of adherence. Accurate and reliable methods for monitoring user adherence to microbicide-releasing vaginal rings have yet to be established.MethodsA silicone elastomer vaginal ring prototype containing an embedded, miniature temperature logger has been developed and tested in vitro and in cynomolgus macaques for its potential to continuously monitor environmental temperature and accurately determine episodes of ring insertion and removal.Results In vitro studies demonstrated that DST nano-T temperature loggers encapsulated in medical grade silicone elastomer were able to accurately and continuously measure environmental temperature. The devices responded quickly to temperature changes despite being embedded in different thickness of silicone elastomer. Prototype vaginal rings measured higher temperatures compared with a subcutaneously implanted device, showed high sensitivity to diurnal fluctuations in vaginal temperature, and accurately detected periods of ring removal when tested in macaques.ConclusionsVaginal rings containing embedded temperature loggers may be useful in the assessment of product adherence in late-stage clinical trials.

Lack of in vitro-in vivo correlation for a UC781-releasing vaginal ring in macaques.

This study describes the preclinical development of a matrix-type silicone elastomer vaginal ring device designed to provide controlled release of UC781, a non-nucleoside reverse transcriptase inhibitor. Testing of both human- and macaque-sized rings in a sink condition in vitro release model demonstrated continuous UC781 release in quantities considered sufficient to maintain vaginal fluid concentrations at levels 82-860-fold higher than the in vitro IC50 (2.0 to 10.4 nM) and therefore potentially protect against mucosal transmission of HIV. The 100-mg UC781 rings were well tolerated in pig-tailed macaques, did not induce local inflammation as determined by cytokine analysis and maintained median concentrations in vaginal fluids of UC781 in the range of 0.27 to 5.18 mM during the course of the 28-day study. Analysis of residual UC781 content in rings after completion of both the in vitro release and macaque pharmacokinetic studies revealed that 57 and 5 mg of UC781 was released, respectively. The pharmacokinetic analysis of a 100-mg UC781 vaginal ring in pig-tailed macaques showed poor in vivo-in vitro correlation, attributed to the very poor solubility of UC781 in vaginal fluid and resulting in a dissolution-controlled drug release mechanism rather than the expected diffusion-controlled mechanism.

Selection of a Hormonal Contraceptive Agent for Inclusion with Dapivirine in a Silicone Elastomer Vaginal Ring

AIDS Research and Human RetrovirusesVol. 30, No. S1 MPT DevelopmentSelection of a Hormonal Contraceptive Agent for Inclusion with Dapivirine in a Silicone Elastomer Vaginal RingClare McCoy, Peter Boyd, Susan Fetherston, Ian Major, Diarmaid Murphy, Brid Devlin, Andrew Brimer, Jonathon Holt, Jeremy Nuttall, Chris Gimour, Wendy Blanda, and Karl MalcolmClare McCoyQueen's University Belfast, School of Pharmacy, Belfast, United KingdomSearch for more papers by this author, Peter BoydQueen's University Belfast, School of Pharmacy, Belfast, United KingdomSearch for more papers by this author, Susan FetherstonUniversity of Ulster, School of Pharmacy and Pharmaceutical Sciences, Coleraine, United KingdomSearch for more papers by this author, Ian MajorQueen's University Belfast, School of Pharmacy, Belfast, United KingdomSearch for more papers by this author, Diarmaid MurphyQueen's University Belfast, School of Pharmacy, Belfast, United KingdomSearch for more papers by this author, Brid DevlinInternational Partnership for Microbicides, Silver Spring, MD, United StatesSearch for more papers by this author, Andrew BrimerInternational Partnership for Microbicides, Silver Spring, MD, United StatesSearch for more papers by this author, Jonathon HoltInternational Partnership for Microbicides, Silver Spring, MD, United StatesSearch for more papers by this author, Jeremy NuttallInternational Partnership for Microbicides, Silver Spring, MD, United StatesSearch for more papers by this author, Chris GimourInternational Partnership for Microbicides, Silver Spring, MD, United StatesSearch for more papers by this author, Wendy BlandaInternational Partnership for Microbicides, Silver Spring, MD, United StatesSearch for more papers by this author, and Karl MalcolmQueen's University Belfast, School of Pharmacy, Belfast, United KingdomSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5280.abstractAboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Selection of a Hormonal Contraceptive Agent for Inclusion with Dapivirine in a Silicone Elastomer Vaginal Ring." AIDS Research and Human Retroviruses, 30(S1), p. A140FiguresReferencesRelatedDetailsCited ByAn update on multipurpose prevention technologies for the prevention of HIV transmission and pregnancy22 January 2016 | Expert Opinion on Drug Delivery, Vol. 13, No. 4 Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Clare McCoy, Peter Boyd, Susan Fetherston, Ian Major, Diarmaid Murphy, Brid Devlin, Andrew Brimer, Jonathon Holt, Jeremy Nuttall, Chris Gimour, Wendy Blanda, and Karl Malcolm.Selection of a Hormonal Contraceptive Agent for Inclusion with Dapivirine in a Silicone Elastomer Vaginal Ring.AIDS Research and Human Retroviruses.Oct 2014.A140-A140.http://doi.org/10.1089/aid.2014.5280.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download

Evaluation of the Factors Contributing to Levonorgestrel Binding in Addition Cure Silicone Elastomer Vaginal Rings

AIDS Research and Human RetrovirusesVol. 30, No. S1 MPT DevelopmentEvaluation of the Factors Contributing to Levonorgestrel Binding in Addition Cure Silicone Elastomer Vaginal RingsKarl Malcolm, Diarmaid Murphy, Clare McCoy, Peter Boyd, Susan Fetherston, Andrew Brimer, Jonathon Holt, Wendy Blanda, Brid Devlin, Jeremy Nuttall, Chris Gimour, and Tiffany DerrickKarl MalcolmQueen's University Belfast, School of Pharmacy, Belfast, United KingdomSearch for more papers by this author, Diarmaid MurphyQueen's University Belfast, School of Pharmacy, Belfast, United KingdomSearch for more papers by this author, Clare McCoyQueen's University Belfast, School of Pharmacy, Belfast, United KingdomSearch for more papers by this author, Peter BoydQueen's University Belfast, School of Pharmacy, Belfast, United KingdomSearch for more papers by this author, Susan FetherstonUniversity of Ulster, School of Pharmacy and Pharmaceutical Sciences, Coleraine, United KingdomSearch for more papers by this author, Andrew BrimerInternational Partnership for Microbicides, Silver Spring, MD, United StatesSearch for more papers by this author, Jonathon HoltInternational Partnership for Microbicides, Silver Spring, MD, United StatesSearch for more papers by this author, Wendy BlandaInternational Partnership for Microbicides, Silver Spring, MD, United StatesSearch for more papers by this author, Brid DevlinInternational Partnership for Microbicides, Silver Spring, MD, United StatesSearch for more papers by this author, Jeremy NuttallInternational Partnership for Microbicides, Silver Spring, MD, United StatesSearch for more papers by this author, Chris GimourInternational Partnership for Microbicides, Silver Spring, MD, United StatesSearch for more papers by this author, and Tiffany DerrickInternational Partnership for Microbicides, Silver Spring, MD, United StatesSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5278.abstractAboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Evaluation of the Factors Contributing to Levonorgestrel Binding in Addition Cure Silicone Elastomer Vaginal Rings." AIDS Research and Human Retroviruses, 30(S1), p. A139FiguresReferencesRelatedDetailsCited byAn update on multipurpose prevention technologies for the prevention of HIV transmission and pregnancy22 January 2016 | Expert Opinion on Drug Delivery, Vol. 13, No. 4 Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Karl Malcolm, Diarmaid Murphy, Clare McCoy, Peter Boyd, Susan Fetherston, Andrew Brimer, Jonathon Holt, Wendy Blanda, Brid Devlin, Jeremy Nuttall, Chris Gimour, and Tiffany Derrick.Evaluation of the Factors Contributing to Levonorgestrel Binding in Addition Cure Silicone Elastomer Vaginal Rings.AIDS Research and Human Retroviruses.Oct 2014.A139-A139.http://doi.org/10.1089/aid.2014.5278.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download

Pre-clinical development of a combination microbicide vaginal ring containing dapivirine and darunavir.

Combination microbicide vaginal rings may be more effective than single microbicide rings at reducing/preventing sexual transmission of HIV. Here, we report the pre-clinical development and macaque pharmacokinetics of matrix-type silicone elastomer vaginal rings containing dapivirine and darunavir. Macaque rings containing 25 mg dapivirine, 100 mg dapivirine, 300 mg darunavir or 100 mg dapivirine+300 mg darunavir were manufactured and characterized by differential scanning calorimetry. In vitro release was assessed into isopropanol/water and simulated vaginal fluid. Macaque vaginal fluid and blood serum concentrations for both antiretrovirals were measured during 28 day ring use. Tissue levels were measured on day 28. Ex vivo challenge studies were performed on vaginal fluid samples and IC50 values were calculated. Darunavir caused a concentration-dependent reduction in the dapivirine melting temperature in both solid drug mixes and in the combination ring. In vitro release from rings was dependent on drug loading, the number of drugs present and the release medium. In macaques, serum concentrations of both microbicides were maintained between 10(1) and 10(2) pg/mL. Vaginal fluid levels ranged between 10(3) and 10(4) ng/g and between 10(4) and 10(5) ng/g for dapivirine and darunavir, respectively. Both dapivirine and darunavir showed very similar concentrations in each tissue type; the range of drug tissue concentrations followed the general rank order: vagina (1.8 × 10(3)-3.8 × 10(3) ng/g) > cervix (9.4 × 10(1)-3.9 × 10(2) ng/g) > uterus (0-108 ng/g) > rectum (0-40 ng/g). Measured IC50 values were >2 ng/mL for both compounds. Based on these results, and in light of recent clinical progress of the 25 mg dapivirine ring, a combination vaginal ring containing dapivirine and darunavir is a viable second-generation HIV microbicide candidate.

Partial protection against multiple RT-SHIV162P3 vaginal challenge of rhesus macaques by a silicone elastomer vaginal ring releasing the NNRTI MC1220

Partial protection against multiple RT-SHIV162P3 vaginal challenge of rhesus macaques by a silicone elastomer vaginal ring releasing the NNRTI MC1220

A silicone elastomer vaginal ring for HIV prevention containing two microbicides with different mechanisms of action

Vaginal rings are currently being developed for the long-term (at least 30days) continuous delivery of microbicides against human immunodeficiency virus (HIV). Research to date has mostly focused on devices containing a single antiretroviral compound, exemplified by the 25mg dapivirine ring currently being evaluated in a Phase III clinical study. However, there is a strong clinical rationale for combining antiretrovirals with different mechanisms of action in a bid to increase breadth of protection and limit the emergence of resistant strains. Here we report the development of a combination antiretroviral silicone elastomer matrix-type vaginal ring for simultaneous controlled release of dapivirine, a non-nucleoside reverse transcriptase inhibitor, and maraviroc, a CCR5-targeted HIV-1 entry inhibitor. Vaginal rings loaded with 25mg dapivirine and various quantities of maraviroc (50–400mg) were manufactured and in vitro release assessed. The 25mg dapivirine and 100mg maraviroc formulation was selected for further study. A 24-month pharmaceutical stability evaluation was conducted, indicating good product stability in terms of in vitro release, content assay, mechanical properties and related substances. This combination ring product has now progressed to Phase I clinical testing.

Partial protection against multiple RT-SHIV162P3 vaginal challenge of rhesus macaques by a silicone elastomer vaginal ring releasing the NNRTI MC1220

The non-nucleoside reverse transcriptase inhibitor MC1220 has potent in vitro activity against HIV type 1 (HIV-1). A liposome gel formulation of MC1220 has previously been reported to partially protect rhesus macaques against vaginal challenge with a simian HIV (SHIV). Here, we describe the pre-clinical development of an MC1220-releasing silicone elastomer vaginal ring (SEVR), including pharmacokinetic (PK) and efficacy studies in macaques. In vitro release studies were conducted on SEVRs loaded with 400 mg of MC1220, using simulated vaginal fluid (SVF, n = 4) and 1 : 1 isopropanol/water (IPA/H(2)O, n = 4) as release media. For PK evaluation, SEVRs were inserted into adult female macaques (n = 6) for 30 days. Following a 1 week washout period, fresh rings were placed in the same animals, which were then challenged vaginally with RT-SHIV162P3 once weekly for 4 weeks. SEVRs released 1.66 and 101 mg of MC1220 into SVF and IPA/H(2)O, respectively, over 30 days, the differential reflecting the low aqueous solubility of the drug. In macaque PK studies, MC1220 was consistently detected in vaginal fluid (peak 845 ng/mL) and plasma (peak 0.91 ng/mL). Kaplan-Meier analysis over 9 weeks showed significantly lower infection rates for animals given MC1220-containing SEVRs than placebo rings (hazard ratio 0.20, P = 0.0037). An MC1220-releasing SEVR partially protected macaques from vaginal challenge. Such ring devices are a practical method for providing sustained, coitally independent protection against vaginal exposure to HIV-1.