Effect of non-absorbent intravaginal menstrual/contraceptive products on Staphylococcus aureus and production of the superantigen TSST-1.

Tampons are associated with toxic shock syndrome (mTSS). One reason for this association is oxygen introduction within tampons into the anaerobic vagina. Oxygen is required for Staphylococcus aureus to produce TSS toxin-1 (TSST-1). There have been changes in use of medical devices to control menstrual flow, including increased use of menstrual discs and cups. These devices composed of solid, flexible materials do not absorb menstrual fluid and thus do not trap oxygen. This study evaluates tampons and non-absorbent devices for effect on S. aureus and TSST-1 production. There are three in vitro tests to evaluate devices for effect on TSST-1 production: (1) stationary flask, (2) shake flask, and (3) tampon sac. In this study, 100% rayon and 100% cotton tampons with three absorbencies, contraceptive diaphragms, and menstrual discs and cups were tested for effect on S. aureus growth and TSST-1 production. Product composition did not affect bacterial growth or TSST-1 production. Tampons showed no effect on S. aureus growth compared with no-tampon controls, but tampons showed enhanced TSST-1 production as a function of trapped oxygen in stationary cultures and tampon sacs but not in shake flasks. The non-absorbent devices showed no enhanced S. aureus growth or TSST-1 production compared with no-device controls. These studies are consistent with the association of tampons with mTSS as a function of absorbency, but they suggest the occasional association of mTSS with non-absorbent devices may be coincidental as opposed to co-causative.

Surface roughness of different contraceptive vaginal rings: evaluation by scanning electron microscope (SEM).

Objective: The aim of the study was to evaluate whether the compositions of the ethylene vinyl acetate (EVA) membrane of two different contraceptive vaginal rings could influence the surface roughness, which is associated with the possible accumulation of vaginal biomass on the rings during use.Methods: We measured and compared the surface roughness of unused vaginal rings, NuvaRing and Ornibel, using a scanning electron microscope (SEM) and dedicated software that can convert SEM images into 3D models. Average roughness (Ra), average quadratic roughness (Rq) and mean height of the irregularities at 10 points (Rz) were calculated.Results: Different thicknesses of the EVA membranes between the two rings were noted. No significant differences were found between the two rings in the three evaluated values of surface roughness (NuvaRing vs Ornibel, respectively: Ra, 1.53 ± 0.14 vs 1.61 ± 0.14 µm, p = 0.141; Rq, 2.03 ± 0.25 vs 2.07 ± 0.16 µm, p = 0.688; Rz, 11.4 ± 3.1 vs 11.4 ± 2.4 µm, p = 0.987).Conclusion: The different composition of the vaginal rings' EVA membrane is not associated with different surface roughness. Ornibel is equivalent to NuvaRing in terms of surface roughness, despite the different composition of the membrane polymers.

The development of a silicone vaginal ring with a prostaglandin analogue for potential use in the treatment of canine reproductive disorders.

In veterinary medicine, vaginal rings (VRs) are rarely used. However, there are diseases of female dogs' reproductive system which represent a suitable possibility for their usage. An example of such a disease is canine pyometra which can be treated by lipophilic prostaglandin drugs, unfortunately with harmful side effects after systemic administration. The aim of the study was to prove that the matrix VR based on silicone and channel-forming substance can be successfully used as a carrier for a three-day delivery of prostaglandin E2 (PGE2). Based on an in-vitro release study, an optimum channel-forming substance and its concentration were selected. The results were implemented during the construction of VR from the medical grade silicone DDU-4840 with PGE2 (5 mg). Glucose anhydrous in the 30% concentration was chosen as the most functional channel-forming substance due to synergism of osmotic activity and solubility. The DDU-VR containing PGE2 and 30% of glucose anhydrous exhibited excellent mechanical characteristics and ensured 29% drug release through water-filled channels in first-order kinetic manner. This is eight times higher than a sample without glucose where molecular diffusion through the silicone matrix was dominating the release mechanism. Moreover, drug-free VRs were tested for mechanical resistance and the design of removal thread.

A Dose Ranging Pharmacokinetic Evaluation of IQP-0528 Released from Intravaginal Rings in Non-Human Primates.

PURPOSE: Design of intravaginal rings (IVRs) for delivery of antiretrovirals is often guided by in vitro release under sink conditions, based on the assumption that in vivo release will follow a similar release profile. METHODS: We conducted a dose-ranging study in the female reproductive tract of pigtail macaques using matrix IVRs containing IQP-0528, a poorly soluble but highly potent antiretroviral drug with an IC90 of 146 ng/mL. These IVRs consisted of drug-loaded segments, 15.6% IQP-0528 in Tecoflex 85A, comprising either all, half, or a quarter of the entire ring. RESULTS: In vitro release under sink conditions demonstrates loading-proportional release, with a cumulative 30-day release of 48.5 ± 2.2 mg for our 100% loaded ring, 24.8 ± .36 mg from our 50% loaded ring, and 13.99 ± 1.58 mg from our 25% loaded ring. In vivo, while drug concentration in vaginal fluid is well in excess of IQP-0528's EC90, we find no statistical difference between the different ring loadings in either swab drug levels or drug released from our rings. CONCLUSIONS: We show that in vitro release may not accurately reflect in vivo release, particularly for poorly soluble drugs. All tested loadings of our IVRs are capable of delivering IQP-0528 well in excess of the IC90.

Application of nanotechnology for the development of microbicides.

The vaginal route is increasingly being considered for both local and systemic delivery of drugs, especially those unsuitable for oral administration. One of the opportunities offered by this route but yet to be fully utilised is the administration of microbicides. Microbicides have an unprecedented potential for mitigating the global burden from HIV infection as heterosexual contact accounts for most of the new infections occurring in sub-Saharan Africa, the region with the highest prevalent rates. Decades of efforts and massive investment of resources into developing an ideal microbicide have resulted in disappointing outcomes, as attested by several clinical trials assessing the suitability of those formulated so far. The highly complex and multi-level biochemical interactions that must occur among the virus, host cells and the drug for transmission to be halted means that a less sophisticated approach to formulating a microbicide e.g. conventional gels, etc may have to give way for a different formulation approach. Nanotechnology has been identified to offer prospects for fabricating structures with high capability of disrupting HIV transmission. In this review, predominant challenges seen in microbicide development have been highlighted and possible ways of surmounting them suggested. Furthermore, formulations utilising some of these highly promising nanostructures such as liposomes, nanofibres and nanoparticles have been discussed. A perspective on how a tripartite collaboration among governments and their agencies, the pharmaceutical industry and academic scientists to facilitate the development of an ideal microbicide in a timely manner has also been briefly deliberated.

Pharmacokinetic bioequivalence, safety and acceptability of Ornibel®, a new polymer composition contraceptive vaginal ring (etonogestrel/ethinylestradiol 11.00/3.474 mg) compared with Nuvaring® (etonogestrel/ethinylestradiol 11.7/2.7 mg).

OBJECTIVE: To show the clinical development of Ornibel® (ExeltisHealthcare, Spain) a contraceptive vaginal ring manufactured with a new polymer composition and containing etonogestrel/ethinylestradiol, compared to Nuvaring® (MSD, Spain). SUBJECTS AND METHODS: Randomised, single dose, 2-period, 2-sequence, 2-stage crossover, comparative bioavailability study conducted in 40 healthy female subjects. All subjects received both treatments for 28 days in each of two periods, separated by a 28 days washout. Ornibel® contains etonogestrel/ethinylestradiol 11.00/3.47 mg and Nuvaring® contains etonogestrel/ethinylestradiol 11.7/2.7 mg, both rings delivering 120/15 µg/day. For the calculation of pharmacokinetic parameters, 37 blood samples were collected up to 840 h after each ring insertion to quantify plasma concentrations of etonogestrel and ethinylestradiol using a validated MS/MS-HPLC. Safety was assessed by adverse events recording, clinical laboratory and vital signs and tolerability by vaginal examination. Acceptability was investigated by a 5-point scale questionnaire. RESULTS: Bioequivalence was demonstrated in the first stage as the 94.12% Confidence Intervals of the primary parameters laid within the 80-125% acceptance range for both etonogestrel (Cmax: 96.81-112.20%; AUC0-504h: 98.71-108.61%; AUC0-t: 100.14-109.10%) and ethinylestradiol. (Cmax: 105.91-120.62%; AUC0-504h: 105.47-114.59%; AUC0-t: 108.31-117.61%). During the first day of use a burst effect was observed with Nuvaring®, with significantly higher level of ethinylestradiol (Cmax0-24h ratio: 78.34%, 94.12CI: 73.55-83.45%). Both products were well tolerated and accepted, without significant differences between them. CONCLUSION: Ornibel® is bioequivalent to Nuvaring® in terms of efficacy, safety, tolerability and acceptability. The new polymer composition provides Ornibel® with more stability and gradual hormonal release during the first day of use, particularly for ethinylestradiol.

A phase 2, randomized, double-blind, efficacy and safety study of oxybutynin vaginal ring for alleviation of overactive bladder symptoms in women.

PURPOSE: We evaluated the efficacy and safety of a once monthly oxybutynin vaginal ring in women with overactive bladder. MATERIALS AND METHODS: This randomized, multicenter, double-blind, 12-week phase 2 study compared oxybutynin vaginal ring (4 or 6 mg daily) to a placebo vaginal ring in women with well-defined overactive bladder symptoms. The primary efficacy variable was the change from baseline to week 12 in the total weekly number of incontinence episodes (stress and urge). Safety was measured in terms of treatment emergent adverse events, laboratory, physical, gynecologic examinations, electrocardiogram and vital signs. RESULTS: After a 3-week post-randomization placebo run-in phase (sample size 720) 445 women entered the treatment phase (safety population). Of these women 323 met all 3 overactive bladder specific baseline characteristics of 10 or more urinary urge incontinence episodes weekly, urinary frequency 8 or more voids per 24 hours and voided volume 3 L or less per 24 hours) (analysis population). Women treated with 4 and 6 mg daily oxybutynin vaginal ring had significantly fewer incontinence episodes weekly (p = 0.036 and p = 0.018, respectively), lower daily urinary frequency (p = 0.014, p = 0.002) and a higher proportion had no incontinence episodes at week 12 (p = 0.026, p = 0.027) compared with placebo. The change in severity of urgency and voided volume was similar for all groups (p >0.05). Except for a higher incidence of dry mouth and urinary tract infections that were not always culture confirmed, the oxybutynin vaginal ring was well tolerated and had a safety profile similar to that of the placebo vaginal ring. CONCLUSIONS: The oxybutynin vaginal ring appears to be an effective and safe once monthly treatment option for women with overactive bladder characterized primarily by urinary urge incontinence that merits further evaluation in a phase 3 study.

The optimization of an intravaginal ring releasing progesterone using a mathematical model.

PURPOSE: Progering® is the only intravaginal ring intended for contraception therapies during lactation. It is made of silicone and releases progesterone through the vaginal walls. However, some drawbacks have been reported in the use of silicone. Therefore, ethylene vinyl acetate copolymer (EVA) was tested in order to replace it. METHODS: EVA rings were produced by a hot-melt extrusion procedure. Swelling and degradation assays of these matrices were conducted in different mixtures of ethanol/water. Solubility and partition coefficient of progesterone were measured, together with the initial hormone load and characteristic dimensions. A mathematical model was used to design an EVA ring that releases the hormone at specific rate. RESULTS: An EVA ring releasing progesterone in vitro at about 12.05 ± 8.91 mg day(-1) was successfully designed. This rate of release is similar to that observed for Progering®. In addition, it was observed that as the initial hormone load or ring dimension increases, the rate of release also increases. Also, the device lifetime was extended with a rise in the initial amount of hormone load. CONCLUSIONS: EVA rings could be designed to release progesterone in vitro at a rate of 12.05 ± 8.91 mg day(-1). This ring would be used in contraception therapies during lactation. The use of EVA in this field could have initially several advantages: less initial and residual hormone content in rings, no need for additional steps of curing or crosslinking, less manufacturing time and costs, and the possibility to recycle the used rings.

Spermicidal and antifertility effects of an imbibing and soluble nonoxynol-9 diaphragm (ISND) in rabbits.

OBJECTIVE: To determine the minimum effective concentration (MEC) of an imbibing and soluble nonoxynol-9 (N-9) diaphragm (ISND) required for immobilisation of all spermatozoa in vitro and in vivo. The speed of semen absorbance, time of ISND to dissolution, and the antifertility effects were also investigated in rabbits. METHODS: In vitro spermicidal tests with ISND were conducted using fresh semen from humans and rabbits. Spermicidal and antifertility effects were observed in vivo after the ISND was placed directly into the vagina of rabbits. RESULTS: The MEC of N-9 required in the ISND to totally immobilise sperm within 20 seconds was 0.15 mg/ml for human sperm, and 0.5 mg/ml for rabbit sperm. The human semen was absorbed into the ISND in 45 minutes; the diaphragm dissolved in the vagina 3.5 hours later. In vivo, in rabbits, the MEC of N-9 required to immobilise sperm within five minutes of mating was 1 mg/kg in the ISND, and 10 mg/kg for the nonoxynol-9 film. The median effective dose of N-9 in the ISND was 1.07 mg/kg, whereas for the film it was 3.30 mg/kg. CONCLUSION: The spermicidal and antifertility activities of a low dose N-9 in the ISND were high, with properties of imbibition and solubility confirmed.

Potential for revitalisation of the diaphragm for family planning in Uganda: a rapid assessment of the feasibility of introducing the SILCS Diaphragm.

This health systems assessment evaluated the feasibility of introducing a new contraceptive device, the SILCS single-size diaphragm, into the existing family planning method mix in Uganda. A total of 26 focus group discussions with 201 female and 77 male potential users and 98 key informant interviews with policymakers and providers were conducted between June and August 2010. Potential users, providers, and policymakers recognised that the SILCS Diaphragm could fill a gap in the method mix and expressed eagerness to make the SILCS Diaphragm available, particularly because it is nonhormonal and woman initiated. The diaphragm was viewed by all stakeholders as a method that would increase choice and could improve women's reproductive health in Uganda. Like many countries, Uganda's family planning programme is financially stretched, and clear support for the SILCS Diaphragm by end-users will need to be demonstrated before the product will be considered for public-sector introduction.

[Preparation and release mechanism of gestodene reservoir-type intravaginal rings].

This study taking gestodene (GEST) as a model, investigated the factors affecting reservoir-type intravaginal ring (IVR)'s drug release. This paper reported a gestodene intravaginal ring of reservoir design, comprising a gestodene silicone elastomer core encased in a non-medicated silicone sheath, separately manufactured by reaction injection moulding at 80 degrees C and heating vulcanization at 130 degrees C is reported. The test investigated the factors affecting drug release through a single variable method, taking the drug release rates of 21 days as standards. When changing the thickness of the controlling sheath outside, the ratio of the first day of drug release and mean daily release (MDR), named the relatively burst effect, is closing to 1 with the thickness of controlling sheath increasing, while the 1.25 mm sheath corresponding to 1.04 controlled the burst release effectively; a positive correlation (r = 0.992 2) existed between the average drug release (Q/t) and drug loading (A) within a certain range. The C6-165 controlling sheath with high solubility of GEST is easier to achieve controlled release of the drug; GEST crystalline power is more effective to implement controlled release of drugs among difficent states of the drug. A 1/4 fractional segment core gives a relatively burst effect of 1.76, while the 1/1 and 1/2 are 1.93 and 1.87 separately, at the same drug loading, concluding that use of a fractional segment core would allow development of a suitable GEST reservoir IVR. In summary, GEST reservoir-type IVR could be adjusted by the thickness of controlling sheath, the loading of drug, the material properties of controlling sheath, the dispersion state of drug, the additive composition and structure of intravaginal ring, to control the drug release behavior and achieve the desired drug release rate.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

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.

Safe and sustained vaginal delivery of pyrimidinedione HIV-1 inhibitors from polyurethane intravaginal rings.

The potent antiretroviral pyrimidinediones IQP-0528 (PYD1) and IQP-0532 (PYD2) were formulated in polyurethane intravaginal rings (IVRs) as prophylactic drug delivery systems to prevent the sexual transmission of HIV-1. To aid in the selection of a pyrimidinedione candidate and the optimal loading of the drug in the IVR delivery system, four pyrimidinedione IVR formulations (PYD1 at 0.5 wt% [PYD1(0.5 wt%)], PYD1(1 wt%), PYD2(4 wt%), and PYD2(14 wt%)) were evaluated in pigtail macaques over 28 days for safety and pyrimidinedione vaginal biodistribution. Kinetic analysis of vaginal proinflammatory cytokines, native microflora, and drug levels suggested that all formulations were safe, but only the high-loaded PYD2(14 wt%) IVR demonstrated consistently high pyrimidinedione vaginal fluid and tissue levels over the 28-day study. This formulation delivered drug in excess of 10 µg/ml to vaginal fluid and 1 µg/g to vaginal tissue, a level over 1,000 times the in vitro 50% effective concentration. The in vitro release of PYD1 and PYD2 under nonsink conditions correlated well with in vivo release, both in amount and in kinetic profile, and therefore may serve as a more biologically relevant means of evaluating release in vitro than typically employed sink conditions. Lastly, the pyrimidinediones in the IVR formulation were chemically stable after 90 days of storage at elevated temperature, and the potent nanomolar-level antiviral activity of both molecules was retained after in vitro release. Altogether, these results point to the successful IVR formulation and vaginal biodistribution of the pyrimidinediones and demonstrate the usefulness of the pigtail macaque model in evaluating and screening antiretroviral IVR formulations prior to preclinical and clinical evaluation.

Safety and pharmacokinetics of aciclovir in women following release from a silicone elastomer vaginal ring.

OBJECTIVES: Systemic aciclovir and its prodrug valaciclovir are effective in treating and reducing recurrences of genital herpes simplex virus (HSV) and reducing transmission. Local aciclovir delivery, if it can achieve and maintain comparable intracellular genital tract levels, may be equally effective in the treatment and suppression of genital HSV. Intravaginal ring (IVR) delivery of aciclovir may provide pre-exposure prophylaxis against HSV acquisition. METHODS: Tolerability and pharmacokinetics were evaluated in six HIV-negative women with recurrent genital HSV who switched their daily oral valaciclovir suppression to an aciclovir IVR for 7 days (n = 3) or 14 days (n = 3). Blood and cervicovaginal lavage (CVL) were collected after oral and IVR dosing to measure aciclovir concentrations and genital swabs were obtained to quantify HSV shedding by PCR. RESULTS: The rings were well tolerated. Median plasma aciclovir concentrations were 110.2 ng/mL (IQR, 85.9-233.5) 12-18 h after oral valaciclovir. Little or no drug was detected in plasma following IVR dosing. Median (IQR) CVL aciclovir levels were 127.3 ng/mL (21-660.8) 2 h after oral valaciclovir, 154.4 ng/mL (60.7-327.5) 12-18 h after oral valaciclovir and 438 ng/mL (178.5-618.5) after 7 days and 393 ng/mL (31.6-1615) after 14 days of aciclovir ring use. Median CVL aciclovir levels 2 h after oral dosing were similar to levels observed 7 (P = 0.99) and 14 (P = 0.75) days after ring use. HSV DNA was not detected in genital swabs and there was no significant change in inflammatory mediators. CONCLUSIONS: This first-in-human study demonstrated that an IVR could safely deliver mucosal levels of aciclovir similar to oral valaciclovir without systemic absorption. More intensive site-specific pharmacokinetic studies are needed to determine whether higher local concentrations are needed to achieve optimal drug distribution within the genital tract.

Preference between precoital and daily use of Duet® and BufferGel in Zimbabwe.

Duet® is a microbicide-delivery system and cervical barrier for use daily or precoitally. We conducted a crossover study among 80 Zimbabwean women to explore factors associated with use-regimen preference. Women were assigned in random order to 14 days of precoital and 14 days of daily Duet and BufferGel use. About 51 % of women preferred precoital use, 39 % preferred daily use, and 10 % liked both equally. Overall product adherence during sex was similar for both use-regimens. In multivariable analysis, diaphragm experience was associated with preference for precoital use (AOR 2.80, 95 % CI 1.01-7.76). Reasons for preferring precoital use included use only when needed, cleanliness, and discomfort with daily use. Daily use preference included convenience, discreetness, and being prepared for "sex-on-demand." Different personal and life circumstances may result in varying use-regimen preferences. Methods that can accommodate both coitally-related and daily use may be advantageous by providing more choice to users.

In Vitro Corrosion Assessment of the Essure® Medical Device in Saline, Simulated Inflammatory Solution and Neutral Buffered Formalin.

The Essure® permanent contraceptive implant, comprised of four alloys (nickel-titanium, 316L stainless steel, platinum-iridium, and tin-silver solder) and Dacron (PET) fibers, has been approved for use in the US for about two decades. However, little has been published on this implant's biomaterials performance, and as this implant gains interest in terms of in vivo performance, methods of implant post-retrieval storage also need to be assessed. This study investigated the electrochemical properties and ion release profile of Essure® during storage in phosphate buffered saline (PBS), 10 mM H2O2/PBS, a simulated inflammatory solution, and 10% neutral buffered formalin (NBF) to investigate the corrosion behavior and metal ion release. First, a galvanic test method was used to measure the galvanic interactions between alloys within the device. Second, an ion-release study over 107 days was performed. Ions were measured using inductively-coupled plasma mass spectrometry and the implants were assessed using digital optical microscopy, scanning electron microscopy, and energy dispersive x-ray spectrometry. The tin-silver (SnAg) solder continuously corroded in PBS and H2O2/PBS. In the presence of H2O2, nickel and titanium ions were released from the nickel-titanium (NiTi) coil, whereas release of these ions was minimal in PBS alone. Overall, corrosion of the SnAg solder, which holds the NiTi and 316L SS together, was significant in both PBS and H2O2/PBS and may result in loss of connection of the NiTi and 316L stainless steel portions of the implant. Storage in NBF exhibited very low corrosion rates for all alloys and low levels of ion release were observed indicating that formalin storage minimally affects the implant's corrosion status. STATEMENT OF SIGNIFICANCE: The Essure® device is an FDA premarket-approved female permanent sterilization device containing four different metal alloys and poly(ethylene terephthalate) polymer fibers. Significant concerns related to this device have been raised by the FDA since its introduction in 2002. This study is the first published in vitro work to specifically assess the corrosion mechanisms in this multi-alloy device and the role of different solution environments, including formalin storage, inorganic physiological saline and a simulated inflammatory condition. Significant evidence of corrosion of the tin-silver solder is documented, the release of Ni and Ti under simulated inflammatory conditions, and the relative inertness of storage of these implants in neutral buffered saline is presented. The tin-silver corrosion corroborates recent clinical evidence of tin corrosion products in tissues adjacent to these devices in vivo.

Performance of Male Condoms When Used With and Without a Silicone Placebo Vaginal Ring-A Randomized, Crossover Trial.

BACKGROUND: The dapivirine vaginal ring reduced the risk of HIV infection by approximately 30% in Phase III trials. To ensure higher levels of protection against HIV and sexually transmitted infections, women should be counseled to use condoms when using the vaginal ring. This article evaluates the compatibility of male condoms with a placebo vaginal ring. METHODS: This was a 2-period crossover, randomized, noninferiority trial. Couples in 2 sites in the United States were randomized to male condom use, with and without a placebo silicone vaginal ring, and asked to use 4 male condoms in each period. The primary noninferiority end points were total clinical failure and their component failure events (clinical breakage or slippage). Frequencies and percentages were calculated for each failure mode and differences in performance of the 2 periods using the male condom without the ring as reference. Noninferiority was defined using a 3% margin at the 5% significance level. Safety and acceptability were also assessed. RESULTS: Seventy couples were enrolled, and 68 completed the trial with a total of 275 male condoms used in each period. Total condom clinical failure rates were 2.2% and 4.0% in the presence and absence of the vaginal ring, respectively, with a difference of -1.9% (95% confidence interval: -5.3% to 1.5%), thereby demonstrating noninferiority when used with the ring. There was no difference in safety between the 2 periods. DISCUSSION: Concurrent use of the placebo silicone vaginal ring had no significant effect on male condom functionality or safety outcomes.

Transient analysis of drug delivery from a toroidal membrane: Applications for medicated vaginal rings.

A mathematical construct is proposed to analyze drug released from matrix-type vaginal rings. This work is intended to support experimental studies and promote the fabrication of these devices. The transport of a dissolved drug through a toroidal membrane was predicted using diffusion equations and their solutions. This dynamic framework led to the estimation of the time elapsed before releasing 98% of the ethynodiol diacetate from the polymer. Closed-form expressions, easily adaptable to spreadsheet implementation, were developed to simulate the controlled delivery of levonorgestrel initially dispersed in a silicone vaginal ring. As the loading increased, a greater amount of medication was delivered. However, the fractional release decreased from 32.6% to 23.1% when the dosage changed from 4.137 g/cm3 to 8.274 mg/cm3. The expressions were further simplified for thin rings.

Dapivirine-releasing vaginal rings produced by plastic freeforming additive manufacturing.

Here we report the first use of an additive manufacturing (AM) technique based on high pressure material jetting of molten thermoplastic for the fabrication of dapivirine (DPV) loaded vaginal rings (VRs). The VRs are compared to those produced conventionally using injection molding (IM). VRs (outer diameter 54.0 mm, cross-sectional diameter 4.0 mm) were manufactured by either injection molding or Arburg Plastic Freeforming (APF) - a proprietary droplet deposition modelling (DDM) process, using medical grade thermoplastic polyurethanes (TPUs) loaded with 10% w/w DPV. This unique DDM process was used to produce rings of 100, 50 and 10% matrix infill density. DDM printed VRs with 10% density (57-62 mg drug load) exhibited up to seven-fold increase in DPV release compared to injection molded rings containing 190-194 mg DPV. This work has shown that DDM using the APF technique can be used to manufacture drug delivery devices of varying geometries, densities and surface areas to give precise levels of control over the drug release kinetics. This work presents a new opportunity to increase the release of poorly water-soluble compounds or to achieve desired dosing levels using lower drug loadings than those required using conventional thermoplastic processing techniques.