Microbicide Delivery Research Articles

Soft nanoparticles as antimicrobial agents and carriers of microbiocides for enhanced inhibition activity.

Antibiotic resistance continues to pose significant health challenges. Considering severe limitations in the discovery and supply of new antibiotics, there is an unmet need to design alternative and more effective strategies for addressing this global issue. Use of polymeric nanoparticles with cationic shell surfaces offers a highly promising approach to coupling their inherent bactericidal action with sustained delivery of small lipophilic microbicides. We have utilized this platform for assembling multi-tasking soft core-shell nanoparticles from star polymers with the desired asymmetric arm composition. These stable nanoparticles with low critical micelle concentration imparted intrinsic antimicrobial potency due to high positive charge density in the corona, as well as the loading of active biocidal agents (such as curcumin and terbinafine) for potential dual and coadjuvant inhibition. This strategic combination allows for both immediate (direct contact) and extended (drug delivery) antibacterial activities for better therapeutic efficacy. Micellar nanoparticles with and without therapeutic cargo were highly efficient against both Escherichia coli (E. coli) and Bacillus subtilis (B. subtilis), representative Gram-negative and Gram-positive bacteria, respectively. Interestingly, we observed bacteria- and concentration-dependent effects, in which higher concentrations of charged nanoparticles were more effective against E. coli, whereas B. subtilis was inhibited only at lower concentrations. This work highlights a valuable platform to achieve combination therapy through nanoparticles with charged coronas and delivery of potent therapeutics to overcome antimicrobial resistance.

The use of objective adherence measures targeting four placebo microbicide delivery forms in the Quatro Clinical Crossover Study

AbstractBackgroundAdherence to topical microbicides for HIV prevention has been a challenge for women using them and those developing novel products. The Quatro Clinical Crossover Study investigated user preference and acceptability of four different placebo‐based vaginal delivery forms among young African women. The objective of this sub‐study was to test the ability of objective adherence measures in assessing placebo product usage.MethodsA total of two hundred women from Zimbabwe and South Africa used placebo vaginal gel, insert, and film once per week, with or without sex, for 1 month and an intravaginal ring continuously for one month (Months 1–4). Women then chose their preferred product and used it with sex each week during Month 5. Women self‐collected vaginal swabs after using the gel, insert and film. Collected vaginal swabs and used intravaginal rings were analysed for placebo‐based adherence measures using spectroscopy and excipient‐based analyses to determine product use. Vaginal insertion and semen exposure was determined using previously developed and published adherence biomarkers. Intravaginal rings were extracted for residual excipient (glycerin) and penetrated bioanalytes.ResultsBoth methodologies showed that women used gel the most during Months 1–4 (75% by excipient methods, 85% by spectroscopy). The methodologies also determined that nearly all swabs from both sites were vaginally inserted, and 51–86% had detectable placebo product. Semen was detected in more swabs collected during Month 5 from women in Zimbabwe than the swabs from women in South Africa, and most of those swabs had placebo product present as well. The majority of women used the ring for the required four weeks. Sixty‐eight per cent of women who used the ring for the required 4 weeks increased to 78% during Month 5.ConclusionThis sub‐study demonstrated how these objective placebo‐based measures of adherence determined product use of various microbicide delivery forms.

Thermosensitive Bioadhesive Hydrogels Based on Poly(N-isopropylacrilamide) and Poly(methyl vinyl ether-alt-maleic anhydride) for the Controlled Release of Metronidazole in the Vaginal Environment.

The development of thermosensitive bioadhesive hydrogels as multifunctional platforms for the controlled delivery of microbicides is a valuable contribution for the in situ treatment of vagina infections. In this work, novel semi-interpenetrating network (s-IPN) hydrogels were prepared by the entrapment of linear poly(methyl vinyl ether-alt-maleic anhydride) (PVME-MA) chains within crosslinked 3D structures of poly(N-isopropylacrylamide) (PNIPAAm). The multifunctional platforms were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, thermal techniques, rheological analysis, swelling kinetic measurements, and bioadhesion tests on porcine skin. The hydrogels exhibited an interconnected porous structure with defined boundaries. An elastic, solid-like behavior was predominant in all formulations. The swelling kinetics were strongly dependent on temperature (25 °C and 37 °C) and pH (7.4 and 4.5) conditions. The s-IPN with the highest content of PVME-MA displayed a significantly higher detachment force (0.413 ± 0.014 N) than the rest of the systems. The metronidazole loading in the s-IPN improved its bioadhesiveness. In vitro experiments showed a sustained release of the antibiotic molecules from the s-IPN up to 48 h (94%) in a medium simulating vaginal fluid, at 37 °C. The thermosensitive and bioadhesive PNIPAAm/PVME-MA systems showed a promising performance for the controlled release of metronidazole in the vaginal environment.

Potential of mucoadhesive chitosan glutamate microparticles as microbicide carriers – antiherpes activity and penetration behavior across the human vaginal epithelium

Chitosan glutamate (gCS) spray-dried microparticles appear promising carriers to overcome challenges associated with vaginal microbicide delivery. This study aimed at elucidating the penetration and mucoadhesive behavior of developed gCS multiunit carriers with zidovudine (ZVD) as a model antiretroviral agent in contact with excised human vaginal epithelium followed with an examination of in vitro antiherpes activity in immortal human keratinocytes HaCaT and human vaginal epithelial cells VK2-E6/E7. Both ZVD dispersion and placebo microparticles served as controls. Microparticles displayed feasible (comparable to commercial vaginal product) mucoadhesive and mucoretention characteristics to isolated human vaginal tissue. Ex vivo penetration studies revealed that gCS increased the accumulation of active agent in the vaginal epithelium but surprisingly did not facilitate its penetration across human tissue. Finally, the obtained antiviral results demonstrated the potential of gCS as an antiherpes adjunctive, whose mode of action was related to blocking viral attachment.

Nanotechnology-Based Platforms for Vaginal Delivery of Peptide Microbicides.

Vaginal drug delivery offers an opportunity for effective microbicide treatments. However, the physiological characteristics of the vagina represent a challenge when preparing microbicide formulations for local delivery that avoid systemic effects. To review recent advances in vaginal microbicides placing special emphasis on nanocarriers that encapsulate peptide microbicides. The review includes an overview of local treatment and prevention strategies for bactericidal, fungal, protozoal and viral vaginal infections that use peptide microbicides. Scientific literature and clinical trials published in the PubMed database since 2015 are analyzed. Peptide microbicides are used for vaginal drug delivery as a means of prevention and treatment of several infectious diseases, especially sexually transmitted infections, and it is clear that such peptide-based microbicides constitute a suitable strategy. Their combination with nanotechnological drug delivery systems improves local peptide administration while avoiding their degradation and adverse effects. To date, only a few polymeric and lipid-based nanocarriers have been used for peptide microbicide vaginal delivery. The combination of nanotechnology and peptide microbicides has emerged over recent years, and different platforms are being used for vaginal peptide delivery. Nanostructured systems for peptide delivery via vaginal rings or hydrogels are increasingly used as platforms capable of providing suitable drug delivery. However, there is still a lack of knowledge about nanocarriers aimed at encapsulating peptides for local microbicide delivery.

Preferences and Acceptability of Vaginal Delivery Forms for HIV Prevention Among Women, Male Partners and Key Informants in South Africa and Zimbabwe: Qualitative Findings.

The attributes of an HIV microbicide may affect its acceptability, uptake and use. Quatro, a clinical study with a qualitative component, was conducted to elicit input from end-users and key informants (KIs) on four different placebo vaginal microbicide delivery forms; fast dissolving insert, ring, film and gel. In-depth interviews and focus group discussions were conducted with young women, their male partners and KIs, to explore acceptability and preferences of the four placebo products, with the intention of improving product attributes, adherence, and consequently, long term effectiveness. None of the four microbicide delivery forms stood well above others as the most preferred. Product attributes; long-action, ease of use, invisibility, female initiated and non-interference during sex were favourable in both countries. Despite preference for the long-action, on-demand products were the most liked by women. Qualitative data from the Quatro study provided rich feedback on specific attributes important to the acceptability of four HIV prevention product platforms currently in development, enabling more informed and guided product development efforts moving forward.

Development of trigger sensitive hyaluronic acid/palm oil-based organogel for in vitro release of HIV/AIDS microbicides using artificial neural networks

BackgroundEfficient and effective chemotherapeutic methods designed to prevent the continuous spread of HIV/AIDS is essential to break the cycle of new infections. The use of condoms has been seen to be effective in prevention of HIV and STIs but its lack of use especially in vulnerable population is a deterrent to its overall success as a control method. Utilization of topical microbicide to curb the spread of HIV follows the current paradigm for HIV prevention in at risk individuals. The objective of this study was to develop and evaluate hyaluronic acid/palm oil-based organogel loaded with maraviroc (MRV) which would be released using hyaluronidase as the trigger for pre-exposure prophylaxis of HIV.ResultsThe organogels had average globules size 581.8 ± 3.9 nm, and were stable after three freeze thaw cycles; the thermosensitive and HA sensitivity was achieved via incorporation of hyaluronic acid and dicaprylate esters in the organogel with thermogelation occurring at 34.1 °C. Artificial neural network was used to model and optimize mucin absorption and flux. These responses were predicted using the multilayer full feed forward (MFFF) and the multilayer normal feed forward (MNFF) neural networks. Optimized organogel showed the mucin adsorption and flux was 70.84% and 4.962 μg/cm2/min1/2, hence MRV was adequately released via triggers of temperature and HA. The MRV organogel showed inhibition HIV − 1 via TZM-bl indicator cells. Compared to control HeLa cells without any treatment, MRV organogel was not cytotoxic for 14 days in vitro.ConclusionThese data highlight the potential use of hyaluronic acid/palm oil-based organogel for vaginal delivery of anti-HIV microbicides. This can serve as a template for more studies on such formulations in the area of HIV prevention.

Perspectives from Young South African and Zimbabwean Women on Attributes of Four (Placebo) Vaginal Microbicide Delivery Forms

IntroductionIncorporating end-user input into the design of new vaginal microbicides for women is key to optimizing their uptake, consistent use, and, ultimately, success in combatting the heterosexual HIV epidemic.MethodsThe Quatro Study assessed four placebo forms of vaginally inserted HIV-microbicides among young microbicide-naïve African women: on-demand film, insert and gel, and monthly ring. Participants randomly used each product for 1 month and provided product satisfaction ratings (1–5 scale), and opinions on product attributes and potential alternative designs. Qualitative data were collected through focus group discussions at study exit. Multivariable associations between attribute opinions and overall product rating were examined using Poisson regression models with robust standard errors to assess the attributes most influential to satisfaction.ResultsOverall opinions of products and their individual attributes were generally positive; all products were rated either 4 or a 5 by ≥ 50% of participants. Attributes related to ease of use and interference with normal activities were the most salient predictors of satisfaction. Preferences for duration of use tended toward relatively shorter use periods for the ring (i.e., 1–3 months vs. 12 months) and for coitally independent dosing for the on-demand products.ConclusionsHow well a product fit in with participants’ lifestyles was important to their overall satisfaction. For on-demand products, greater flexibility around timing of use was desired, to avoid coital dependency of the dosing.

Preclinical Safety Evaluation of HIV-1 gp120 Responsive Microbicide Delivery System in C57BL/6 Female Mice.

Many novel vaginal/rectal microbicide formulations failed clinically due to safety concerns, indicating the need for the early investigation of lead microbicide formulations. In this study, the preclinical safety of an HIV-1 gp120 and mannose responsive microbicide delivery system (MRP) is evaluated in C57BL/6 mice. MRP was engineered through the layer-by-layer coating of calcium carbonate (CaCO3) with Canavalia ensiformis lectin (Con A) and glycogen. MRP mean particle diameter and zeta potential were 857.8 ± 93.1 nm and 2.37 ± 4.12 mV, respectively. Tenofovir (TFV) encapsulation and loading efficiencies in MRP were 70.1% and 16.3% w/w, respectively. When exposed to HIV-1 rgp120 (25 μg/mL), MRP released a significant amount of TFV (∼5-fold higher) in vaginal and seminal fluid mixture compared to the control (pre-exposure) level (∼59 μg/mL) in vaginal fluid alone. Unlike the positive control treated groups (e.g., nonoxynol-9), no significant histological damages and CD45+ cells infiltration were observed in the vaginal and major reproductive organ epithelial layers. This was probably due to MRP biocompatibility and its isosmolality (304.33 ± 0.58 mOsm/kg). Furthermore, compared to negative controls, there was no statistically significant increase in pro-inflammatory cytokines such as IL1α, Ilβ, IL7, IP10, and TNFα. Collectively, these data suggest that MRP is a relatively safe nanotemplate for HIV-1 gp120 stimuli responsive vaginal microbicide delivery system.

Development and clinical assessment of new objective adherence markers for four microbicide delivery systems used in HIV prevention studies

BackgroundAdherence is critical for successful topical, vaginally delivered anti-retroviral (ARV)-based HIV pre-exposure prophylaxis (PrEP). Quantitating systemic or tissue ARV levels through LC–MS/MS is currently viewed as the most reliable measure of adherence. However, for placebo-controlled trials, this is a high cost analysis that measures adherence only in the drug treatment group. A desirable marker of adherence is one that is measured in both placebo and drug treatment groups using a simple on-site clinical laboratory test, which allows necessary interventions for supporting participant adherence. Our objective was to develop adherence markers for four vaginal placebo products currently used as microbicide delivery systems: gel, film, insert, and intravaginal ring. Excipient and spectroscopy-based approaches were used for preclinical development of the placebo markers and subsequently validated by the CONRAD 135 study. The study collected vaginal swabs collected each day for 1 week post vaginal application of gel, film, or insert in the clinic with or without sex. Intravaginal rings were collected after 1 day, 7, and 30 days of use.ResultsPlacebo gel, film, and insert in vaginal swabs were successfully detected by specific excipient colorimetric or probe-based assays for hydroxyethylcellulose, glycerin, and sorbitol respectively, as well as spectroscopy-based prediction models. The range of detection for gel, film, and insert in swabs collected up to 16 h post vaginal application was 70-100% of the total swabs per time point, with some markers showing potential for longer duration. Decreasing residual glycerin levels and increasing bioanalyte penetration of vaginally used intravaginal rings showed significant changes between 1 and 30 days of use.ConclusionsWe demonstrated clinical proof-of-concept that adherence markers for placebo product can be measured using simple, lower cost approaches. Measuring adherence in both placebo and drug arms of a HIV PrEP study would better inform future trial designs.

Spray-Dried Thiolated Chitosan-Coated Sodium Alginate Multilayer Microparticles for Vaginal HIV Microbicide Delivery.

It is hypothesized that novel thiolated chitosan-coated multilayer microparticles (MPs) with enhanced drug loading are more mucoadhesive than uncoated MPs and safe in vivo for vaginal delivery of topical anti-HIV microbicide. Formulation optimization is achieved through a custom experimental design and the alginate (AG) MPs cores are prepared using the spray drying method. The optimal MPs are then coated with the thiolated chitosan (TCS) using a layer-by-layer method. The morphological analysis, in situ drug payload, in vitro drug release profile, and mucoadhesion potential of the MPs are carried out using scanning electron microscopy, solid-state 31P NMR spectroscopy, UV spectroscopy, fluorescence imaging and periodic acid Schiff method, respectively. The cytotoxicity and preclinical safety of MPs are assessed on human vaginal (VK2/E6E7) and endocervical (End1/E6E7) epithelial cell lines and in female C57BL/6 mice, respectively. The results show that the MPs are successfully formulated with an average diameter ranging from 2 to 3μm with a drug loading of 7-12% w/w. The drug release profile of these MPs primarily follows the Baker-Lonsdale and Korsmeyer-Peppas models. The MPs exhibit high mucoadhesion (20-50 folds) compared to native AGMPs. The multilayer MPs are noncytotoxic. Histological and immunochemical analysis of the mice genital tract shows neither signs of damage nor inflammatory cell infiltrate. These data highlight the potential use of TCS-coated AG-based multilayer MPs templates for the topical vaginal delivery of anti-HIV/AIDS microbicides.

Multicompartmental Pharmacokinetic Model of Tenofovir Delivery to the Rectal Mucosa by an Enema.

Rectal enemas that contain prophylactic levels of anti-HIV microbicides such as tenofovir have emerged as a promising dosage form to prevent sexually transmitted HIV infections. The enema vehicle is promising due to its likely ability to deliver a large amount of drug along the length of the rectal canal. Computational models of microbicide drug delivery by enemas can help their design process by determining key factors governing drug transport and, more specifically, the time history and degree of protection. They can also inform interpretations of experimental pharmacokinetic measures such as drug concentrations in biopsies. The present work begins rectal microbicide PK modeling, for enema vehicles. Results here show that a paramount factor in drug transport is the time of enema retention; direct connectivity between enema fluid and the fluid within rectal crypts is also important. Computations of the percentage of stromal volume protected by a single enema dose indicate that even with only a minute of enema retention, protection of 100% can be achieved after around 14 minutes post dose. Concentrations in biopsies are dependent on biopsy thickness; and control and/or knowledge of thickness could improve accuracy and decrease variability in biopsy measurements. Results here provide evidence that enemas are a promising dosage form for rectal microbicide delivery, and offer insights into their rational design.

Development and in vivo safety assessment of tenofovir-loaded nanoparticles-in-film as a novel vaginal microbicide delivery system.

Topical pre-exposure prophylaxis (PrEP) with antiretroviral drugs holds promise in preventing vaginal transmission of HIV. However, significant biomedical and social issues found in multiple past clinical trials still need to be addressed in order to optimize protection and users' adherence. One approach may be the development of improved microbicide products. A novel delivery platform comprising drug-loaded nanoparticles (NPs) incorporated into a thin polymeric film base (NPs-in-film) was developed in order to allow the vaginal administration of the microbicide drug candidate tenofovir. The system was optimized for relevant physicochemical features and characterized for biological properties, namely cytotoxicity and safety in a mouse model. Tenofovir-loaded poly(lactic-co-glycolic acid) (PLGA)/stearylamine (SA) composite NPs with mean diameter of 127nm were obtained with drug association efficiency above 50%, and further incorporated into an approximately 115μm thick, hydroxypropyl methylcellulose/poly(vinyl alcohol)-based film. The system was shown to possess suitable mechanical properties for vaginal administration and to quickly disintegrate in approximately 9min upon contact with a simulated vaginal fluid (SVF). The original osmolarity and pH of SVF was not affected by the film. Tenofovir was also released in a biphasic fashion (around 30% of the drug in 15min, followed by sustained release up to 24h). The incorporation of NPs further improved the adhesive potential of the film to ex vivo pig vaginal mucosa. Cytotoxicity of NPs and film was significantly increased by the incorporation of SA, but remained at levels considered tolerable for vaginal delivery of tenofovir. Moreover, histological analysis of genital tissues and cytokine/chemokine levels in vaginal lavages upon 14days of daily vaginal administration to mice confirmed that tenofovir-loaded NPs-in-film was safe and did not induce any apparent histological changes or pro-inflammatory response. Overall, obtained data support that the proposed delivery system combining the use of polymeric NPs and a film base may constitute an exciting alternative for the vaginal administration of microbicide drugs in the context of topical PrEP. The development of nanotechnology-based microbicides is a recent but promising research field seeking for new strategies to circumvent HIV sexual transmission. Different reports detail on the multiple potential advantages of using drug nanocarriers for such purpose. However, one important issue being frequently neglected regards the development of vehicles for the administration of microbicide nanosystems. In this study, we propose and detail on the development of a nanoparticle-in-film system for the vaginal delivery of the microbicide drug candidate tenofovir. This is an innovative approach that, to our best knowledge, had never been tested for tenofovir. Results, including those from in vivo testing, sustain that the proposed system is safe and holds potential for further development as a vaginal microbicide product.

Coupled gel spreading and diffusive transport models describing microbicidal drug delivery

Gels are a drug delivery platform that is being evaluated for application of active pharmaceutical ingredients, termed microbicides, that act topically against vaginal and rectal mucosal infection by sexually transmitted HIV. Despite success in one Phase IIb trial of a vaginal gel delivering tenofovir, problems of user adherence to designed gel application scheduling have compromised results in two other trials. The microbicides field is responding to this dilemma by expanding behavioral analysis of the determinants of adherence while simultaneously improving the pharmacological, biochemical, and biophysical analyses of the determinants of microbicide drug delivery. The intent is to combine results of these two complementary perspectives on microbicide performance and epidemiological success to create an improved product design paradigm. Central to both user sensory perceptions and preferences, key factors that underlie adherence, and to vaginal gel mucosal drug delivery, that underlies anti-HIV efficacy, are gel properties (e.g. rheology) and volume. The specific engineering problem to be solved here is to develop a model for how gel rheology and volume, interacting with loaded drug concentration, govern the transport of the microbicide drug tenofovir into the vaginal mucosa to its stromal layer. These are factors that can be controlled in microbicide gel design. The analysis here builds upon our current understanding of vaginal gel deployment and drug delivery, incorporating key features of the gel's environment, the vaginal canal, fluid production and subsequent gel dilution, and vaginal wall elasticity. These have not previously been included in the modeling of drug delivery. We consider the microbicide drug tenofovir, which is the drug most completely studied for gels: in vitro, in animal studies in vivo, and in human clinical trials with both vaginal or rectal gel application. Our goal is to contribute to improved biophysical and pharmacological understanding of gel functionality, providing a computational tool that can be used in future vaginal microbicide gel design.

Stimuli-sensitive nanoparticles for multiple anti-HIV microbicides

This study is aimed to develop and evaluate an advanced intravaginal formulation for the delivery of multiple anti-HIV microbicides. Novel stimuli-sensitive nanoparticles (NPs) which protected the encapsulated drugs from being degraded in acidic pH conditions were made of Eudragit S-100® (ES100®), a pH-sensitive polymer. ES100® NPs were prepared using the quasi-emulsion solvent diffusion technique and loaded with two microbicides namely Tenofovir (TNF) and Etravirine (ETV). The effects of various fabrication parameters on the formulation properties were evaluated for the optimization of ES100® NPs. The morphology of the ES100® NPs was examined by scanning electron microscopy. The cytotoxicity of NPs containing microbicides individually or in a combination was assessed using cell viability and trans-epithelial electrical resistance (TEER) measurements. The cellular uptake rates of the model microbicides by human vaginal epithelial cells, VK2 E6/E7 cells, were evaluated using confocal microscopy and florescence-assisted cell sorting technique. ES100® NPs had a spherical shape, smooth surface, and uniform texture with a little aggregation. The average particle size for NPs loaded with TNF ranged from 125 to 230 nm, whereas those for ETV-loaded NPs ranged from 160 to 280 nm. ES100® NPs had zeta potential in the range of −5 to −10 mV. In-vitro release studies displayed the potential benefits of ES100® NPs in retaining and protecting the loaded microbicides at vaginal pH (acidic), but immediately releasing them as the pH changes to neutral or 7.4 (physiological pH). Cell viability studies demonstrated that ES100® NPs did not exert any cytotoxicity individually or in a combination of both microbicides. TEER measurements confirmed that ES100® NPs loaded with TNF and ETV did not cause any changes in the barrier integrity of VK2 E6/E7 cell monolayer. The cellular uptake study revealed that ES100® NPs were taken by vaginal epithelial cells through the endocytosis process and that the uptake rate of the model microbicides loaded in nanoparticles was greater than that in the solution. The ES100® NPs whose degradation rates are dependent on environmental pH would serve as an efficient platform for targeted delivery of multiple microbicides to protect women from sexually transmitted diseases including HIV-1 infection.

Coaxially electrospun fiber-based microbicides facilitate broadly tunable release of maraviroc

Electrospun fibers show potential as a topical delivery system for vaginal microbicides. Previous reports have demonstrated delivery of anti-HIV and anti-STI (sexually transmitted infection) agents from fibers formulated using hydrophilic, hydrophobic, or pH-responsive polymers that result in rapid, prolonged, or stimuli-responsive release, respectively. However, coaxial electrospun fibers have yet to be evaluated as a highly tunable microbicide delivery vehicle. In this research, we explored the opportunities and limitations of a model coaxial electrospun fiber system to provide broad and tunable release rates for the HIV entry inhibitor maraviroc. Specifically, we prepared ethyl cellulose (EC)-shell and polyvinylpyrrolidone (PVP)-core fibers that were capable of releasing actives over a range of hours to several days. We further demonstrated simple and effective methods for combining core-shell fibers with rapid-release formulations to provide combined instantaneous and sustained maraviroc release. In addition, we investigated the effect of varying release media on maraviroc release from core-shell fibers, and found that release was strongly influenced by media surface tension and drug ionization. Finally, in vitro cell culture studies show that our fiber formulations were not cytotoxic and that electrospun maraviroc maintained similar antiviral activity compared to neat maraviroc.

Biomarkers and biometric measures of adherence to use of ARV-based vaginal rings.

IntroductionPoor adherence to product use has been observed in recent trials of antiretroviral (ARV)-based oral and vaginal gel HIV prevention products, resulting in an inability to determine product efficacy. The delivery of microbicides through vaginal rings is widely perceived as a way to achieve better adherence but vaginal rings do not eliminate the adherence challenges exhibited in clinical trials. Improved objective measures of adherence are needed as new ARV-based vaginal ring products enter the clinical trial stage.MethodsTo identify technologies that have potential future application for vaginal ring adherence measurement, a comprehensive literature search was conducted that covered a number of biomedical and public health databases, including PubMed, Embase, POPLINE and the Web of Science. Published patents and patent applications were also searched. Technical experts were also consulted to gather more information and help evaluate identified technologies. Approaches were evaluated as to feasibility of development and clinical trial implementation, cost and technical strength.ResultsNumerous approaches were identified through our landscape analysis and classified as either point measures or cumulative measures of vaginal ring adherence. Point measurements are those that give a measure of adherence at a particular point in time. Cumulative measures attempt to measure ring adherence over a period of time.DiscussionApproaches that require modifications to an existing ring product are at a significant disadvantage, as this will likely introduce additional regulatory barriers to the development process and increase manufacturing costs. From the point of view of clinical trial implementation, desirable attributes would be high acceptance by trial participants, and little or no additional time or training requirements on the part of participants or clinic staff. We have identified four promising approaches as being high priority for further development based on the following measurements: intracellular drug levels, drug levels in hair, the accumulation of a vaginal analyte that diffuses into the ring, and the depletion of an intrinsic ring constituent.ConclusionsWhile some approaches show significant promise over others, it is recommended that a strategy of using complementary biometric and behavioural approaches be adopted to best understand participants’ adherence to ARV-based ring products in clinical trials.

Alginate microbead-encapsulated silver complexes for selective delivery of broad-spectrum silver-based microbicides

In sub-Saharan Africa, human immunodeficiency virus (HIV) infections are predominantly acquired via heterosexual contact, and women are at greatest risk of being infected. This region also has the highest rates of sexually transmitted infections (STIs) per capita worldwide; STIs are strongly associated with increased HIV transmission. Therefore, there is an urgent requirement for microbicides that are active against HIV and STIs. Silver compounds exhibit broad antimicrobial activity, making them potentially ideal broad-spectrum microbicides. However, for silver compounds to be effective microbicides, they must be active within seminal fluid and the delivery vehicle used must protect the silver microbicide from vaginal fluid components but selectively release it during intercourse and/or following ejaculation. In this study, silver complexes were synthesised from the ligands saccharin, benzimidazole and 8-hydroxyquinoline and their microbicidal activity was assessed. We show that a silver saccharinate–benzimidazole complex (AgSB) exhibited activity against HIV-1, herpes simplex virus type 2 (HSV-2) and Neisseria gonorrhoeae at concentrations significantly below LD50 levels for the vaginal mucosal cell line SiHa. Furthermore, we show that alginate microbeads are stable in vaginal fluid simulant but rapidly dissolve in seminal fluid simulant. Finally, we have established that microbead-encapsulated AgSB, dissolved in seminal fluid simulant, is active against the above pathogens, albeit at higher concentrations for HIV-1. This research therefore highlights, for the first time, the potential use of silver complexes encapsulated in alginate microbeads as a novel system for the delivery and selective release of broad-spectrum silver-based microbicides within the vaginal milieu during sexual intercourse/after ejaculation.

Optimizing HIV prevention for women: a review of evidence from microbicide studies and considerations for gender-sensitive microbicide introduction.

IntroductionMicrobicides were conceptualized as a product that could give women increased agency over HIV prevention. However, gender-related norms and inequalities that place women and girls at risk of acquiring HIV are also likely to affect their ability to use microbicides. Understanding how gendered norms and inequalities may pose obstacles to women's microbicide use is important to inform product design, microbicide trial implementation and eventually microbicide and other antiretroviral-based prevention programmes. We reviewed published vaginal microbicide studies to identify gender-related factors that are likely to affect microbicide acceptability, access and adherence. We make recommendations on product design, trial implementation, positioning, marketing and delivery of microbicides in a way that takes into account the gender-related norms and inequalities identified in the review.MethodsWe conducted PubMed searches for microbicide studies published in journals between 2000 and 2013. Search terms included trial names (e.g. “MDP301”), microbicide product names (e.g. “BufferGel”), researchers’ names (e.g. “van der Straten”) and other relevant terms (e.g. “microbicide”). We included microbicide clinical trials; surrogate studies in which a vaginal gel, ring or diaphragm was used without an active ingredient; and hypothetical studies in which no product was used. Social and behavioural studies implemented in conjunction with clinical trials and surrogate studies were also included. Although we recognize the importance of rectal microbicides to women, we did not include studies of rectal microbicides, as most of them focused on men who have sex with men. Using a standardized review template, three reviewers read the articles and looked for gender-related findings in key domains (e.g. product acceptability, sexual pleasure, partner communication, microbicide access and adherence).Results and discussionThe gendered norms, roles and relations that will likely affect women's ability to access and use microbicides are related to two broad categories: norms regulating women's and men's sexuality and power dynamics within intimate relationships. Though norms about women's and men's sexuality vary among cultural contexts, women's sexual behaviour and pleasure are typically less socially acceptable and more restricted than men's. These norms drive the need for woman-initiated HIV prevention, but also have implications for microbicide acceptability and how they are likely to be used by women of different ages and relationship types. Women's limited power to negotiate the circumstances of their intimate relationships and sex lives will impact their ability to access and use microbicides. Men's role in women's effective microbicide use can range from opposition to non-interference to active support.ConclusionsIdentifying an effective microbicide that women can use consistently is vital to the future of HIV prevention for women. Once such a microbicide is identified and licensed, positioning, marketing and delivering microbicides in a way that takes into account the gendered norms and inequalities we have identified would help maximize access and adherence. It also has the potential to improve communication about sexuality, strengthen relationships between women and men and increase women's agency over their bodies and their health.

An Intravaginal Ring for the Sustained Delivery of Antibodies

Human monoclonal antibodies (mAbs) based on IgG and IgA have shown promise as topical microbicide candidates to protect women from HIV infection. Application of mAbs has been limited, however, by the inability of vaginal gels and conventional intravaginal ring (IVR) designs, the predominant vaginal product formulations, to effectively deliver biomolecules in a coitally independent fashion with retention of bioactivity. We have developed a novel pod-IVR platform that delivers ovine IgG (ov-IgG) as a model for IgG and IgA human mAbs. In vitro release of ov-IgG from the pod-IVRs was sustained for 14 days. Facile control of release rate was achieved by changing the size of delivery channels in the ring structure, and the feasibility of ov-IgG delivery in the range 0.5-30 mg day(-1) from a 10-pod IVR was demonstrated. The activity of ov-IgG in pod-IVR formulations was maintained as confirmed by ELISA binding assay. Pod-IVRs delivering ov-IgG show promise for the effective sustained topical delivery of antibody-based microbicides. This significantly broadens the range of microbicides that can be delivered in a sustained fashion from IVRs and enables a new arsenal of topical biologic microbicide candidates beyond small molecule antiretrovirals.