Mosquito-repellent controlled-release formulations for fighting infectious diseases.

Malaria is a principal cause of illness and death in countries where the disease is endemic. Personal protection against mosquitoes using repellents could be a useful method that can reduce and/or prevent transmission of mosquito-borne diseases. The available repellent products, such as creams, roll-ons, and sprays for personal protection against mosquitoes, lack adequate long-term efficacy. In most cases, they need to be re-applied or replaced frequently. The encapsulation and release of the repellents from several matrices has risen as an alternative process for the development of invention of repellent based systems. The present work reviews various studies about the development and use of repellent controlled-release formulations such as polymer microcapsules, polymer microporous formulations, polymer micelles, nanoemulsions, solid-lipid nanoparticles, liposomes and cyclodextrins as new tools for mosquito-borne malaria control in the outdoor environment. Furthermore, investigation on the mathematical modelling used for the release rate of repellents is discussed in depth by exploring the Higuchi, Korsmeyer-Peppas, Weibull models, as well as the recently developed Mapossa model. Therefore, the studies searched suggest that the final repellents based-product should not only be effective against mosquito vectors of malaria parasites, but also reduce the biting frequency of other mosquitoes transmitting diseases, such as dengue fever, chikungunya, yellow fever and Zika virus. In this way, they will contribute to the improvement in overall public health and social well-being.

Properties of Mosquito Repellent-Plasticized Poly(lactic acid) Strands.

Poly(lactic acid) (PLA) is an attractive candidate for replacing petrochemical polymers because it is fully biodegradable. This study investigated the potential of PLA as a sustainable and environmentally friendly alternative material that can be developed into commercially viable wearable mosquito repellent devices with desirable characteristics. PLA strands containing DEET and IR3535 were prepared by twin screw extrusion compounding and simultaneously functioned as plasticizers for the polymer. The plasticizing effect was investigated by thermal and rheological studies. DSC studies showed that the addition of DEET and IR3535 into PLA strands reduced the glass transition temperature consistent with predictions of the Fox equation, thus proving their efficiency as plasticizers. The rheology of molten samples of neat PLA and PLA/repellents blends, evaluated at 200 °C, was consistent with shear-thinning pseudoplastic behaviour. Raman studies revealed a nonlinear concentration gradient for DEET in the PLA strand, indicating non-Fickian Type II transport controlling the desorption process. Release data obtained at 50 °C showed initial rapid release followed by a slower, near constant rate at longer times. The release rate data were fitted to a novel modification of the Peppas-Sahlin desorption model.

Acceptability and effectiveness of a monofilament, polyethylene insecticide-treated wall lining for malaria control after six months in dwellings in Vhembe District, Limpopo Province, South Africa.

BACKGROUND: South Africa uses indoor residual spraying (IRS) for vector control in its malaria control programme (MCP). Insecticide-treated wall linings (ITWLs) offer possible advantages over IRS and long-lasting, insecticide-treated nets (LLINs). This study assessed the user acceptability and perceived effectiveness, and the durability, including efficacy through bioassays, of a newly developed, monofilament polyethylene ITWL. METHODS: Four ITWL formulations/treatments, two incorporated with deltamethrin and two with alpha-cypermethrin in concentrations ranging from 0.29 to 0.85 wt%, and untreated linings were randomly installed on the inner walls of traditional mud huts (n = 20) and modern brick houses (n = 20) in a community village in Vhembe District, Limpopo Province. The linings were exposed to conditions within these dwellings over 6 months. Data were collected monthly through questionnaires and entomological residual efficacy analysis of ITWL, as part of durability testing, was done bimonthly using WHO prescribed bioassays. RESULTS: Monofilament polyethylene ITWLs were successfully installed in traditional sleeping huts and in bedrooms of modern type brick houses. ITWL remained intact throughout the entire 6 months of the study. Participants did not express any dissatisfaction towards the linings although two participants indicated the product should be fitted at a lower level for better results. User perceived effectiveness was very high with participants reporting observed mortality of mosquitoes and other nuisance insects. This perception coincided with results obtained through residual efficacy bioassays where a 100 % knockdown and mortality of mosquitoes was recorded throughout the trial period. Acceptability regarding appearance, including colour, position and attachment method, was also satisfactory with some participants citing the lining as decorative. All participants opted to keep ITWL and residual long-term efficacy will be determined annually for a further 3 years. CONCLUSIONS: The newly developed ITWLs are highly accepted amongst participants in an unsprayed section of a village in a malaria-endemic area. The perceived effectiveness that coincides with results obtained through bioassays and acceptance of the overall appearance of ITWL will be evaluated over a longer term to determine sustainability. With further developing and testing, this ITWL has the potential to become a sustainable and safer alternative vector control method.

A Relatively Simple Look at the Rather Complex Crystallization Kinetics of PLLA.

This work demonstrates that, despite the existence of a significant number of works on PLA crystallization, there is still a relatively simple way, different from those already described, in which its complex kinetics can be observed. The X-ray diffraction (XRD) results presented here confirm that the PLLA under study crystallizes mostly in the α and α' forms. An interesting observation is that at any temperature in the studied range of the patterns, the X-ray reflections stabilize with a given shape and at a given angle, different for each temperature. That means that both α and α' forms coexist and are stable at the same temperatures so that the shape of each pattern results from both structures. However, the patterns obtained at each temperature are different because the predominance of one crystal form over the other depends on temperature. Thus, a two-component kinetic model is proposed to account for both crystal forms. The method involves the deconvolution of the exothermic DSC peaks using two logistic derivative functions. The existence of the rigid amorphous fraction (RAF) in addition to the two crystal forms increases the complexity of the whole crystallization process. However, the results presented here show that a two-component kinetic model can reproduce the overall crystallization process fairly well over a broad range of temperatures. The method used here for PLLA may be useful for describing the isothermal crystallization processes of other polymers.

Sustainable malaria control: transdisciplinary approaches for translational applications.

With the adoption of the Global Malaria Action Plan, several countries are moving from malaria control towards elimination and eradication. However, the sustainability of some of the approaches taken may be questionable. Here, an overview of malaria control and elimination strategies is provided and the sustainability of each in context of vector- and parasite control is assessed. From this, it can be concluded that transdisciplinary approaches are essential for sustained malaria control and elimination in malaria-endemic communities.

Slow-DEET-Release Mosquito-Repellent System Based on Poly(butylene succinate).

Bio-sourced and biodegradable poly(butylene succinate) (PBS) strands containing up to 40 m% mosquito-repellent N,N-diethyl-3-methylbenzamide (DEET) were obtained by extrusion, for an initial evaluation of the DEET evaporation characteristics and the possible application of such strands as biodegradable slow-release repellent-delivery devices. For DEET concentrations up to 20 m%, DEET is entrapped in the semicrystalline spherulitic superstructure of PBS. In contrast, at higher DEET concentrations, the liquid repellent, at least partially, is not fully incorporated in the PBS spherulites rather than segregates to form an own macrophase. Quantification of the release of DEET to the environment by thermogravimetric analysis at different temperatures between 60 and 100 °C allowed estimation of the evaporation rate at lower service temperatures, suggesting an extremely low release rate with a time constant of the order of magnitude of 1-2 years at 25 °C, independent of the initial concentration.

Degradation of insecticides used for indoor spraying in malaria control and possible solutions.

BACKGROUND: The insecticide dichloro-diphenyl-trichloroethane (DDT) is widely used in indoor residual spraying (IRS) for malaria control owing to its longer residual efficacy in the field compared to other World Health Organization (WHO) alternatives. Suitable stabilization to render these alternative insecticides longer lasting could provide a less controversial and more acceptable and effective alternative insecticide formulations than DDT. METHODS: This study sought to investigate the reasons behind the often reported longer lasting behaviour of DDT by exposing all the WHO approved insecticides to high temperature, high humidity and ultra-violet light. Interactions between the insecticides and some mineral powders in the presence of an aqueous medium were also tested. Simple insecticidal paints were made using slurries of these mineral powders whilst some insecticides were dispersed into a conventional acrylic paint binder. These formulations were then spray painted on neat and manure coated mud plaques, representative of the material typically used in rural mud houses, at twice the upper limit of the WHO recommended dosage range. DDT was applied directly onto mud plaques at four times the WHO recommended concentration and on manure plaques at twice WHO recommended concentration. All plaques were subjected to accelerated ageing conditions of 40°C and a relative humidity of 90%. RESULTS: The pyrethroids insecticides outperformed the carbamates and DDT in the accelerated ageing tests. Thus UV exposure, high temperature oxidation and high humidity per se were ruled out as the main causes of failure of the alternative insecticides. Gas chromatography (GC) spectrograms showed that phosphogypsum stabilised the insecticides the most against alkaline degradation (i.e., hydrolysis). Bioassay testing showed that the period of efficacy of some of these formulations was comparable to that of DDT when sprayed on mud surfaces or cattle manure coated surfaces. CONCLUSIONS: Bioassay experiments indicated that incorporating insecticides into a conventional paint binder or adsorbing them onto phosphogypsum can provide for extended effective life spans that compare favourably with DDT's performance under accelerated ageing conditions. Best results were obtained with propoxur in standard acrylic emulsion paint. Similarly, insecticides adsorbed on phosphogypsum and sprayed on cattle manure coated surfaces provided superior lifespans compared with DDT sprayed directly on a similar surface.

Melt-Spun Poly(D,L-lactic acid) Monofilaments Containing N,N-Diethyl-3-methylbenzamide as Mosquito Repellent.

Malaria is still a major tropical disease, with Africa particularly burdened. It has been proposed that outdoor protection could aid substantially in reducing the malaria incidence rate in rural African communities. Recently, melt-spun polyolefin fibers containing mosquito repellents have been shown to be promising materials to this end. In this study, the incorporation of N,N­Diethyl­3­methylbenzamide (DEET)-a popular and widely available mosquito repellent-in commercially available, amorphous poly(D,L-lactic acid) (PDLLA) is investigated with the aim of producing biodegradable mosquito-repelling filaments with a reduced environmental impact. It is shown to be possible to produce macroscopically stable PDLLA-DEET compounds containing up to 20 wt.-% DEET that can be melt-spun to produce filaments, albeit at relatively low take-up speeds. A critical DEET content allows for stress-induced crystallization during the spinning of the otherwise amorphous PDLLA, resulting in the formation of α-crystals. Although the mechanical integrity of the filaments is notably impacted by the incorporation of DEET, these filaments show potential as materials that can be used for Malaria vector control.

Deep eutectic solvents for solid pesticide dosage forms.

Deep eutectic solvents aid the formulation of solid pesticide dosage forms for water-insoluble actives. This was demonstrated by encapsulating Amitraz powder in a low-melting matrix based on the eutectic mixture of urea (32 wt%) and 1,3-dimethylurea. Dissolution in water of melt-cast discs, containing 20 wt% active, led to the rapid release of Amitraz in a finely dispersed form. The order of magnitude reduction in particle size, after dissolution, is ascribed to the solubilization of Amitraz in the hot deep eutectic solvent and its subsequent precipitation as a separate phase on crystallization of the matrix.

Dextrin Nanocomposites as Matrices for Solid Dosage Forms.

Safe application of water-insoluble acaricides requires fast release from solid dosage systems into aquatic environments. Dextrin is a water-soluble form of partially hydrolyzed starch, which may be used as matrix material for these systems if retrogradation can be inhibited by the inclusion of nanofillers. Several glycerol-plasticized thermoplastic dextrin-based nanocomposites were prepared with a twin-screw extrusion-compounding process. The nanofillers included a layered double hydroxide (LDH), cellulose nanofibers (CNF), and stearic acid. The time-dependent retrogradation of the compounds was monitored by X-ray diffraction (XRD) and dynamic mechanical thermal analysis (DMA). XRD showed that composite samples that included stearic acid in the formulation led to the formation of an amylose-lipid complex and a stable crystallinity during aging. The most promising nanocomposite included both stearic acid and CNF. It was selected as the carrier material for the water-insoluble acaricide Amitraz. Fast release rates were observed for composites containing 5, 10, and 20% (w/w) of the pesticide. A significant reduction in the particle size of the released Amitraz powder was observed, which is ascribed to the high-temperature compounding procedure.

Mosquito repellent thermal stability, permeability and air volatility.

BACKGROUND: The effectiveness of mosquito repellents, whether applied topically on the skin or released from a wearable device, is determined by the evaporation rate. This is because a repellent has to be present in the form of a vapour in the vicinity of the exposed skin that needs protection. Therefore, gravimetric techniques were used to investigate the direct evaporation of selected liquid repellents, their permeation through polymer films, and their release from a microporous polyethylene matrix. RESULTS: Evaporation of a repellent into quiescent air is determined by its air permeability. This is a product of the vapour pressure and the diffusion coefficient, i.e. S A = P A sat D A . It was found that repellents could be ranked in terms of decreasing volatility as: ethyl anthranilate > citriodiol > dimethyl phthalate > N,N-diethyl-meta-toluamide (DEET) > decanoic acid > ethyl butylacetylaminopropionate > Icaridin. Experimental SA values, at 50 °C, ranged from 0.015 ± 0.008 mPa m2  s-1 for the least volatile repellent (Icaridin) to 0.838 ± 0.077 mPa m2  s-1 for the most volatile (ethyl anthranilate). The release rate from microporous polyethylene strands, produced by extrusion-compounding into ice water baths followed a similar ranking. These strands featured an integral skin-like membrane that covered the extruded strands and controlled the release of the repellent at a low effective rate. CONCLUSION: The high thermal and thermo-oxidative stability together with the low volatility of the mosquito repellents ethyl butylacetylaminopropionate and Icaridin make them attractive candidates for long-lasting wearable mosquito-repellent devices. Such anklets/bracelets may have utility for outdoor protection against infective mosquito bites in malaria-endemic regions. © 2019 Society of Chemical Industry.

Malathion-filled trilayer polyolefin film for malaria vector control.

The emergence of pyrethroid resistance in mosquitoes is complicating malaria elimination efforts in Africa and alternative insecticides have to be considered for indoor residual spray. Unfortunately, the high volatility of WHO-approved organophosphate alternatives, e.g. malathion, translates into an early loss of residual efficacy. This laboratory study explored the concept of trilayer films as potential wall or ceiling linings. In the proposed design, the fugitive liquid insecticide is trapped in an inner core layer. The two sheath layers act as low-permeability membranes controlling the release of the insecticide. The concept was explored using poly(ethylene-co-vinyl acetate) (EVA) and low density polyethylene (LDPE) as core and sheath polymers respectively. The polarity of the EVA polymer matrix allowed incorporation of substantial quantities (up to 30 wt%) of malathion. The low polarity of the LDPE provided the necessary barrier properties and, in addition, allowed film blowing to be conducted at relatively low processing temperatures. Trilayer films containing about 6 wt% malathion were prepared on a film blowing line. Scanning electron microscopy confirmed the trilayer film structure. Confocal Raman microscopy studies revealed a malathion concentration gradient across the thickness of the polyethylene layers. Mass loss measurements and FTIR spectroscopy studies showed that the malathion release followed first-order kinetics. Bioassays, on samples aged at 22 °C, indicated that the residual efficacy against mosquitoes can be maintained for up to about six months. This suggests that trilayer films impregnated with organophosphates, may have potential as alternative mosquito control interventions in pyrethroid resistant settings.

Burn Rate of Calcium Sulfate Dihydrate-Aluminum Thermites.

The energetics of cast calcium sulfate dihydrate-aluminum thermites were investigated. The casts were prepared from water slurries with a solids content below 65 wt %. The base case thermite comprised 60 wt % calcium sulfate dihydrate as the oxidizer with 40 wt % aluminum as fuel. The heat of hydration of the base case was 83 ± 4 kJ·kg-1 (dihydrate basis) and the initial setting time was about 100 min. The compressive strength reached 2.9 ± 0.2 MPa after 3 days of drying in ambient air. The open air burn rate was 12.0 ± 1.6 mm· s-1 and a maximum surface temperature of 1370 ± 64 °C was recorded with a pyrometer. Bomb calorimetry indicated an energy output of 8.0 ± 1.1 MJ·kg-1, slightly lower than predicted by the Ekvi thermodynamic simulation. Substitution of 10 wt % of the oxidant with copper sulfate pentahydrate significantly decreased the initial setting time of the casts to less than 30 min but a secondary aluminum oxidation reaction commenced after 2 h. The density of the castings was varied by either adding hollow sodium borosilicate microspheres or by adding excess water during the casting process. The addition of the hollow glass microspheres caused a decrease in the burning rate. Dehydration of the casts by thermal treatments at either 155 or 200 °C led to significant increases in the burning rate.

Bicomponent fibres for controlled release of volatile mosquito repellents.

Core-sheath structured fibres were developed for application as part of an alternative malaria vector control intervention aimed at reducing outdoor malaria transmission. The fibres were prepared by melt spinning of high density polyethylene (HDPE) as sheath and with a concentrate containing volatile N,N-Diethyl-m-toluamide (DEET) in poly(ethylene-co-vinyl acetate) (EVA) as core. The concentrate was prepared by a simple absorption processes to a content up to 40 wt% DEET. Scanning electron microscope imaging confirmed the formation of a bicomponent core-sheath fibre structure. Confocal Raman spectroscopy revealed the development of a concentration gradient of DEET in the sheath layer, suggesting a diffusion controlled release process. Excellent processability was demonstrated on an extrusion system melt spinning with take up speeds reaching 3000 m min-1. Sample textiles knitted from such filaments showed high residual repellence activity even after 20 cold washes or after eight months ageing under laboratory conditions. These findings indicate that this technology offers an alternative way to prevent outdoor mosquito bites in an effective and affordable manner.

Kinetic interpretation of log-logistic dose-time response curves.

A Hill-type time-response curve was derived using a single-step chemical kinetics approximation. The rate expression for the transformation is a differential equation that provides an interpolation formula between the logistic growth curve and second order kinetics. The solution is equivalent to the log-logistic cumulative distribution function with the time constant expressed in terms of a kinetic rate constant. This expression was extended to a full dose-time-response equation by postulating a concentration dependence for the rate constant. This was achieved by invoking a modified form of Haber's law that connects an observed toxic effect with the concentration of the active agent and the elapsed exposure time. Analysis showed that the concept of Concentration Addition corresponds to a special case where the rate constant for the overall transformation rate is proportional to the sum of the rate constants that apply when the agents act individually. Biodiesel "survival" curves were measured and used to test the applicability of the empirical model to describe the effects of inhibitor dosage and binary inhibitor mixtures. Positive results suggest that the proposed dose-response relationship for the toxicity of agents to organisms can be extended to inanimate systems especially in cases where accurate mechanistic models are lacking.

A promising azeotrope-like mosquito repellent blend.

Topical repellents play a key role in reducing the outdoor transmission of mosquito-borne diseases by reducing human-vector contact. Excellent repellents are available, but there is always room for improvement. This article reports on a particularly effective binary repellent blend of ethyl butylacetylaminopropionate and nonanoic acid. A composition containing 25 mol% of the acid exhibits negative pseudo-azeotrope behaviour at 50 °C, meaning that the liquid vapour pressure is lower than that of the parent compounds and evaporation occurs without a change in the liquid composition. In tests performed using the South African Medical Research Council's cup-on-arm procedure, this mixture provided better protection for a longer time than the "gold standard of mosquito repellents", namely N,N-diethyl-m-toluamide, commonly known as DEET.