Elsevier

Chemical Engineering Journal

Volume 360, 15 March 2019, Pages 435-444
Chemical Engineering Journal

Microporous polyolefin strands as controlled-release devices for mosquito repellents

https://doi.org/10.1016/j.cej.2018.11.237Get rights and content

Highlights

  • Polymer strands containing insect repellent prepared by extrusion compounding.

  • Microporous polymer matrix obtained by spinodal decomposition.

  • Internal voids provided a reservoir for the liquid insect repellent.

  • Facilitated slow but effective repellent release for up to ninety days.

Abstract

The main vectors of malaria in Africa, i.e. An. arabiensis, An. gambiae s.s. and An. funestus, are attracted by human foot odour and they tend to bite victims in the ankle area. Hence, affordable mosquito-repellent polymer-foot bracelets with long lasting protection could reduce infective lower limb bites and therefore help to reduce the overall malaria transmission rate. This study investigated the possibility of increasing the duration of repellence activity by incorporating repellents into inexpensive thermoplastic polymers, namely poly(ethylene-co-vinyl acetate) (EVA) and linear low-density polyethylene (LLDPE). Volatile repellents need to be released into the surrounding air to be effective, i.e. they are continuously lost to the atmosphere. This means that the bracelet should also act as a reservoir for relatively large quantities of the active compound. Towards this goal, polymer strands containing mosquito repellent were prepared by twin-screw extrusion compounding. A co-continuous phase structure was achieved by rapid quenching in an ice bath of the homogeneous polymer-repellent melt mixture exiting the extruder. Phase separation occurred through spinodal decomposition that trapped the liquid repellent in the microporous polymer matrix. A skin-like membrane that covered the extruded polymer strands controlled the release rate. Strands that contained up to 30 wt-% of either DEET or Icaridin provided effective protection against mosquito bites even after 12 weeks of ageing at 50 °C.

Introduction

Malaria is a deadly disease with a large proportion of the world population at risk of infection. The annual number of malaria cases significantly exceeds 200 million and results in upwards of 400,000 deaths each year. Typically 90% of these occur in Africa with approximately 74% of them children under the age of 5 years [1]. The World Health Organisation (WHO) is targeting elimination of malaria. For this to be achieved, the transmission of the malaria parasite from one person to the next by female Anopheles mosquito vectors must be prevented or at least significantly reduced [2]. This may be done by preventing or reducing the frequency of infective mosquito bites.

The continued prevalence of malaria in endemic areas is partly due to insufficient vector control measures. Long life insecticide treated nets (LLINs) and indoor residual spray (IRS) are the flagship interventions recommended by the WHO. The implementation of these vector control interventions led to significant success in reducing malaria transmission. However, LLIN and IRS only protect against indoor biting and resting mosquitoes. It is still possible for people to be infected with malaria whilst outdoors.

Judicious use of repellents might help prevent, or at least reduce, outdoor malaria transmission. Repellents are typically applied to exposed skin via topical formulations such as lotions, sprays, emulsions, etc. [3]. N,N-diethyl-3-methylbenzamide (DEET) is a popular topical repellent in widespread use [4]. It is applied to the skin at high concentrations (10–70%) and has a residual effectiveness of a few hours [5], [6]. This short residual effectiveness necessitates repeated application in order to maintain constant repellent activity. This makes the use of topical repellents expensive particularly for resource-limited African communities where malaria is mostly prevalent. Slow and controlled release at effective levels may render the repellent long lasting [7], [8], [9], [10], [11].

Three of the main vectors of malaria in Africa (An. arabiensis, An. gambiae s.s. and An. funestus) are attracted by human foot odour, a smell similar to limburger cheese, and they tend to bite victims in the ankle area [12], [13], [14]. These vectors prefer feeding close to the ground level, i.e., at lower leg, ankles and feet [14], [15]. It has been shown that if these areas are protected, then vector mosquitoes do not move higher up the body to seek alternate biting areas, leading to a reduction in biting intensity [15]. Hence, a long-life mosquito repellent polymer-foot bracelet could reduce infective lower limb bites by these vectors and therefore help to reduce the overall malaria transmission rates especially under outdoor conditions.

Malaria is highly endemic in the poorer regions of Africa [1]. Consequently, vector control interventions must meet two objectives. They should be highly affordable and should provide long lasting protection. Possible solutions include microdispensers [16] and polymer-based carrier systems [17] for insect repellent delivery. This study investigated the possibility of increasing the duration of repellence activity by incorporating repellents into thermoplastic polymers, namely poly(ethylene-co-vinyl acetate) (EVA) and linear low-density polyethylene (LLDPE). If feasible, it could allow cost-effective bracelet manufacture via a conventional plastics extrusion processes. The objective is to develop systems with long-lasting efficacy, i.e., slow release of the active ingredient over an extended period. In this way, it may be possible to protect people against malaria infection during the time they spend outdoors.

The mechanism of slow release from polymers varies. An additive that is added to a polymer at loading levels that exceeds its solubility limit will form a separate phase or bleed to the surface of the polymer. This so-called “blooming” is desirable for contact poisons as the active accumulates at the polymer surface. In fact, LLINs rely on this phenomenon of active blooming of the incorporated insecticides [18]. In order to be effective, the insecticide must migrate to the surface and be retained there. Compared to solids, liquid additives migrate more rapidly out of a polymer matrix. They are also removed more easily by washing [18]. Liquid repellents also tend to be more volatile than solid insecticides used in the manufacture of LLINs. In contrast to the contact insecticides, repellents must be released into the surrounding air to be effective. This means that in the case of the repellents, comparatively higher loadings are required than for insecticides since they are continuously lost to the surroundings. It is therefore unlikely that polymer-based liquid repellent-release systems will be able to maintain efficacy for very long times (e.g. more than one year) achieved with LLINs. However, premature loss of efficacy of repellent-containing bracelets must be avoided. Fortunately, the insights and experience gained during the study of LLINs can help to guide the development of long lasting repellent bracelets.

Consider the situation in which the active ingredient is dissolved in the polymer matrix. Since repellents are liquid at ambient conditions, the polymer matrix must be chosen carefully to maximise the range of thermodynamic miscibility. The solubility limit cannot be exceeded as this may result in an oily film forming at the surface of the bracelet, which may cause discomfort to the user. The repellent is released into the surrounding atmosphere as soon as it reaches the polymer surface. Therefore, the active loading must be high in order to maintain activity over an extended period. This implies that large quantities of the active should be available and this requires a significant solubility in the polymer matrix.

Unfortunately using a polymer matrix in which the active is dissolved has additional drawbacks. Firstly, the solubility of an active in a polymer matrix may be limited. This is because the driving force for miscibility, the Gibbs energy of mixing, is low when polymers are involved. On the other hand, high solubility implies extensive swelling of the polymer. This leads to dimensional stability issues, e.g., extensive shrinking as the active is depleted over time.

The alternative concept proposed herewith utilises porous polymer strands for this purpose. The internal open-cell polymer foam structure serves both as a reservoir and a protective environment for the active ingredient trapped inside. Ideally, an outer dense skin layer should provide the diffusion barrier that controls the release of repellent at effective levels over a considerable period of time.

Microporous polymer matrices may provide a solution to these problems [19]. In this case, the insoluble or only partially soluble active liquid is trapped in the open pores of the polymer matrix. Extrusion processes that facilitate the formation of a co-continuous phase structure comprising polymer-rich and repellent-rich domains can generate such a system. This can be achieved through the phase separation phenomenon of spinodal decomposition provided the repellent and the polymer melt form a homogeneous mixture, i.e. a solution, at high temperatures only. This type of phase separation occurs when such a mixture is rapidly cooled to a temperature inside the spinodal region of the phase diagram [20], [21], [22], [23], [24]. Besides the crystallization-induced solid–liquid phase separation technique which recently has been applied to entrap DEET in poly(lactic acid) [25], [26], spinodal decomposition-based liquid–liquid phase separation is widely used in the manufacture of porous membranes. A typical phase diagram showing the phase behaviour of a polymer-liquid repellent combination is shown in Fig. 1 [27]. The system exhibits an upper critical solution temperature (TUC) and features a stable single-phase region together with a metastable and an unstable two-phase region.

In polymer-repellent mixtures the loci of the phase boundaries can be described by the Flory-Huggins theory [28]. At temperatures above the upper critical solution temperature, the system is fully miscible for all compositions. Below this temperature, phase separation can occur below a temperature that depends on the concentration of the system components. The binodal line in Fig. 1 defines the compositions of the two phases in equilibrium at any given temperature. In the meta-stable region indicated in the phase diagram, the phase separation will occur via a nucleation and growth mechanism. This is the usual scenario for liquid–liquid phase separation. If the polymer represents the minority phase, it may initially lead to the undesirable formation of separate polymer particles that are suspended in the continuous liquid repellent phase.

Inside the two-phase region, there is another set of phase envelopes, the spinodal curves. In this region of the phase diagram, a homogeneous mixture is thermodynamically completely unstable. In contrast to the metastable bimodal region, the solution will spontaneously split into two phases via spinodal decomposition, a polymer-rich phase and a solvent-rich phase. Phase separation by this mechanism leads to a finely dispersed microstructure via diffusion processes that amplify intrinsic thermodynamic spatial composition fluctuations. Ultimately, this co-continuous structure may be fixed either by the subsequent crystallization of the polymer, or by vitrification of the polymer-rich phase. This means that the majority liquid phase is trapped inside a solid polymer-rich phase (which still may contain a minor amount of repellent) with a porous structure. In practice, such microporous microstructures may be achieved by rapid quenching of a homogeneous melt in an ice-cold water bath.

Briefly, the novel concept explored in this study is the following. A straightforward melt-extrusion process yields microporous polyolefin strands, covered by a dense integral skin layer. At elevated temperatures, the mixture is homogeneous as the liquid repellent dissolves in the polymer melt. This is extruded directly into the into an ice-cold water bath. The rapid cooling forces phase separation to occur via spinodal decomposition with the development of co-continuous phase domains. The end-result is an open cell, finely structured, solid polymer scaffold that holds the liquid repellent in place by capillary forces. The anticipated advantages of this process are two-fold. Firstly, the thin but dense outer skin layer formed on the outside of the strand constitutes a rate controlling diffusion barrier membrane such that repellent release by evaporation occurs at a nearly constant rate. Secondly, a large quantity of repellent is effectively trapped inside the pores at loadings that far exceed the solubility limit of the repellent in the polymer matrix itself. This provides the required reservoir needed for evaporation to proceed over extended periods.

It is important to note that the emphasis of this communication is to report on the conceptual development of a suitable carrier material for incorporation of repellent substances and subsequent stable release of the repellent over an extended period. The paper therefore emphasizes the physical and chemical elements and basic entomological impact. With proof-of-concept achieved, it will be possible to refine the microporous polyolefin strands into various products for field application to reduce malaria transmission, such as by way of anklets, footlets, or bracelets. More extensive and rigorous entomological and epidemiological testing will be required on products that are more refined before they could become commercially acceptable.

Section snippets

Materials

The insect repellent N,N-diethyl-3-methylbenzamide (DEET) [CAS No. 134-62-3] was obtained from Sigma-Aldrich. It had a purity of ≥ 97% and a density of 0.998 g cm−3 at 20 °C. 1-(1-methylpropoxycarbonyl)-2-(2-hydroxyethyl)piperidine (Icaridin) [CAS No. 119515-38-7] was supplied by Saltigo under the trade name Saltidin®. According to the supplier, the purity exceeded 97%, the boiling point is 272 °C and the density is 1.0362 g cm−3 at 20 °C. Dichloromethane [CAS No. 75-09-2] of purity is 99.9%

Modelling the repellent release from strands

Fig. 3 shows a schematic of a long cylindrical microporous strand covered by a thin membrane-like outer skin layer, serving as a model for discussion of the repellent-release characteristics. The geometric features of this model were informed by the SEM results presented below. The cross-section is circular and the structure of the inner polymer section was assumed microporous. Conceptually it corresponds to an open-cell polymer foam that is initially completely filled with the liquid

Polymer swelling and film permeability

Ageing of the microporous repellent-filled strands were conducted at 50 °C. This represents an upper limit to the ambient temperatures that could be experienced in malaria-endemic regions. Selecting this temperature also reduced the required experimental time as evaporation is expected to be faster at elevated temperatures. Consequently, in order to obtain relevant physical data, the repellent absorption and permeability tests were also conducted at 50 °C.

Table 1 lists the amount of repellent

Conclusions

Mosquito repelling polyolefin strands, containing significant quantities of mosquito repellents (20 or 30 wt-%) can be produced by an extrusion-compounding process. The rapid cooling induced by extruding the exiting strands directly into ice-cold water bath facilitates phase separation of the repellent oil and the polymer via spinodal decomposition. This leads to an open-cell microporous polymer scaffold that traps the liquid repellent in the polymer matrix. The extrusion process also yields a

Acknowledgements

Financial support from the Deutsche Forschungsgemeinschaft (DFG), Germany, under Grant AN 212/22-1 is gratefully acknowledged. Mr Cyril Ndonyane is thanked for maintaining the Anopheles colony of the insectary. We also express our gratitude to him and Mr Robert Tewo for assisting with the repellent testing trials. Saltigo (Germany) is thanked for the generous gift of Saltidin® samples and Laviosa Chimica Mineraria S.p.A (Italy) for providing the Dellite 43B organoclay sample.

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