Using different structure types of microemulsions for the preparation of poly(alkylcyanoacrylate) nanoparticles by interfacial polymerization

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Abstract

A phase diagram of the pseudoternary system ethyloleate, polyoxyethylene 20 sorbitan mono-oleate/sorbitan monolaurate and water with butanol as a cosurfactant was prepared. Areas containing optically isotropic, low viscosity one-phase systems were identified and systems therein designated as w/o droplet-, bicontinuous- or solution-type microemulsions using conductivity, viscosity, cryo-field emission scanning electron microscopy and self-diffusion NMR. Nanoparticles were prepared by interfacial polymerization of selected w/o droplet, bicontinuous- or solution-type microemulsions with ethyl-2-cyanoacrylate. Morphology of the particles and entrapment of the water-soluble model protein ovalbumin were investigated. Addition of monomer to the different types of microemulsions (w/o droplet, bicontinuous, solution) led to the formation of nanoparticles, which were similar in size (∼ 250 nm), polydispersity index (∼ 0.13), zeta-potential (∼− 17 mV) and morphology. The entrapment of the protein within these particles was up to 95%, depending on the amount of monomer used for polymerization and the type of microemulsion used as a polymerization template. The formation of particles with similar characteristics from templates having different microstructure is surprising, particularly considering that polymerization is expected to occur at the water–oil interface by base-catalysed polymerization. Dynamics within the template (stirring, viscosity) or indeed interfacial phenomena relating to the solid–liquid interface appear to be more important for the determination of nanoparticle morphology and characteristics than the microstructure of the template system.

Introduction

Poly(alkylcyanoacrylate) (PACA) nanoparticles have gained extensive interest as drug carriers due to the biocompatibility and biodegradability of the polymer [1], [2], the simplicity of the polymerization process [3], [4] and their ability to entrap bioactive compounds [5]. Many new drugs are proteins, which require protection from the physiological environment, strategies to enhance their bioavailability or even targeting of certain delivery sites [6]. Some of these issues may be overcome by encapsulation of proteins within PACA nanoparticles [5], [6]. Extensive information on the different types of particles, particle formation and delivery of bioactives can be found in these reviews [7], [8], [9].

Gasco and Trotta first introduced the technique of interfacial polymerization of w/o microemulsions for the preparation of PACA nanoparticles [10]. The use of a microemulsion instead of a coarse or submicron emulsion frequently used as a template for the preparation of nanoparticles offers advantages in terms of enhanced physical stability of the system, the minimal need of energy input to form the polymerization template, and their small and uniform droplet size that is reflected in the size of the nanoparticles produced there from. Gasco and Trotta used an organic solution containing isopropylmyristate, aerosol AOT and butanol for microemulsion formation.

Watnasirichaikul et al. demonstrated that PACA nanoparticles could be readily prepared in a one-step process by the interfacial polymerization of biocompatible w/o droplet microemulsions using ethylcyanoacrylate as a monomer [5]. The use of biocompatible oils and surfactants overcomes the need for isolation of nanoparticles from the preparation medium following polymerization. Further, having nanoparticles dispersed in a microemulsion may be beneficial for their use in protein delivery exploiting the permeability enhancing effects of microemulsions [11], [12]. Indeed, it was shown that the intragastric administration of nanoparticles encapsulating insulin dispersed in a biocompatible microemulsion resulted in significantly greater reduction in blood glucose levels in diabetic rats than insulin formulated in the microemulsion [13]. This demonstrated that the encapsulation of peptides within PACA nanoparticles, administered dispersed in a microemulsion, can facilitate oral absorption. However, due to a possible toxicity of the degraded polymer (which in part depends on the chain length of the alkyl chain of the polymer [14]) and its overall fast biodegradation, these systems might not be ideal for repeated oral use. As particulate protein carriers, they are, however, potentially very useful oral vaccine delivery systems (especially for subunit vaccines), as such systems would be administered much less frequently than in pharmacotherapy [15], [16], [17]. A fast degradation after uptake in antigen presenting cells might also be advantageous [18]. In the current study, ovalbumin was used as a model subunit vaccine in line with previous work from our group and other authors [15], [16], [17].

The proposed mechanism of nanoparticle formation when using a w/o droplet microemulsion template is the polymerization of the alkylcyanoacrylate monomer around the water droplets, initiated by the nucleophilic hydroxyl ion from the autoprotolysis of water. This purportedly results in nanoparticles with a core/shell-type structure [10]. Watnasirichaikul et al. proposed that the formation of nanocapsules, however, does not simply occur around the water-droplet (swollen micelles), as this would result in particles with a size comparable to that of the swollen micelle (∼ 10–20 nm). Rather, polymerization occurs at the water–oil interface of the micelles with a concomitant structural collapse of micelle-clusters resulting in nanoparticles with a size of approximately 250 nm [19].

Microemulsions can have droplet-, bicontinuous- and solution-type microstructure [20]. Bicontinuous microemulsions have a sponge-like microstructure, where large oil and water domains intertwine and are separated by a surfactant layer [21]. Solution-type microemulsions are molecular dispersions of all components [20]. Despite the absence of “droplets” or swollen micelles in these microemulsions, it has been shown that nanoparticles can be prepared by interfacial polymerization of such systems [22]. The aim of this study was to see whether PACA nanoparticles could be prepared from different structure types of microemulsions and to investigate the entrapment of a model protein from nanoparticles prepared by interfacial polymerization of such systems. An advantage of a bicontinuous microemulsion over w/o droplet microemulsions as a polymerization template might be its higher water content and the lower degree of structure of the water in these systems. This may allow for a higher drug loading capacity. Butanol was used as a cosurfactant in the current study to increase the microemulsion area in a phase diagram consisting of ethyloleate, polyoxyethylene 20 sorbitan mono-oleate/sorbitan monolaurate and water, and to prepare microemulsions having a bicontinuous structure [23].

Section snippets

Materials

Ethyloleate (Crodamol EO™) was used as the oil, sorbitan monolaurate (Crill 1™) and polyoxyethylene 20 sorbitan mono-oleate (Crillet 4 super™) were used as surfactants and were kindly donated by BTB Chemicals (Auckland, NZ). 1-Butanol, sodium chloride, chloroform, ethanol, methanol, calcium carbonate, sodium dihydrogen phosphate and potassium dihydrogen phosphate were obtained from BDH Chemicals Ltd. (Poole, UK). The monomer ethyl-2-cyanoacrylate was purchased from EMI Inc. (Delaware, OH).

Characterization of microemulsions

The phase diagram for the pseudoternary system ethyloleate/polyoxyethylene 20 sorbitan mono-oleate/sorbitan monolaurate/water with butanol as a cosurfactant is shown in Fig. 1. The location of the microemulsion phase boundary is in agreement with earlier work by our group [23]. Several optically clear, one-phase systems within the microemulsion region were selected and characterized as w/o droplet-, bicontinuous- or solution-type microemulsions (Fig. 1).

Conclusions

This study has shown that nanoparticles can be prepared from different structure-type microemulsions, i.e., w/o droplet-, bicontinuous- and solution-type. The size, size distribution, surface charge and morphology of the particles appear to be independent of the template used for their preparation and only the nanoparticles prepared from the systems having the composition s/o 9:1, 20–50% water showed a significance increase in size compared to the other formulations. The entrapment of protein

Acknowledgements

We would like to thank the New Zealand National School of Pharmacy for supplying a scholarship (for KK). Thanks also go to Liz Girvan for assistance with electron microscopy techniques and Mervyn Thomas for his help with the NMR measurements.

References (26)

  • P. Couvreur et al.

    Biodegradable polymeric nanoparticles as drug carriers for antitumor agents

  • P. Couvreur et al.

    Nanoparticles: preparation and characterization

  • E. Allemann et al.

    Drug-loaded nanoparticles—preparation methods and drug targeting issues

    European Journal of Pharmaceutics and Biopharmaceutics

    (1993)
  • Cited by (0)

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