Starch-based Pickering emulsions for topical drug delivery: A QbD approach
Graphical abstract
Introduction
Dosage forms for dermatological use are intended to produce the desired therapeutic action at specific sites in the skin tissue. Pharmaceutical emulsions emerge as a good solution for skin drug deposition in spite of their thermodynamic instability that makes their development a complex challenge in pharmaceutical technology. Current pharmaceutical emulsions are mostly stabilized by synthetic surfactants, which can be intrinsically toxic or may alter the distribution and elimination of co-administered drugs [1]. Consequently, solid-stabilized emulsions, i.e. Pickering emulsions, constitute an interesting alternative whereby [2] the stabilization of emulsion droplets by solid particles is due to particle dual wettability. This interesting property allows the spontaneous accumulation of particles at the oil–water interface, which is stabilized against coalescence by volume exclusion and steric hindrances [3]. In this type of emulsions, the liquid with the poorest wetting properties is considered the disperse phase. The wettability of the particles at the oil–water interface is quantified by the contact angle, θ between the particle and the interface. If the contact angle is lower than 90° the emulsion is o/w and, conversely, if the contact angle is higher than 90° the emulsion is w/o. However, if the particles have very low contact angles (too hydrophilic) or very high contact angles (too lipophilic), they tend to be dispersed in either the aqueous phase or oil phase, respectively, leading to unstable emulsions [4], [5]. These solid-stabilized emulsions avoid the application of hazardous surfactants, and show improved stability, especially at high internal phase ratio, allowing easy fabrication of stable large droplets up to millimeter size, when compared to classical surfactant-based emulsions [6]. Many types of solid particles, either organic (e.g. polymer latex or starch) or inorganic (e.g. silica and clay particles) have been used for stabilizing Pickering emulsions [2], [7], [8]. The use of starch to stabilize emulsions has been attracting substantial research interest due to their distinctive characteristics and promising technological applications.
In this study, a Quality-by-Design (QbD) approach was applied to the development of starch-based Pickering emulsions, so the quality is built by detailed understanding of the product and process [9]. It includes the definition of a Design Space thus creating a multidimensional combination and interaction of formulation variables and process parameters that have been demonstrated to provide assurance of quality. In this context the Design of experiments (DoE) allows the measurement of interaction effects and includes the complete multidimensional experimental region. For these reasons, DoE is the perfect strategy to develop and optimize a pharmaceutical product, aiming at the product quality at a cost-effective manner [10]. Therefore, it the present work the QbD approach was performed not only to extract the maximum amount of information from the collected data, but also to establish the influence of multiple factors on the formulation properties of starch-based Pickering emulsions. The direct effect of each factor was studied and the respective interaction with other factors was also evaluated in detail, demonstrating the emulsifying ability of starch granules and its successful application on pharmaceutical and cosmetic fields.
Section snippets
Materials
The oils used were liquid paraffin obtained from Mosselman (Ghlin, Belgium) and Tegosoft® CT (caprylic/capric acid triglyceride), a kind gift from Evonik Industries AG (Essen, Germany). Aluminum starch octenylsuccinate (ASt) (DryFlo® Plus) was obtained from AkzoNobel (Amsterdam, Netherlands). Purified water was obtained by inverse osmosis (Millipore, Elix 3) being afterwards filtered (pore 0.22 μm) and sterilized.
Particle size and morphology of ASt granules
Particle size distribution was determined using a Malvern Mastersizer 2000 (Malvern
Particle size measurements of ASt granules
As native starch granules are not hydrophobic, they are inappropriate to adsorb in oil–water interface. Nevertheless, the hydrophobicity can be added to starch granules by chemical or physical modifications [11]. A common way to chemically modify starch is by using octenyl succinic anhydride, resulting in the aluminum starch octenylsuccinate (ASt) used in the present study for its amphiphilic character. It is used in pharmaceutical and personal care products at concentrations as high as 30% as
Conclusions
The design planning methodology has clearly shown its usefulness in the optimization of process and formula and, therefore, the present work provides a framework for the understanding the formation of emulsions stabilized by ASt. The production of these emulsions was optimized in terms of composition (qualitative and quantitative) and process using a QbD approach. It was possible to obtain a Design Space for ASt-emulsion preparation with minimum variability and assuring product quality, thus
Acknowledgments
This work was supported by the Fundação para a Ciência e a Tecnologia, Portugal (UID/DTP/04138/2013 to iMed.ULisboa and grant SFRH/BDE/51599/2011) and Laboratórios Atral S.A., Portugal.
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