Viewpoint pubs.acs.org/macroletters
Capsules: Their Past and Opportunities for Their Future Esther Amstad* Soft Materials Laboratory, Institute of Materials, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland ABSTRACT: Capsules are often used as mobile delivery vehicles, for example, in pharmacy, food, and cosmetics, or as stationary containers that are embedded in a matrix to functionalize materials. Progress achieved in polymer chemistry opened up new possibilities to tune the properties of capsules with a much higher precision, thereby allowing the fabrication of advanced materials. This viewpoint summarizes recent developments in the design of functional capsules and highlights some of the challenges involved in the use of capsules to functionalize existing and to build new materials.
robably the first things that come to mind in the context of capsules are millimeter-sized containers loaded with drugs or food supplements. These capsules have been on the market for many decades, and during this time a lot of research and development has been conducted to optimize them. This begs the question: Is there still need for improvements and innovation in this field? Capsules are usually loaded with active ingredients, such as drugs,1 cosmetics,2 food supplements,3 fragrances,4 agricultural substances,5 and chemical reagents.6 They are employed to prolong the shelf life of active ingredients by delaying their degradation or to protect them from substances in the surroundings that could prematurely interact or react with them. Alternatively, capsules are used to carry active ingredients to specific sites where they are released such that their concentration is locally very high. In many applications, localized release allows reduction of the total amount of active ingredients that must be administered to achieve the desired effect. This decreases costs and potentially diminishes negative side effects,7 which is particularly beneficial in pharmaceutical applications. Indeed, targeting of capsules is a key aspect in the development of capsules directed toward their use in personalized medicine. Large millimeter-sized capsules are most frequently fabricated through injection molding because of its low production costs and high throughput.8 The production of these large capsules is well-established, and their properties can be tuned to satisfy the needs of the specific applications: The size and shell thickness of these capsules is controlled by the dimensions of the mold and their composition by that of the melt they are produced from. Smaller capsules with diameters ranging from a few tens of nanometers up to a few hundred micrometers are often made from emulsion drops that are subsequently converted into capsules. One of the most frequently used methods to generate capsules intended for food, cosmetic, and certain pharmaceutical applications is the electrostatic association of two oppositely charged reagents at liquid−liquid interfaces, the so-called coacervation. This is achieved by dissolving one of the
P
© XXXX American Chemical Society
reagents in an oil phase that has a low solubility in water and the other reagent in an aqueous phase. After the two phases are emulsified, the oppositely charged reagents meet at the drop surface where they associate. Thereby, they form thin shells composed of aggregates of these charged reagents, so-called coacervates, as schematically shown in Figure 1a.9 Capsules made from coacervates are most frequently formed from single emulsion drops. These drops can be produced at low costs and high throughputs. The size of the resulting capsules scales with that of the drops. The degree of control over the drop size depends on the technique used to fabricate them: It is low if they are formed through mechanical agitation, for example, using rotor−stator systems10 or high-pressure homogenization.11 It is much higher if drops are formed using membranes12 and even higher if they are formed with microfluidics.13 Hence, the size of these capsules can be accurately controlled if needed. However, the choice of materials these capsules are made from is limited to charged reagents that very often are polyelectrolytes, as summarized in Table 1. Moreover, these capsules have thin walls and are thus rather fragile.9c The mechanical stability of capsules increases if their shell is composed of a percolating covalently cross-linked network. A frequently employed method to produce these capsules is in situ polymerization: Reagents are dissolved in an appropriate liquid, usually an aqueous phase, that forms the dispersed phase. This liquid is mixed with a second, immiscible liquid and emulsified before the reagents are polymerized to create covalently crosslinked shells, as schematically shown in Figure 1b. This method is attractive because capsules can be produced from single emulsion drops. However, this process only results in capsules, if monomers and solvents are selected appropriately: Monomers must be soluble in the dispersed phase, but the polymers must have a low solubility in either phase. If this is the case, the continuous phase is initially homogeneous. Polymers Received: June 29, 2017 Accepted: July 24, 2017
841
DOI: 10.1021/acsmacrolett.7b00472 ACS Macro Lett. 2017, 6, 841−847
Viewpoint
ACS Macro Letters
cross-linked shells that encompass liquid cores, as schematically shown in Figure 1b.29 The dimensions of the resulting capsules depend on the size of drops as well as on the processing conditions such as the reaction temperature, pH, and the surfactants used to stabilize the emulsion drops.30 However, the stringent requirements on the solubility of monomers and polymers restrict the number of materials that can be processed into capsules through in situ polymerization, as exemplified in Table 1. Moreover, the control over the capsule structure is limited. As a result, possibilities to adjust the properties of capsules or make them responsive to certain external stimuli are reduced. Capsules composed of a much wider range of materials can be fabricated if double emulsion drops are employed as templates.31 Double emulsions are small drops contained in larger drops that are dispersed in a third fluid. They can be converted into capsules through solidification of their shell, as schematically shown in Figure 1c. This solidification is often achieved through polymerization of monomers, cross-linking of oligomers or polymers that are contained in the double emulsion shell, or solvent extraction.32 The capsule size and shell thickness scale with the dimensions of the double emulsion drops. The degree of control over these dimensions depends on the fabrication method. Double emulsions are frequently made in a two-step process by forming single emulsions and re-emulsifying them in a third fluid using bulk emulsification methods.33 These methods allow production of double emulsions at high throughputs. However, they typically suffer from a poor control over the size and shell thickness of double emulsion drops.33b Moreover, one double emulsion drop often encompasses multiple small emulsion drops, resulting in ill-defined,
Figure 1. Schematic illustration of the formation of capsules through (a) coacervation, (b) in situ polymerization, and (c) solidification of double emulsion shells. Capsules are made from emulsion drops (top) that serve as templates to form shells (bottom). (a) Oppositely charged reagents are dissolved in the oil and aqueous phases, respectively (top), and associate at the liquid−liquid interphase to form a shell whose thickness is often below 1 μm (bottom). (b) Surfactant-stabilized emulsion drops are dispersed in a fluid containing reagents (top) that precipitate and form a shell when they are polymerized that often attains a thickness up to a few μm (bottom). (c) The shell of surfactant-stabilized double emulsions is loaded with reagents (top) that are solidified to form a shell that ranges from a few μm up to a few tens of μm (bottom).
that start to form after the polymerization reaction is initiated become insoluble and diffuse toward the drop surface where they continue to polymerize. This process results in covalently
Table 1. Overview of the Composition, Diameter, dc, Shell Thickness, ts, and Application of Capsules Produced through Different Techniques shell material hydroxypropylcellulose/poly(ethylene glycol) gelatin/gum arabic gelatin/gum arabic soybean protein isolate/gum arabic gelatin/sodium lauryl sulfonate/ sodium carboxymethylcellulose poly(diallyldimethyl-ammonium) chloride/adenosine triphosphate poly(urea-formaldehyde)
encapsulant acetaminophen lycopene flaxseed oil sweet orange oil tetrachloroethylene fluorophores, dextran, nanoparticles epoxy + CuBr2(2-Melm)4
poly(melamine-urea-formaldehyde)
epoxy
poly(melamine-urea-formaldehyde) poly(melamine formadehyde)
diglycidyl 1,2cyclohexanedicarboxylate glycidyl methacrylate
poly(styrene) poly(phenylene oxide)
poly(vinyl alcohol) tetrachloroethylene
poly(lactic acid)
Saccharomyces cerevisiae yeast cells triethylenetetramine and diethylenetriamine hepatocytes K2CO3/m-cresol purple
poly(acrylate) poly(ethylene glycol) silicon rubber
fabrication method
dc (μm)
ts (μm)
mode of release
application
ref
injection molding coacervation coacervation coacervation coacervation
8000 × 19000
300−900
degradation
drug delivery
8a
60−140 20−100 ≈7 40−80
