Full length articleElectrospun pH-sensitive core–shell polymer nanocomposites fabricated using a tri-axial process
Graphical abstract
Introduction
The fabrication of advanced drug delivery systems (DDSs) is increasingly dependent on the creation of complex architectures and understanding structure-activity relationships at the nanoscale [1], [2], [3]. To this end, core–shell nanostructures have been very widely studied in the production of functional nanomaterials, including those for biomedical applications [4], [5], [6]. For drug delivery and controlled release, both the core and shell can be loaded with an active pharmaceutical ingredient (API) and/or with different types of pharmaceutical excipients. Applications of such systems include improving the solubility of poorly water-soluble drugs, controlled release of multiple APIs from a single dosage form, or tunable multiple phase release [7], [8], [9].
Over recent years, polymers and lipids have been the most widely used pharmaceutical excipients, and these materials have acted as the basis for a broad gamut of novel DDSs, being exploited to alter the biopharmaceutical and pharmacokinetic properties of the drug molecule for favorable clinical outcomes [3], [10], [11]. Numerous core–shell polymeric nanoparticles (NPs) and lipid-based DDS (such as solid lipid dispersions and liposomes) have been investigated for drug delivery through varied administration routes [12], [13], [14], [15]. Novel strategies derived from the combined usage of polymers and phospholipids (PLs) have been reported for some biomedical applications (including controlled release) and are presently of intense interest in the pharmaceutics field. However, virtually all the reported polymer–lipid composites are in the form of microparticles or NPs [4], [8], [16], [17], [18]. Core–shell nanofiber-based DDS have received relatively little attention, and to the best of our knowledge there are no reports of drug-loaded polymer–lipid nanofibers being used in drug delivery.
Electrospun nanofibers, comprising an API loaded into a filament-forming polymer, have been the focus of much research. They are prepared from a co-dissolving solution of a drug and polymer; this is ejected from a syringe with electrical energy used to rapidly evaporate the solvent and yield one-dimensional fibers with diameters frequently on the nanoscale. This technique is scalable, and several recent reports address large scale fabrication and the potential for commercial products [19], [20], [21], [22]. The intense research effort invested in these materials thus appears to be about to yield products which can make a major difference to patients’ lives. Electrospinning is a facile, one-step procedure, and the products form as a visible and flexible mat which can easily be recovered from the collector without significant loss of material or damage. The nanofibers produced can further be used as templates to manipulate molecular self-assembly to create drug-loaded NPs or liposomes; the electrospinning technique thus provides not only a bridge between fiber-based and NP-based DDSs, but also between solid and liquid dosage forms [23], [24], [25], [26].
The most simple, single-fluid, electrospinning process has been explored for approaching two decades, and the applications of the resultant monolithic nanofibers have been probed in a wide range of fields. Current developments in electrospinning are focused in two key areas. The first is the manufacture of electrospun nanofibers on an industrial scale [27], [28], [29]. The second line of research involves developing advanced electrospinning techniques to yield nanofibers with sophisticated structural characteristics (such as multiple-compartment nanofibers, core–shell nanofibers, or structured fibers with varied distributions of the API), which in turn impart tunable and multiple functionalities [30], [31], [32]. Because of the popularity of core–shell nanostructures and the relative ease of the process, coaxial electrospinning (in which two needles, one nested inside another, are used to handle two working fluids) has been the focus of much research. Other advanced approaches such as side-by-side electrospinning (to yield Janus fibers), tri-axial electrospinning (giving three-layer composites), and other types of multiple-fluid electrospinning have been neglected in comparison [6], [9], [33].
Compared with single-fluid electrospinning, the standard coaxial experiment has greatly expanded the range of fibers which can be produced. These include not only core–shell fibers [34], [35], but also fibers prepared from materials without filament-forming properties [36] and used as templates for creating nanotubes (from the fiber as a whole) or the “bottom-up” generation of NPs (self-assembled from the components loaded in the fibers) [26], [37]. For biomedical applications, core–shell nanofibers proffer a series of new possibilities; for instance, it is possible to protect a fragile active ingredient such as a protein from the stresses of the electrospinning processes by confining it to the core, or to vary the APIs concentration in the core and shell to achieve complex drug release profiles [38], [39], [40], [41]. In the traditional coaxial process the sheath working fluid must be electrospinnable, but a modified process in which one can utilize unspinnable liquids as the sheath fluid is also possible. The number of polymers which can be directly electrospun is rather limited, but there are numerous unspinnable liquids, and the modified coaxial process should hence further expand the range of functional nanofibers which can be produced [38], [42], [43].
The above discussion is focused on the simultaneous processing of two fluids; working with three or even four fluids simultaneously is also possible, however [44], [45], [46], [47], [48], [49]. For example, Han and Steckl reported tri-layer nanofibers for biphasic controlled release, using dyes as model active ingredients [49]. In very recent work, we successfully developed a tri-axial electrospinning process to generate nanofibers with a gradient distribution of the API, allowing us to achieve zero-order drug release profiles [31]. However, in all the tri-axial electrospinning processes reported to date, the three working fluids are all electrospinnable. This limits the applications of the process. If unspinnable liquids can be processed in combination with spinnable working solutions, a much broader selection of functional products could be designed and generated.
Building on our previous work developing modified coaxial [38], [42], [43] and standard tri-axial electrospinning [50], here we report the first modified tri-axial electrospinning process. We have used this process to create core–shell fibers comprising a lipid-drug core and a pH sensitive shell, thereby allowing us to demonstrate that only an electrospinnable central fluid is required to achieve a successful tri-axial process. The polymer–lipid nanocomposites produced showed desirable functional performance in altering the release behavior of the model drug diclofenac sodium and improving its permeation through the colonic membrane.
Section snippets
Materials
Eudragit S100 (ES100, Mw = 135,000), a methacrylic acid/methyl methacrylate copolymer which only dissolves at pH > 7.0, was obtained from Röhm GmbH (Darmstadt, Germany). Diclofenac sodium (DS, a non-steroidal anti-inflammatory drug with potent anti-inflammatory, analgesic and antipyretic properties) was purchased from the Hubei Biocause Pharmaceutical Co., Ltd. (Hubei, China). Lecithin (PL, extracted from egg yolk, and containing lysophosphatidylcholine, sphingomyelin, and neutral lipids in minor
Implementation of modified tri-axial electrospinning
A diagram illustrating the modified tri-axial electrospinning process is shown in Fig. 1. The system consists of four components: three syringe pumps to drive the working fluids, a power supply, a fiber collector, and a three layer concentric spinneret. In modified coaxial electrospinning, the use of a spinnable core solution can ensure a successful process regardless of the electrospinnability of the sheath fluid [43]. Here, the central solution is electrospinnable, and this is utilized to
Conclusions
A modified tri-axial electrospinning process was successfully implemented to create core–shell nanofibers, in which a spinnable Eudragit S100 (ES100) solution was used as the middle fluid to support the outer solvent and an unspinnable phosphatidyl choline (PL)/diclofenac sodium (DS) inner solution. This resulted in a continuous and trouble-free nanofabrication process. The resultant core–shell nanofibers have a linear morphology with an obvious core–shell structure. XRD demonstrated that the
Acknowledgements
This work was supported by the China NSFC/UK Royal Society cost share international exchanges scheme (No. 51411130128/IE131748), the National Natural Science Foundation of China (Nos. 51373101 and 51373100), the Natural Science Foundation of Shanghai (No. 13ZR1428900) and the Hujiang Foundation of China (No. B14006). DP and LXK are also indebted to the Key Laboratory of Advanced Metal-based Electrical Power Materials, Shanghai Municipal Commission of Education.
References (61)
- et al.
Micro and nano-fabrication of biodegradable polymers for drug delivery
Adv. Drug Deliv. Rev.
(2004) - et al.
Electrospun biphasic drug release polyvinylpyrrolidone/ethyl cellulose core/sheath nanofibers
Acta Biomater.
(2013) - et al.
Preparation of multi-component drug delivery nanoparticles using a triple-needle electrohydrodynamic device
J. Colloid Interface Sci.
(2013) - et al.
Core–shell designed scaffolds for drug delivery and tissue engineering
Acta Biomater.
(2015) - et al.
Lipid–polymer hybrid nanoparticles as a new generation therapeutic delivery platform: a review
Eur. J. Pharm. Biopharm.
(2013) - et al.
Coaxial electrospinning for encapsulation and controlled release of fragile water-soluble bioactive agents
J. Control. Release
(2014) - et al.
High-throughput and high-yield fabrication of uniaxially-aligned chitosan-based nanofibers by centrifugal electrospinning
Carbohydr. Polym.
(2015) - et al.
Advances in three-dimensional nanofibrous macrostructures via electrospinning
Prog. Polym. Sci.
(2014) - et al.
High speed electrospinning for scaled-up production of amorphous solid dispersion of itraconazole
Int. J. Pharm.
(2015) - et al.
Alternating current electrospinning for preparation of fibrous drug delivery systems
Int. J. Pharm.
(2015)
Functional materials by electrospinning of polymers
Prog. Polym. Sci.
Electrospun PLA/MWCNTs composite nanofibers for combined chemo- and photothermal therapy
Acta Biomater.
Controlled release of bone morphogenetic protein 2 and dexamethasone loaded in core–shell PLLACL-collagen fibers for use in bone tissue engineering
Acta Biomater.
Linear drug release membrane prepared by a modified coaxial electrospinning process
J. Membr. Sci.
Phase equilibria and structure of dry and hydrated egg lecithin
J. Lipid Res.
Adverse reactions to nonsteroidal anti-inflammatory drugs. Diclofenac compared with other nonsteroidal anti-inflammatory drugs
Am. J. Med.
Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications
Int. J. Pharm.
Diclofenac release from phospholipid drug systems and permeation through excised human stratum corneum
Int. J. Pharm.
Preparation and pharmaceutical evaluation of nano-fiber matrix supported drug delivery system using the solvent-based electrospinning method
Int. J. Pharm.
Downstream processing of polymer-based amorphous solid dispersions to generate tablet formulations
Int. J. Pharm.
Dual functional core-sheath electrospun hyaluronic acid/polycaprolactone nanofibrous membranes embedded with silver nanoparticles for prevention of peritendinous adhesion
Acta Biomater.
Impact of nanotechnology on drug delivery
ACS Nano
Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies
Nat. Rev. Drug Discov.
Tunable rigidity of (polymeric core)–(lipid shell) nanoparticles for regulated cellular uptake
Adv. Mater.
Diffusion through the shells of yolk–shell and core–shell nanostructures in the liquid phase
Angew. Chem. Int. Ed.
Structure-tunable Janus fibers fabricated using spinnerets with varying port angles
Chem. Commun.
Solid dispersions, Part II: new strategies in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs
Expert Opin. Drug Deliv.
Electrosprayed core–shell polymer–lipid nanoparticles for active component delivery
Nanotechnology
Nanomaterials for drug delivery
Science
Liposomes self-assembled from electrosprayed composite microparticles
Nanotechnology
Cited by (143)
Multifunctional embelin- poly (3-hydroxybutyric acid) and sodium alginate-based core-shell electrospun nanofibrous mat for wound healing applications
2024, International Journal of Biological MacromoleculesMulti-material electrospinning: from methods to biomedical applications
2023, Materials Today BioApplication of artificial intelligence driving nano-based drug delivery system
2023, A Handbook of Artificial Intelligence in Drug DeliveryKaempferol loaded albumin nanoparticles and dexamethasone encapsulation into electrospun polycaprolactone fibrous mat – Concurrent release for cartilage regeneration
2021, Journal of Drug Delivery Science and TechnologyBiomedical application of responsive ‘smart’ electrospun nanofibers in drug delivery system: A minireview
2021, Arabian Journal of Chemistry