Electrospinning: From Benchtop to Bedside?

Introduction

Electrospinning is rapidly emerging as a new pharmaceutical processing technology with great potential in medicines development. In the most common experimental set-up, a solution of a polymer and functional component (in this context an active pharmaceutical ingredient (API) is prepared in a volatile solvent. This is then loaded into a syringe fitted with a metal needle (the spinneret). A pump is used to extrude the solution through the needle at a controlled rate.

The solution is ejected towards a collector, and a power supply is used to apply a high voltage between the spinneret and the collector (Figure 1). This results in the evaporation of solvent and the formation of a non-woven mat of one-dimensional fibers on the collector. The fibers typically have diameters on the nanoscale, and comprise amorphous solid dispersions (ASDs) of drug in polymer (Figure 1). This gives them significant promise for the development of drug delivery systems, particularly where very rapid release is required.

The term “electrospinning” is derived from “electrostatic spinning”, and has been used since the early 1990s. The phenomenon was first observed in 1897 by Rayleigh, and the first patent for an experimental set-up was filed in 1899.¹ Electrospinning can be used to prepare formulations from both natural and synthetic polymers, either using solutions or melts.² These formulations can contain the full gamut of active pharmaceutical ingredients, ranging from small molecules through peptides and proteins to cells. While the simplest experimental set-up uses a single needle to generate monolithic drug-in-polymer dispersions, it is also possible to design spinnerets comprising multiple needles and use these to process multiple fluids simultaneously to yield more complex nanoscale architectures (Figure 2). Most electrospinning experiments are performed using direct current, but alternating current can also be applied. In this case there is no need for a collector because the emitted fibers act as a counter-electrode.³

A number of experimental parameters (voltage, solution flow rate, solution concentration and viscosity, etc.) affect the electrospinning process and the nature of the materials produced, and all need to be carefully controlled during fiber fabrication.

The optimization of these variables can be achieved in the lab using design of experiments type approaches, but becomes more complex as the number of fluids being processed increases. In addition, the environmental parameters (temperature and humidity) also need to be monitored and controlled to ensure that production is trouble-free and reproducible.

One of the key processing parameters is the solution viscosity, which is determined by the molecular weight and concentration of the polymer. This needs to be at a certain critical level to permit fiber formation. If the viscosity is too low, then instead of electrospinning a related process termed electrospraying takes place. Here, rather than fibers being generated the products comprise micron to nanometer sized particles, also typically as ASDs.

Ignatious and Baldoni first described the use of electrospun fibers for drug delivery in a patent in 2001,⁴ and the first literature report followed from Kenawy in 2002.⁵ Since then, a myriad of authors have explored the potential of electrospinning in pharmaceutical science. A Web of Knowledge search for “electrospinning AND drug delivery” performed on 1 January 2020 yielded 2,338 hits, with more than 50% of these published in the last five years. Electrospinning has a number of advantages over other pharmaceutical processing technologies used to generate ASDs. Compared to spray drying, the drying process is more rapid in electrospinning, and no heat is used. This is advantageous for handling thermally labile APIs such as proteins, and also more energy efficient (in spray drying, electricity is converted into heat energy, while in electrospinning it is used directly to dry the product). Electrospinning is a much more rapid and simple process than freeze drying, which again renders the former attractive for industrial applications.6

Applications

The most common application where electrospun fibers have attracted attention is for the development of fast dissolving drug delivery systems. The nanoscale diameter of the fibers, the fact that they collect in highly porous non-woven mats, and the amorphous nature of the materials means they can lead to very significant increases in dissolution rate and solubility, particularly if a hydrophilic polymer is used. For instance, a range of drug loaded polyvinylpyrrolidone (PVP) based fibers have been reported, containing APIs as diverse as irbesartan (used for treating high blood pressure),⁷ mebeverine hydrochloride (an antispasmodic drug also used for dental analgesia),⁸ isosorbide dinitrate (used for treating angina),⁹ and vitamin D.10 The fiber mats disintegrate very rapidly (in a few seconds) and free all their drug loading into solution in a few minutes. This, coupled with the fact that the fiber mats can easily be cut into a range of shapes, means that electrospun formulations are particularly helpful for the development of oral fast dissolving films. For instance, Illangakoon et al. have reported a family of PVP/paracetamol/caffeine fibers which disintegrate in < 300 ms (Figure 3),¹¹ and could find application for the treatment of those who have difficulty swallowing (e.g. pediatric and geriatric patients).

Electrospun fibers offer many more possibilities than simply fast dissolving drug delivery systems.⁶ Permeation enhancers can be included in the fibers, and thus some of the problems of working with Class III or IV APIs can be ameliorated.¹² Taste-masking – likely to be particularly important in the context of an oral fast-dissolving drug delivery system – can be achieved by including a sweetener or flavoring agent.¹¹ Using a slow-dissolving or insoluble polymer can result in extended release,¹³ while pH-sensitive polymers such as Eudragits¹⁴ may be employed to target release to particular parts of the gastrointestinal tract¹⁴ or provide pulsatile release.¹⁵

Monolithic fibers do come with some limitations however, because of the homogeneous distribution of drug throughout the fiber matrix. This results in there being a significant amount of drug at the fiber surface. With a fast-dissolving system, this is not a problem: the formulations are designed to free their drug cargo very rapidly.

In contrast, the presence of API at the surface can be a major issue when extended or targeted release is required, because the API at the surface can be rapidly freed into solution, typically giving a burst of release immediately after the formulation comes into contact with physiological fluids.

This issue can usually be overcome using multi-fluid electrospinning processes. Coaxial spinning, using two needles (one nested inside another) generates fibers with a core/shell structure (Figure 2). If the drug is confined to the core compartment with the shell comprising an insoluble or slow-degrading polymer, then a reservoir-type system is generated and the problem of burst release can often (but not always) be ameliorated.16 A pH-sensitive shell can assist with effective targeting.¹⁷ Coaxial electrospinning also aids the handling of protein active ingredients. In general, the solvents used for electrospinning are organic in nature and thus cause degradation of biologics; using a coaxial set-up permits the protein to be localized in an aqueous core compartment while a polymer solution in an organic solvent is used for the shell solution. This minimizes contact between the two, and helps to preserve protein integrity.

Perhaps one of the most sought-after release profiles in pharmaceutical science is zero-order release, providing a constant rate of drug release with time. This has been successfully obtained on a number of occasions with electrospun formulations. For instance, Angkawinitwong et al. prepared fibers with a poly(ε-caprolactone) (PCL) shell and a core loaded with the antibody bevacizumab.¹⁸ Through judicious choice of the processing parameters, it proved possible to prepare a system providing zero-order release over more than two months in an in vitro model of the eye (Figure 4a). This formulation could have great potential for the treatment of ocular conditions such as acute macular degeneration, a blinding disease currently treated with once monthly intravitreal injections. Triaxial electrospinning, yielding three layer fibers, has additionally been employed to provide zero-order release of the non-steroidal anti-inflammatory drug ketoprofen from fibers based on the insoluble polymer ethylcellulose (Figure 4b).¹⁹

The literature also shows that cells can be processed using multi-fluid electrospinning without any noticeable loss of viability.^20,21

Stability

A major concern around ASDs is their stability. This has been studied for a number of hygroscopic electrospun systems, and most authors have reported that the fibers retain their amorphous characteristics after storage for at least twelve months under low-humidity conditions (60% or lower), but that some recrystallization does occur at 75% relative humidity.^8,22 Given the great benefits offered by electrospun formulations, the challenges of storage stability can in the authors’ view be cost-effectively ameliorated by careful packaging (e.g. under nitrogen).²²

Scale-Up and GMP Manufacture

A typical lab electrospinning set-up can deliver a maximum daily yield of perhaps 20 grams of fibers, which is clearly insufficient for industrial applications. However, a number of developments over the last decade or so have led to the process being fully scalable, and implemented in GMP conditions. In the lab, the collector will generally comprise a flat plate or a rotating drum; for scaled up production, a conveyor-belt or cyclone is required. Major changes to the spinneret are also required for industrial application. Scale-up can be achieved by dispensing the working fluid through a large number of needles simultaneously or using a porous injector,²³ although both come with some caveats in terms of handling blockages and the fact that the electric field around one needle will affect its neighbors. Alternatively, a needle-free approach can be employed. This applies a voltage to eject polymer jets directly from the surface of a solution. A much higher voltage here is required than in the needle-based process, and because a large surface area of a volatile solvent is exposed there is the risk of evaporation independent of the electric field, and in extreme cases also of explosion. To ameliorate this, a range of innovations have been explored to minimize the exposed surface area.²⁴

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A number of authors have investigated the effect of scaling up on the products of electrospinning. It has been found that while the fiber diameters rise and more inhomogeneities are introduced as the production rate of the process increases, the functional performance in terms of dissolution profile and stability do not vary significantly (Figure 5).²⁵ Furthermore, it has been shown that the fiber products from high-throughput electrospinning can be easily processed into tablets.^26,27

A number of manufacturers now offer off-the-shelf equipment which can perform electrospinning under precisely controlled conditions (temperature and humidity) in the laboratory, helping to ensure that experiments can be easily reproduced in different locations. High throughput apparatus can also be procured commercially, and there exist several companies who can perform electrospinning under GMP conditions. These innovations in terms of control and scale-up means that electrospun formulations are now under active consideration by the pharmaceutical industry, with at least one product currently in clinical trials (e.g. for the treatment of oral lichen planus).²⁸

Extremely rapid advances are also being made in scaling up multi-fluid electrospinning processes, meaning that in the near future it will be possible to produce more complex architectures under GMP conditions and at a scale required for industrial application. This acceleration in technological developments, coupled with the ever increasing challenge of formulating poorly soluble active ingredients, means that in the authors’ view electrospinning has a very bright future in the field of medicines development.

References

1. US Patent US692631A.
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3. Pokorny P, Kostakova E, Sanetrnik F, et al. Effective AC needleless and collectorless electrospinning for yarn production. Phys Chem Chem Phys. 2014;16(48):26816-26822.
4. Australian Patent AU20010031134.
5. Kenawy E-R, Bowlin GL, Mansfi eld K, et al. Release of tetracycline hydrochloride from electrospun poly(ethylene-co-vinylacetate), poly(lactic acid), and a blend. J Control Release. 2002;81:57-64.
6. Yu DG, Li JJ, Williams GR, Zhao M. Electrospun amorphous solid dispersions of poorly water soluble drugs: A review. J Control Release. 2018;292:91-110.
7. Adeli E. Irbesartan-loaded electrospun nanofibers-based PVP K90 for the drug dissolution improvement: Fabrication, in vitro performance assessment, and in vivo evaluation. J Appl Polym Sci. 2015;132(27):42212.
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9. Chen J, Wang X, Zhang W, et al. A novel application of electrospinning technique in sublingual membrane: characterization, permeation and in vivo study. Drug Dev Ind Pharm. 2016;42(8):1365-1374.
10. Li X, Lin L, Zhu Y, Liu W, Yu T, Ge M. Preparation of ultrafine fast-dissolving cholecalciferolloaded poly(vinyl pyrrolidone) fiber mats via electrospinning. Polym Composite. 2013;34(2):282-287.
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About the Authors

Gareth R. Williams received a MChem (Hons) degree from the University of Oxford in 2002. He remained in Oxford for a DPhil (Ph.D.), which was completed in 2005. In September 2010 he joined London Metropolitan University as a Senior Lecturer in Pharmaceutical Science, and in November 2012 was appointed to the UCL School of Pharmacy as a Lecturer in Pharmaceutics. He was promoted to Associate Professor in 2016 and became Head of Pharmaceutics in 2020.

Zsombor K. Nagy received a MSc degree in Chemistry from the Eötvös Loránd University. He completed his Ph.D. in Pharmaceutical Technology at the Budapest University of Technology and Economics (BME) in 2012 and then was appointed to BME as a lecturer. He was promoted to Associate Professor in 2018. From 2013, he has worked to investigate the scalability and applicability of electrospinning in the pharmaceutical industry in collaboration with Janssen Pharmaceutica.

Jose M. Lagaron received a MSc in Chemical Sciences and a Ph.D. in Polymer Physics from the University of Valladolid, Spain. He worked for several years at DSM Research and BP Chemicals and then joined the Spanish Council of Scientific Research, where he founded the Novel Materials and Nanotechnology Group. He has published over 300 papers and is inventor of more than 50 patents, some of which relate to high-throughput electrospinning technologies.