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Nanofiber for drug delivery system - principle and application.

Byline: R.Rathinamoorthy

Abstract

The use of nanotechnology in the textile industry has increased rapidly due to its unique and valuable properties. Electrospinning is a novel process for producing superfine nanofibers. Special properties make them suitable for a wide range of applications from medical to consumer products and industrial to high-tech applications. This paper details the different nanofiber manufacturing methods and its pro and cons. Further it explores the different principles of drug delivery and the application of nanofiber in pharmaceutical Drug Delivery System (DDS).

Keywords: Nanofiber, Self-assembly, Phase Separation, Electro Spinning, Drug Loading, Drug Delivery.

Introduction

According to the National Nanotechnology Initiative (NNI), nanotechnology is defined as the utilization of structure with at least one dimension of nanometer size for the construction of material, devices or systems with novel or significantly improved properties due to their nano size1. Nanotechnology alters physical properties of a substance on molecular level, it blurs the boundaries between physics, chemistry and biology.

Nanofibers are an exciting new class of material used for several value added applications such as medical, filtration, barrier, wipes, personal care, composite, garments, insulation, and energy storage. Low density, large surface area to mass, high pore volume, and tight pore size are the characteristics of the nanofiber2-3.

Nanofiber exhibit special properties mainly due to extremely high surface to weight ratio compared to conventional fibers. These Special properties make them suitable for a wide range of applications from medical to consumer products and industrial to high-tech applications for aerospace, capacitors, transistors, drug delivery systems, battery separators, energy storage, fuel cells, and information technology4. In this report, the first phase describes the manufacturing methods of nanofiber and its importance. The second phase details the principles of Drug Delivery System (DDS), which includes the method of drug loading and different release mechanism, further it deals with the different applications of nanofiber as drug delivery vehicle.

Nano fibers

Three distinct techniques have proven successful in routinely creating nanofibrous tissue structures: self assembly, phase separation, and electrospinning5-7. The electrospinning method is the most simple and efficient. Electrospinning as a polymer-processing technology has been known for more than 70 years. Patents involving electrospinning first appeared in the 1930s8.

Self-assembly

Self-assembly involves the spontaneous organization of individual components into an ordered and stable structure with preprogrammed non-covalent bonds9-10. Self-assembly, that is, the autonomous organization of molecules into patterns or structures without human intervention, are common throughout nature and technology11. Self-assembly of natural or synthetic macromolecules produces nanoscaled supramolecular structures, sometimes nanofibers12. Compared with electrospinning, self-assembly can produce much thinner nanofibers only several nanometers in diameter, but requires much more complicated procedures and extremely elaborate techniques. The low productivity of the self-assembly method is another limitation.

Phase separation

Phase separation is a method frequently used to prepare 3-D tissue-engineering scaffolds. Phase separation of a polymer solution can produce a polymer-rich domain and a solvent-rich domain, of which the morphology can be fixed by quenching under low temperature. Removal of the solvent through freeze-drying or extraction can produce porous polymer scaffolds. Phase separation can be induced by changing the temperature or by adding nonsolvent to the polymer solution, thus called thermal induced or non-solvent-induced phase separation, respectively. Polymer scaffolds obtained by the phase separation method usually have a spongelike porous morphology with microscale spherical pores13,14.

Unlike self-assembly, phase separation is a simple technique that does not require much specialized equipment. It is also easy to achieve batch-to-batch consistency, and tailoring of scaffold mechanical properties and architecture is easily achieved by varying polymer/porogen concentrations. However, this method is limited to being effective with only a select number of polymers and is strictly a laboratory scale technique15.

Electrospinning

Generally, polymeric nano fibres are produced by electrospinning, which spins fibers of diameters ranging from 10 nm to several hundred nanometers. This method has been known since 1934, when the first patent on electrospinning was filed. Electrospinning can be carried out from polymer melt or solution16. A majority of the published work on electrospinning has been focused on solution-based electrospinning rather than on melt electrospinning due to higher capital investment requirements and the difficulty in producing submicron by melt electrospinning.

A schematic diagram demonstrating the process of electrospinning of polymer nanofibers is shown in Figure 1. There are basically three components: a high voltage supplier, a capillary tube with a pipette or needle of small diameter, and a metal collecting screen.

In electrospinning a high voltage is used to create an electrically charged jet of polymer solution or melt out of the pipette. Before reaching the collecting screen, the solution jet evaporates or solidifies, and is collected as an interconnected web of small fibers.

One electrode is placed into the spinning solution/melt and the other attached to the collector. Another interesting aspect of using nanofibers is that it is feasible to modify not only their morphology and their (internal bulk) content but also the surface structure to carry various functionalities.

In the electrospinning process, fibers ranging from 50 nm to 1000 nm or greater17 can be produced by applying an electric potential to a polymeric solution18. A wide range of polymers has been used to electrospin nanofibers. Natural polymers such as collagen, gelatin, chitosan, hyaluronic acid, and silk fibroin have been used to produce nanofibers that can form potential scaffolds for tissue engineering applications. More recently, nanofibers of protein have been demonstrated to have promising use in tissue engineering19. The unique properties of electrospun mats - high specific surface area and small pores are very favorable for the adsorption of liquids and for preventing bacteria penetration and thus provide good conditions for wound healing. The simplicity allows for electrospinning to be the only nanofibrous processing technique that can be taken out of a laboratory setting and be utilized successfully in scale-up and mass production.

The following table explains the merits and demerits of different nanofiber manufacturing methods20.

The use of polymer nanofibers for biomedical and biotechnological applications has some intrinsic advantages. From a biological point of view, a great variety of natural biomaterials are deposited in fibrous forms or structures. polymer nanofibers can provide a proper route to emulate or duplicate biosystems-a biomimetic approach. On the other hand, many researches21,22 have shown evidences that apart from surface chemistry, the nanometer scale surface features and topography also have important effect on regulating cell behavior in terms of cell adhesion, activation, proliferation, alignment and orientation. The biomedical application of nanofiber include tissue engineering, controlled drug release, dressings for wound healing, medical implants, nanocomposites for dental applications, molecular separation, biosensors and preservation of bioactive agents.

Nanofibers for controlled drug delivery

Delivery of drugs or pharmaceutical agents to patients in a most physiologically acceptable manner has always been an important concern. The objective of drug delivery systems is to deliver a defined amount of drug efficiently, precisely and for a defined period of time. New technologies and materials will have a profound impact on drug delivery. Either biodegradable or non-degradable materials can be used to control whether drug release occurs via diffusion alone or diffusion and scaffold degradation. Additionally, due to the flexibility in material selection a number of drugs can be delivered including: antibiotics, anticancer drugs, proteins, and DNA. Using the various electro spinning techniques a number of different drug loading methods can also be utilized: coatings, embedded drug, and encapsulated drug (coaxial and emulsion electrospinning). These techniques can be used to give finer control over drug release kinetics23.

Principle

Drug delivery with polymer nanofibers is based on the principle that dissolution rate of a drug particulate increases with increased surface area of both the drug and the corresponding carrier if necessary. For controlled drug delivery, in addition to their large surface area to volume ratio, polymer nanofibers also have other additional advantages. For example, unlike common encapsulation involving, Controlled delivery systems are used to improve the therapeutic efficacy and safety of drugs by delivering them to the site of action at a rate dictated by the need of the physiological environment. A wide variety of polymeric materials have been used as delivery matrices, and the choice of the delivery vehicle polymer is determined by the requirements of the specific application24. Polymeric nanofibers have recently been explored for their ability to encapsulate and deliver bioactive molecules for therapeutic applications.

Drug loading

One method to incorporate therapeutic drugs into nanofibers involves solubilizing the drug into the polymer solution to be spun25. Using this method, a loading efficiency of 90% into PDLA nanofibers was reported for the antibiotic drug Mefoxin. Covalent conjugation to polymers represents another method to modulate drug release26. It has also been suggested that the high porosity of nanofibers allows for rapid diffusion of degradation byproducts27. However, the burst release may also be indicative of the drug being attached only on the surface. As the drug and carrier materials can be mixed together for electrospinning of nanofibers, the likely modes of the drug in the resulting nanostructed products are28:

1 Drug as particles attached to the surface of the carrier which is in the form of nanofibers,

2 Both drug and carrier are nanofiber-form, hence the end product will be the two kinds of nanofibers interlaced together,

3 The blend of drug and carrier materials integrated into one kind of fibers containing both components, and

4 The carrier material is electrospun into a tubular form in which the drug particles are encapsulated.

Mechanism of drug delivery

Nanofiber drug delivery systems may provide insight into the direct incorporation of bioactive growth factors into scaffolds. Additionally, drug delivery systems can be combined with implantable tissue engineering scaffolds to prevent infection while repair and regeneration occur. Biodegradable polymers release drug in one of two ways29: erosion and diffusion. Release from biodegradable polymers in vivo is governed by a combination of both mechanisms, which depends on the relative rates of erosion and diffusion.

Most biodegradable polymers used for drug delivery are degraded by hydrolysis. Hydrolysis is a reaction between water molecules and bonds in the polymer backbone, typically ester bonds, which repeatedly cuts the polymer chain until it is returned to monomers. Other biodegradable polymers are enzymatically degradable, which is also a type of chain scission. As water molecules break chemical bonds along the polymer chain, the physical integrity of the polymer degrades and allows drug to be released. The different mechanisms were given below29.

Types of drug release

In general a few typical different types of release can be recognised relevant in textile drug delivery systems; immediate release, extended release and triggered or delayed release The different mechanisms are 30,31.

Immediate release

The drugs are available within a relatively Short time.

This type of release is required in situations where immediate action is essential.

Extended release

The availability of drugs is maintained at a lower concentration and for a prolonged time compared to immediate release systems.

The drug is delivered at a (very) slow rate and for a prolonged period of Hours, days or even years, thereby usually reducing dosing frequency.

Triggered or delayed release

The release of drugs from triggered or delayed release systems is determined by an (external) trigger/stimulus or time. The resulting release can be of the immediate type or slow-release type.

The release of the drug from the delivery system might also be triggered by a specific event, situation, or change in the environment such as a change in pH, temperature, ionic strength or even by an externally controllable trigger-like ultrasound.

When selecting a material to use in a drug delivery device a number of requirements must be met. As with materials used in tissue engineering applications, materials that undergo biodegradation are generally more popular due to the fact that they eliminate the need for explantation. However, biodegradable materials add an extra level of complexity to drug delivery devices as compared to non-degradable materials, which tend to release drug primarily by diffusion. Generally it is desirable to design a drug delivery device that gives controlled release of the desired agent; however, this may be difficult if the material begins degrading as the drug is being released.

In a biodegradable system the drug may be released by diffusion as well as degradation of the material, which in somecases can lead to dose dumping resulting in local drug concentrations reaching toxic levels. Thus, special care must be taken to tailor both the release rate and the degradation rate if a degradable material is to be used.

The drug release profile can be easily finely tailored by modulation not only of the composition of the nanofiber mats but also the morphology of nanofibers, the process and the micro-structure. Core-sheath structure is a very useful structure for all kinds of applications. Xu et al.32 reported that uniform core-sheath nanofibers were prepared by electro-spinning a water-in-oil emulsion in which the aqueous phase consists of a poly(ethylene oxide) (PEO) solution in water and the oily phase is a chloroform solution of an amphiphilic poly(ethylene glycol)-poly(L-lactic acid) (PEG-PLA) diblock copolymer. The obtained fibers are composed of a PEO core and a PEG-PLA sheath with a sharp boundary in between. By adjusting the emulsion composition and the emulsification parameters, the overall fiber size and the relative diameters of the core and the sheath can be altered. Different release rates may be obtained by simply varying the fiber diameter or loading dosage.

Application

The first report about electrospinning fibers as DDS was noted by Kenawy et al.33 Electrospun fiber mats were explored as drug delivery vehicles using tetracycline hydrochloride as a model drug. The mats were made either from poly (lactic acid) (PLA), poly (ethylene-co-vinyl acetate) (PEVA), or from a 50:50 blend of the two from chloroform solutions. Release profiles showed promising results when they were compared to a commercially available DDS--Actisite(r) (Alza Corpora-tion, Palo Alto, CA).

Ignatious et al 34 attempted making nanofibrous polymer carriers by electrospinning for pharmaceutical application. The release of pharmaceutical dosage can be designed as rapid, immediate, delayed, or modified dissolution depending on the polymer carrier used. It was found that the electrospun nanofibrous mats gave relatively smooth release of drug over a period of five days. In a different report 35, bioabsorbable nanofiber membranes of poly(lactic acid) was used for loading an antibiotic drug mefoxin. The efficiency of this nanofiber membrane compared to bulk film was demonstrated. For potential use in topical drug administration and wound healing, poorly water-soluble drugs loaded in water-soluble and wateri-in-soluble nanofibrous polymer carriers were investigated. It was shown that drug loaded polymer nanofibers by electrospinning were able to make the drugs dispersed in an amorphous state which would facilitate the drug dissolution.

In another study, Verreck et al37 have demonstrated the use of (nonbiodegradable polymer scaffolds) PU nanofibrous scaffolds produced by electrospinning for the delivery of water-insoluble drugs such as intraconazole and ketanserin. In their study, the authors obtained an amorphous nanodispersion of the waterinsoluble drug on the nanofibrous scaffold.

Later studies on the preparation of nanofibers from polymers with different drug-loaded capabilities and the corresponding DDS were reported, such as transdermal, fast dissolving and implantable DDS. Electrospun nanofibers are often used to load insoluble drugs for enhancing their dissolution properties due to their high surface area per unit mass. Taepaiboon et al. reported that the molecular weight of the model drugs played a major role on both the rate and the total amount of drugs released from the prepared drug-loaded electrospun PVA nanofibers. The rate and the total amount of the drugs released decreasing with increasing molecular weight of the encapsulated drugs38. Verreck et al. confirmed that the application of electrostatic spinning to pharmaceutical applications resulted in dosage forms with better useful and controllable dissolution properties than the simple physical mixture, solvent cast or melt extruded samples39.

Summary

The advantages of employing electrospinning technology to prepare DDS are not as yet fully exploited. Nanotechnology is now having an impact in biotechnology, pharmaceutical and medical diagnostics sciences. Furthermore electro-spinning as noted before has gained more attention due in part to a surging interest in nanotechnology, as ultrafine fibers or fibrous structures of various polymers with small diameters40. On the other hand, electro-spinning should exert more influence on new DDS development through providing novel strategies for conceiving and fabricating them. Still several problems must be resolved for further applications such as the drug loading, the initial burst effect, the residual organic solvent, the stability of active agents, and the combined usage of new biocompatible polymers.

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Author:R.Rathinamoorthy
Publication:Pakistan Textile Journal
Geographic Code:9PAKI
Date:Feb 29, 2012
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