Advances in Topical Drug Delivery System: Micro to Nanofibrous Structures

Review Journal of Nanoscience and Nanotechnology

Copyright © 2014 American Scientific Publishers All rights reserved Printed in the United States of America

Vol. 14, 853–867, 2014 www.aspbs.com/jnn

Advances in Topical Drug Delivery System: Micro to Nanofibrous Structures Mangala Joshi∗ , B. S. Butola, and Kasturi Saha Department of Textile Technology, Indian Institute of Technology Delhi, New Delhi 110016, India This paper is a review of the latest developments in the field of topical drug delivery via which the drug is directly applied onto the skin with high selectivity and efficiency. Advances in microfiberbased medical textiles such as sutures and wound dressings, especially those containing a drug or an antimicrobial agent, have been covered briefly. A special focus is on recent developments in the area of nanofibrous drug delivery systems, which have several advantages due to their large surface area to volume ratio, high porosity and flexibility. The electrospinning technique to produce nanofibers has also been discussed with reference to latest advances such as multiple needles, needleless and coaxial forms of electrospinning. The applications of nanofibers in different areas such as wound dressing, periodontal and anticancer treatment have also been discussed.

Keywords: Sutures, Nanofibrous Webs, Topical Drug Delivery, Wound Dressings, Electrospinning.

CONTENTS 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Topical Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Topical Drug Delivery via Microfibrous Structures . . . . . . . . . . 4.1. Sutures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Wound Dressing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Topical Drug Delivery via Nanofibrous Structures . . . . . . . . . . . 5.1. Advantages of Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Electrospinning: Producing Nanofibers . . . . . . . . . . . . . . . 5.3. Advances in Electrospun Nanofibrous Systems for Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . 6. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References and Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. INTRODUCTION Advances in medical textiles and polymer science have led to the development of a variety of novel drug delivery systems. The aim is to deliver pharmaceutical agent to the action site and consequently to the systemic circulation to produce the desired pharmacological effect. The accomplishment of predictable and consistent release of an active therapeutic agent into a target site over a long period has much significant merit. It creates specific surroundings with optimal release, minimum adverse effects and long-term efficiency. Controlled drug release forms also ∗

Author to whom correspondence should be addressed.

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enhance safety, efficiency and reliability of drug therapy. Therefore, there is a need to develop suitable drug delivery systems that not only administer the active therapeutic agents to the action site without affecting healthy tissues but also release drug in appropriate amount and over prolonged periods. In a topical system, a drug is applied directly onto the skin and thus protects it from degradation during systemic circulation. Advantages of topical drug delivery systems include high efficacy with very little dose to a specific site, improving physiological and pharmacological response and patient compliance, convenience and ease of application along with the option of termination of the medication whenever required. Fibrous textile structures are popularly used in designing topical drug delivery systems such as sutures, wound dressings, bandages etc. Conventional textile fibers or filaments generally have a diameter in the micron (10–100
m) range. They are converted to different types of structures, such as monofilament or multifilament yarns, which can be twisted or braided and then converted to different fabric forms, such as woven, nonwoven and knitted. These textile structures have a wide range of properties such as flexibility, elasticity, strength, etc., and therefore are used in a variety of biomedical applications. Textiles used for medical purposes need to be non-allergic, non-carcinogenic, non-toxic, biocompatible,

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doi:10.1166/jnn.2014.9083

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flameproof, antistatic in nature and should have optimum fatigue endurance. Antimicrobial property is also one of the important attributes for medical textiles as they remain in intimate contact of human body for most of the time during use and provide congenial environment and surface required for growth of microbes, leading to infection. Recent developments in the field of nanomaterials and their possible application in a wide variety of products including nanomedicine and targeted drug delivery are evident from the current literature.1 2 Nano-biotechnology researchers are actively focused towards drug delivery at a controlled and sustained rate to the site of action using nanoparticles.3–5 Such nanoparticle-based drug delivery systems not only reduce the number of doses required but also makes the treatment a better experience with a reduction in treatment expenses. With the advent of nanotechnology, there is increased interest in nanofibers, which are typically 50–500 nm in diameter. Advantages of nanofibrous delivery systems include the possibility of delivering uniform, large and controlled doses of pharmaceutical agents at the action site as a result of high surface area to volume ratio, high porosity and high

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flexibility of the lightweight nanofibrous system as compared to conventional topical drug delivery systems based on microstructures.6

2. DRUG DELIVERY A drug is recognized as a substance, used in the diagnosis, treatment or prevention of a disease, or as a component of medication according to Federal Food, Drug and Cosmetic Act (FD&C Act). Drug delivery is the process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals.7 An optimal drug delivery system assures availability of the active drug molecule at the site of action for the appropriate time and duration. Drug concentration at the correct site must remain above the minimal effective concentration (MEC) and below the minimal toxic concentration (MTC). This concentration interval is known as the therapeutic range as shown in Figure 1. Most preferred routes of drug delivery include oral, injection, transmucosal, inhalation and topical routes.8 Oral route (through the mouth) is the most familiar route

Mangala Joshi is a Professor in the Department of Textile Technology at IIT Delhi. She is an alumnus of IIT Delhi having obtained her M.Tech. and Ph.D. degrees in Polymer Science and Technology, and she has 13 years of teaching experience in the area of fiber science and technology. Her current research interests include nanotechnology applications in textiles, polymer nanocomposites, nano-biomaterials, nanocoatings and nanofibers, bioactive and functional textiles. She is a member of a nano research group at IIT Delhi and is associated with an interdisciplinary team researching nanobiotechnology with a focus on bioactive nanocomposites.

B. S. Butola is a Ph.D. from and currently working as Assistant Professor in the Department of Textile Technology, IIT Delhi. He has around four years of working experience in the industry of melt spinning area and around 11 years’ experience in teaching and research. His areas of interest include Protective textiles, Enzymatic processing of textiles and Polymeric nanocomposites. Currently he is also working in the area of durable antimicrobial textiles and drug loaded textile structure for wound healing applications.

Kasturi Saha obtained her M.Tech. and B.Tech. degrees in Polymer Science and Engineering in India. She started her research in polymer-clay nanocomposites in 2009 under joint supervision of Professor Mangala Joshi and Dr. B. S. Butola in Indian Institute of Technology, Delhi. Her research field is mainly focusing towards wound dressing and drug delivery application employing film and nanofibrous nanocomposites.

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(e) easy to terminate the medication whenever needed (f) availability of larger application area in comparison with nasal or buccal cavity (g) delivers drug to the appropriate action site with higher selectively (h) easy route of application (i) avoid gastro-intestinal incompatibility (j) better utilization of short biological half-life drug with narrow therapeutic range (k) improves the physiological and pharmacological response and patient compliance.

Figure 1. Different ranges of drug delivery.

for drug administration.9 Another drug administration route directly into the body via the injection or infusion route is known as parenteral drug delivery. Mucosal membrane is the most important route of drug administration into the body. The gastrointestinal tract is one of the most common mucosal membranes, allowing oral drug delivery.10 Other mucosal absorption sites include buccal, sublingual, ocular, rectal, vaginal, lung and nasal. Inhalation route is an effective way of delivering medication locally to the lungs and is used extensively to treat respiratory conditions such as asthma and chronic obstructive pulmonary disease. Another preferred route of drug administration is through the skin, commonly known as topical delivery system. This drug delivery system is designed to give a local drug effect and is not exposed to systemic circulation. This will be discussed in more depth in the subsequent sections.

3. TOPICAL DRUG DELIVERY Topical drug delivery is defined as the application of a drug containing formulation to the skin to treat cutaneous disorders (e.g., acne) directly or for the treatment of any other wound and wound-related infection. This is achieved in two ways: external and internal topicals. External topicals are sprayed, spread or dispersed directly on to the cutaneous tissues to cover the affected site. However, internal topicals are applied to the mucous membrane via oral, vaginal or on anorectal route for local activity. The advantages of topical drug delivery over more popular oral route are summarized below:11 (a) avoids metabolic route (b) avoids risk and issues of intravenous medication under various situations of absorption, like changes of pH, presence of enzymes, stomach emptying time etc. (c) high efficiency using very low total daily dosage via continuous input of drug (d) avoids fluctuations in drug level and inter- and intrapatient variations J. Nanosci. Nanotechnol. 14, 853–867, 2014

Few disadvantages associated with topical drug delivery are as listed below:12 (a) Occurrence of contact dermatitis or skin irritation due to the drug and/or excipient (b) possibility of allergic reactions (c) denaturation of drug due to presence of enzyme in epidermal skin layer (d) difficulty of absorbing bigger particle size drug through the skin. Various forms of topical therapeutic agents are mostly used on wound sites for cleansing and debridement (surgical removal of foreign material and dead tissue from a wound) with antiseptic and antibacterial action. But for highly exudating wounds, topical formulating agents are not very effective in staying in contact with the wound area as it can rapidly absorb fluid, lose its rheological features and become mobile. So, new generations of medicated products with superior therapeutic value have come into play. These are active directly or indirectly either as cleansing or debriding agent for removal of necrosis tissue or as antimicrobials, which can prevent or treat infection or may also has active growth agents to assist in regeneration of tissue in the wound healing process.

4. TOPICAL DRUG DELIVERY VIA MICROFIBROUS STRUCTURES The two most common examples of topical drug delivery products are medicated sutures and wound dressings where microfibrous structures are used. 4.1. Sutures Currently used suture materials are mainly polymeric in nature. The ideal suture should be strong in nature, able to form a secure knot and should be easy to handle.13 14 Moreover, it is important that it causes minimal tissue inflammation and infection. Additionally it must be capable of stretching up to a certain length, accommodate wound edema and undergo recoiling to the original length along with contraction of wound. Sutures are generally made from synthetic or natural micron-sized polymeric fibers. Sutures are either monofilament, multifilament or braided textile structures made up of non-biodegradable polymers (non-absorbable) or biodegradable polymers 855

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(absorbable). The common methods for manufacturing sutures are: wet spinning, dry spinning, melt spinning and gel spinning.15–18 The current trend in direction of developing bioactive surgical and radioactive sutures has been covered in detail. A recent research activity reports fabrication of drug-loaded sutures via blend or coaxial electrospinning.19 Antimicrobial surgical sutures, with the antibiotics embedded in their structure, are utilized for treatment of operative sepsis. Sutures with anesthetic and anti-cancerous properties are also important. Antibiotics (clindamycin, gentamycin, lincomycin etc.), anesthetics (lidocaine, novocaine, trimecaine and pyrocaine), proteolytic enzymes (tripsin and pepsin) and anti-tumor medications (prospydin, 5-fluorocyl, sarcolysin, etc.) have been incorporated into sutures to meet specific requirement.20 Antimicrobial agents such as Triclosan have been added in some sutures i.e., Monocryl Plus, PDS Plus and Coated Vicryl Plus to impart additional antimicrobial functionality to the suture material.21 Radioactive surgical suture is another modern kind of biologically active fiber that can act by the emission of ionizing irradiation from radioactive isotopes settled in its structure.22 Isotopes of sulphur-35 emitting soft betarays and phosphorus-32 isotopes emanating much harder rays have been incorporated in polypropylene, polyamide, polyvinyl alcohol and polyethylene terephthalate fibers by strong covalent bonds and can be used as radioactive surgical sutures. This kind of suture has found an application in treating advanced malignancy of the head and neck and also in ophthalmology.23 24 4.2. Wound Dressing Dressing is a material applied onto a wound with or without medication, to give it protection and also assist in healing. An ideal wound dressing should have the ability to: (a) absorb exudates and toxic substances from wound site (b) maintain sufficient humidity at the interface of wound and dressing (c) provide gaseous permeability (both water vapor and air) (d) allow thermal insulation (e) protect the damaged site from penetration of microorganisms (f) should be non-toxic and non-traumatic in nature.25 26 Other assessed parameters desired are (a) it must have satisfactory handling qualities; i.e., should be tear-resistant and should not disintegrate in both wet and dry conditions (b) should be comfortable and sterilizable (c) cost effectiveness (needing low frequency of dressing change). Wound dressing materials are placed in the physiological and biological environment of a wound. 856

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4.2.1. Classification Dressings are categorized into primary, secondary and island dressings.27 Primary dressings remain in physical contact with the affected site while secondary dressings lead to complete coverage of the primary dressing, such as adsorbent pad or bandage. Island dressing consists of a central absorbent region that is further encircled by an adhesive component. Another route of classification includes Passive, Interactive and Bioactive dressings.28 29 Passive dressings only provide coverage over the wound site; e.g., gauze and tulle dressings. Interactive dressings comprising various polymeric forms are largely transparent, can permeate water vapor and oxygen, but are impermeable to bacteria, e.g., hydrogels, hyaluronic acid or foam dressings. Bioactive dressings deliver active components needed for wound treatment, e.g., hydrocolloids, alginates, collagens, chitosan, etc. 4.2.2. Advances in Wound Dressing Various forms of wound dressing available for topical drug delivery are film, foam, fibrous, particulate and gel.30–34 Table I summarizes the various topical wound dressings commercially available in the market. However, current trends in development of natural polymer-based as well as bioactive wound dressing is being discussed in detail in the following sections: 4.2.2.1. Natural Polymer Based Dressings. Naturally occurring materials such as alginates and chitins, the main members of the polysaccharide group are becoming popular in making fibrous dressings. These dressings are generally hydrophilic (absorptive) in nature and suitable for the treatment of bleeding wounds. Alginate dressings in fibrous forms are derived from alginic acid salts obtained from algae Phaeophyceae found in seaweed. Their best use is for moderate to heavily exuding wounds. This dressing is haemostatic, hydrophilic (absorbs up to 20 to 30 times its weight) and non-traumatic in nature.35 It provides a moist environment that leads to rapid granulation and reepithelialization helping in the wound healing process.36 Curasorb® , Nu-Derm® etc. are commercially available alginate-based wound dressings.32 Chitin is a polymeric N-octyl-D glucosamine, one of the main constituents of the skeletal substances of crustaceans and insects. Chitin non-woven fabric has been directly used as a dressing exhibiting excellent property with respect to pain relief, wound adherence and drying without dissolution even in cases of deep dermal burns that contain a large number of exudates.32 This dressing is effective for treatment of superficial burns, relief of pain and epidermalization, and also provides effective barrier against bacterial infection.37 38 The dressing is also applicable as a mesh or patch for skin grafting with good adhesive quality. 4.2.2.2. Bioactive Dressings. Infection and bacterial colonization is the most important factor in delayed J. Nanosci. Nanotechnol. 14, 853–867, 2014

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Table I. Commercially available topical wound dressings.

Type Film

Commercial name Op-Site® Tegaderm® Bioclusive® Omiderm® Mitraflex® Topkin®

Dressing material Polyurethane

Biodegradable lactide-caprolactone copolymers

Oprafol® Lyofoam® Allevyn® Hydrosorb® Sof-Foam® Tielle® Biopatch® Fibrous Curasorb® Nu-Derm® Particulate Debrisan® Avalon® Intracell® Gel Intrasite® Tegagel® Others Cutisorb® Foam

Polyurethane

Calcium alginate

Dextranomer beads Dextranomer flakes Dextranomer powders Carboxymethylcellulose Alginate Multi-layered pad containing polyester, viscose and cotton Collatamp G® Gentamicin/Collagen Sponge Iodosord® and Cadexomer matrix or gel Iodoflex® containing Iodine Acticoat®

Multilayered silver coated dressing

Manufacturer Smith & Nephew 3M Health Care Johnson & Johnson Latro Medical BritCair Biomet, Europe

References

Burn wound treatment, Post-operative wounds and Minor injuries including abrasions and lacerations

[30]

Lohmann and Rauscher, Germany Conva Tec Leg and decubitus ulcers, Burn injury, initial wound treatment, Smith & Nephew catheter-related blood stream Wound Care Products, Avitar Inc. infections Johnson & Johnson Johnson & Johnson Johnson & Johnson Kendall Treatment of bleeding wounds Johnson & Johnson Johnson & Johnson Treatment of exuding wound Summit Hill Laboratories Macleod Pharmaceuticals Smith & Nephew Leg ulcers and Pressure sores 3M Health Care BSN Medical Ltd. Sutured wounds, abrasions, lacerations and minor burns Schering-Plough Corporation Surgical wound infection Smith & Nephew Venous ulcers, pressure sores, diabetic foot ulcers and traumatic surgical wounds Smith & Nephew Protect the wound from invasive pathogens

wound healing. Hence antimicrobial dressings containing certain antibiotics or antiseptics are important for infection control as well as in promoting topical wound recovery or healing. Antibiotic eluting wound dressings are able to provide tissue compatibility, resistivity to bacterial contamination with minimum interference during the wound healing process.39 Cutisorb® is one of the commonly used cotton wool dressing containing the antibiotic dialkylcarbamoylchloride. Other antibiotic eluting wound dressings are collagen sponges containing gentamycin (Collatamp G® , Schering Plough), silicone gel sheets containing ofloxacin, gentamicin impregnated PMMA beads and collagen dressings impregnated with amikacin drug.40–42 Some other novel antimicrobial dressings reported in literature are freeze dried fibrin discs for the delivery of tetracycline, lactic acid polymer for the delivery of ofloxacin and the dressing containing chlorohexidine (Biopatch® , Johnson & Johnson) which is commercially available.43–45 Wound dressing containing iodine gets hydrated in a moist environment followed by the release of elemental iodine, which is effective in the inflammatory phase of wound healing due to its antibacterial effect. Commercially available iodine based dressing are—Iodosord® , which is J. Nanosci. Nanotechnol. 14, 853–867, 2014

Use

[31, 45]

[32] [33]

[34] [39] [40] [46]

[47]

manufactured from crosslinked polymerized dextran, and Iodoflex® , where iodine is released in a slow manner (from Smith & Nephew, Hull, UK).46 PRN® (from PRN Pharmacal, Pensacola, FL) is a povidone iodine powderbased bioactive dressing. Another effective antimicrobial gauze dressing, Kerlix® (from Tyco Health Care Kendall, Mansfield, MA) containing polyhexamethylene biguanide (PHMB) with a broad range of antimicrobial activity has been commercialized. Silver is being widely used in wound dressings because of its antibacterial characteristics as silver toxicity to microorganisms is well established. Silverlon® (from Argentum, Lakemont, GA); Acticoat® (from Smith & Nephew, UK); Actisorb® Silver 220 (from Johnson & Johnson Products Inc., New Brunswick, NJ) etc. are commercially available silver-based antibacterial wound dressings. The factors like distribution of silver in the dressing, its chemical and physical nature and moisture affinity influences the antibacterial activity of silver of the dressing.47 Activated charcoal encased into nylon sleeve has also been used in antimicrobial dressings. Absorption was believed as the mechanism responsible for the reduction of bacteria onto the activated charcoal component.48 Commercially available charcoal dressings are Activate® (from 857

Advances in Topical Drug Delivery System: Micro to Nanofibrous Structures

3M Center, St. Paul, MN); Actisorb® (from Johnson & Johnson Products Inc., New Brunswick, NJ); CarboFlex® (from ConvaTec Ltd, USA) and Lyoform® (from Seton Healthcare Group plc, Oldham, UK).49 Suggested advantages of these activated dressings are: they provide a moist atmosphere needed for autolytic debridement, effectively prevents bacterial colonization via absorption, prevent the growth of granulating tissue and minimizes the wound odor.

5. TOPICAL DRUG DELIVERY VIA NANOFIBROUS STRUCTURES 5.1. Advantages of Nanofibers Electrospun nanofibers exhibit interesting characteristics; e.g., high surface area and flexibility for surface functionalization; at the same time the as-spun fibrous mat exhibits high porosity with pore size in sub-micrometer length scale.50 Therefore, the overall drug release from the nanofibrous web is much higher than that of bulk films. Electrospun mats also demonstrate a good combination of mechanical and physical properties with controlled release of antibiotic drug from the porous binding matrix and are also able to prevent bacterial colonization and infection.51 52 Specific degradation characteristics and adjustable drug delivery profile by variation of fiber characteristics make the nonwoven nanofibrous mat a potent drug delivery route as compared to polymeric films and particles. These unique properties make electrospun fiber mats as excellent candidates for the potential use in biomedical field such as tissue engineering, DNA delivery and drug delivery systems.53 Nanofibrous systems used directly as wound dressing show controlled evaporative water loss, excellent oxygen permeability and promote fluid drainage ability. Nanofibrous non-woven mat was also found to be useful for preventing post-surgery-induced abdominal adhesion. Maximum benefit is achieved when the release of an antibiotic is conjugated with the nanofibrous barrier. Recent studies report that nanofibrous web in combination with drug release therapy is useful for specific application, such as anticancer treatment via the topical application route.53 The nanofibers have several advantages as compared to other microsystems for applications in wound dressing as listed below:54 Hemostasis: This is the first stage of wound healing and plays a protective role. Small diameter nanofibers with a large effective surface area can promote a hemostasis phase by absorbing the maximum amount of wound exudates without using any additional hemostatic agent during topical application. Absorbability: Nanofibers with high surface area to volume ratio are able to absorb and retain extremely large amounts of a liquid relative to their own mass. Nanofibrous dressings exhibit water absorption in the range of 18–213% as compared to conventional film dressings which show only limited water absorption of around 2–3%.55 858

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Semi-permeability: A semi-permeable nanofibrous structure allows selective permeation of fluids or gases through it but acts as a barrier to others (e.g., bacteria). High porosity of a nanofibrous web is ideal for the cell respiration and it also appropriately controls the moist surroundings suitable for the wound healing. Moreover, small pore size can efficiently protect the affected site from any bacterial infection. Conformability: Conformability, defined as the ability to conform to the actual shape of the wound, is one of the characteristics related to the flexibility and resiliency during topical application. According to theory of textile structures, the fabric conformability is directly associated with the fiber fineness.56 Finer fabrics can fit easily around the complicated three-dimensional contours. Therefore, ultrafine fibers are able to furnish excellent conformability, better coverage and maximum protection against bacterial contamination suitable for the topical application. Surface modification: Modification of electrospun fibers by incorporating therapeutic compounds is mainly accomplished by post processing routes via conjugating active molecules onto the nanofibrous surface.57 Various surface modification techniques to make polymeric nanofibers suitable for drug delivery application are plasma treatment, wet chemical method and graft polymerization. Coelectrospinning is another route in which surface active agents are integrated into the dope used for spinning. Active compounds including pharmaceutical agents such as antiseptics, antifungal and vasodilators that cause dilation of blood vessels, etc., can be incorporated into the nanofibrous system depending on the treatment route and specified role of the active agents. Other active additives integrated into nanofibrous structures are the growth factor proteins that are involved in cell differentiation and growth, and other cells like keratinocytes which constitute 95% of the cells in the outermost epidermis layer of human skin. Further, to achieve multi-functionality (allin-one wound dressing), medication and growth factors together can be incorporated into single blended layer via electrospinning, which helps to avoid use of commercial dressings with a multilayered configuration. This contributes to extra benefits such as cost reduction and cutting down frequency of change in the dressing that otherwise hinders the regeneration of neotissues. Scar-free: Nanofibers also promote wound healing without leaving any scar marks. For example, they assist in the growth of normal skin without any scarring due to good cell connectivity.57 They also facilitate blood and tissue compatibility that in turn leads to healing and regeneration of skin and provides better road map to skin cells for self-repair. 5.2. Electrospinning: Producing Nanofibers With emerging new areas of nanoscience and nanotechnology, electrospinning has generated a lot of interest in J. Nanosci. Nanotechnol. 14, 853–867, 2014

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producing nanofibers not only on the laboratory scale but also for mass production of continuous nanofibers from various polymers. This process of using electrostatic forces to spin fibers was first patented by Formhals in 1934 and later developed by Reneker et al. of University of Akron, USA.58 59 A number of synthetic polymers; e.g., nylon, polyester, polyacrylonitrile, cellulose acetate, polyurethane, polycaprolactone, poly(lactic acid) as well as natural polymers; e.g., chitin, collagen, silk fibroin, etc. have been used to produce nanofibers through electrospinning.60 61 In last decade, there has been significant progress in the development of electrospinning technology, such as producing nanofibrous webs at a faster rate or making modifications in spinneret design to make different morphology (coresheath, hollow fibers or side-by-side) structures. A brief overview of these developments is given in the following section. (i) Depending upon the nature of the precursor, electrospinning process can be subdivided into solution and melt electrospinning. In solution electrospinning, a polymer solution is held at the end of a capillary tube by surface tension which is further subjected to an electric field. When the electric field reaches a critical value, a charged jet of solution is ejected from the tip of the Taylor cone and continuous fibers are collected onto the grounded collector. In melt electrospinning, instead of solution, a polymer melt is introduced into the capillary tube and spun into nanofibers. Unlike for solutions, the electrospinning process for a polymer melt has to be performed under a vacuum. Advantages associated with this process are high throughput rate, no need to eliminate harsh organic solvents and easy preparation of nanofibers from those polymers that do not have appropriate solvents at room temperature such as Polypropylene, Polyethylene etc. (ii) Depending upon the feed system and its distribution manner, the electrospinning system can be categorized into confined or unconfined feed systems.62 Confined feed system (CFS) includes a syringe and a syringe pump which can control the flow rate for stable electrospinning. But clogging of the electrospinning setup is the main drawback of this system. This system can be further subdivided into needle or needleless systems. In conventional single needle electrospinning (SNE), one single jet is formed during the application of electrostatic force. Apart from this, multi-jets from the single needle are formed when the polymeric jet undergoes interaction with the broad electrostatic field.63 Multi-jet formation has been attributed either to discrepancy in electric field distribution or occurrence of solution blockage at the needle tip. There are several reports on multiple needle electrospinning (MNE) systems in which needles are designed either in a linear or two dimensional arrays such as elliptical, triangular, square or hexagonal.64 65 Work has also been reported to increase the productivity of electrospinning process J. Nanosci. Nanotechnol. 14, 853–867, 2014

using needleless arrangement.66 In this system, when the electric field intensity reaches a threshold value, multiple jets from the free liquid surface eject onto a grounded collector. Successful commercialization of this process has been done by Elmarco Company’s “NanospiderTM .” In case of unconfined feed system (UFS), flow of the polymeric melt or solution over the surface of another material is unrestricted in nature.67 This system includes bubble electrospinning, electroblowing, roller electrospinning, electrospinning from porous hollow tube and microfluidic manifold.68–72 Advantage of the unconfined system is the ability to form more jets without using any fine engineered parts which require maintenance.62 But this kind of electrospinning leads to the formation of larger diameter fibers with a broad distribution. (iii) Depending upon the spinneret modification and solvent evaporation rate, electrospun bicomponent nanofibers can adopt either a core–shell, porous, hollow or side-byside structure. In coaxial electrospinning, one solution is injected into another at the tip of the spinneret.73 If the two solutions are immiscible in nature then a core–shell structure is formed. However, miscible solutions are reported to form porous morphology due to phase segregation during solidification of the nanofibers. Emulsion electrospinning is another way to form continuous core-sheath fibers if the volume fraction of inner fluid in the emulsion droplet is sufficiently high.74 Hollow fibers can also be produced by using coaxial spinneret. Core sheath fibers can be transformed into hollow fibers by extracting the core using an appropriate solvent.75 Side-by-side bicomponent fibers are fabricated by using dual-opposite-spinneret electrospinning.76 5.3. Advances in Electrospun Nanofibrous Systems for Drug Delivery In the following section various ongoing research activities both in the academia as well as in the industry related to topical drug delivery are discussed, focusing mainly on release kinetics and area of application. Various modified fabrication techniques are also taken into account so as to improve the site-specific drug delivery with high efficiency. 5.3.1. According to Release Kinetics The main advantage of solution electrospun nanofibrous system is the deliberate avoidance of melt processing route that is not suitable for heat-sensitive drugs. It also minimizes the immediate burst release of a drug as observed in conventional topical drug delivery forms based on microfibrous structures. The drug-release pattern (controlled, burst or sustained) from polymeric system is related to fiber diameter, efficiency of drug loading, drug–polymer compatibility, polymer degradation rate, addition of surfactants and polymer biodegradability. 859

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The release rate of drug from electrospun ultrafine fiber mat depends upon the immersion time, molecular weight of the drug, nature of drug (hydrophobic or hydrophilic) etc. Other release controlling factors are drug solubility in the polymer matrix and medium of testing, swelling ability and solvability of the polymeric matrix in the eluting medium, drug diffusion rate from the matrix, etc.77 Peng et al. studied in vitro paracetamol release profiles for biodegradable poly(d,l-lactide) and poly(ethylene glycol)-co-poly(d,l-lactide) electrospun nanofibrous mats.78 The results indicate an initial burst release which depends on drug–polymer compatibility whereas sustained delivery which follows is related to the polymer degradation behavior. Paracetamol release and matrix degradation of poly(d,l-lactide) nanofiber was studied by Xiaohong et al.79 Larger diameter fibers exhibited a zero-order kinetic profile for a longer period and a higher concentration of drug encapsulation was also responsible for initial burst release after initial incubation in the phosphate buffer solution. Nanofibrous mat showed no molecular weight decrease while remarkable mass reduction was found in small and medium-size fibers due to surface erosion. Release of tetracycline hydrochloride drug from electrospun poly(lactic acid), polyethylene-co-vinylacetate and their blends (50:50) was first examined by Kenawy et al.80 The release pattern showed continuous release for up to 120 days of the examination. Zhiwei et al.81 loaded tetracycline or chlorotetracycline in poly(D,L-lactide) by electrospinning and demonstrated that electrospun fibers exhibited controlled drug delivery. Kanawung et al.53 investigated the delivery of diclofenac sodium and tetracycline hydrochloride from polycaprolactone and poly(vinyl alcohol) nanofibrous mats. Drug release was increased in a monotonical way with increasing submerging time and exhibited constancy at long immersion times. Zong et al.82 fabricated bioabsorbable amorphous poly(D,L-lactic acid) and semi-crystalline poly(L-lactic acid) non-woven membranes containing Mefoxin antibiotic by electrospinning. Initial burst drug release due to the concentration gradient was observed, which is useful for prevention of post-operative infection because most infections occur within the first few hours after surgery. Kim et al.83 confirmed the controlled release of a hydrophilic antibiotic Mefoxin® from electrospun nanofibers composed of poly(lactide-co-glycolide) (PLGA) and poly(ethylene glycol)–poly(L-lactic acid) (PEG-b-PLA). Ketoprofen, a non-steroidal anti-inflammatory drug (NSAID) release was studied by Kenawy et al.84 Fibers were derived either from biodegradable polycaprolactone or non-biodegradable polyurethane polymer or from the blending of the two. Results indicate that release rates from all the systems are almost similar. In another study, release of ketoprofen from partially and fully hydrolyzed electrospun poly(vinyl alcohol) fibers showed that upon the treatment of electrospun PVA with methanol, the initial 860

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burst release was eliminated.85 Geert et al. also prepared water-soluble polymers; i.e., hydroxylpropylmethylcellulose (HPMC) based nanofibers with poorly water-soluble drug, itraconazole by electrospinning.86 Here, complete and controlled release of drugs was achieved. 5.3.2. According to Application Area Recent ongoing research activities aim to develop electrospun ultrafine fibers containing drug formulations, which can be used as potential drug carriers for wound dressing applications, periodontal disease and anticancer treatment. One advantage of using the drug-loaded nanofibers includes a biomaterial with nanoscale dimension and optimum porosity that can be designed for desirable drug delivery.87 Katti et al. studied electrospun biodegradable polymer poly(lactide-co-glycolide) (PLGA) with cefazolin, a broad spectrum antibiotic.88 This system shows potential as antibiotic delivery system for the treatment of wound. Geert et al. applied electrostatic spinning for incorporating poorly water-soluble drug, itraconazole and ketanserin into nonbiodegradable segmented polyurethane (PU) nanofiber mainly used in topical drug delivery and wound healing.89 Itraconazole was released as a linear function of the square root of time, suggesting Fickian kinetics with no initial burst release. For ketanserin, a biphasic release pattern with two sequential linear components was observed. In another study, Bolgen et al. performed in vivo studies to examine nanofibrous drug delivery system for intra-abdominal treatment.90 Both ornidazole (active antibiotic against anaerobic intestinal bacteria) and biteral antibiotic were embedded into biodegradable polycaprolactone by simply dropping antibiotic solution onto the membranes. They reported that due to the combined synergistic effect of membrane and the antibiotic, the healing process becomes better and faster. Supaphol et al. successfully prepared ultra-fine fiber mats of cellulose acetate comprising of four model drugs, i.e., naproxen, indomethacin, ibuprofen and sulindac by electrospinning.77 Mats of poly(vinyl alcohol) nanofibers with four different types of non-steroidal anti-inflammatory drug with variable water solubility; e.g., sodium salicylate, diclofenac sodium, naproxen, and indomethacin were also developed by them for transdermal drug delivery systems.91 Results indicate that with an increasing molecular weight of a drug, the rate and amount of drug release decreases. Also the drug-loaded mats exhibited better release characteristics as compared to solvent cast films due to a high porosity of the electrospun nonwoven mats. Khil et al. reported that electrospun polyurethane (PU) membranes are useful as wound dressing material because it is able to absorb wound exudates well, as it does not accumulate under the covering and does not lead to any type of wound desiccation.92 93 Histological examination suggests that the epithelialization rate is increased when wounds are covered with nanofibrous PU membrane. J. Nanosci. Nanotechnol. 14, 853–867, 2014

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Natural biopolymers such as chitosan, collagen, and silk fibroin are also being used in combination to make nanofibrous mats. These natural polymeric materials are reported to have inherent properties helpful in wound dressing.94–96 Chitosan, a natural polysaccharide derived from chitin provides bacteriostatic and fungistatic activities. It therefore finds use in various biomedical applications, such as surgical sutures, drug delivery carriers, bone healing and wound dressing materials, etc. It is able to speed up healing of wound injury by accelerating the fibroblastic generation via collagen, promotes hemostasis phase and achieve natural tissue regeneration. Due to the abovementioned reasons, chitosan in membrane form is currently considered as one of the most efficient biomaterials for wound healing.97 Other reported electrospun drug delivery systems using chitosan nanofibrous membranes include a chitosan-polyvinyl alcohol blend with a nanofibrous membrane, biocompatible carboxyethyl chitosan/poly(vinyl alcohol) composite membrane, blended chitosan and silk fibroin nanofibrous membrane, chitosancoated poly(vinyl alcohol) nanofibrous matrix, etc., which can be directly used as a wound dressing material.98–101 In another study, Chen et al. fabricated composite nanofibrous membranes (NFM) composed of collagen and chitosan by electrospinning.102 Use of these membranes promoted wound curing and induced migration and proliferation phase. NFM are also able to attract fibroblasts cell to the dermis layer, which can egest extracellular components, such as collagen, growth and angiogenic factors to repair the injured tissues. Liu et al. reported that nanofibrous PLGA/collagen membranes were effective in response to human fibroblasts functionally and also act as early stage wound-healing accelerators.103 There are some reports of herbal extracts and antimicrobial peptide being introduced in nanofibers which help in wound management and drug delivery.104 Recently Supaphol et al. studied release characteristics of Centella asiatica herbal extract which is familiar for its wound healing ability from electrospun gelatin fibers.105 According to the unit weight of wound-healing agent present in the samples, total amount releasing from the film was higher than the fiber mat; whereas depending upon the unit weight of the sample, an inverse trend was noticed. Another study reports the performance of electrospun hyperbranched polyglycerol nanofibers containing Calendula officinalis as a wound-healing and anti-inflammatory agent suitable for wound dressing applications.106 Other than suture or wound-dressing applications, electrospun nanofibrous systems are also efficient in facilitating targeted drug delivery for treatment of cancer cells. Xie et al. developed Poly(lactide-co-glycolide) based microfibers and nanofibers which are suitable for sustained release of anticancer drug (paclitaxel) for treating brain tumors.107 Zeng et al. studied electrospun mats containing paclitaxel (lipophilic anticancer drug), doxorubicin hydrochloride (hydrophilic drug with antitumor J. Nanosci. Nanotechnol. 14, 853–867, 2014

activity) and doxorubicin base (lipophilic in nature) as model drugs. Release of drugs followed zero-order kinetics with no burst release, along with degradation of PLLA fibers in the presence of enzyme proteinase K added as a lyophilized powder.108 In another study, anticancer drug doxorubicin hydrochloride was electrospun in a solution of poly(ethylene glycol)–poly(L-lactic acid) copolymer (PEG–PLLA) with homogeneous distribution of the anticancer agent within the nanofiber.109 Results indicate that the initial burst release was diminished in case of water-in-oil emulsion electrospun fiber as compared with the suspension electrospun nanofibers. Here release kinetics followed a combined mechanism of diffusion and enzymatic degradation. Chen et al. studied the potential application of blends of nano-TiO2 and PLA nanofibers with the anticancer drug doxorubicin to facilitate efficient delivery in targeted cancer cells.110 Another drug, 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) was encapsulated in PEG–PLLA diblock copolymeric fibers by Xu et al. to treat malignant glioma. Drug release from the fibers was dependent on the initial drug-loading and primarily followed a diffusion route.111 Zing et al. studied the effect of addition of three types of surfactants (anionic, cationic, and nonionic) into poly(L-lactic acid) electrospun fibers.112 These surfactants were able to reduce the diameter size (from 4.2
m to 0.5
m) and distribution of ultrafine fibers. For this study, Rifampin (tuberculosis drug) and paclitaxel (anti-cancer drug) were employed as model drugs. The drugs were released constantly from fibers with no initial burst release associated with degradation of such ultrafine fiber mats. This study thus established that the nanofibrous nonwoven mat is superior to polymer films and particles as a potential drug delivery system for cancer treatment. Maedeh et al. successfully electrospun PCL nanofibers containing metronidazole benzoate (MET), which is useful for periodontal disease treatment.113 Sustained release of drug through the nanofibers was achieved for at least 19 days with a low burst release, which could be an ideal treatment period for periodontal diseases. 5.3.3. According to Different Morphology via Modified Electrospinning Electrospinning is a versatile method for generating monolithic fibers from a variety of polymers. In addition to the conventional single needle electrospinning, various other modified electrospinning techniques such as coaxial, blend, emulsion and sequential electrospinning have been studied for controlled drug delivery applications. Core–shell nanofibers are able to minimize burst release effects whereas blend fibers are able to prevent bacterial colonization and infection due to initial burst release. Also advanced multi-drug therapy with specific application is achieved either by emulsion or sequential electrospinning. 861

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Table II. Comparative chart of various single polymeric nanofibrous forms for topical application. Polymer

Solvent

Drug

Form

Release profile

Remarks

Poly(lactideco-glycolide) (PLGA)

Tetrahydrofuran and Dimethyl formide

Cefazolin, (broad spectrum antibiotic)

Biodegradable nonwoven nanofiber

Poly(L-lactic acid) (PLLA)

Chloroform and Acetone

Lipophilic drugs: Rifampin and Paclitaxel; Hydrophilic drug: Doxorubicin hydrochloride

Ultrafine Zero order nonwoven fiber kinetics indicate constant release with no initial burst release

Poly(L-lactic acid) (PLLA)

1,1,1,3,3,3Tetracycline Hexafluorohydrochloride 2-propanol (antibiotic drug)

Poly(D,L-lactide) Chloroform (PDLLA) and Methanol

Not mentioned

Core-shell fibre Sustained release by co-axial and from blend fiber by core–shell blend fiber and burst electrospinning release from blend fiber

Tetracycline and Nanofiber web Chlorotetracycline (antibiotic)

Controlled

Poly(D,L-lactide) Acetone and Paracetanol (PDLLA) Chloroform

Fiber mat

Polyvinyl alcohol Methanol and (PVA) Water

Ketoprofen

Biodegradable nanofiber

Poly(vinyl Water alcohol) (PVA)

NSAID: Sodium Ultrafine fiber mat SS exhibits burst salicylate (SS) release but (water soluble), others follow Diclofenac sodium monotonous (DS) (sparingly increase with water soluble), immersion Naproxen (NAP) time and and Indomethacin become level (IND) (both water at long insoluble) immersion time NSAID: Naproxen Ultrafine fiber mat Drug to release • Absence of drug (NAP) from matrix aggregates on the fiber Indomethacin maintaining surface indicated well (IND) Ibuprofen the following encapsulation of drugs (IBU) Sulindac order: within the fibers (SUL) IBU > NAP > • Smaller the difference in IND > SUL solubility parameters between the drug and polymer, greater is their miscibility and lower is the drug release mainly occur by diffusion

Celluloce acetate Acetone/N ,N (CA) dimethylacetamide (DMAc)

862

Burst release followed by sustained release Controlled

• Used as antibiotic delivery systems • Drug loading caused an increase in nanofiber diameter • Addition of surfactants can reduce diameter size and distribution of electrospun fibers • Rifampin and Paclitaxel compatible with PLLA but phase separation takes place in case of Doxorubicin hydrochloride • Blend fibers showed smaller diameter whereas core–shell fibers showed larger average diameter • Core–shell fiber suitable for releasing the growth factor or therapeutic drugs but blend fiber useful to prevent bacterial infection • Different in vitro release profiles and swelling behaviors showed different drug release mechanisms • Choice of solvent system used to control the drug release • Degradation behavior and drug release kinetics related with variation of fiber characteristic • Release medium with higher temperature showed higher release rates • Methanol treated mats showed lower release than untreated ones • Electrospinning did not alter the chemical integrity of the drugs • Drug release rate and amount decreasing with increasing molecular weight of the drug

Application

Ref.

Wound treatment

[88]

Clinical application

[112]

Tissue [115] suturing and tissue regeneration applications

Biomedical application

[81]

Drug delivery

[79]

Drug delivery

[85]

Transdermal drug delivery system

[91]

Management of painful and inflammatory conditions

[77]

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Table II. Continued. Polymer

Solvent

HydroxypropylEthanol and methylcellulose Methylene (HPMC) chloride

Polycaprolactone (PCL)

Segmented polyurethane (PU)

Drug Itraconazole (poorly water soluble)

Chloroform, Resveratrol Ethanol and (antioxidant) Water and Gentamycin Sulfate (antibiotic) Dimethyl Itraconazole formide and (antifungal Dimethyldrug) and acetamide Ketanserin (acute renal failure drug)

Form

Release profile

Nonwoven fabric

Complete and controlled in vitro release over time

Application

Ref.

• Complete release of poorly Wound [86] water soluble drugs achieved healing, • Rate of drug release buccal and controlled by drug/polymer topical ratio, nanofiber diameters application and the presentation used Bioabsorbable Sustained • Finer and beadless fiber Functional [114] doubleresults in better mechanical dressing for layered performance wound ultrafine • Degradation and release rate healing core–shell of the fiber correlated with fiber the drug hydrophilicity Non• Fickian kinetics • Release of poorly Topical drug [89] biodegradable without any water-soluble drugs achieved administranonwoven burst release from water-insoluble tion and fabric • Biphasic release polymer wound with initial • Drug release controlled by healing burst release drug/polymer ratio and fiber morphology

In summary, by controlling the morphology and mode of encapsulation of electrospun nanofiber, appropriate drug release pattern can be achieved. Huang et al. incorporated drugs like Resveratrol (antioxidant) and Gentamycin Sulfate (antibiotic) separately in biodegradable polycaprolactone nanofibers via coaxial electrospinning.114 Polymer was used as the shell and two medically pure drugs were used as the core. Release pattern of both type of drugs exhibited a sustained nature with no initial burst release. Chuang et al. employed blend and coaxial electrospinning to fabricate poly(L-lactic acid) (PLLA) fibers containing tetracycline hydrochloride as a model drug for suture application.115 Coaxial electrospinning resulted in core–shell structure with uniform fiber morphology and homogeneous drug distribution throughout the core of the fibers. Tiwari et al. investigated release profile of various monolithic polymeric fibers such as PCL, PVA, PLGA and PLLA and core–shell fibers such as PCL, PLLA and PLGA by electrospinning.116 Metoclopramide hydrochloride (a dopamine receptor antagonist with antiemetic and prokinetic characteristics) was used as a model drug for this study which reports that control release was achieved in coaxial electrospun core–shell fibers with better preservation of drug’s activity as compared to monolithic fibers. In contrast to that, bead-like fibers with a heterogeneous drug distribution were observed in the blend electrospun fibers. The core–shell threads provide a sustained release suitable for the release of the growth factor or another therapeutic drug.117 However, the blend fibers exhibited initial burst release, which is useful to prevent bacterial infection. In another study Xu et al. loaded paclitaxel (PTX) and doxorubicin hydrochloride (DOX) as model drugs into PEG–PLA mats by emulsion electrospinning.118 Hydrophilic DOX diffuses out at a faster rate from the J. Nanosci. Nanotechnol. 14, 853–867, 2014

Remarks

fibers than hydrophobic PTX. In vitro cytotoxicity against rat C6 cells suggested that a dual drug combination imposed a higher rate of inhibition against C6 cells rather than a single drug-loaded system. Modified electrospinning was used by Wagner et al. for synthesis of elastomeric, fibrous composite sheets with two distinguishable submicrometer fibers.119 In this study, the tetracycline hydrochloride drug was embedded into poly(lactide-coglycolide) with sustained in vitro antibacterial activity in the presence of biodegradable poly(ester urethane) urea, which gave it strength. Here, one component is delivering the antibiotic release profile while the other is providing the mechanical properties suitable for practical application. Tatsuya et al. demonstrated drug delivery via a single formulation tetralayered meshes through sequential electrospinning.120 Chromazurol B and 5,10,15,20-tetraphenyl-21H, 23H-porphinetetrasulfonic acid disulfuric acid (TPPS) were utilized as model drugs, embedded into distinguishable meshes of biodegradable polymer, poly(L-lactide-co--caprolactone). The sustained timeprogrammed dual delivery system was useful for advance multidrug therapy with a regiospecific local application of various drugs at different times, especially in sequential chemotherapy. In another study, Dario et al. fabricated poly(lactic-co-glycolic acid) meshes loaded with retinoic acid by electrospinning.121 Retinoic acid has been proposed for the treatment of human malignant gliomas as well as epithelial and hematological malignancies. In this study biocompatibility of retinoic acid and advantages of electrospun mesh gets combined to enhance the mass transfer features of the controlled release system. All the recent developments regarding single and multi-polymeric nanofibrous forms for topical drug delivery applications are summarized in Tables II and III respectively. 863

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Table III. Comparative chart of various multi-polymeric nanofibrous forms for topical application. Polymer

Solvent

Poly(lactic acid) Chloroform (PLA) and and Poly(ethylene-coMethanol vinyl acetate) (PEVA)

Drug

Form

Tetracycline Nonwoven hydrochloride fabric sheet (antibiotic)

Poly(lactide-coDimethyl Mefoxin® , Biodegradable glycolide) formide (hydrophilic nonwoven (PLGA) and antibiotic) nanofibrous diblock scaffolds copolymer (PEG-b-PLA) Poly(d,l-lactide) Acetone Paracetanol Fiber mat (PDLLA) and (analgesic poly(ethylene and glycol)-coantipyretic) poly(d,l-lactide) (PELA) Poly(ester urethane) 1,1,1,3,3,3Tetracycline Biodegradable urea (PEUU) and Hexafluorohydrochloride fibrous Poly(lactide-co2-propanol (antibiotic) composite glycolide) sheet by two (PLGA) stream electrospinning Poly-l-lactide Chloroform, Metoclopramide Core–shell and (PLLA) Dimethyl hydrochloride monolithic Polycaprolactone formide and (dopamine electrospun (PCL) Water receptor fibre Poly(lactide-co antagonist glycolide) with (PLGA) antiemetic Polyvinyl alcohol and (PVA) prokinetic properties) Polycaprolactone DichloromeDiclofenac Fiber mat (PCL) and thane, sodium and Poly(vinyl Chloroform Tetracycline alcohol) (PVA) and Water hydrochloride

Polycaprolactone (PCL) and Polyurethane (PU)

Chloroform and Methanol

Smooth release

Sustained

Burst release followed by sustained release

Controlled

Remarks

Application

Ref.

• Crystallinity of PLA Controlled inhibited drug delivery for release short times technology • Total drug release percentage from the cast film is lower than the electrospun mats due to much lower surface area of the film • Used as local antibiotic Prevention of delivery systems post • Morphology and density of surgical the scaffold dependent on adhesion the drug concentration and infections • Polymer degradation and Drug delivery drug release adjusted by controlling fiber diameter and its porosity

[80]

• One component allowing antibiotic release whether the other responsible for mechanical support

Controlled release • For effective drug release, from core–shell sufficient hydrophilicity fiber difference and interfacial compatibility between the core and shell polymers must exist • Drug must have higher solubility in the core rather than in the shell

The current trends in drug delivery research and development clearly show that nanomaterials, especially nanofibers are increasingly being explored for possible applications in targeted drug delivery through topical route. Drug delivery via nanofibrous systems has many advantages compared to conventional microfibrous systems such as improved therapeutic efficiency with lower

[83]

[78]

Abdominal [119] wall closure and infection control Drug delivery application

Monotonous • Fiber diameter increased – increase in with increasing solution drug release concentration, amount of with increasing drug incorporation and immersion time decreased with increasing and release applied voltage and the become collection distance constant at long immersion time Ketoprofen, Nonwoven Initial burst • Release rates from the neat Controlling (non-steroidal nanofiber release polymers and their blend are pain and anti(Biodegradfollowed by almost similar inflammainflammatory able and slow release • Drug released increased with tion in drug) nonincrease in temperature rheumatic biodegradable) diseases

6. SUMMARY

864

Release profile

[116]

[53]

[84]

dosage, reduced toxicity by delivering drug to the specific site, availability of large application area and minimal side effects. A variety of polymers, mostly biodegradable and a few non-biodegradables have been electrospun with a range of drugs, including those meant for infection control in wound dressing to anticancer drugs. These electrospun nanostructures have several advantages over other forms of drug delivery such as films, foams, sponges, J. Nanosci. Nanotechnol. 14, 853–867, 2014

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hydrogels, etc., in terms of high surface area to volume ratio, low density, flexibility and high porosity. Immediate burst release of drugs is observed in conventional microfibrous systems such as sutures. This kind of release profile is advantageous for treating surgical infection where immediate action of a drug is necessary to inhibit the growth of bacteria. For acquiring long-term activity with high efficiency, such as oral and wound related infection, nanofibrous drug delivery systems are preferable. Nanofibrous delivery systems are also desirable for site-specific actions, such as periodontal infection and anticancer treatment. The release kinetics of nanofibrous systems can be controlled by controlling the nanofiber diameter or controlling mode of encapsulation of therapeutic agents or changing the morphology to core–shell type. For example, monolithic and blend nanofibers exhibit burst release kinetics whereas core–shell fibers are responsible for sustained release kinetics. However, there are still several challenges in upscaling the electrospinning process. The first one is control of the pore size and elimination of bead defects from electrospun nanofibers. The second one is maintaining the consistency of the nanofiber diameter. Measurement of mechanical properties of nanofibers poses technical difficulties and very few literature reports target this aspect. Electrospinning, the fabrication technique for nanofiber production is also quite expensive due to slow production rate and high cost of technology as compared to conventional microfibrous systems. In addition to that, inhalation of nanofibers and solvent vapor also leads to health hazards. Due to these limitations, there are not many commercialized nanofibrous products in the market; although nanofibrous systems hold great promise and potential for novel drug delivery applications. The limited speed of production of nanofibers via electrospinning is presently the major bottleneck in taking the technology to commercial scale. Several companies like Donaldson, Elmarco, Nano FMG, SurModics are actively working toward upscaling electrospinning technologies in terms of faster production rates as well as larger area coverage. A new venture called “The Electrospinning Company Limited,” founded in 2010, has initiated design and commercial manufacturing of nanofibrous scaffolding that supports the cell growth in a 3D structure. Finally, future collaborations and greater communication between various disciplines, including medicine, engineering, material science, information technology and physics, will be instrumental in addressing these issues and taking this technology to commercial success.

References and Notes 1. N. Jain, R. Jain, N. Thakur, B. P. Gupta, D. K. Jain, J. Banveer, and S. Jain, Asian J. Pharm. Clin. Res. 3, 159 (2010). 2. K. Savolainen, L. Pylkkänen, H. Norppa, G. Falck, H. Lindberg, T. Tuomi, M. Vippola, H. Alenius, K. Hämeri, J. Koivisto, D. Brouwer, D. Mark, D. Bard, M. Berges, E. Jankowska,

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3. 4. 5. 6. 7.

8. 9.

10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.

36.

M. Posniak, P. Farmer, R. Singh, F. Krombach, P. Bihari, G. Kasper, and M. Seipenbusch, Safety Sci. 48, 957 (2010). R. Misra, M. Upadhyay, and S. Mohanty, J. Nanopharmaceutics Drug Delivery 1, 103 (2013). M. Vallet-Regí, E. Ruiz-Hernández, B. González, and A. Baeza, J. Biomater. Tissue Eng. 1, 6 (2011). Y. Liu, S. Shah, and J. Tan, Rev. Nanosci. Nanotechnol. 1, 66 (2012). C. P. Caracciolo, R. C. P. Tornello, M. F. Ballarin, M. Florencia, and A. G. Abraham, J. Biomater. Tissue Eng. 3, 39 (2013). M. N. V. Ravi Kumar (ed.), Handbook of Particulate Drug Delivery, American Scientific Publishers, Los Angeles, USA (2008), Vols. 1–2. M. E. Aulton, Aulton’s Pharmaceutics: The Design, and Manufacture of Medicines, Elsevier Health Sciences, London, UK (2007). R. L. Carrier and K. C. Waterman, Handbook of Biodegradable Polymeric Materials and Their Applications, edited by S. K. Mallapragada and B. Narasimhan, American Scientific Publishers, Los Angeles, USA (2005), Vol. 2. A. T. Florence and D. Attwood, Physicochemical Principles of Pharmacy, Pharmaceutical Press, London (2008). A. N. Misra, Controlled and Novel Drug Delivery, CBS Publishers and Distributors, New Delhi (1997). B. Mishra, J. K. Pandit, and S. K. Bhattacharya, Ind. J. Exp. Biol. 28, 1001 (1990). R. L. Moy, B. Waldman, and D. W. Hein, J. Dermatol. Surg. Oncol. 18, 785 (1992). M. H. Kudur, S. B. Pai, H. Sripathi, and S. Prabhu, Indian J. Dermatol. Venereol. Leprol. 75, 425 (2009). S. W. Ha, A. E. Tonelli, and S. M. Hudson, Biomacromolecules 6, 1722 (2005). N. Kojic, M. Kojic, S. Gudlavalleti, and G. McKinley, Biomacromolecules 5, 1698 (2004). L. Fambri, S. Bragagna, and C. Migliaresi, Macromolecules Symp. 234, 20 (2006). K. Yamaura and R. Kumakura, J. Appl. Polym. Sci. 77, 2872 (2000). L. H. Chuang, M. H. Zheng, and J. H. Xiao, J. Biomed. Mater. Res. A 89A, 80 (2009). K. Y. Lin, H. M. Farinholt, V. R. Reddy, R. F. Edlich, and G. T. Rodeheaver, J. Long-Term Eff. Med. Implants 11, 29 (2001). W. van Winkle, Jr and J. C. Hastings, Surg. Gynecol. Obstet. 135, 113 (1972). V. Zhukovsky, Autex Research Journal 3, 41 (2003). L. G. Richard, F. Willard, Jr, G. Donald, and M. Alvaro, Laryngoscope 89, 349 (1979). K. Gündüz, J. S. Pulido, P. D. Yeakel, M. King, K. L. Classic, and K. M. Furutani, Clin. Ophthalmol. 4, 159 (2010). T. D. Turner, Pharma. J. 222, 421 (1979). M. Choucair and T. Phillips, Skin Aging J. Geriatr. Dermatol. 6, 37 (1998). L. van Rijswijk, J. Wound Care 15, 11 (2006). D. Queen, H. Orsted, H. Sanada, and G. Sussman, Int. Wound J. 1, 59 (2004). A. F. Falabella, Dermatol. Ther. 19, 317 (2006). S. Ganlanduik, W. R. Wrigtson, S. Young, S. Myers, and H. C. Polk, Jr, Am. Surgeon. 63, 831 (1997). D. A. Morgan, Pharma. J. 263, 820 (1999). W. Paul and C. P. Sharma, Trends Biomater. Artif. Organs. 18, 18 (2004). T. D. Turner, Vet. Dermatol. 8, 235 (1997). K. Lay-Flurrie, Prof. Nurse 19, 269 (2004). W. Paul and C. P. Sharma, Encyclopedia of Surface and Colloid Science, edited by P. Somasundaran, Taylor and Francis, New York (2006). I. Yuvarani, S. Senthil Kumar, V. Jayachandran, S. K. Kim, and P. N. Sudha, J. Biomater. Tissue Eng. 2, 53 (2012).

865

Advances in Topical Drug Delivery System: Micro to Nanofibrous Structures 37. P. T. S. Kumar, V. K. Lakshmanan, R. Biswas, S. V. Nair, and R. Jayakumar, J. Biomed. Nanotechnol. 8, 891 (2012). 38. R. Ramya, J. Venkatesan, K. S. Kim, and P. N. Sudha, J. Biomater. Tissue Eng. 2, 100 (2012). 39. C. J. Doillon and F. H. Silver, Biomaterials 7, 3 (1986). 40. H. J. T. Rutten and P. H. A. Nijhuis, Eur. J. Surg. 578, 31 (1997). 41. Y. Sawada, M. Ara, T. Yotsuyanagi, and K. Sone, Burns 16, 347 (1990). 42. J. Grzybowski, W. Kolodziez, E. A. Trafny, and S. Jerzy, J. Biomed. Mater. Res. A 36, 163 (1997). 43. T. R. Kumar, M. V. Bai, and L. K. Krishnan, Biologicals 32, 49 (2004). 44. Y. Sawada, O. Tadashi, K. Masazumi, S. Kazunobu, O. Koichi, and J. Sasaki, Brit. J. Plast. Surg. 47, 158 (1994). 45. B. L. Roberts and D. Cheung, Aust. Crit. Care 11, 16 (1998). 46. K. Moore, A. Thomas, and K. G. Harding, Int. J. Biochem. Cell Biol. 29, 163 (1997). 47. I. Chopra, J. Antimicrob. Chemother. 59, 587 (2007). 48. M. R. Frost, S. W. Jackson, and P. J. Stevens, Microbios Lett. 13, 135 (1980). 49. J. C. Kerihuel, Wounds 5, 87 (2009). 50. Z. M. Huang, Y. Z. Zhang, M. Kotaki, and S. Ramakrishna, Compos. Sci. Technol. 63, 2223 (2003). 51. S. Zhang, M.S. Dissertation, North Carolina State University (2009). 52. M. Gorji, A. A. Jeddi, and A. A. Gharehaghaji, J. Appl. Polym. Sci. 125, 4135 (2012). 53. K. Kanawung, K. Panitchanapan, S. Puangmalee, W. Utok, N. Kreua-ongarjnukool, R. Rangkupan, C. Meechaisue, and P. Supaphol, Polym. J. 39, 369 (2007). 54. Y. Zhang, C. T. Lim, S. Ramakrishna, and Z. M. Huang, J. Mater. Sci. Mater. Med. 16, 933 (2005). 55. S. E. Dabney, Ph.D. Dissertation, University of Akron, Akron, USA (2002). 56. P. Zahedi, I. Rezaeian, S. Siadatb, S. Jafari, and P. Supaphol, Polymer. Adv. Tech. 21, 77 (2010). 57. Q. P. Pham, U. Sharma, and A. G. Mikos, Tissue Eng. 12, 1197 (2006). 58. A. Formhals, U.S. Patent, 1-975-504 (1934). 59. D. H. Reneker and A. L. Yarin, Polymer 49, 2387 (2008). 60. N. Bhardwaj and S. C. Kundu, Biotechnol. Adv. 28, 325 (2010). 61. Z. Huang, Y. Z. Zhang, M. Kotaki, and S. Ramakrishna, Compos. Sci. Technol. 63, 2223 (2003). 62. R. Nayak, R. Padhye, I. L. Kyratzis, Y. B. Truong, and L. Arnold, Text. Res. J. 82, 129 (2011). 63. A. Yarin, W. Kataphinan, and D. Reneker, J. Appl. Phys. 98, 64501 (2005). 64. W. Tomaszewski and M. Szadkowski, Fibers Text. East. Eur. 13, 22 (2005). 65. S. Theron, A. Yarin, E. Zussman, and E. Kroll, Polymer 46, 2889 (2005). 66. H. Niu, T. Lin, and X. Wang, J. Appl. Polym. Sci. 114, 3524 (2009). 67. N. M. Thoppeya, J. R. Bochinski, L. I. Clarke, and R. E. Gorga, Polymer 51, 4928 (2010). 68. J. H. He, H. Y. Kong, R. R. Yang, H. Dou, N. Faraz, L. Wang, and C. Feng, Them. Sci. 16, 1263 (2012). 69. Y. M. Kim, K. R. Ahn, Y. B. Sung, and R. S. Jang, U.S. Patent, 7618579 (2009). 70. F. Cengiz, T. A. Dao, and O. Jirsak, Polym. Eng. Sci. 50, 936 (2010). 71. G. G. Chase, J. S. Varabhas, and D. H. Reneker, J. Eng. Fibr. Fabr. 6, 32 (2011). 72. Y. Srivastava, I. Loscertales, M. Marquez, and T. Thorsen, Microfluid. Nanofluid. 4, 245 (2008). 73. A. V. Bazilevsky, A. L. Yarin, and C. M. Megaridis, Langmuir 23, 2311 (2007).

866

Joshi et al.

74. X. Xu, X. Zhuang, X. Chen, X. Wang, L. Yang, and X. Jing, Macromol. Rapid Commun. 27, 1637 (2006). 75. D. Li, J. T. McCann, and Y. Xia, Small 1, 83 (2005). 76. F. Xu, L. Li, and X. Cui, J. Nanomater. 2012, 1 (2012). 77. T. Santi, J. Ittipol, and P. Supaphol, Polymer 48, 5030 (2007). 78. P. Hongsen, Z. G. Shaobing, L. Yanshan, L. Xiaohong, W. Jianxin, and W. Jie, Colloids Surf. B 66, 206 (2008). 79. C. Wenguo, L. Xiaohong, Z. Xinli, Y. Guo, Z. Shaobing, and W. Jie, Biomacromolecules 7, 1623 (2006). 80. E. Kenawy, G. L. Bowlin, K. Mansfield, J. Layman, D. G. Simpson, E. H. Sanders, and G. E. Wnek, J. Control. Release 81, 57 (2002). 81. X. Zhiwei and B. Gisela, J. Appl. Polym. Sci. 115, 1 (2009). 82. X. H. Zong, K. Kim, D. F. Fang, S. F. Ran, B. S. Hsiao, and B. Chu, Polymer 43, 4403 (2002). 83. K. Kim, Y. K. Luu, C. Chang, D. Fang, B. S. Hsiao, B. Chu, and M. Hadjiargyrou, J. Control. Release 98, 47 (2004). 84. E. R. Kenawy, I. A. H. Fouad, H. E. N. Mohamed, and E. W. Gary, Mater. Chem. Phys. 113, 296 (2009). 85. E. R. Kenawy, I. A. H. Fouad, H. E. N. Mohamed, and E. W. Gary, Mat. Sci. Eng. A-Struct. 459, 390 (2007). 86. V. Geert, C. Iksoo, R. Joel, P. Jef, and E. B. Marcus, Pharmaceut. Res. 20, 810 (2003). 87. M. Jaiswal, A. Gupta, A. K. Agrawal, M. Jassal, A. K. Dinda, and V. Koul, J. Biomed. Nanotechnol. 9, 1495 (2013). 88. D. S. Katti, K. W. Robinson, F. K. Ko, and C. T. Laurencin, J. Biomed. Mater. Res. Part B Appl. Biomater. 70, 286 (2004). 89. V. Geert, C. Iksoo, R. Joel, P. Jef, V. D. Alex, M. Jurgen, N. Marc, and E. B. Marcus, J. Control. Release 92, 349 (2003). 90. N. Bölgen, I. Vargel, P. Korkusuz, Y. Z. Mencelo˘glu, and E. Pi¸skin, J. Biomed. Mater. Res. Part B Appl. Biomater. 81, 530 (2007). 91. P. Taepaiboon, U. Rungsardthong, and P. Supaphol, Nanotechnology 17, 2317 (2006). 92. M. S. Khil, D. I. Cha, H. Y. Kim, I. S. Kim, and N. Bhattarai, J. Biomed. Mater. Res. Part B Appl. Biomater. 67, 675 (2003). 93. D. N. Heo, D. H. Yang, J. B. Lee, M. S. Bae, J. H. Kim, S. H. Moon, J. H. Chun, C. H. Kim, H. Lim, and K. Kwon, J. Biomed. Nanotechnol. 9, 511 (2013). 94. K. Tomihata and Y. Ikada, Biomaterials 18, 567 (1997). 95. S. P. Victor, W. Paul, and P. C. Sharma, J. Nanopharmaceutics Drug Delivery 1, 193 (2013). 96. R. Deepa, W. Paul, T. V. Anilkumar, and P. C. Sharma, J. Biomater. Tissue Eng. 3, 261 (2013). 97. L. Y. Chung, R. J. Schmidt, P. F. Hamlyn, B. F. Sagar, A. M. Andrews, and T. D. Turner, J. Biomed. Mater. Res. 28, 463 (1994). 98. A. G. Kanani, S. H. Bahrami, H. A. Taftei, S. Rabbani, and M. Sotoudeh, IET Nanobiotechnol. 4, 109 (2010). 99. Y. Zhou, D. Yang, X. Chen, Q. Xu, F. Lu, and J. Nie, Biomacromolecules 9, 349 (2008). 100. Z. Cai, X. Mo, K. Zhang, L. Fan, A. Yin, C. He, and H. Wang, Int. J. Mol. Sci. 11, 3529 (2010). 101. Y. O. Kang, I. Yoon, S. Y. Lee, D. Kim, S. J. Lee, W. H. Park, and S. M. Hudson, J. Biomed. Mater. Res. Part B Appl. Biomater. 92, 568 (2010). 102. J. P. Chen, G. Y. Chang, and J. K. Chen, Colloids Surf., A 313, 183 (2008). 103. S. Liu, Y. Kau, C. Chou, J. Chen, R. Wu, and W. Yeh, J. Membr. Sci. 355, 53 (2010). 104. T. H. B. Eriksen, E. Skovsen, and P. Fojan, J. Biomed. Nanotechnol. 9, 492 (2013). 105. P. Sikareepaisan, A. Suksamrarn, and P. Supaphol, Nanotechnology 19, 1 (2008). 106. V. E. A. Torres, N. C. Baracho, J. D. Brito, and A. A. A. Queiroz, Acta Biomater 6, 1069 (2010). 107. J. Xie and C. H. Wang, Pharmaceut. Res. 23, 1817 (2006).

J. Nanosci. Nanotechnol. 14, 853–867, 2014

Joshi et al.

Advances in Topical Drug Delivery System: Micro to Nanofibrous Structures

108. Z. Jing, Y. Lixin, L. Qizhi, Z. Xuefei, G. Huili, X. Xiuling, C. Xuesi, and J. Xiabin, J. Control. Release 105, 43 (2005). 109. X. Xu, L. Yang, X. Xu, X. Wang, X. Chen, Q. Liang, J. Zeng, and X. Jing, J. Control. Release 108, 33 (2005). 110. C. Chen, L. Gang, P. Chao, S. Min, W. Chunhui, G. Dadong, W. Xuemei, C. Baoan, and G. Zhongze, Biomed. Mater. 2, L1 (2007). 111. X. Xu, X. Chen, X. Xu, T. Lu, X. Wang, L. Yang, and X. Jing, J. Control. Release 114, 307 (2006). 112. Z. Jing, X. Xiaoyi, C. Xuesi, L. Qizhi, B. Xinchao, Y. Lixin, and J. Xiabin, J. Control. Release 92, 227 (2003). 113. Z. Maedeh, M. Mohammad, V. Jaleh, and J. Marziyeh, Eur. J. Pharm. Biopharm. 75, 179 (2010). 114. Z. M. Huang, C. L. He, A. Yang, Y. Zhang, X. J. Han, and J. Yin, J. Biomed. Mater. Res. A 77A, 169 (2006).

115. L. H. Chuang, M. H. Zheng, and J. H. Xiao, J. Biomed. Mater. Res. A 89A, 80 (2009). 116. S. K. Tiwari, R. Tzezana, E. Zussman, and S. S. Venkatraman, Int. J. Pharm. 392, 209 (2010). 117. X. Ji, W. Yang, T. Wang, C. Mao, L. Guo, J. Xiao, and N. He, J. Biomed. Nanotechnol. 9, 1672 (2013). 118. X. Xiuling, C. Xuesi, W. Zhanfeng, and J. Xiabin, Eur. J. Pharm. Biopharm. 72, 18 (2009). 119. Y. Hong, K. Fujimoto, R. Hashizume, J. Guan, J. J. Stankus, K. Tobita, and W. R. Wagner, Biomacromolecules 9, 1200 (2008). 120. O. Tatsuya, T. Kengo, and K. Satoru, J. Control. Release 143, 258 (2010). 121. P. Dario, M. P. Anna, D. Nicola, D. Dinuccio, and C. Federica, Acta Biomater. 6, 1258 (2010).

Received: 29 August 2013. Accepted: 15 September 2013.

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