Advances in Drug-delivery Systems Based on

CHAPTER 11

Advances in Drug-delivery Systems Based on Intrinsically Conducting Polymers MANISHA SHARMA,a DARREN SVIRSKISa AND SANJAY GARG*b a

School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, New Zealand; b School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia *Email: [email protected]

11.1 Introduction Intrinsically conducting polymers (ICPs) are organic polymers with unique capabilities including the conductance of electricity. In 2000, the Nobel Prize in Chemistry was awarded to Heeger, MacDiarmid and Shirakawa for the pioneering work they achieved discovering and developing ICPs in the late 1970s. In over three decades since, research into the properties and abilities of these materials has exploded. There has been a movement of late from fundamental science into more applied areas, with ICPs finding use in integrated circuits, light-emitting devices, electromagnetic shielding, antistatic coatings, corrosion inhibitors, functional coatings, field effect transistors and sensing devices.1,2 ICPs have been used in the biomedical setting as biosensors and devices for nerve regeneration and wound healing, and have an increasing interest as components in drug-delivery systems (DDS).3–5 The contribution this group of materials can make to drug delivery is the ability to electrically RSC Smart Materials No. 2 Smart Materials for Drug Delivery: Volume 1 Edited by Carmen Alvarez-Lorenzo and Angel Concheiro r The Royal Society of Chemistry 2013 Published by the Royal Society of Chemistry, www.rsc.org

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tune drug release rates depending on patient need. The release of drugs from ICP-based DDS can be modified using electrical signaling to alter the redox state of the ICP, which leads to subsequent changes in polymer charge and volume.5 Polypyrrole (PPy) is the most investigated ICP for drug-delivery purposes; however, other ICPs including PPy derivatives,6 polyanaline (PANI)7 and PEDOT (poly(3,4-ethylenedioxythiophene))8 have also been used.

11.2 Polymerisation ICPs are polymerised through oxidation of monomer units. Oxidation, as represented in Figure 11.1, can be achieved either chemically or electrochemically. An increasing range of monomers and functionalised monomers have been used to form various polymers with different properties.2 The final polymer product is not only the result of the monomer selected, but is also influenced by the dopant anions used (A), the rate and extent of polymerisation, the concentration of reactants, temperature, stirring and the physical setup of the electrochemical cell.9 Common chemical oxidants include ferric chloride and ammonium persulfate. However, it is difficult to control the rate and extent of polymerization chemically, and often electrochemical approaches are used. By using a set current to cause oxidation, the rate and the extent of polymerization are controlled by the magnitude and the time interval that the current flows for, respectively. Keeping other parameters constant, more rapid polymerization results in relatively irregular polymers, with rougher surfaces, more porous structure and lower densities.10–12 For drug-delivery purposes, polymerization conditions must be optimized not only for drug loading, but also to provide ideal polymer morphology as this will influence the mobility of drug in the polymer and the release profiles. Although the efficiency of electrochemical oxidation is less than 100%, the total amount of current passed during polymerisation will dictate the quantity of polymer formed. This can provide a rough estimation, and efficiency appears to change with the total thickness of polymer produced, but reported estimates of charge density of 240 mC cm2 to 600 mC cm2 are required to produce a 1 mm thickness of PPy.12–14 To create an electrochemical cell for polymerization either two or three electrodes can be used; a working electrode, a counter electrode and optionally a reference electrode. Both the working and the counter electrodes should be clean, inert materials so as not to take part in any electrolysis reaction themselves. The working electrode surface is the site of polymer formation, and the surface material can influence the initial polymerization reaction. However,

Figure 11.1

Polypyrrole polymerization.

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while this influences very thin polymer films, the influence of the material is lost in the formation of thicker films, as the newly forming polymer is laid down on the existing polymer.15 Ideally the voltage generated in the cells is monitored using a reference electrode (commonly a silver/silver chloride or saturated calomel electrode), to ensure the polymer is not exposed to too large a voltage. Excessive voltage results in overoxidation and subsequent loss of conductivity and reversible redox activity.14,16 During synthesis, solutions are usually left unstirred, since stirring can negatively influence the deposition of insoluble oligomer units onto the growing polymer film.17 As displayed in Figure 11.1 the newly formed polymer is in the oxidized form with positive charges distributed along the backbone, with a single positive charge every three to four subunits.18–21 These positive charges must be balanced by anionic dopant molecules for the successful formation of the polymer. The dopant anion selected will have a major influence on the morphology, properties and the function of the polymers produced.17,18 For example, keeping other variables constant, the same PPy films prepared with chloride ions (Cl) were two to eight times thicker than those prepared using p-toluene sulfonate (pTS) or poly(styrene sulfonate) (PSS), with PPy-Cl having the roughest surface and PPy-PSS the smoothest surface.22

11.3 Properties 11.3.1

Conductivity

ICPs, as the name suggests, conduct electricity. The degree of conductivity usually falls into the range commonly associated with the semi-conductors. The conductivity is due to the uninterrupted p-conjugated backbone. The level of conductivity is variable and ultimately it depends on mobility of the electrons to carry charge along the polymer.1,23 In the oxidized state, electrons have been removed from the ICP backbone leaving ‘‘holes’’. Surrounding mobile electrons are able to move into these holes effectively shifting the hole along the polymer backbone explaining the resultant conductivity. The regularity and degree of branching of the polymer backbone are, therefore, major determinants to conductivity.

11.3.2

Stability

Various ICPs display differing levels of stability. PPy is regarded as relatively stable in the oxidized form.17,18,24 There are very few reports on the stability of ICP based DDS,25 and this is an area that will require more in-depth investigation in the future. Conductivity has been used as a marker for stability.26–29 The dopant used influences stability; PPy films prepared with pTS have been shown to be more stable than PPy prepared with ClO4, BF4, NO326 or with dodecyl sulfate.27 Temperature plays an important role in environmental breakdown. With increasing temperatures, conductivity has been shown to reduce in shorter time periods.26,28,29 Truong et al.27 found that

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for PPy-pTS stored at 150 1C in air, the conductivity began to fall immediately. However, when the same polymer films were stored in oxygen-free environment at 150 1C there was no decrease in conductivity after 3 days. Subsequent introduction of oxygen resulted in an immediate decline in conductivity. The reaction between PPy and oxygen seems to be accelerated at high temperatures, leading to an irreversible loss of conjugation and consequently of conductivity.26 This has been examined by FTIR where the appearance of a band at 1690 cm1, characteristic of a, b-unsaturated ketones, indicates the irreversible oxidation at the b 0 -position of PPy.30

11.3.3

Biosensing

ICPs biosensing capabilities are constantly being developed.3,31,32 Immobilized enzymes on ICP films form amperometric biosensing devices with the ability to signal a concentration-based response to glucose,33–35 cholesterol,36 lactate37 or urea.38 Looking forward, it may be possible to combine the biosensing and the drug-delivery capabilities of ICPs, creating a single material with the ability to self-tune the rate of drug release as a function of a sensed change in the local environment.39

11.3.4

Solubility

While oligomers of ICP monomers may be soluble, the polymer products are almost always insoluble due to strong inter- and intra-molecular forces.23 However, soluble PPy can be produced through chemical polymerization by doping with sulfate anions.40 Chemical modification of the monomer units has also been used to produce PPy with limited solubility.41 These approaches have resulted in solubility in some organic solvents, however the polymers remain insoluble in water.

11.4 Characterization Several techniques are frequently utilised to characterize ICPs including Infrared and Raman spectroscopy, Atomic Force Microscopy and Cyclic Voltammetry. Here we briefly discuss these techniques and how they can be used to assess the ability of ICPs to act as DDS.

11.4.1

Infrared (IR) and Raman Spectroscopy

Infrared (IR) and Raman spectroscopy are complementary techniques that are used to examine the vibration, stretching and bending of intra-molecular bonds. These techniques allow for ICP identification,12,42–44 can give an indication of doping levels45,46 and can be used to detect overoxidation of PPy,44 and enable the identification of dopants or other molecules that may be present in the ICP.12,42,44,47


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Atomic Force Microscopy

Atomic Force Microscopy (AFM) is a useful surface probing technique that has been utilised to assess both the surface characteristics and volume changes in ICP films.5,48–51 The surface features are important as they can influence drug release and biological interactions, including cell adhesion.22 Out-of-plane volume changes of PPy films have been linked to drug release5 and, therefore, the assessment of this feature by means of AFM is highly useful.

11.4.3

Cyclic Voltammetry

Cyclic Voltametry (CV) is an electrochemical technique used to assess reversible electroactivity and to determine the potentials at which the redox state of the polymer can be switched. During CV analysis, the potential is increased or decreased between two set points, at a predetermined scan rate, while the current is measured. By constructing potential vs. current plots, useful information can be extracted. When a redox active material or species, including an ICP, is examined, peaks may be observed correlating to oxidation or reduction processes. A peak represents current flow into or out of the material, indicating reduction or oxidation, respectively. By integrating the area under each peak, the amount of charge passed during the redox process can be calculated. The peak’s position roughly indicates the potentials at which oxidation or reduction occurs. As a change in the redox state can be utilized to trigger drug release, this technique provides information on the potentials required to force such a change. An ideal reversible system exhibits very little difference between the potential at which oxidation and reduction occur.52 However, ICPs typically show significant separation between broad oxidation and reduction peaks (Figure 11.2).16

11.5 Biocompatibility For biomedical applications the biocompatibility of ICPs must be considered. Polypyrrole is the ICP that has been most widely investigated for biomedical applications and is regarded as biocompatible.3,47 As ICP synthesis requires the presence of anionic dopants, it is not only the biocompatibility of the polymer be considered, but also that of the entire system. Specific dopants can be used to promote the biocompatibility of the polymer.53 However, while some dopants are capable of imparting desirable functionality into the polymer, they should be avoided for biomedical applications due to their toxicity. Ideally a biologically inert dopant molecule will be used, however it may be possible to use a non-biocompatible dopant for synthesis, and to impart desired functionality, and subsequently exchange it out of the polymer. In addition to the dopants used, the physical properties of the material, including morphology and mechanics, can modify biocompatibility.49,54 As seen in the polymerization section, the physical properties of the polymer can be controlled to some degree depending on the synthesis conditions employed.

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Figure 11.2

Cyclic voltammogram of PPy doped with dodecyl benzene sulfonate cycled in 0.1 M NaNO3 between þ0.8 V and 0.8 V at a scan rate of 50 mV s1.

Another way to improve the biocompatibility is by modifying the surface of the ICP after polymerization.55 The electrical stimulation used to regulate drug release from ICP-based DDS can also be used to modify cell behavior and, thus, the biocompatibility.56,57 As ICP-based DDSs advance toward clinical applications, the biocompatibility aspects of these systems need to be more completely investigated.

11.6 Mechanisms for Controlled Drug Release In a broad sense, modifiable drug delivery from ICPs is achieved by utilizing either alterations in electrostatic forces or volume, as ICPs undergo a change in redox state. Hydrophilic–hydrophobic interactions also play a role, but have not been fully investigated. Frequently, it is a combination of these different mechanisms that results in drug incorporation as well as release. However, for the purposes of explanation, electrostatic forces and volume changes will be discussed separately.

11.6.1

Utilizing Electrostatic Forces in ICPs

When the redox state of an ICP is altered, there is an accompanying change in the charge of the polymer backbone. PPy is positively charged in the oxidized state (PPy1) and neutral in the reduced state (PPy0). In the simplest scenario, a negatively charged drug can be used as the dopant anion during

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polymerization. Subsequent reduction of PPy to PPy leads to a loss of electrostatic attraction between the anionic drug and the polymer, and the excess negative charge along with diffusion drive drug release.58 Often, however, polymer is not formed or desired polymer properties are not attained when using a drug as the dopant anion. To overcome this, an ideal anionic dopant can be selected and, if it is mobile, following polymerization it can be exchanged out of the polymer by redox cycling in favor of an anionic drug.10 The anionic drug is subsequently available for release on reduction of the polymer. The release of cationic drugs can also be controlled through electrostatic forces. If an ICP is prepared with an immobile anion, when the polymer is reduced from PPy1 to PPy0, a net negative charge remains due to the immobilized anions. This feature can be utilized to load the polymer with a cationic drug. Subsequently, if the polymer is oxidized back to PPy1, the cationic drug is expelled out of the polymer due to electrostatic repulsion.59 Clearly the utilization of electrostatic forces is somewhat limited in requiring the drug to be charged. When selecting candidate drugs, attention must be paid to their pKa and to the pH of the intended environment of the ICP based delivery system.

11.6.2

Volume Changes in ICPs

When the redox state of the polymer changes, the charge of the polymer backbone is also altered. These changes in polymer charge need to be balanced and solvated ions move into and/or out of the polymer.48 In predicting alterations in volume of an ICP, the polymer structure and the mobility of ions in and around the polymer must be considered. Expansion or shrinkage of the polymer can be designed to occur solely on either oxidation or reduction of the polymer, or a mixed response may be observed. If PPy was prepared with an immobile anion (often large and multi-charged), when PPy shifts from the oxidized state (PPy1) to the reduced state (PPy0), there is a net negative charge in the polymer due to the presence of the immobile anion. This net negative charge is balanced by an influx of mobile cations and thus the polymer expands. Subsequent oxidation of the polymer from PPy0 to PPy1 results in a net positive charge, which causes the mobile cations to be expelled out and the polymer to shrink. This phenomenon is referred to as cation driven actuation. Conversely, if PPy is polymerized with a mobile anion, as PPy is reduced from PPy1 to PPy0 a net negative charge evolves in the polymer. Some of the anion will therefore be expelled out, and the polymer will shrink. It follows that expansion of the polymer will occur on oxidation of PPy0 back to PPy1 and the re-entry of the solvated anions into the polymer bulk. The situation described is referred to anion driven actuation. Such clear cation driven or anion driven actuations are rarely seen since they require precise control over ionic species present in the polymer and surrounding environment. Certainly in in vivo environments or environments mimicking the in vivo situation a broad mix of species is present. In this situation mixed-ion actuations are likely to be observed, where both anions and cations are mobile to enter and exit the polymer.60

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11.7 Drug-delivery Systems In the last two decades many different ICP based DDSs have been described in both academic literature and as intellectual property. Recent work has described combinations of ICPs with other biomaterials to enhance the performance of the DDS. For easy understanding, this section has been divided according to the method of drug loading and the mechanism of drug release. The following categories are presented; reservoir systems, actuating devices, matrix systems and miscellaneous systems.

11.7.1

Reservoir Systems

Reservoir systems have been quite successful for controlled release of therapeutic agents as they can provide zero-order kinetics for longer periods. Youngnam et al.61 detailed the preparation of a reservoir type drug delivery system by encapsulating a growth factor in PPy. Two approaches were used to encapsulate the biomolecule. In the first approach, neural growth factor (NGF) was absorbed into mesoporous silica nanoparticles (MSNs) by electrostatic interactions between free silanol groups on the wall of the pores and the positively charged amine groups on the NGF at neutral pH (Figure 11.3). The particles were then used as a template on a clean indium tin oxide (ITO) surface for PPy or COOH-PPy electropolymerization at a constant þ0.7 V to form PPy/MSN-NGF composites. Carboxylation was used to impart hydrophilicity to the polymer. The inorganic MSNs provide a protective shell to the biological agent against in vivo degradation and thus enhances stability and increases therapeutic effect. In the second approach NGF was immobilized into the porous PPy films applying the N-hydroxysuccinimide (NHS), ethyl3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride (EDC) coupling

Figure 11.3

Schematic representation of MSN particles assembled within PPy. Application of electric potential releases NGF from PPy/MSN-NGF composites by redox cycling. (Reproduced with the permission of IOPScience from Ref. 62.)


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reaction. The PPy films were made porous by dissolving the MSN templates in 20% hydrofluoric acid for 24 hours. Delivery systems prepared by both methods were tested for their efficacy to promote proliferation of PC 12 cells. In vitro release of NGF from PPy/MSN-NGF composites was observed with and without electrical stimulation. Cells grown on electrically stimulated composites showed 40% greater proliferation and neurite extension, compared to nerve cells cultured without stimulation. This was further confirmed by SEM analysis, which showed increased attachment and neurite extensions as shown in Figure 11.4.62 Similarly, various conducting polymer based reservoir-type devices have been investigated by Carlsson et al.63 The devices include a conducting polymer element and a substance incorporating element, i.e. a drug reservoir assembled together on to the substrate. The release of the drug from the reservoir is characterized by the redox property of the ICPs. On application of the appropriate potential, the ICPs can switch between oxidized and reduced states. This redox change is also accompanied by a volume change and, as a result, a significant amount of the solvent and associated ions can be dragged in and out of the ICPs. However, the applications of such kinds of devices in drug delivery are limited by the fact that many drugs are uncharged or are hydrophobic in nature.

Figure 11.4

SEM images of cells and neuritis cultured on unstimulated (a and b) and electrically stimulated (c and d) PPy/MSN-NGF composites. (Reproduced with permission of IOPScience from Ref. 62.)

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Microchips

Over the past decade there has been much interest in the application of microfabrication technology to drug delivery. Ge et al.64 developed a microchip by electrochemically depositing a drug-doped PPy film onto gold microelectrode arrays. Such reservoir based microchips have numerous advantages such as the ablility to release multiple drugs at a given time, small size, and the ability to release small precise amount of drug and provide pulsatile drug release. Each microchip consisted of gold microelectrodes microfabricated on a silicon substrate. Each of the gold microelectrodes can be controlled individually. PPy containing drug (sulfosalicyclic acid) was electropolymerized on gold microelectrodes by galvanostatic polymerization using a current density of 2.5 mA cm2 for 800 s. The study showed that over 2 to 4 hours, 100% of loaded sulfosalicylic acid was released on electrical stimulation. However, when a second layer of PPy was electropolymerized onto the chip, the bilayer setup prevented spontaneous release of the drug from the microchip, and stimulated pulsatile release of drug was achieved over a period of several days.64

11.7.2 Actuating Devices 11.7.2.1 Peristaltic Pumps The general structure of an ICP actuating device comprises a closed fluid delivery channel (drug reservoir) with inlet and outlet ports, an ICP as an actuator and a controller to regulate the expansion and contraction of actuators. Morgan et al.65 discloses a conducting polymer actuating peristaltic pump for the delivery of a therapeutic agent to selected sites. The peristaltic pump consists of a flexible tubing, the outer surface of which is composed of the electroactive polymer actuators. The conducting polymers, when electrically stimulated, generate a mechanical force or movement. This dimensional change occurs due to the transfer of ions into and out of the polymer, therefore causing expansion and contraction of the polymer. As a result, the fluid from the reservoir is conveyed from one end of the flexible tube to the other, imparting a peristaltic pumping action. The developed device could be in the form of an endocardial medical lead or catheter. Similarly, Cannell et al.66 reported the development of a ‘‘micropump’’, a microfabricated pumping device for the delivery of drugs. The device consists of a drug reservoir, an actuator made of conducting polymer arranged within the reservoir and an electrode array, which acts as a controller. The electrode array facilitates phased cyclic actuation of the conducting polymer to effect the peristaltic pumping action. Particularly polypyrrole, polypyrrole derivatives and polyaniline are used as actuating elements because, compared to other materials, they have low voltage requirements (1–5 volts). The micropump can be integrated with a microprocessor to provide refined control for drug delivery. Therefore dosages can be altered externally to the patient’s body by means of a processor and a wireless interface.66 Such pumps also have application as infusion devices for infusing


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liquid medications such as insulin for the treatment of diabetes, opiates infusion for use in severe pain, local infusion of drugs for cancer chemotherapy, infusion of stimulants for the treatment of heart failure or arrhythmia and infusion of drugs for seizure treatment.67

11.7.2.2

Microneedle-based Nanoactuators

Microneedles represent a breakthrough technology in drug delivery, science. These can be inserted into the skin without any pain to create micrometer size pathways across the skin to deliver the drug molecules. Gabriela et al.68 reported the development of a multiplexed novel drug delivery system consisting of an array of microneedles coupled with conducting polymer nanoactuators for the controlled release of therapeutic molecules. The device consists of several components as shown in the Figure 11.5. PPY act as the actuating element after it has been electrodeposited on the gold sputtered polycarbonate membrane. The release characteristics of the developed device were evaluated by loading the reservoir with the dye methylene green. On application of a negative potential, the PPy membrane switches to the reduced relaxed state, resulting in closure of the pores with no dye release. On switching the membrane to the oxidized state by applying positive potential, the

Figure 11.5

(A) Schematic representation of the microneedle-based multi-plexed drug-delivery system. The main components are (i) hollow microneedle array, (ii) gold-sputtered polycarbonate membrane electrodeposited with dodecylbenzenesulfonate-doped polypyrrole (PC/Au/PPy/DBS) and (iii) polydimethylsiloxane (PDMS) reservoir. (B) Schematic illustration of the assembled dual-channel drug-delivery system outlining the reservoirs for (iv) drug 1 and (v) drug 2. (C) Schematic of main components of single microneedle during drug delivery: (i) reservoir, (ii) lumen (342 mm diameter), (iii) hollow microneedle, (iv) Au/PPy/DBS nanoporous membrane, (v) PC membrane and (vi) the released drug. (Reproduced with permission from Ref. 67.)

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membrane contracted thereby facilitating the opening of the pores, allowing the dye to flow through the membrane. The actual actuation of the PPy membrane was well demonstrated and was stable for up to 10 actuating cycles. This type of microdevice provides an avenue for targeted therapy where the drug doses can be modulated according to the patient’s conditions.

11.7.2.3

Smart Membranes

Smart membranes are delivery devices specifically designed to achieve pulsatile release of drugs on electrical stimulation. Jeon et al.69 developed nanoporous PPy membranes doped with dodecylbenzenesulfonate (DBS). The PPy was electropolymerized on anodized aluminium oxide (a hard template to create porous PPy). PPy/DBS exhibits a very large volume change (up to 35%) depending on the electrochemical state and has excellent biocompatibility. The polymeric membrane was actuated by altering the electrochemical state. The activating potential is less than 1.1 V, which is relatively low compared to the voltage, required for the operation of an artificial heart (c.a. 3 V). The actuation of the pore size was successfully demonstrated by an in situ AFM study; a reduction in pore size was observed in the reduced state, while the pore size increased in the oxidized state (Figure 11.6). These smart membranes showed a quick response time (less than 10 s) and pulsatile drug release, and therefore could have potential application in emergency conditions such as angina pectoris, migraine and hormone-related disorders, which requires precise and on-demand drug delivery.69

11.7.2.4

Hydrogel-conducting Polymer Composites (Electro-conductive Hydrogels)

The combination of the electrically switchable properties of conducting polymers and the swelling/deswelling capabilities of hydrogels, make these composite materials an exciting prospect for various biomedical purposes, including drug delivery. Tsai et al.70 fabricated a cylindrical electro-conductive hydrogel to investigate the electro-tunable release of the drug indomethacin. The ICP polyaniline was co-blended with poly(vinyl alcohol) and cross-linked with diethyl acetamidomalonate to form a polymeric hydrogel system. The drug entrapment efficiency of the polymeric hydrogel ranged from 65 to 70%. On application of different electrical potentials, between þ0.3 V and þ5.0 V for 60 seconds, cumulative drug release ranged from 4.7 to 25.2% after four release cycles respectively. It was observed that there was an increase in the percentage of drug released with an increase in the applied potential difference. However, a constant drug release was obtained between þ1.5 V and þ3.5 V. The electrostimulated release of indomethacin was associated with the degree of crosslinking, the polymeric ratio and the drug content. The main mechanism of indomethacin release was ascribed to the erosion of the hydrogel upon exposure to electrical stimulation.70 Similarly, Torresi et al.71 blended

Figure 11.6

(A) Schematic representation of smart electro-responsive nanoporous membrane.72 (a) Fabrication of anodized aluminium oxide (AAO) membrane. (b) Thermal deposition of thin gold (Au) layer on the AAO membrane. (c) Polypyrrole was electropolymerized on the Au layer. (d) Reversible change of pore size between oxidation and reduction states on electrical stimulation. (B) In situ flux and AFM results of a membrane with initial pore diameter of 200 nm at two different electrochemical states. (a) In situ flux versus time. Data points were taken every 15 s. Open (blue) and closed (magenta) circles indicate the oxidization and reduction states. (b, c) Figure represents the in situ AFM height images corresponding to the oxidization and reduction states. (Reproduced with the permission of Elsevier from Ref. 68.)

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polyacrylamide hydrogel with PPy electrochemically to characterize the controlled release of model drug safranin. The synthesis parameters were optimized using a fractional factorial design. The hydrogel was quite stable under neutral pH conditions, which is essential for in vivo applications. Sirivat and Chansai72 developed blends of PPy and poly(acrylic acid) doped with an anionic drug for transdermal delivery. Such stimuli-responsive hydrogels exhibit great potential for triggered drug therapy.

11.7.3

Matrix Type

Dubois-Rande et al.73 described an implantable metallic stent for the prevention of post-angioplastic restenosis. The stent was coated with conducting polymer with an encapsulated antisense oligoneuclotide to selectively inhibit the expression of genes preventing the proliferation of smooth muscle cells on the arterial wall. The polymerization of the ICP onto the stent is two stage processes. In the first stage the ICPs is electropolymerized directly on to the metallic support in presence of another hydrophilic polymer like polyethylene glycol, polyvinylpyrrolidone or polyethylene oxide. This is followed by stage two where the oligoneucleotide is attached to the polymer by oxidation or reduction. The presence of hydrophilic polymers in the polymer matrix enhances the permeability of the polymer to anionic molecules such as oligonucleotides. Oligoneucleotides have a very short life as they are rapidly digested by nucleases in the body. Therefore, the present invention is advantageous as it protects the oligoneuclotides in the polymer matrix and delivers them on the desired site where they can act effectively. In-vivo studies were carried out in New Zealand rabbits and the coated stents were implanted in abdominal aorta. After 15 days the artery was removed and histology was performed. It was observed that there was no thrombus formation and the proliferative layer which covered the stent was more organized and had a layer of endothelial cells on the top. This shows that the stents were well tolerated after implantation.73 A similar device has been described by Jager et al.74 Medical devices such as catheters, guidewires, pacemakers and defibrillators coated with conducting polymer doped with therapeutic molecule have proved quite effective. Minteer and Ulyanova75 are inventors on a patent which also discussed similar matrix type devices and their method of fabrication. The patent classifies the therapeutic agent as an imprint molecule (IM) and the conducting polymer as an electroactive molecularly imprinted polymer (EMIP). The release of the drug molecule at the target location is dependent upon the change in electro-conformation of the conducting polymer on the application of electric potential. The state of the art defines the IM incorporated into the polymer during electropolymerization occupies a three dimensional space, the binding site, within the EMIP. The IM is encapsulated within the polymer matrix and is held by various electrical and mechanical forces without the formation of any covalent chemical bound. Such a device has wide application in drug delivery and biosensing.


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Weber et al. reported the development of implantable drug delivery device for localized drug delivery, specifically to the interior of the blood vessel. The device is also equipped with a sensor that detects the presence of any lesions or plaques on the interior of the vessels. By combining sensing and drug delivery elements the drug can be delivered by the electroactive polymer matrix according to the conditions in the local environment.

11.7.4 Miscellaneous Devices 11.7.4.1 Implantable Electrodes Cochlear implants consist of an electrode array implanted into the scala tympani of the cochlea to electrically stimulate spiral ganglionic neurons (SGNs) and, therefore, provide auditory perception to individuals with hearing loss. However, such implants can themselves cause loss of residual hair cells and apoptosis of SGNs due to the delivered charge. To overcome this problem Richardson et al.77 developed an electrode array in which PPy encapsulating therapeutic neutrophins (NT3) was coated on to the implantable electrodes. The developed electrode array is presented in the Figure 11.7. Neutrophins have protective effects and prevent the loss of SGNs. About 2 ng of NT3 was encapsulated in the electrode array and was able to release 0.1 ng/day with electrical stimulation when implanted into deafened guinea pig cochleae. The electrode array not only provided electrical stimulation but was also able to deliver the trophic agents to the SGNs preventing its degeneration after hearing loss.

11.7.4.2

Nanostructured Conducting Polymers for Drug Delivery Systems

To date functionalized nanostructured conducting polymer surfaces have gained much interest in the field of DDS. Various methods such as hardtemplates and soft-templates have been introduced in the synthesis of conducting polymer micro- or nanostructures.78 The references cited here particularly highlight the specific attributes in the synthesis of nanostructured surfaces and their application to drug delivery. Luo and Cui79 developed electrically controlled DDS based on sponge-like nanostructured PPy. They utilized self-assembled polystyrene nanobeads as the hard template for forming nanostructures. After electropolymerization of PPy, the template was removed leaving nanopores in the PPy film. The proposed system can load multiple drug molecules in the polymer backbone during PPy polymerization as a dopant, and a second drug can be loaded into the nanostructures inside the polymer film. These nanostructures then can be sealed by electroploymerizing a second thin layer of PPy on top. This kind of system therefore significantly improves the drug loading capacity as the overall effective surface area of the film is increased and the initial burst effect is prevented by the bilayer. Upon electrical stimulation, drug molecules incorporated in the backbone were released via a

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Four-ring platinum electrode array for implantation in guinea pigs (GP). (a) The electrode array consisted of four active electrodes individually wired for stimulation as electrode pairs and an extra-cochlear electrode as a marker for insertion depth. Diagram is not drawn to scale. (b) An electrode array coated with Ppy/pTS implanted into a GP cochlea. The fourth electrode can be seen protruding from the cochleostomy in this example. The fifth uncoated platinum extra-cochlear electrode is also visible. (Reproduced with permission from Ref. 76.)

dedoping process, while those physically encapsulated in the nanopores were squeezed out owing to the actuation of the nanoporous film. This kind of drug delivery system has applicability in cases where delivery of a combination of drugs is necessary. The actuation of conducting polymer nanotubes is another approach that has been used to achieve controlled release.80,81 An advantage of this approach is that drug loading and release can be achieved regardless of whether or not the drug is charged. Nanotubes consist of an open lumen enclosed by a cylindrical ICP layer. The lumen can be filled with drug. Presumably, drug release is achieved by electrically altering the permeability of drug through the ICP wall.


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Sirivisoot et al. used multi-walled carbon nanotubes grown out of anodized titanium (MWNT-Ti) as a template to electrodeposit PPy by cyclic voltammetry. PPy was doped with therapeutic agents such as penicillin/ streptomycin or dexamethasone. Drug release was studied on application of a negative voltage. The results showed a controllable biphasic release profile and the cumulative amount released was about 80% after 5 cycles of the applied voltages at a scan rate of 0.1 Vs1. Abidian et al.80 developed conducting polymer nanotubes utilizing biodegradable poly(L-lactide) (PLLA) or poly(lactide-co-glycolide) (PLGA) as templates onto gold coated silicon wafers as a substrate. The drug (dexamethasone) was incorporated into the template. The biodegradable polymer was electrospun onto the substrate, followed by electropolymerization of conducting polymer (PEDOT). The PLLA/PLGA nanofibers were then dissolved creating nanotubular PEDOT. The nanotubes were electrically actuated by applying a positive potential of 1 V. With the electrical stimulation of nanotubes the release of bioactives can be precisely controlled and achieved for 58 days. Later the approach was transformed into an implantable medical device capable of controlled delivery of bioactives.82 Such devices can be useful, in the manufacture of improved microelectromechanical systems (MEMS), electrode-based devices for long-term implantation in the central nervous system (CNS), development of new generation of cardiac, musculoskeletalelectrophysiological devices, and implantable electrical and biomolecule sensors and drug delivery devices. Ferain et al.83 disclosed the development of a drug eluting nanowire array. The nanoscopic sized wire in the array is available in two configurations. In one configuration it is a conductive metallic wire, made up of metals including Cu, Pt, Au, Ni or Pd coated with conducting polymer doped with drug molecules. In the second configuration the array is present as hollow nanoscopic wire formed from electroactive conjugated polymer, containing a therapeutic molecule. Such types of nanowire array can be incorporated into stimulation electrodes at the interface with biological tissues. They can act to reduce both nerve damage and contact impedance. Impedance is reduced as the capillary like structure of the nanowires increases the real area to geometric area ratio of the electrode in contacts. Such systems also provide an accurate and controlled local drug delivery and therefore are suitable for neurological disorders related to spinal cord injuries.

11.8 Demonstration of Biological Applications The exciting potential of ICPs to achieve tunable drug delivery is frequently described in the literature; this is slowly becoming a reality in biological systems. Ge et al.84 developed a novel dual stimuli responsive nanoparticle system in which the rates of drug release can electrically controlled. Polypyrrole nanoparticles loaded with drug molecules were prepared by an emulsion polymerization technique. These nanoparticles are then suspended in a temperature sensitive hydrogel, which is a liquid at low temperature but

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becomes a gel at body temperature. They successfully demonstrated the in-vivo drug release in mice by applying an external electric field. Similarly cochlear implants loaded with neutrophins as developed by Richardson et al.77 have demonstrated their in-vivo effectiveness in delivering neurotrophic agents neurons in a controlled manner to preserve their activity. In addition the electrical stimulation provided by the implant minimizes the degeneration of SGNs after hearing loss. Implantable heart valve prosthetic devices including annuloplasty rings and bands coated with ICPs when implanted in animals exhibited a tremendous reduction in inflammation and pannus formation.85 As DDS based on ICPs become more sophisticated and reliable we will see an increasing number of reports moving these systems from the lab bench into biological models. To date, these delivery systems have found use where local delivery of drug is required. Before these systems can be applied to a wider range of medical conditions the level of drug that can be loaded and released must be increased. This will allow the systemic delivery of drug and will demonstrate the versatility of ICPs to act as a drug delivery platform which can be used to treat a range of health conditions.

11.9 Conclusions ICP based devices are beginning to fulfill their exciting potential in drug delivery science. The inherent redox properties and the actuation behavior on electrical stimulation make ICPs a promising platform for delivering drugs at a controlled rate to desired locations. The rate of drug release can be modulated according to an individual patient’s condition. Apart from reservoir and matrix systems, nanostructured systems such as nanotubes, nanowires, nanofibers and nanofilms appear to be promising, as increased surface area allows enhanced loading of the therapeutic molecule. These nanostructured ICPs can be appropriately functionalized or tagged and can act as excellent biosensing materials. ICP-hydrogel composites combine the swelling properties of hydrogels and the electroactivity of ICPs making them a versatile tool for delivering drugs at a controlled rate. On-demand release of drug is possible from these smart polymers by simply switching between redox states. With the novel technologies discussed in this chapter practical applications of ICPs are imminent. Hence research and development is currently exploring further applications of these interesting materials in drug delivery and biomedical science.

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