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Electrochemical bubble rip: A new approach to controlled drug release
Electrochemistry Communications 60 (2015) 88–91
Contents lists available at ScienceDirect
Electrochemistry Communications journal homepage: www.elsevier.com/locate/elecom
Electrochemical bubble rip: A new approach to controlled drug release Ashleigh Anderson, Aaron McConville, James Davis ⁎ School of Engineering, University of Ulster, Jordanstown, Northern Ireland, BT37 0QB, UK
a r t i c l e
i n f o
Article history: Received 4 August 2015 Received in revised form 7 August 2015 Accepted 7 August 2015 Available online 14 August 2015 Keywords: Electrode Electrochemical Drug release MEMS Methotrexate Hydrogen
a b s t r a c t Cellulose acetate phthalate films are widely used as controlled release enteric coatings within the pharmaceutical industries but their properties have hitherto been unexplored within electrochemical devices. A novel approach employing controlled electrolysis has been investigated to develop a means through which the protective films can be compromised thereby enabling the release of candidate drugs. The generation of bubbles and local pH manipulation are considered and the former shown to enable rapid removal of the film and initiate reagent release. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Patient compliance with treatment regimes is a perennial problem and considerable effort is being expended to develop new approaches to controlled drug release [1,2]. Microdevices whether implants, lab on a pill or smart patch formats have long been proposed as the next stage in enhancing patient healthcare through facilitating the automatic regulation of therapeutic delivery [3–5]. Sensor-actuator systems are beginning to emerge and are typified by the commercial availability of insulin pumps [6] but while there is a significant knowledge base dedicated to the sensing component, controlling the release of drugs at smaller scales remains a challenge. One area which is particularly ripe for exploration relates to the development of unobtrusive smart devices that can detect and respond to allergen anaphylaxis where a rapid response is often required and where issues over availability, responsibility for administration and the associated time delays in administering the appropriate antidote can be life threatening [7,8]. The aim of the present communication has been to investigate the development of an electrochemical trigger mechanism which could facilitate the controlled release of a model drug. Conventional oral delivery technologies tend to be based around encapsulant systems in which polymeric binders or gels respond to changes in the local environment (typically pH) with dissolution of the coating resulting in the release of the therapeutic agent [9–13]. Rather than rely on exposure of such films to a physico-chemical trigger (i.e. high pH intestinal fluid), the intention herein has been to initiate
⁎ Corresponding author. Tel.: +44 28 903 66407. E-mail address: [email protected] (J. Davis).
http://dx.doi.org/10.1016/j.elecom.2015.08.008 1388-2481/© 2015 Elsevier B.V. All rights reserved.
rupture of the protective film as a consequence of simply employing a reducing potential. The mechanism is based on a cellulose acetate phthalate (CAP) film, commonly used as an enteric coating in oral tablet formulations [9], which is supported on a conductive carbon fibre (CF) mesh. Upon employing a sufficient reducing potential, it could be expected that hydrogen evolution will commence leading to bubble formation at the CAP-CF interface introducing a degree of mechanical stress which will induce rupture of the film. The basic approach is highlighted in the schematic in Fig. 1. The imposition of the reducing potential will also lead to an increase in local pH at the protective film interface which will also compromise the integrity of the film through gradual solubilisation and dissolution – much in the same way as would be expected with its conventional use as an enteric coating. The exploitation of electrolytic processes in small scale microdevices has been previously investigated and include: dissolution of metallic wrappers [14] and the inflation of parylene micro pumps [15,16] but this is the first description of the controlled physical rupture of an impermeable organic seal that could be useful for incorporation within drug delivery devices. 2. Experimental details Electrochemical analysis and set up was performed utilizing a μAutolab Type III computer operated potentiostat (Eco-Chemie, Utrecht, The Netherlands). All measurements were conducted at 22 °C ± 2 °C. Conductive carbon films and other electrode substrates were supplied by Goodfellow Research Materials. The initial measurements were set up applying a three electrode configuration comprising of carbon (composite film or microfiber) working electrode, a counter electrode in the form of a platinum wire and a standard silver/silver chloride
A. Anderson et al. / Electrochemistry Communications 60 (2015) 88–91
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2.1. Preparation of the Electrode Reservoir Gate Carbon fibre mat (Toray) consisting of 10 μm fibres compressed into a thin three dimensional mesh was used as the working electrode with the circuit connection accomplished through the use of an adhesive copper tape. A thin layer of cellulose acetate phthalate (Sigma) was solvent cast from a 10 mg/mL acetonitrile solution on to a layer of carbonpolyethylene (Goodfellow). The CAP film was carefully removed and placed on top of the carbon fibre and both sandwiched between polyester laminate sheets that had been pre-patterned to reveal a square window on either side. The basic approach has been described previously [17] but in this instance, rather than have carbon exposed on both sides of the window, the CAP film completely blocks and insulates one side. 3. Results and discussion
Fig. 1. Cyclic voltammograms detailing the responses recorded at the carbon fibre electrode after electrolysis (−2 V, 30 s) and subsequent rupture of the cellulose acetate phthalate film. Scan rate: 50 mV/s. Inset: schematic of the cell configuration.
(3 M NaCl, BAS Technicol UK) reference electrode. Methotrexate, (2S)2-[(4-{[(2,4-Diaminopteridin-6-yl)methyl] (methyl)amino}benzoyl) amino] pentanedioic acid, was obtained from Sigma Aldrich.
The carbon fibre electrode was sealed between two reservoirs as indicated in the schematic in Fig. 1. The CAP film side of the electrode faced the drug reservoir which, in this instance, contained ferrocyanide (2 mM, 0.1 M KCl) as the model drug. The exposed carbon side resided in the delivery reservoir which contained only 0.1 M KCl adjusted to pH 3 in order to minimise the hydrolysis/dissolution of the film. The counter and reference electrodes were also placed within the delivery side and completed the electrochemical cell. Cyclic voltammograms were recorded and showed only the background as indicated in Fig. 1. This was anticipated as the ferrocyanide is blocked from passing from one side to the other as a consequence of the CAP film being intact. Upon holding the potential of the carbon fibre electrode at − 2 V for 30 s, electrolysis commences with generation of hydrogen bubbles at the electrode typically occurring within the first 5 s. It was envisaged
Fig. 2. Pictures of the CAP-CF film before and after commencing the electrolysis. Square wave voltammograms detailing the influence of local pH on the carbon-quinoid moieties peak position pre and post electrolysis.
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A. Anderson et al. / Electrochemistry Communications 60 (2015) 88–91
that these would rupture the film resulting in the transport of ferrocyanide through the carbon fibre matrix leading to the delivery side of the cell. Cyclic voltammograms detailing the response obtained at the carbon fibre electrode with time post rupture are compared in Fig. 1. The peak responses can be seen to increase as the ferrocyanide passes through the fibre network. Confirmation that the bubble formation is indeed responsible for the rapid rupture of the film is provided in Fig. 2 where video stills capture the electrolysis process before and after the commencement of the reducing potential. It can be seen from Fig. 2 that a minor rip emerges in the film as the bubble of hydrogen is released. It must also be noted that there will be an increase in the local pH within the fibre mesh as the protons are reduced. This was confirmed through examining the peak position of quinoid functionalities on the surface of the anodised carbon fibre [18,19]. Such species are endogenous to carbon substrates and their population can be markedly increased through the use of electrochemical anodisation [18]. Crucially, the peak position is pH dependent and thus can serve as an indirect marker of local pH. In the present investigation, the carbon fibre was anodised as described previously and a calibration group detailing the response of the quinoid oxidation peak to varying pH covers the range pH 3 to pH 10. The response was found to be linear (E/V = −0.069 pH + 0.428; N = 8; R2 = 0.994) although the gradient is larger than Nernstian predictions [18,19]. In order to assess the change in pH as a consequence of the electrolysis, the anodised carbon fibre was placed in the KCl electrolyte (adjusted to pH 3 in accordance with the previous study detailed in Fig. 1). Square wave voltammograms were recorded before and after the imposition of the electrolysis conditioning step and are detailed in Fig. 2. It can be seen that there is a distinct shift in the peak process and can be attributed to the increase in local pH. The peak returns to the pre conditioning potential shortly after the electrolysis has finished as the bulk solution returns the pH to the initial state. CAP films are known to undergo hydrolysis/dissolution at pH 8 or above and therefore the fact that the pH can be manipulated within the film offers an alternative approach to controlling the release. The electrolytic approach therefore offers two modes of action: rapid release as a consequence of the mechanical force exerted by the formation of the bubbles. The ability of the approach to release an actual drug was assessed through replacing the ferrocyanide with methotrexate, a common chemotherapeutic agent [20,21]. The electrochemical properties of the drug are not as pronounced as those of ferrocyanide – exhibiting irreversible oxidation as a consequence of the tertiary amino group. As such, the decision was made to monitor the transport of the drug through the fibre to the delivery side through UV–vis spectroscopy. The drug was dissolved in pH 7 buffer to yield a 0.2 mM solution and placed on the CAP side. The delivery side contained only KCl. A spectrum of the delivery side was taken before the imposition of the electrolysis potential and then at 5 min intervals after the CAP film had been ruptured. The resulting spectra are shown in Fig. 3 along with the spectrum of methotrexate before any manipulation (Inset) had taken place. The spectra show the sustained transport of the methotrexate through the carbon fibre gate by diffusion transport. The structure of methotrexate is relatively complex and contains a number of electrochemically active groups and it could be suggested that electrochemical control would lead to the drug being altered and its bioactivity compromised. It must be remembered that the electrolysis is only applied for a matter of seconds and therefore, with the exception of the material directly at the interface, is unlikely to affect the majority of the material within the drug reservoir. The release of hydrogen as the bubble rip initiator must be viewed with a modicum of caution but it must be remembered that the intention is for its implementation on a microdevice and not at the macro scale. The quantity of hydrogen being released will be very small and, in any case, there are numerous studies that have shown the beneficial aspects of the gas within physiological systems [22–24] – albeit at low level. The presence of hydrogen should not directly preclude its consideration.
Fig. 3. UV spectra detailing the emergence of methotrexate through the ruptured CAP-CF gate into the delivery chamber. Solution sampled at 5 min intervals following the electrolysis.
4. Conclusions Protective coatings are widely used in conventional drug release systems but it has been shown in this report that electrochemical activation through the imposition of a sufficiently negative potential can induce controlled rupture of a cellulose acetate phthalate film. Electrochemical generation of hydrogen bubbles and the subsequent mechanical strain can enable rapid, on demand, release rather than relying on the gradual solubilisation of the film in solutions of higher pH. Acknowledgments The authors acknowledge the support of the Department of Education and Learning (DEL) Northern Ireland in funding the work. References [1] G. Dailey, M.S. Kim, J.F. Lian, Clin. Ther. 23 (2001) 1311–1320. [2] M.L. Tarrants, M.F. Denarié, J. Castelli-Haley, J. Millard, D. Zhang, Am. J. Geriatr. Pharmacother. 8 (2010) 374–383. [3] A. Cobo, R. Sheybani, E. Meng, Adv. Healthcare Mater. 4 (2015) 969–982. [4] A. Anderson, J. Davis, Electroanalysis 27 (2015) 872–878. [5] E. Nuxoll, Adv. Drug Deliv. Rev. 65 (2013) 1611–1625. [6] E. Renard, C. Cobelli, B.P. Kovatchev, Diabetes Res. Clin. Pract. 102 (2013) 79–85. [7] R.L. Campbell, V. Manivannan, M.F. Hartz, A.T. Sadosty, Pediatr. Emerg. Care 28 (2012) 938–942. [8] V. Manivannan, R.J. Hyde, D.G. Hankins, M.F. Bellolio, M.G. Fedko, W.W. Decker, R.L. Campbell, Am. J. Emerg. Med. 32 (2014) 1097–1102. [9] L.A. Felton, S.C. Porter, Expert Opin. Drug Deliv. 10 (2013) 421–435.
A. Anderson et al. / Electrochemistry Communications 60 (2015) 88–91 [10] A. Bertz, S. Wohl-Bruhn, S. Miethe, B. Tiersch, J. Koetz, M. Hust, H. Bunjes, H. Menzel, J. Biotechnol. 163 (2013) 243–249. [11] A. Abbaspourrad, N.J. Carroll, S.H. Kim, D.A. Weitz, J. Am. Chem. Soc. 135 (2013) 7744–7750. [12] K.P. Dasan, C. Rekha, Curr. Drug Deliv. 9 (2012) 588–595. [13] R. Cheng, F.H. Meng, C. Deng, H.A. Klok, Z.Y. Zhong, Biomaterials 34 (2013) 3647–3657. [14] J.T. Santini, M.J. Cima, R. Langer, Nature 397 (1999) 335–358. [15] U.B. Kompella, A.C. Amrite, R.P. Ravi, S.A. Durazo, Prog. Retin. Eye Res. 36 (2013) 172–198. [16] R. Shebani, H. Gensler, E. Meng, Biomed. Microdevices 15 (2013) 37–48. [17] J.S.N. Dutt, M.F. Cardosi, S.J. Wilkins, C. Livingstone, J. Davis, Mater. Chem. Phys. 97 (2006) 267–272.
91
[18] A. Anderson, J. Phair, J. Benson, B.J. Meenan, J. Davis, Mater. Sci. Eng. C. 43 (2014) 533–537. [19] M. Lu, R.G. Compton, Analyst 139 (2014) 4599–4605. [20] E.G. Favalli, M. Biggioggero, P.L. Meroni, Autoimmun. Rev. 13 (2014) 1102–1108. [21] P. Cipriani, P. Ruscitti, F. Carubbi, V. Liakouli, R. Giacomelli, Expert Rev. Clin. Immunol. 10 (2014) 1519–1530. [22] J. Qu, X. Li, J. Wang, W.J. Mi, K.L. Xie, J.H. Qiu, Int. J. Pediatr. Otorhinolaryngol. 76 (2012) 111–115. [23] T. Lekic, A. Manaenko, W. Rolland, N. Fathali, M. Peterson, J. Tang, J.H. Zhang, Acta Neurochir. 111 (2012) 237–241. [24] K.L. Xie, Y.H. Yu, Z.S. Zhang, W.B. Liu, Y.P. Pei, L.Z. Xiong, L.C. Hou, G.L. Wang, Shock 34 (2010) 495–501.
Contents lists available at ScienceDirect
Electrochemistry Communications journal homepage: www.elsevier.com/locate/elecom
Electrochemical bubble rip: A new approach to controlled drug release Ashleigh Anderson, Aaron McConville, James Davis ⁎ School of Engineering, University of Ulster, Jordanstown, Northern Ireland, BT37 0QB, UK
a r t i c l e
i n f o
Article history: Received 4 August 2015 Received in revised form 7 August 2015 Accepted 7 August 2015 Available online 14 August 2015 Keywords: Electrode Electrochemical Drug release MEMS Methotrexate Hydrogen
a b s t r a c t Cellulose acetate phthalate films are widely used as controlled release enteric coatings within the pharmaceutical industries but their properties have hitherto been unexplored within electrochemical devices. A novel approach employing controlled electrolysis has been investigated to develop a means through which the protective films can be compromised thereby enabling the release of candidate drugs. The generation of bubbles and local pH manipulation are considered and the former shown to enable rapid removal of the film and initiate reagent release. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Patient compliance with treatment regimes is a perennial problem and considerable effort is being expended to develop new approaches to controlled drug release [1,2]. Microdevices whether implants, lab on a pill or smart patch formats have long been proposed as the next stage in enhancing patient healthcare through facilitating the automatic regulation of therapeutic delivery [3–5]. Sensor-actuator systems are beginning to emerge and are typified by the commercial availability of insulin pumps [6] but while there is a significant knowledge base dedicated to the sensing component, controlling the release of drugs at smaller scales remains a challenge. One area which is particularly ripe for exploration relates to the development of unobtrusive smart devices that can detect and respond to allergen anaphylaxis where a rapid response is often required and where issues over availability, responsibility for administration and the associated time delays in administering the appropriate antidote can be life threatening [7,8]. The aim of the present communication has been to investigate the development of an electrochemical trigger mechanism which could facilitate the controlled release of a model drug. Conventional oral delivery technologies tend to be based around encapsulant systems in which polymeric binders or gels respond to changes in the local environment (typically pH) with dissolution of the coating resulting in the release of the therapeutic agent [9–13]. Rather than rely on exposure of such films to a physico-chemical trigger (i.e. high pH intestinal fluid), the intention herein has been to initiate
⁎ Corresponding author. Tel.: +44 28 903 66407. E-mail address: [email protected] (J. Davis).
http://dx.doi.org/10.1016/j.elecom.2015.08.008 1388-2481/© 2015 Elsevier B.V. All rights reserved.
rupture of the protective film as a consequence of simply employing a reducing potential. The mechanism is based on a cellulose acetate phthalate (CAP) film, commonly used as an enteric coating in oral tablet formulations [9], which is supported on a conductive carbon fibre (CF) mesh. Upon employing a sufficient reducing potential, it could be expected that hydrogen evolution will commence leading to bubble formation at the CAP-CF interface introducing a degree of mechanical stress which will induce rupture of the film. The basic approach is highlighted in the schematic in Fig. 1. The imposition of the reducing potential will also lead to an increase in local pH at the protective film interface which will also compromise the integrity of the film through gradual solubilisation and dissolution – much in the same way as would be expected with its conventional use as an enteric coating. The exploitation of electrolytic processes in small scale microdevices has been previously investigated and include: dissolution of metallic wrappers [14] and the inflation of parylene micro pumps [15,16] but this is the first description of the controlled physical rupture of an impermeable organic seal that could be useful for incorporation within drug delivery devices. 2. Experimental details Electrochemical analysis and set up was performed utilizing a μAutolab Type III computer operated potentiostat (Eco-Chemie, Utrecht, The Netherlands). All measurements were conducted at 22 °C ± 2 °C. Conductive carbon films and other electrode substrates were supplied by Goodfellow Research Materials. The initial measurements were set up applying a three electrode configuration comprising of carbon (composite film or microfiber) working electrode, a counter electrode in the form of a platinum wire and a standard silver/silver chloride
A. Anderson et al. / Electrochemistry Communications 60 (2015) 88–91
89
2.1. Preparation of the Electrode Reservoir Gate Carbon fibre mat (Toray) consisting of 10 μm fibres compressed into a thin three dimensional mesh was used as the working electrode with the circuit connection accomplished through the use of an adhesive copper tape. A thin layer of cellulose acetate phthalate (Sigma) was solvent cast from a 10 mg/mL acetonitrile solution on to a layer of carbonpolyethylene (Goodfellow). The CAP film was carefully removed and placed on top of the carbon fibre and both sandwiched between polyester laminate sheets that had been pre-patterned to reveal a square window on either side. The basic approach has been described previously [17] but in this instance, rather than have carbon exposed on both sides of the window, the CAP film completely blocks and insulates one side. 3. Results and discussion
Fig. 1. Cyclic voltammograms detailing the responses recorded at the carbon fibre electrode after electrolysis (−2 V, 30 s) and subsequent rupture of the cellulose acetate phthalate film. Scan rate: 50 mV/s. Inset: schematic of the cell configuration.
(3 M NaCl, BAS Technicol UK) reference electrode. Methotrexate, (2S)2-[(4-{[(2,4-Diaminopteridin-6-yl)methyl] (methyl)amino}benzoyl) amino] pentanedioic acid, was obtained from Sigma Aldrich.
The carbon fibre electrode was sealed between two reservoirs as indicated in the schematic in Fig. 1. The CAP film side of the electrode faced the drug reservoir which, in this instance, contained ferrocyanide (2 mM, 0.1 M KCl) as the model drug. The exposed carbon side resided in the delivery reservoir which contained only 0.1 M KCl adjusted to pH 3 in order to minimise the hydrolysis/dissolution of the film. The counter and reference electrodes were also placed within the delivery side and completed the electrochemical cell. Cyclic voltammograms were recorded and showed only the background as indicated in Fig. 1. This was anticipated as the ferrocyanide is blocked from passing from one side to the other as a consequence of the CAP film being intact. Upon holding the potential of the carbon fibre electrode at − 2 V for 30 s, electrolysis commences with generation of hydrogen bubbles at the electrode typically occurring within the first 5 s. It was envisaged
Fig. 2. Pictures of the CAP-CF film before and after commencing the electrolysis. Square wave voltammograms detailing the influence of local pH on the carbon-quinoid moieties peak position pre and post electrolysis.
90
A. Anderson et al. / Electrochemistry Communications 60 (2015) 88–91
that these would rupture the film resulting in the transport of ferrocyanide through the carbon fibre matrix leading to the delivery side of the cell. Cyclic voltammograms detailing the response obtained at the carbon fibre electrode with time post rupture are compared in Fig. 1. The peak responses can be seen to increase as the ferrocyanide passes through the fibre network. Confirmation that the bubble formation is indeed responsible for the rapid rupture of the film is provided in Fig. 2 where video stills capture the electrolysis process before and after the commencement of the reducing potential. It can be seen from Fig. 2 that a minor rip emerges in the film as the bubble of hydrogen is released. It must also be noted that there will be an increase in the local pH within the fibre mesh as the protons are reduced. This was confirmed through examining the peak position of quinoid functionalities on the surface of the anodised carbon fibre [18,19]. Such species are endogenous to carbon substrates and their population can be markedly increased through the use of electrochemical anodisation [18]. Crucially, the peak position is pH dependent and thus can serve as an indirect marker of local pH. In the present investigation, the carbon fibre was anodised as described previously and a calibration group detailing the response of the quinoid oxidation peak to varying pH covers the range pH 3 to pH 10. The response was found to be linear (E/V = −0.069 pH + 0.428; N = 8; R2 = 0.994) although the gradient is larger than Nernstian predictions [18,19]. In order to assess the change in pH as a consequence of the electrolysis, the anodised carbon fibre was placed in the KCl electrolyte (adjusted to pH 3 in accordance with the previous study detailed in Fig. 1). Square wave voltammograms were recorded before and after the imposition of the electrolysis conditioning step and are detailed in Fig. 2. It can be seen that there is a distinct shift in the peak process and can be attributed to the increase in local pH. The peak returns to the pre conditioning potential shortly after the electrolysis has finished as the bulk solution returns the pH to the initial state. CAP films are known to undergo hydrolysis/dissolution at pH 8 or above and therefore the fact that the pH can be manipulated within the film offers an alternative approach to controlling the release. The electrolytic approach therefore offers two modes of action: rapid release as a consequence of the mechanical force exerted by the formation of the bubbles. The ability of the approach to release an actual drug was assessed through replacing the ferrocyanide with methotrexate, a common chemotherapeutic agent [20,21]. The electrochemical properties of the drug are not as pronounced as those of ferrocyanide – exhibiting irreversible oxidation as a consequence of the tertiary amino group. As such, the decision was made to monitor the transport of the drug through the fibre to the delivery side through UV–vis spectroscopy. The drug was dissolved in pH 7 buffer to yield a 0.2 mM solution and placed on the CAP side. The delivery side contained only KCl. A spectrum of the delivery side was taken before the imposition of the electrolysis potential and then at 5 min intervals after the CAP film had been ruptured. The resulting spectra are shown in Fig. 3 along with the spectrum of methotrexate before any manipulation (Inset) had taken place. The spectra show the sustained transport of the methotrexate through the carbon fibre gate by diffusion transport. The structure of methotrexate is relatively complex and contains a number of electrochemically active groups and it could be suggested that electrochemical control would lead to the drug being altered and its bioactivity compromised. It must be remembered that the electrolysis is only applied for a matter of seconds and therefore, with the exception of the material directly at the interface, is unlikely to affect the majority of the material within the drug reservoir. The release of hydrogen as the bubble rip initiator must be viewed with a modicum of caution but it must be remembered that the intention is for its implementation on a microdevice and not at the macro scale. The quantity of hydrogen being released will be very small and, in any case, there are numerous studies that have shown the beneficial aspects of the gas within physiological systems [22–24] – albeit at low level. The presence of hydrogen should not directly preclude its consideration.
Fig. 3. UV spectra detailing the emergence of methotrexate through the ruptured CAP-CF gate into the delivery chamber. Solution sampled at 5 min intervals following the electrolysis.
4. Conclusions Protective coatings are widely used in conventional drug release systems but it has been shown in this report that electrochemical activation through the imposition of a sufficiently negative potential can induce controlled rupture of a cellulose acetate phthalate film. Electrochemical generation of hydrogen bubbles and the subsequent mechanical strain can enable rapid, on demand, release rather than relying on the gradual solubilisation of the film in solutions of higher pH. Acknowledgments The authors acknowledge the support of the Department of Education and Learning (DEL) Northern Ireland in funding the work. References [1] G. Dailey, M.S. Kim, J.F. Lian, Clin. Ther. 23 (2001) 1311–1320. [2] M.L. Tarrants, M.F. Denarié, J. Castelli-Haley, J. Millard, D. Zhang, Am. J. Geriatr. Pharmacother. 8 (2010) 374–383. [3] A. Cobo, R. Sheybani, E. Meng, Adv. Healthcare Mater. 4 (2015) 969–982. [4] A. Anderson, J. Davis, Electroanalysis 27 (2015) 872–878. [5] E. Nuxoll, Adv. Drug Deliv. Rev. 65 (2013) 1611–1625. [6] E. Renard, C. Cobelli, B.P. Kovatchev, Diabetes Res. Clin. Pract. 102 (2013) 79–85. [7] R.L. Campbell, V. Manivannan, M.F. Hartz, A.T. Sadosty, Pediatr. Emerg. Care 28 (2012) 938–942. [8] V. Manivannan, R.J. Hyde, D.G. Hankins, M.F. Bellolio, M.G. Fedko, W.W. Decker, R.L. Campbell, Am. J. Emerg. Med. 32 (2014) 1097–1102. [9] L.A. Felton, S.C. Porter, Expert Opin. Drug Deliv. 10 (2013) 421–435.
A. Anderson et al. / Electrochemistry Communications 60 (2015) 88–91 [10] A. Bertz, S. Wohl-Bruhn, S. Miethe, B. Tiersch, J. Koetz, M. Hust, H. Bunjes, H. Menzel, J. Biotechnol. 163 (2013) 243–249. [11] A. Abbaspourrad, N.J. Carroll, S.H. Kim, D.A. Weitz, J. Am. Chem. Soc. 135 (2013) 7744–7750. [12] K.P. Dasan, C. Rekha, Curr. Drug Deliv. 9 (2012) 588–595. [13] R. Cheng, F.H. Meng, C. Deng, H.A. Klok, Z.Y. Zhong, Biomaterials 34 (2013) 3647–3657. [14] J.T. Santini, M.J. Cima, R. Langer, Nature 397 (1999) 335–358. [15] U.B. Kompella, A.C. Amrite, R.P. Ravi, S.A. Durazo, Prog. Retin. Eye Res. 36 (2013) 172–198. [16] R. Shebani, H. Gensler, E. Meng, Biomed. Microdevices 15 (2013) 37–48. [17] J.S.N. Dutt, M.F. Cardosi, S.J. Wilkins, C. Livingstone, J. Davis, Mater. Chem. Phys. 97 (2006) 267–272.
91
[18] A. Anderson, J. Phair, J. Benson, B.J. Meenan, J. Davis, Mater. Sci. Eng. C. 43 (2014) 533–537. [19] M. Lu, R.G. Compton, Analyst 139 (2014) 4599–4605. [20] E.G. Favalli, M. Biggioggero, P.L. Meroni, Autoimmun. Rev. 13 (2014) 1102–1108. [21] P. Cipriani, P. Ruscitti, F. Carubbi, V. Liakouli, R. Giacomelli, Expert Rev. Clin. Immunol. 10 (2014) 1519–1530. [22] J. Qu, X. Li, J. Wang, W.J. Mi, K.L. Xie, J.H. Qiu, Int. J. Pediatr. Otorhinolaryngol. 76 (2012) 111–115. [23] T. Lekic, A. Manaenko, W. Rolland, N. Fathali, M. Peterson, J. Tang, J.H. Zhang, Acta Neurochir. 111 (2012) 237–241. [24] K.L. Xie, Y.H. Yu, Z.S. Zhang, W.B. Liu, Y.P. Pei, L.Z. Xiong, L.C. Hou, G.L. Wang, Shock 34 (2010) 495–501.