Fractional laser ablation breaches the skin barrier by simply removing the skin tissue – energy of a specific wavelength is focused to create the micropore array. This energy can be controlled to enable selective removal of SC or the entire epidermis. At higher laser energies pores reaching deeper into dermis can also be created. Since the barrier is compromised intensively, formulation needs to be manufactured under sterile conditions. From a practical point of view laser skin ablation can provide faster, more reliable and reproducible results in comparison to solid microneedles. It has also been used to treat some skin conditions and diseases alone; plus can be used with tissues like nails, where the absorption of drugs is very limited [50]. Currently, the laser is principally used in aesthetics and odontology with different purposes, but recent studies on laser-assisted drug delivery into the skin appears very promising [6,51-54].
23 reaction and can differ depending on the laser used. The laser energy interacts with the tissue causing its vaporization; depending on the emission wavelength different structures can be affected. Mid-infrared lasers i.e. Er:YAG emits light at 2936 nm, produce a photomechanical reaction with the skin. The maximum absorption of the water molecules corresponds to the emission wavelength of these lasers. When the laser beam hits the skin, it produces an excitation of the water molecules, leading to an explosive evaporation that forms the craters or micropores.
Given the “water selectivity” of these lasers, the thermal damage to the nearby tissue is reduced.
Far infrared lasers i.e. CO2 emits at 10600 nm, produce a thermomechanical reaction that can affect the dermal proteins and vessels [55,56]. Similar to emission wavelength, the pulse duration is an important factor too. Applying a pulse duration shorter than the water relaxation time, the heat transfer to the surrounding tissue is reduced [6]. The energy applied in function of the area (J/cm2), known as fluence, is a very important parameter that allows controlling the depth of the micropores. The more energy applied in the same spot, the deeper the pore will be.
It is important to highlight that the lasers currently used for drug delivery are fractional ablation lasers that can ablate from 5 to 20% of the skin surface that means there are regions of intact skin between ablated area (total >80 % of the total treated area) which expedites skin healing and closure of pores [57]. The specificity of these lasers allows minimizing the skin damage, reducing the risks of scarring, irritation and erythema. Several commercially available laser instruments are presented in Figure 3.
Figure 3. Laser instruments: (a) Epiture Easytouch by Norwood Abbey, Ltd. [58]; (b) P.L.E.A.S.E. Professional (painless laser epidermal system) device by Pantec Biosolutions [59]; (c) P.L.E.A.S.E. Private device by Pantec Biosolutions [59]; and (d) PinPointe FootLaser by PinPointe USA, Inc [60].
Work to-date has demonstrated that the technique can increase the rate and the extent of the delivery of small molecules [6,61-63], peptides and proteins [51,53] into and across the skin
a. b. c. d.
24 ablation by definition completely removes the SC at the very least; hence the formulation approach must be re-considered. Once the skin barrier is gone, drug can be continuously delivered from any kind of formulation. This enables the delivery to be controlled by varying the formulation characteristics. In principle, formulation application could be repeated at the same microporation site as long as the pores remained open − a conservative estimate would be for 48 to 72 h – beyond that time interval, a new micropore array must be created. However, from a clinical perspective, it would be of considerable interest to be able to introduce an intraepidermal drug depot where the natural healing process after microporation would close the skin around it. The depot would have different drug release kinetics to a formulation applied topically to the skin surface and would enable sustained drug release over a more prolonged time frame. This intraepidermal drug depot is clearly analogous to the well-known subcutaneous and intramuscular depots that are frequently used in therapy to enable prolonged systemic release of peptide therapeutics, e.g. gonadotropin-releasing hormone agonists and antagonists [65].
The efficacy of some dermatological therapies might be improved by the use of “high dose”
intraepidermal drug reservoir systems that enable sustained and targeted local drug delivery.
The Chapter 5 and Chapter 6 investigates an interesting approach of creating intraepidermal depot of triamcinolone acetonide for the management of keloids and hypertrophic scars and depot of cetuximab, a monoclonal antibody, for treating psoriasis. The specific objectives of this study were to develop and to optimize a new technique to prepare stable drug loaded microparticles with high drug loading. The sustained delivery of drugs from the developed and optimized microparticles were then evaluated using the confocal laser scanning microscopy (CLSM) technique (qualitatively) and finally, quantitative biodistribution (the amounts of drug as a function of position) in the skin following release from the skin deposited microparticles was also evaluated.
25 [1] R.O. Potts, M.L. Francoeur, The influence of stratum corneum morphology on water permeability, J. Invest. Dermatol., 96 (1991) 495-499.
[2] A. Naik, Y.N. Kalia, R.H. Guy, Transdermal drug delivery: overcoming the skin's barrier function, Pharm. Sci. Technolo. Today, 3 (2000) 318-326.
[3] M.N. Pastore, Y.N. Kalia, M. Horstmann, M.S. Roberts, Transdermal patches: history, development and pharmacology, Br. J. Pharmacol., 172 (2015) 2179-2209.
[4] Y.N. Kalia, A. Naik, J. Garrison, R.H. Guy, Iontophoretic drug delivery, Adv. Drug Deliv.
Rev., 56 (2004) 619-658.
[5] E. Larraneta, M.T. McCrudden, A.J. Courtenay, R.F. Donnelly, Microneedles: A New Frontier in Nanomedicine Delivery, Pharm. Res., 33 (2016) 1055-1073.
[6] Y.G. Bachhav, S. Summer, A. Heinrich, T. Bragagna, C. Bohler, Y.N. Kalia, Effect of controlled laser microporation on drug transport kinetics into and across the skin, J. Control.
Release, 146 (2010) 31-36.
[7] E.P. Spugnini, A. Melillo, L. Quagliuolo, M. Boccellino, B. Vincenzi, P. Pasquali, A. Baldi, Definition of novel electrochemotherapy parameters and validation of their in vitro and in vivo effectiveness, J. Cell Physiol., 229 (2014) 1177-1181.
[8] G. Merino, Y.N. Kalia, M.B. Delgado-Charro, R.O. Potts, R.H. Guy, Frequency and thermal effects on the enhancement of transdermal transport by sonophoresis, J. Control. Release, 88 (2003) 85-94.
[9] C. Cullander, G. Rao, R.H. Guy, Why silver/silver chloride? Criteria for iontophoresis electrodes, in: K.R. Brian, V.J. James, K.A. Walters (Eds.) 3rd International conference on prediction of percutaneous penetration, STS Publishing, Cardiff (Wales), La Grande Motte, France, 1993, pp. 381-390.
[10] D.R. Kalaria, P. Patel, V. Merino, V.B. Patravale, Y.N. Kalia, Controlled iontophoretic transport of huperzine A across skin in vitro and in vivo: effect of delivery conditions and comparison of pharmacokinetic models, Mol. Pharm., 10 (2013) 4322-4329.
[11] R.J. Scheuplein, I.H. Blank, Permeability of the skin, Physiol. Rev., 51 (1971) 702-747.
[12] S. Monash, Location of the superficial epithelial barrier to skin penetration, J. Invest.
Dermatol., 29 (1957) 367-376.
[13] Y. Chen, I. Alberti, Y.N. Kalia, Topical iontophoretic delivery of ionizable, biolabile aciclovir prodrugs: A rational approach to improve cutaneous bioavailability, Eur. J. Pharm.
Biopharm., 99 (2016) 103-113.
26 delivery of pramipexole: electrotransport kinetics in vitro and in vivo, Eur. J. Pharm.
Biopharm., 88 (2014) 56-63.
[15] D.R. Kalaria, P. Patel, V. Patravale, Y.N. Kalia, Comparison of the cutaneous iontophoretic delivery of rasagiline and selegiline across porcine and human skin in vitro, Int.
J. Pharm., 438 (2012) 202-208.
[16] M.F. Piercey, Pharmacology of pramipexole, a dopamine D3-preferring agonist useful in treating Parkinson's disease, Clin. Neuropharmacol., 21 (1998) 141-151.
[17] M. Horstink, E. Tolosa, U. Bonuccelli, G. Deuschl, A. Friedman, P. Kanovsky, J.P. Larsen, A. Lees, W. Oertel, W. Poewe, O. Rascol, C. Sampaio, Review of the therapeutic management of Parkinson's disease. Report of a joint task force of the European Federation of Neurological Societies and the Movement Disorder Society–European Section. Part I: early (uncomplicated) Parkinson's disease, Eur. J. Neurol., 13 (2006) 1170-1185.
[18] L.W. Elmer, J.M. Bertoni, The increasing role of monoamine oxidase type B inhibitors in Parkinson's disease therapy, Expert Opin. Pharmacother., 9 (2008) 2759-2772.
[19] P. Jenner, Preclinical evidence for neuroprotection with monoamine oxidase-B inhibitors in Parkinson’s disease, Neurology, 63 (2004) S13-S22.
[20] P.A. LeWitt, MAO-B inhibitor know-how: back to the pharm, Neurology, 73 (2009) 2048.
[21] R. Wang, H. Yan, X.C. Tang, Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine, Acta Pharmacol. Sin., 27 (2006) 1-26.
[22] X.C. Tang, P. De Sarno, K. Sugaya, E. Giacobini, Effect of huperzine A, a new cholinesterase inhibitor, on the central cholinergic system of the rat, J. Neurosci. Res., 24 (1989) 276-285.
[23] B.S. Wang, H. Wang, Z.H. Wei, Y.Y. Song, L. Zhang, H.Z. Chen, Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis, J. Neural. Transm. (Vienna), 116 (2009) 457-465.
[24] N. Abla, A. Naik, R.H. Guy, Y.N. Kalia, Contributions of electromigration and electroosmosis to peptide iontophoresis across intact and impaired skin, J. Control. Release, 108 (2005) 319-330.
[25] J. Cazares-Delgadillo, C. Balaguer-Fernandez, A. Calatayud-Pascual, A. Ganem-Rondero, D. Quintanar-Guerrero, A.C. Lopez-Castellano, V. Merino, Y.N. Kalia, Transdermal iontophoresis of dexamethasone sodium phosphate in vitro and in vivo: effect of experimental parameters and skin type on drug stability and transport kinetics, Eur. J. Pharm. Biopharm., 75 (2010) 173-178.
27 of thyrotropin releasing hormone across excised nude mouse skin, J. Pharm. Sci., 75 (1986) 738-743.
[27] V. Merino, A. Lopez, Y.N. Kalia, R.H. Guy, Electrorepulsion versus electroosmosis: effect of pH on the iontophoretic flux of 5-fluorouracil, Pharm. Res., 16 (1999) 758-761.
[28] D. Marro, R.H. Guy, M. Begoña Delgado-Charro, Characterization of the iontophoretic permselectivity properties of human and pig skin, J. Control. Release, 70 (2001) 213-217.
[29] S.R. Patel, H. Zhong, A. Sharma, Y.N. Kalia, In vitro and in vivo evaluation of the transdermal iontophoretic delivery of sumatriptan succinate, Eur. J. Pharm. Biopharm., 66 (2007) 296-301.
[30] I.K. Moppett, K. Szypula, P.M. Yeoman, Comparison of EMLA and lidocaine iontophoresis for cannulation analgesia, Eur. J. Anaesthesiol., 21 (2004) 210-213.
[31] EMA, European Medicines Agency recommends the suspension of the marketing authorisation of Ionsys (fentanyl hydrochloride), (2008) http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2009/11/news_
detail_000249.jsp&mid=WC0b01ac058004d5c1.
[32] EMA, Summary of opinion 1 (initial authorisation) for Ionsys, (2015) http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002715/sm ops/Positive/human_smop_000883.jsp&mid=WC0b01ac058001d127.
[33] B. Schmitt, T. Bernhardt, H.J. Moeller, I. Heuser, L. Frolich, Combination therapy in Alzheimer's disease: a review of current evidence, CNS drugs, 18 (2004) 827-844.
[34] L. Patel, G.T. Grossberg, Combination therapy for Alzheimer's disease, Drugs Aging, 28 (2011) 539-546.
[35] J.P. Lopes, G. Tarozzo, A. Reggiani, D. Piomelli, A. Cavalli, Galantamine potentiates the neuroprotective effect of memantine against NMDA-induced excitotoxicity, Brain Behav., 3 (2013) 67-74.
[36] M. Samochocki, A. Hoffle, A. Fehrenbacher, R. Jostock, J. Ludwig, C. Christner, M.
Radina, M. Zerlin, C. Ullmer, E.F. Pereira, H. Lubbert, E.X. Albuquerque, A. Maelicke, Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors, J. Pharmacol. Exp. Ther., 305 (2003) 1024-1036.
[37] M.D. Santos, M. Alkondon, E.F. Pereira, Y. Aracava, H.M. Eisenberg, A. Maelicke, E.X.
Albuquerque, The nicotinic allosteric potentiating ligand galantamine facilitates synaptic transmission in the mammalian central nervous system, Mol. Pharmacol., 61 (2002) 1222-1234.
28 Tarozzo, A. Reggiani, C. Martini, D. Piomelli, C. Melchiorre, M. Rosini, A. Cavalli, Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer's disease, Journal of medicinal chemistry, 55 (2012) 9708-9721.
[39] A.M. Reggiani, E. Simoni, R. Caporaso, J. Meunier, E. Keller, T. Maurice, A. Minarini, M. Rosini, A. Cavalli, In vivo characterization of ARN14140, a memantine/galantamine-based multi-target compound for Alzheimer's disease, Sci. Rep., 6 (2016) 33172.
[40] S. Del Rio-Sancho, C. Cros, B. Coutaz, M. Cuendet, Y.N. Kalia, Cutaneous iontophoresis of mu-conotoxin CnIIIC-A potent NaV1.4 antagonist with analgesic, anaesthetic and myorelaxant properties, Int. J. Pharm., 518 (2016) 59-65.
[41] S. Dubey, Y.N. Kalia, Non-invasive iontophoretic delivery of enzymatically active ribonuclease A (13.6 kDa) across intact porcine and human skins, J. Control. Release, 145 (2010) 203-209.
[42] S. Dubey, Y.N. Kalia, Electrically-assisted delivery of an anionic protein across intact skin:
cathodal iontophoresis of biologically active ribonuclease T1, J. Control. Release, 152 (2011) 356-362.
[43] Y.B. Schuetz, A. Naik, R.H. Guy, E. Vuaridel, Y.N. Kalia, Transdermal iontophoretic delivery of triptorelin in vitro, J. Pharm. Sci., 94 (2005) 2175-2182.
[44] Y.B. Schuetz, A. Naik, R.H. Guy, E. Vuaridel, Y.N. Kalia, Transdermal iontophoretic delivery of vapreotide acetate across porcine skin in vitro, Pharm. Res., 22 (2005) 1305-1312.
[45] B.R. Meyer, W. Kreis, J. Eschbach, V. O'Mara, S. Rosen, D. Sibalis, Transdermal versus subcutaneous leuprolide: a comparison of acute pharmacodynamic effect, Clin. Pharmacol.
Ther., 48 (1990) 340-345.
[46] T. Gratieri, D. Kalaria, Y.N. Kalia, Non-invasive iontophoretic delivery of peptides and proteins across the skin, Expert Opin. Drug. Deliv., 8 (2011) 645-663.
[47] M.B. Delgado-Charro, R.H. Guy, Iontophoretic delivery of nafarelin across the skin, Int.
J. Pharm., 117 (1995) 165-172.
[48] S. Dubey, Y.N. Kalia, Understanding the poor iontophoretic transport of lysozyme across the skin: when high charge and high electrophoretic mobility are not enough, J. Control.
Release, 183 (2014) 35-42.
[49] A.J. Hoogstraate, V. Srinivasan, S.M. Sims, W.I. Higuchi, Iontophoretic enhancement of peptides: behaviour of leuprolide versus model permeants, J. Control. Release, 31 (1994) 41-47.
29 efficacy on onychomycosis: a case series of 30 patients, Mycoses, 59 (2016) 7-11.
[51] J. Yu, D.R. Kalaria, Y.N. Kalia, Erbium:YAG fractional laser ablation for the percutaneous delivery of intact functional therapeutic antibodies, J. Control. Release, 156 (2011) 53-59.
[52] R. Weiss, M. Hessenberger, S. Kitzmüller, D. Bach, E.E. Weinberger, W.D. Krautgartner, C. Hauser-Kronberger, B. Malissen, C. Boehler, Y.N. Kalia, J. Thalhamer, S. Scheiblhofer, Transcutaneous vaccination via laser microporation, J. Control. Release, 162 (2012) 391-399.
[53] Y.G. Bachhav, A. Heinrich, Y.N. Kalia, Controlled intra- and transdermal protein delivery using a minimally invasive Erbium:YAG fractional laser ablation technology, Eur. J. Pharm.
Biopharm., 84 (2013) 355-364.
[54] Y.G. Bachhav, A. Heinrich, Y.N. Kalia, Using laser microporation to improve transdermal delivery of diclofenac: Increasing bioavailability and the range of therapeutic applications, Eur.
J. Pharm. Biopharm., 78 (2011) 408-414.
[55] Y.N. Kalia, Y.G. Bachhav, T. Bragagna, C. Böhler, P.L.E.A.S.E.® (Painless Laser Epidermal System). A new laser microporation technology, Drug Deliv. Technol., 8 (2008) 26–
31.
[56] E.V. Ross, Y. Domankevitz, M. Skrobal, R.R. Anderson, Effects of CO2 laser pulse duration in ablation and residual thermal damage: implications for skin resurfacing, Lasers Surg. Med., 19 (1996) 123-129.
[57] C.K. Rokhsar, R.E. Fitzpatrick, The treatment of melasma with fractional photothermolysis: a pilot study, Dermatol. Surg., 31 (2005) 1645-1650.
[58] B. Stening, Making drugs hurt less and work better, http://www.curvelive.com/Magazine/Archives/three/Making-drugs-hurt-less-and-work-better Accessed on 05.07.2017.
[59] PantecBiosolutions, P.L.E.A.S.E.® Devices, https://www.pantec-biosolutions.com/en/technology/p-l-e-a-s-e-devices Accessed on 03.09.2017.
[60] Cynosure, PinPointe FootLaser, https://www.cynosure.com/product/pinpointe/ Accessed on 05.09.2017.
[61] E.H. Taudorf, C.M. Lerche, A.C. Vissing, P.A. Philipsen, J. Hannibal, J. D'Alvise, S.H.
Hansen, C. Janfelt, U. Paasch, R.R. Anderson, M. Haedersdal, Topically applied methotrexate is rapidly delivered into skin by fractional laser ablation, Expert Opin. Drug Deliv., (2015) 1-11.
30 Anderson, M. Haedersdal, Ablative fractional laser alters biodistribution of ingenol mebutate in the skin, Arch Dermatol Res, 307 (2015) 515-522.
[63] J. Yu, Y.G. Bachhav, S. Summer, A. Heinrich, T. Bragagna, C. Bohler, Y.N. Kalia, Using controlled laser-microporation to increase transdermal delivery of prednisone, J. Control.
Release, 148 (2010) e71-73.
[64] D. Terhorst, E. Fossum, A. Baranska, S. Tamoutounour, C. Malosse, M. Garbani, R. Braun, E. Lechat, R. Crameri, B. Bogen, S. Henri, B. Malissen, Laser-assisted intradermal delivery of adjuvant-free vaccines targeting XCR1+ dendritic cells induces potent antitumoral responses, J. Immunol., 194 (2015) 5895-5902.
[65] D. Teutonico, S. Montanari, G. Ponchel, Leuprolide acetate: pharmaceutical use and delivery potentials, Expert Opin. Drug Deliv., 9 (2012) 343-354.