Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the stratum corneum

The skin offers an accessible and convenient site for the administration of medications. To this end, the field of transdermal drug delivery, aimed at developing safe and efficacious means of delivering medications across the skin, has in the past and continues to garner much time and investment with the continuous advancement of new and innovative approaches. This review details the progress and current status of the transdermal drug delivery field and describes numerous pharmaceutical developments which have been employed to overcome limitations associated with skin delivery systems. Advantages and disadvantages of the various approaches are detailed, commercially marketed products are highlighted and particular attention is paid to the emerging field of microneedle technologies.

[1]  F. Hetzel,et al.  Laser-assisted penetration of topical anesthetic in adults. , 2003, Archives of dermatology.

[2]  Thakur Raghu Raj Singh,et al.  Hydrogel-Forming Microneedle Arrays for Enhanced Transdermal Drug Delivery , 2012, Advanced functional materials.

[3]  R. Guy,et al.  Iontophoresis of Bases, Nucleosides, and Nucleotides , 1996, Pharmaceutical Research.

[4]  P. Laurent,et al.  Evaluation of the clinical performance of a new intradermal vaccine administration technique and associated delivery system. , 2007, Vaccine.

[5]  M. Kendall,et al.  Intradermal ballistic delivery of micro-particles into excised human skin for pharmaceutical applications. , 2004, Journal of biomechanics.

[6]  G. E. El Maghraby,et al.  Liposomes and skin: from drug delivery to model membranes. , 2008, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[7]  Joseph Kost,et al.  Ultrasound mediated transdermal drug delivery. , 2014, Advanced drug delivery reviews.

[8]  Y. Kalia,et al.  Transdermal drug delivery: overcoming the skin's barrier function. , 2000, Pharmaceutical science & technology today.

[9]  Ajay K Banga,et al.  Electrically enhanced transdermal delivery of a macromolecule , 2002, The Journal of pharmacy and pharmacology.

[10]  H. Maibach,et al.  Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement , 2015 .

[11]  Mark R Prausnitz,et al.  Microneedles for transdermal drug delivery. , 2004, Advanced drug delivery reviews.

[12]  Ritesh Kumar,et al.  Modified Transdermal Technologies: Breaking the Barriers of Drug Permeation via the Skin , 2007 .

[13]  Viness Pillay,et al.  Current advances in the fabrication of microneedles for transdermal delivery. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[14]  Dinesh Dhamecha,et al.  Physical Approaches to Penetration Enhancement , 2011 .

[15]  Hyunjin Park,et al.  Sonophoresis in transdermal drug deliverys. , 2014, Ultrasonics.

[16]  L. Scapozza,et al.  Noninvasive transdermal iontophoretic delivery of biologically active human basic fibroblast growth factor. , 2011, Molecular pharmaceutics.

[17]  N. Dixit,et al.  Iontophoresis - an approach for controlled drug delivery: a review. , 2007, Current drug delivery.

[18]  Adam C. Watkinson,et al.  Topical and Transdermal Drug Delivery: Principles and Practice , 2011 .

[19]  I. Alberti,et al.  Next generation intra- and transdermal therapeutic systems: using non- and minimally-invasive technologies to increase drug delivery into and across the skin. , 2013, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[20]  Ryan F. Donnelly,et al.  Hydrogel-Forming Microneedle Arrays Can Be Effectively Inserted in Skin by Self-Application: A Pilot Study Centred on Pharmacist Intervention and a Patient Information Leaflet , 2014, Pharmaceutical Research.

[21]  Corona M. Cassidy,et al.  Microneedle mediated intradermal delivery of adjuvanted recombinant HIV-1 CN54gp140 effectively primes mucosal boost inoculations , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[22]  O. Pillai,et al.  Transdermal iontophoresis of insulin: IV. Influence of chemical enhancers. , 2004, International journal of pharmaceutics.

[23]  F. Newman,et al.  Safety and immunogenicity of varying dosages of trivalent inactivated influenza vaccine administered by needle-free jet injectors. , 2001, Vaccine.

[24]  B. W. Barry,et al.  Novel mechanisms and devices to enable successful transdermal drug delivery. , 2001, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[25]  J. Subramony,et al.  Needle free parenteral drug delivery: leveraging active transdermal technologies for pediatric use. , 2013, International journal of pharmaceutics.

[26]  P. Mishra,et al.  Iontophoresis: A Potential Emergence of a Transdermal Drug Delivery System , 2011, Scientia pharmaceutica.

[27]  A. Singer,et al.  Low-frequency sonophoresis: pathologic and thermal effects in dogs. , 1998, Academic emergency medicine : official journal of the Society for Academic Emergency Medicine.

[28]  Robert Langer,et al.  Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and emerging trends. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[29]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[30]  S. Dubey,et al.  Non-invasive iontophoretic delivery of enzymatically active ribonuclease A (13.6 kDa) across intact porcine and human skins. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[31]  M. Sarno,et al.  Clinical immunogenicity of measles, mumps and rubella vaccine delivered by the Injex jet injector: comparison with standard syringe injection. , 2000, The Pediatric infectious disease journal.

[32]  J. Leroux,et al.  Breakthrough discoveries in drug delivery technologies: the next 30 years. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[33]  M. Roustit,et al.  Effect of continuous vs pulsed iontophoresis of treprostinil on skin blood flow. , 2015, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[34]  A. Hussain,et al.  Potential Enhancers for Transdermal Drug Delivery: A Review , 2014 .

[35]  S L Jacques,et al.  Mid-infrared laser ablation of stratum corneum enhances in vitro percutaneous transport of drugs. , 1991, The Journal of investigative dermatology.

[36]  Kevin Ita,et al.  Transdermal Delivery of Drugs with Microneedles—Potential and Challenges , 2015, Pharmaceutics.

[37]  Y. Kalia,et al.  Mathematical models to describe iontophoretic transport in vitro and in vivo and the effect of current application on the skin barrier. , 2013, Advanced drug delivery reviews.

[38]  P. Lambert,et al.  Intradermal vaccine delivery: will new delivery systems transform vaccine administration? , 2008, Vaccine.

[39]  G. A. Hofmann,et al.  The effect of electroporation on iontophoretic transdermal delivery of calcium regulating hormones. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[40]  Kosmas Kretsos,et al.  A geometrical model of dermal capillary clearance. , 2007, Mathematical biosciences.

[41]  R. Guy,et al.  Transdermal iontophoresis of amino acids and peptides in vitro , 1992 .

[42]  Kl L. Yung,et al.  Sharp tipped plastic hollow microneedle array by microinjection moulding , 2011 .

[43]  J. du Plessis,et al.  Breaching the skin barrier through temperature modulations. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[44]  Young Bin Choy,et al.  The Rule of Five for Non-Oral Routes of Drug Delivery: Ophthalmic, Inhalation and Transdermal , 2011, Pharmaceutical Research.

[45]  Atul Nayak,et al.  Lidocaine carboxymethylcellulose with gelatine co-polymer hydrogel delivery by combined microneedle and ultrasound , 2016, Drug delivery.

[46]  F. Rinaldi,et al.  Niosomes from 80s to present: the state of the art. , 2014, Advances in colloid and interface science.

[47]  José Juan Escobar-Chávez,et al.  The tape-stripping technique as a method for drug quantification in skin. , 2008, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[48]  Ryan F. Donnelly,et al.  Novel Delivery Systems for Transdermal and Intradermal Drug Delivery: Donnelly/Novel Delivery Systems for Transdermal and Intradermal Drug Delivery , 2015 .

[49]  Véronique Préat,et al.  Skin electroporation for transdermal and topical delivery. , 2004, Advanced drug delivery reviews.

[50]  Akira Yamamoto,et al.  Transdermal delivery of relatively high molecular weight drugs using novel self-dissolving microneedle arrays fabricated from hyaluronic acid and their characteristics and safety after application to the skin. , 2014, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[51]  H. Katsumi,et al.  Development of a novel self-dissolving microneedle array of alendronate, a nitrogen-containing bisphosphonate: evaluation of transdermal absorption, safety, and pharmacological effects after application in rats. , 2012, Journal of pharmaceutical sciences.

[52]  Ryan F. Donnelly,et al.  Design, Optimization and Characterisation of Polymeric Microneedle Arrays Prepared by a Novel Laser-Based Micromoulding Technique , 2010, Pharmaceutical Research.

[53]  Ying Zhang,et al.  Development of Lidocaine-Coated Microneedle Product for Rapid, Safe, and Prolonged Local Analgesic Action , 2011, Pharmaceutical Research.

[54]  Véronique Préat,et al.  Transdermal delivery of timolol by electroporation through human skin. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[55]  Michael R Hamblin,et al.  Physical energy for drug delivery; poration, concentration and activation. , 2014, Advanced drug delivery reviews.

[56]  W. Blackwelder,et al.  Preventing contamination between injections with multiple-use nozzle needle-free injectors: a safety trial. , 2008, Vaccine.

[57]  J. A. Gimm,et al.  Transdermal Delivery of Heparin by Skin Electroporation , 1995, Bio/Technology.

[58]  J Lademann,et al.  The tape stripping procedure--evaluation of some critical parameters. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[59]  Aarti Naik,et al.  Iontophoretic drug delivery. , 2004, Advanced drug delivery reviews.

[60]  Véronique Préat,et al.  Transdermal Delivery of Macromolecules Using Skin Electroporation , 2004, Pharmaceutical Research.

[61]  N. Yu,et al.  Efficient electroporation of liposomes doped with pore stabilizing nisin , 2013, Journal of liposome research.

[62]  Ajay K. Banga,et al.  Electrically Assisted Transdermal And Topical Drug Delivery , 1998 .

[63]  Conor O'Mahony,et al.  Coated microneedle arrays for transcutaneous delivery of live virus vaccines. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[64]  M. H. Zulfakar,et al.  Recent advances in gel technologies for topical and transdermal drug delivery , 2014, Drug development and industrial pharmacy.

[65]  J. Yankaskas,et al.  Diagnostic sweat testing: the Cystic Fibrosis Foundation guidelines. , 2007, The Journal of pediatrics.

[66]  Keizo Fukushima,et al.  Two-layered dissolving microneedles formulated with intermediate-acting insulin. , 2012, International journal of pharmaceutics.

[67]  A. Banga,et al.  Controlled delivery of ropinirole hydrochloride through skin using modulated iontophoresis and microneedles , 2013, Journal of drug targeting.

[68]  Adrian C. Williams,et al.  Can drug‐bearing liposomes penetrate intact skin? , 2006, The Journal of pharmacy and pharmacology.

[69]  Toshiyuki Sato,et al.  Evaluation of the effect of polymeric microneedle arrays of varying geometries in combination with a high-velocity applicator on skin permeability and irritation , 2014, Biomedical microdevices.

[70]  M. Ameri,et al.  Human Growth Hormone Delivery with a Microneedle Transdermal System: Preclinical Formulation, Stability, Delivery and PK of Therapeutically Relevant Doses , 2014, Pharmaceutics.

[71]  E. Krueger,et al.  Iontophoresis: principles and applications , 2014 .

[72]  Damijan Miklavčič,et al.  Active enhancement methods for intra- and transdermal drug delivery: a review. , 2013 .

[73]  Mark G. Allen,et al.  Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: Fabrication methods and transport studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[74]  A. Naik,et al.  Transdermal Delivery of Cytochrome C—A 12.4 kDa Protein—Across Intact Skin by Constant–Current Iontophoresis , 2007, Pharmaceutical Research.

[75]  J. Matriano,et al.  Parathyroid Hormone (1-34)-Coated Microneedle Patch System: Clinical Pharmacokinetics and Pharmacodynamics for Treatment of Osteoporosis , 2010, Pharmaceutical Research.

[76]  Xiaoyun Hong,et al.  Hydrogel Microneedle Arrays for Transdermal Drug Delivery , 2014 .

[77]  J. Simonin On the mechanisms of in vitro and in vivo phonophoresis , 1995 .

[78]  Samir Mitragotri,et al.  Current status and future prospects of needle-free liquid jet injectors , 2006, Nature Reviews Drug Discovery.

[79]  T. Sun,et al.  Carbon nanotube composites for glucose biosensor incorporated with reverse iontophoresis function for noninvasive glucose monitoring , 2010, International journal of nanomedicine.

[80]  Samir Mitragotri,et al.  Needle-free delivery of macromolecules across the skin by nanoliter-volume pulsed microjets , 2007, Proceedings of the National Academy of Sciences.

[81]  B. Ongpipattanakul,et al.  Characterization of the permselective properties of excised human skin during iontophoresis. , 1987, Journal of pharmaceutical sciences.

[82]  Mark R. Prausnitz,et al.  Effect of Microneedle Design on Pain in Human Volunteers , 2008, The Clinical journal of pain.

[83]  M. Meltzer,et al.  Influenza cost and cost-effectiveness studies globally--a review. , 2013, Vaccine.

[84]  S. Mitragotri,et al.  Enhancement of transdermal drug delivery via synergistic action of chemicals. , 2009, Biochimica et biophysica acta.

[85]  Maelíosa T. C. McCrudden,et al.  Microneedles for intradermal and transdermal drug delivery. , 2013, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[86]  P. Uzor,et al.  Transdermal Drug Delivery , 2012 .

[87]  Mark R. Prausnitz,et al.  Stability of influenza vaccine coated onto microneedles. , 2012, Biomaterials.

[88]  Adrian C. Williams,et al.  Penetration enhancers. , 2004, Advanced drug delivery reviews.

[89]  C. Porter,et al.  Subcutaneous drug delivery and the role of the lymphatics. , 2005, Drug discovery today. Technologies.

[90]  Wijaya Martanto,et al.  Microinfusion Using Hollow Microneedles , 2006, Pharmaceutical Research.

[91]  M. Roustit,et al.  Cutaneous Iontophoresis of Treprostinil in Systemic Sclerosis: A Proof‐of‐Concept Study , 2014, Clinical pharmacology and therapeutics.

[92]  Ryan F. Donnelly,et al.  Design and physicochemical characterisation of novel dissolving polymeric microneedle arrays for transdermal delivery of high dose, low molecular weight drugs , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[93]  Conor O'Mahony,et al.  Hydrogel-forming microneedle arrays exhibit antimicrobial properties: potential for enhanced patient safety. , 2013, International journal of pharmaceutics.

[94]  I. Aljuffali,et al.  Lasers as an approach for promoting drug delivery via skin , 2014, Expert opinion on drug delivery.

[95]  Weien Yuan,et al.  A scalable fabrication process of polymer microneedles , 2012, International journal of nanomedicine.

[96]  R. Moy,et al.  Laser assisted drug delivery: A review of an evolving technology , 2014, Lasers in surgery and medicine.

[97]  J. Weaver,et al.  Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[98]  K. Ita Transdermal drug delivery: progress and challenges , 2014 .

[99]  G. P. Martin,et al.  Transdermal drug delivery systems: skin perturbation devices. , 2008, Methods in molecular biology.

[100]  D. L. Parsons,et al.  Microneedle assisted iontophoretic transdermal delivery of prochlorperazine edisylate , 2012, Drug development and industrial pharmacy.

[101]  Majella E Lane,et al.  Skin penetration enhancers. , 2013, International journal of pharmaceutics.

[102]  E. Neumann,et al.  Gene transfer into mouse lyoma cells by electroporation in high electric fields. , 1982, The EMBO journal.

[103]  Jung-Hwan Park,et al.  Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery , 2004, The 26th Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[104]  Regina Luttge,et al.  Silicon micromachined hollow microneedles for transdermal liquid transport , 2003 .

[105]  D. Das,et al.  Potential of combined ultrasound and microneedles for enhanced transdermal drug permeation: a review. , 2015, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[106]  K. A. Walters,et al.  Dermatological And Transdermal Formulations , 2002 .

[107]  T. Ghosh,et al.  Theory and Practice of Contemporary Pharmaceutics , 2004 .

[108]  R. Guy,et al.  lontophoretic Delivery of Amino Acids and Amino Acid Derivatives Across the Skin in Vitro , 1991, Pharmaceutical Research.

[109]  L. Newby,et al.  Age Moderates the Short-Term Effects of Transdermal 17β-Estradiol on Endothelium-Dependent Vascular Function in Postmenopausal Women , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[110]  Richard H Guy,et al.  Transdermal drug delivery: 30+ years of war and still fighting! , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[111]  Koen van der Maaden,et al.  Microneedle technologies for (trans)dermal drug and vaccine delivery. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[112]  Jung-Hwan Park,et al.  Microneedles for drug and vaccine delivery. , 2012, Advanced drug delivery reviews.

[113]  Yu Zhou,et al.  Current micropump technologies and their biomedical applications , 2009 .

[114]  Clive G. Wilson,et al.  Laser-engineered dissolving microneedles for active transdermal delivery of nadroparin calcium. , 2012, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[115]  Yannic B Schuetz,et al.  Emerging strategies for the transdermal delivery of peptide and protein drugs , 2005, Expert opinion on drug delivery.

[116]  P. V. Subramanyam,et al.  ON MICRONEEDLES : AN EMERGING TRANSDERMAL DRUG DELIVERY SYSTEM , 2022 .

[117]  J. Stockman,et al.  Dissolving polymer microneedle patches for influenza vaccination , 2012 .

[118]  Pin Dong,et al.  Investigation on fabrication process of dissolving microneedle arrays to improve effective needle drug distribution. , 2015, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[119]  Maelíosa T. C. McCrudden,et al.  Strategies for enhanced peptide and protein delivery. , 2013, Therapeutic delivery.

[120]  Gopinathan K Menon,et al.  New insights into skin structure: scratching the surface. , 2002, Advanced drug delivery reviews.

[121]  Y. Nagasaki,et al.  Anti-cancer vaccination by transdermal delivery of antigen peptide-loaded nanogels via iontophoresis. , 2015, International journal of pharmaceutics.

[122]  S. Giannos Skin microporation: strategies to enhance and expand transdermal drug delivery , 2014 .

[123]  H. Maibach,et al.  Using skin for drug delivery and diagnosis in the critically ill. , 2014, Advanced drug delivery reviews.

[124]  M. Prausnitz,et al.  Minimally invasive insulin delivery in subjects with type 1 diabetes using hollow microneedles. , 2009, Diabetes technology & therapeutics.

[125]  C. Rielly,et al.  Microneedle-assisted microparticle delivery by gene guns: experiments and modeling on the effects of particle characteristics , 2015, Drug delivery.

[126]  Priyanka Ghosh,et al.  Challenges and opportunities in dermal/transdermal delivery. , 2010, Therapeutic delivery.

[127]  M. Asif,et al.  Iontophoretic drug delivery: History and applications , 2011 .

[128]  Asim Nisar,et al.  Optimization of Fabrication Process for MEMS Based Microneedles Using ICP Etching Technology , 2011 .

[129]  D. Mahvi,et al.  A Phase I Study of Immunization Using Particle-Mediated Epidermal Delivery of Genes for gp100 and GM-CSF into Uninvolved Skin of Melanoma Patients , 2007, Clinical Cancer Research.

[130]  Yeu‐Chun Kim,et al.  Microneedle patches for vaccine delivery , 2013, Clinical and experimental vaccine research.

[131]  Akira Yamamoto,et al.  The development and characteristics of novel microneedle arrays fabricated from hyaluronic acid, and their application in the transdermal delivery of insulin. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[132]  Ryan F. Donnelly,et al.  Microneedle-mediated Transdermal and Intradermal Drug Delivery , 2012 .

[133]  R. Langer,et al.  Skin permeabilization for transdermal drug delivery: recent advances and future prospects , 2014, Expert opinion on drug delivery.

[134]  Y. Demir,et al.  Sodium Alginate Microneedle Arrays Mediate the Transdermal Delivery of Bovine Serum Albumin , 2013, PloS one.

[135]  Samir Mitragotri,et al.  An overview of clinical and commercial impact of drug delivery systems. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[136]  S. Mitragotri Devices for overcoming biological barriers: the use of physical forces to disrupt the barriers. , 2013, Advanced drug delivery reviews.

[137]  Y. Kalia,et al.  Targeted local simultaneous iontophoresis of chemotherapeutics for topical therapy of head and neck cancers. , 2014, International journal of pharmaceutics.

[138]  Jung-Hwan Park,et al.  Microsecond thermal ablation of skin for transdermal drug delivery. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[139]  Samir Mitragotri,et al.  Dynamic control of needle-free jet injection. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[140]  Samir Mitragotri,et al.  Immunization without needles , 2005, Nature Reviews Immunology.

[141]  Wenjuan Yang,et al.  Transdermal protein delivery by a coadministered peptide identified via phage display , 2006, Nature Biotechnology.

[142]  Mark R Prausnitz,et al.  Coated microneedles for transdermal delivery. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[143]  Clara Gómez,et al.  Laser treatments on skin enhancing and controlling transdermal delivery of 5‐fluorouracil , 2008, Lasers in surgery and medicine.

[144]  Mark R Prausnitz,et al.  Microneedle patches: usability and acceptability for self-vaccination against influenza. , 2014, Vaccine.

[145]  B. Guy,et al.  Intradermal, epidermal and transcutaneous vaccination: from immunology to clinical practice , 2008, Expert review of vaccines.

[146]  R. Potts,et al.  Effect of Electroporation on Transdermal lontophoretic Delivery of Luteinizing Hormone Releasing Hormone (LHRH) in Vitro , 1994, Pharmaceutical Research.

[147]  M. Kermode Unsafe injections in low-income country health settings: need for injection safety promotion to prevent the spread of blood-borne viruses. , 2004, Health promotion international.

[148]  A Adamo,et al.  Microfluidic jet injection for delivering macromolecules into cells , 2013, Journal of Micromechanics and Microengineering.

[149]  Samir Mitragotri,et al.  Micro-scale devices for transdermal drug delivery. , 2008, International journal of pharmaceutics.

[150]  Ajazuddin,et al.  Approaches for breaking the barriers of drug permeation through transdermal drug delivery. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[151]  Ryan F. Donnelly,et al.  Microneedle-based drug delivery systems: Microfabrication, drug delivery, and safety , 2010, Drug delivery.

[152]  S. Dubey,et al.  Understanding the poor iontophoretic transport of lysozyme across the skin: when high charge and high electrophoretic mobility are not enough. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[153]  Woan‐Ruoh Lee,et al.  Erbium: YAG Laser Pretreatment Accelerates the Response of Bowen's Disease Treated by Topical 5‐Fluorouracil , 2004, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.].