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Recent Patents on Drug Delivery & Formulation


ISSN (Print): 1872-2113
ISSN (Online): 2212-4039

Review Article

Recent Patents on Permeation Enhancers for Drug Delivery Through Nails

Author(s): Tainá Kreutz, Sheila Porto de Matos and Letícia Scherer Koester *

Volume 13 , Issue 3 , 2019

Page: [203 - 218] Pages: 16

DOI: 10.2174/1872211313666191030155837


The human nail is a unique barrier with a keratinized constitution that favors protection and fine touch. However, many disorders can affect the nail, among them, are the onychomycosis and psoriasis. Systemic oral therapy has been applied to treat these diseases, even presenting disadvantages, including side effects, drug interactions, contraindications, toxicity, high cost and low patient compliance. A great option to succeed in dealing with the problems associated with oral therapy is the topical administration of drugs. However, nail composition, low diffusion through ungual route and reduced tissue bioavailability for topical treatments are limiting factors. These drawbacks can be overcome by promoting penetration through the nails by employing penetration enhancers. The review focuses on patents that highlight permeation enhancers applied to nail drug delivery for the treatment of onychomycosis and psoriasis. Literature and patent searches were conduced regarding the topic of interest. The substantial literature and patent search revealed that permeation enhancers, especially chemicals, are great strategies for promoting the ungual delivery of drugs. Nail topical therapy containing permeation enhancers is an attractive option for delivering localized treatments.

Keywords: Nail drug delivery, ungual drug delivery, permeation enhancer, patent, onychomycosis, psoriasis.

Graphical Abstract
Murthy SN, Maibach HI. Topical nail products and ungual drug delivery. Boca Raton: CRC Press 2013.
Shanbhag PP, Jani U. Drug delivery through nails: Present and future. New Horiz Transl Med 2017; 3: 252-63.
Murdan S. Drug delivery to the nail following topical application. Int J Pharm 2002; 236(1-2): 1-26.
[] [PMID: 11891066]
Lipner SR, Scher RK. Onychomycosis: Clinical overview and diagnosis. J Am Acad Dermatol 2019; 80(4): 835-51.
[] [PMID: 29959961]
Jiaravuthisan MM, Sasseville D, Vender RB, Murphy F, Muhn CY. Psoriasis of the nail: Anatomy, pathology, clinical presentation, and a review of the literature on therapy. J Am Acad Dermatol 2007; 57(1): 1-27.
[] [PMID: 17572277]
Lecha M, Effendy I. Feuilhade de CM, Di Chiacchio N, Baran R. Taskforce on Onychomycosis Education. Treatment options-development of consensus guidelines. J Eur Acad Dermatol Venereol 2005; 19(Suppl. 1): 25-33.
[] [PMID: 16120203]
Joshi M, Sharma V, Pathak K. Nail psoriasis: An updated review of clinical reports on therapy and formulation aspects for topical delivery. J Drug Deliv Sci Technol 2015; 30: 63-73.
Gupta AK, Paquet M, Simpson FC. Therapies for the treatment of onychomycosis. Clin Dermatol 2013; 31(5): 544-54.
[] [PMID: 24079583]
Shivakumar HN, Juluri A, Desai BG, Murthy SN. Ungual and transungual drug delivery. Drug Dev Ind Pharm 2012; 38(8): 901-11.
[] [PMID: 22149347]
Warren RB, Griffiths CEM. Systemic therapies for psoriasis: Methotrexate, retinoids, and cyclosporine. Clin Dermatol 2008; 26(5): 438-47.
[] [PMID: 18755362]
Vlahovic TC. Onychomycosis: Evaluation, treatment options, managing recurrence, and patient outcomes. Clin Podiatr Med Surg 2016; 33(3): 305-18.
[] [PMID: 27215153]
Murdan S. Nail disorders in older people, and aspects of their pharmaceutical treatment. Int J Pharm 2016; 512(2): 405-11.
[] [PMID: 27180233]
Elkeeb R. AliKhan A, Elkeeb L, Hui X, Maibach HI. Transungual drug delivery: Current status. Int J Pharm 2010; 384(1-2): 1-8.
[] [PMID: 19819318]
Khengar RH, Jones SA, Turner RB, Forbes B, Brown MB. Nail swelling as a pre-formulation screen for the selection and optimisation of ungual penetration enhancers. Pharm Res 2007; 24(12): 2207-12.
Nolting S, Korting HC. Onychomycoses-local antimycotic treatment. Berlin, Heidelberg: Springer Berlin Heidelberg 1990.
Naumann S, Meyer JP, Kiesow A, Mrestani Y, Wohlrab J, Neubert RHH. Controlled nail delivery of a novel lipophilic antifungal agent using various modern drug carrier systems as well as in vitro and ex vivo model systems. J Control Release 2014; 180: 60-70.
[] [PMID: 24560884]
Narasimha MS, Wiskirchen DE, Bowers CP. Iontophoretic drug delivery across human nail. J Pharm Sci 2007; 96(2): 305-11.
[] [PMID: 17080425]
Murdan S. Enhancing the nail permeability of topically applied drugs. Expert Opin Drug Deliv 2008; 5(11): 1267-82.
[] [PMID: 18976136]
Bronaugh RL, Maibach HI. Percutaneous absorption: Drugs, cosmetics, mechanisms, methodology. Boca Raton: Taylor & Francis Group 2005.
Chouhan P, Saini TR. Hydration of nail plate: A novel screening model for transungual drug permeation enhancers. Int J Pharm 2012; 436(1-2): 179-82.
[] [PMID: 22705091]
Christi JM, Aundhia C, Seth A, Shah N, Kondhia D, Patel S. Review on transungual drug delivery system. Indo Am J Pharm Res 2017; 7: 686-706.
Zaias N. The nail in health and disease. Lancaster: MTP Press Limited 1980.
Garson JC, Baltenneck F, Leroy F, Riekel C, Müller M. Histological structure of human nail as studied by synchrotron X-ray microdiffraction. Cell Mol Biol 2000; 46(6): 1025-34.
[PMID: 10976860]
Lynch MH, O’Guin WM, Hardy C, Mak L, Sun TT. Acidic and basic hair/nail (“hard”) keratins: Their colocalization in upper cortical and cuticle cells of the human hair follicle and their relationship to “soft” keratins. J Cell Biol 1986; 103(6 Pt 2): 2593-606.
[] [PMID: 2432071]
Egawa M, Ozaki Y, Takahashi M. In vivo measurement of water content of the fingernail and its seasonal change. Skin Res Technol 2006; 12(2): 126-32.
[] [PMID: 16626387]
Helmdach M, Thielitz A, Röpke EM, Gollnick H. Age and sex variation in lipid composition of human fingernail plates. Skin Pharmacol Appl Skin Physiol 2000; 13(2): 111-9.
[] [PMID: 10754459]
Jemec GB, Agner T, Serup J. Transonychial water loss: Relation to sex, age and nail-plate thickness. Br J Dermatol 1989; 121(4): 443-6.
[] [PMID: 2624837]
Krönauer C, Gfesser M, Ring J, Abeck D. Transonychial water loss in healthy and diseased nails. Acta Derm Venereol 2001; 81(3): 175-7.
[] [PMID: 11558871]
Scher RK, Daniel CRI. Nail: Diagnosis, therapy, and surgery. 3rd ed. Philadelphia: Elsevier Saunders 2005.
Shanbhag PP, Jani U. Drug delivery through nails: Present and future. New horizons. Transl Med (Sunnyvale) 2017; 5: 252-63.
Scher RK. Onychomycosis is more than a cosmetic problem. Br J Dermatol 1994; 130(Suppl. 43): 15-5.
[] [PMID: 8186135]
Ghannoum MA, Hajjeh RA, Scher R, et al. A large-scale North American study of fungal isolates from nails: The frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol 2000; 43(4): 641-8.
[] [PMID: 11004620]
Debruyne D, Coquerel A. Pharmacokinetics of antifungal agents in onychomycoses. Clin Pharmacokinet 2001; 40(6): 441-72.
[] [PMID: 11475469]
Kumar S, Kimball AB. New antifungal therapies for the treatment of onychomycosis. Expert Opin Investig Drugs 2009; 18(6): 727-34.
[] [PMID: 19426118]
Coleman NW, Fleckman P, Huang JI. Fungal nail infections. J Hand Surg Am 2014; 39(5): 985-8.
[] [PMID: 24766830]
Lipner SR, Scher RK. Onychomycosis: Current and investigational therapies. Cutis 2014; 94(6): E21-4.
[PMID: 25566580]
Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol 2010; 28(2): 151-9.
[] [PMID: 20347657]
de Berker D. Clinical practice. Fungal nail disease. N Engl J Med 2009; 360(20): 2108-16.
[] [PMID: 19439745]
Singal A, Khanna D. Onychomycosis: Diagnosis and management. Indian J Dermatol Venereol Leprol 2011; 77(6): 659-72.
[] [PMID: 22016272]
Iorizzo M, Piraccini BM, Tosti A. Aktuelle behandlungsoptionen der onychomykose. JDDG J Ger Soc Dermatology 2010; 8: 875-9.
van der Velden HM, Klaassen KM, van de Kerkhof PC, Pasch MC. Fingernail psoriasis reconsidered: A case-control study. J Am Acad Dermatol 2013; 69(2): 245-52.
[] [PMID: 23541759]
Nestle FO, Conrad C. Mechanisms of psoriasis. Drug Discov Today Dis Mech 2004; 1: 315-9.
Bayliffe AI, Brigandi RA, Wilkins HJ, Levick MP. Emerging therapeutic targets in psoriasis. Curr Opin Pharmacol 2004; 4(3): 306-10.
[] [PMID: 15140425]
Committee for Medicinal Products for Human Use - European Medicines Agency. Guideline on clinical investigation of medicinal products indicated for the treatment of psoriasis 2004.
Kyriakou A, Patsatsi A, Sotiriadis D. Biologic agents in nail psoriasis: Efficacy data and considerations. Expert Opin Biol Ther 2013; 13(12): 1707-14.
[] [PMID: 24156504]
Sala M, Diab R, Elaissari A, Fessi H. Lipid nanocarriers as skin drug delivery systems: Properties, mechanisms of skin interactions and medical applications. Int J Pharm 2018; 535(1-2): 1-17.
[] [PMID: 29111097]
Wozel G. Psoriasis treatment in difficult locations: Scalp, nails, and intertriginous areas. Clin Dermatol 2008; 26(5): 448-59.
[] [PMID: 18755363]
Murthy SN, Vaka SRK, Sammeta SM, Nair AB. TranScreen-N: Method for rapid screening of trans-ungual drug delivery enhancers. J Pharm Sci 2009; 98(11): 4264-71.
[] [PMID: 19363796]
Kushwaha AS. The screening of permeation enhancers for trans-nail delivery of terbinafine hydrochloride. J Bioequivalence Bioavailab 2018; 10: 75-7.
Akhtar N, Sharma H, Pathak K. Onychomycosis: Potential of nail lacquers in transungual delivery of antifungals. Scientifica 2016; 2016 1387936
[] [PMID: 27123362]
Täuber A, Müller-Goymann CC. In vitro permeation and penetration of ciclopirox olamine from poloxamer 407-based formulations- Comparison of isolated human stratum corneum, bovine hoof plates and keratin films. Int J Pharm 2015; 489(1-2): 73-82.
[] [PMID: 25895717]
Repka MA, Mididoddi PK, Stodghill SP. Influence of human nail etching for the assessment of topical onychomycosis therapies. Int J Pharm 2004; 282(1-2): 95-106.
[] [PMID: 15336385]
Chiu WS, Belsey NA, Garrett NL, et al. Drug delivery into microneedle- porated nails from nanoparticle reservoirs. J Control Release 2015; 220(Pt A): 98-106.
[] [PMID: 26478016]
Thomas RL. Medical device for controlled nail penetration. US2014371751A1 (2014).
Napolez A. Nail penetration device for delivery of anti-fungal treatments US2018207414A1 (2018)
Abadi D, Zderic V. Ultrasound-mediated nail drug delivery system. J Ultrasound Med 2011; 30(12): 1723-30.
[] [PMID: 22124008]
Neev J, Nelson JS, Critelli M, et al. Ablation of human nail by pulsed lasers. Lasers Surg Med 1997; 21(2): 186-92.
[<186:AID-LSM10>3.0.CO;2-D] [PMID: 9261796]
Ward AR, Ward TO, McBride Z. Hand held system for antifungal treatment. US2013211481A1 (2013)
Barsness M, Davis S, Etheredge R, Chang K, Kim H. Controlling drug transport and current in iontophoretic onychomycosis treatment. US2011066134A1 (2011).
Hao J, Li SK. Transungual iontophoretic transport of polar neutral and positively charged model permeants: Effects of electrophoresis and electroosmosis. J Pharm Sci 2008; 97(2): 893-905.
[] [PMID: 17683062]
Susilo R, Korting HC, Greb W, Strauss UP. Nail penetration of sertaconazole with a sertaconazole-containing nail patch formulation. Am J Clin Dermatol 2006; 7(4): 259-62.
[] [PMID: 16901186]
Inaba Y. Simple device for treating tinea unguium. US2011245785A1 (2011).
Inaba Y. Bubble-type tinea unguium treatment implement. JP2012115596A (2012).
Weinfield TA. Enchanced trans-keratin drug delivery. WO2010011354A2 (2010).
Gupta AK, Paquet M. Improved efficacy in onychomycosis therapy. Clin Dermatol 2013; 31(5): 555-63.
[] [PMID: 24079584]
Gunt HB, Kasting GB. Effect of hydration on the permeation of ketoconazole through human nail plate in vitro. Eur J Pharm Sci 2007; 32(4-5): 254-60.
[] [PMID: 17928205]
Gunt H, Kasting GB. Hydration effect on human nail permeability. J Cosmet Sci 2006; 57(2): 183-4.
[PMID: 16758557]
Vejnovic I, Simmler L, Betz G. Investigation of different formulations for drug delivery through the nail plate. Int J Pharm 2010; 386(1-2): 185-94.
[] [PMID: 19941943]
Stüttgen G, Bauer E. Bioavailability, skin and nailpenetration of topically applied antimycotics. Mykosen 1982; 25(2): 74-80.
[] [PMID: 7062934]
Kobayashi Y, Miyamoto M, Sugibayashi K, Morimoto Y. Enhancing effect of N-acetyl-l-cysteine or 2-mercaptoethanol on the in vitro permeation of 5-fluorouracil or tolnaftate through the human nail plate. Chem Pharm Bull 1998; 46(11): 1797-802.
[] [PMID: 9845958]
Quintanar-Guerrero D, Ganem-Quintanar A, Tapia-Olguín P, Kalia YN, Buri P. The effect of keratolytic agents on the permeability of three imidazole antimycotic drugs through the human nail. Drug Dev Ind Pharm 1998; 24(7): 685-90.
[] [PMID: 9876516]
Malhotra GG, Zatz JL. Investigation of nail permeation enhancement by chemical modification using water as a probe. J Pharm Sci 2002; 91(2): 312-23.
[] [PMID: 11835191]
Brown MB, Khengar RH, Turner RB, et al. Overcoming the nail barrier: A systematic investigation of ungual chemical penetration enhancement. Int J Pharm 2009; 370(1-2): 61-7.
[] [PMID: 19071202]
Mohorčič M, Torkar A, Friedrich J, Kristl J, Murdan S. An investigation into keratinolytic enzymes to enhance ungual drug delivery. Int J Pharm 2007; 332(1-2): 196-201.
[] [PMID: 17097244]
Nair AB, Sammeta SM, Vaka SRK, Narasimha MS. A study on the effect of inorganic salts in transungual drug delivery of terbinafine. J Pharm Pharmacol 2009; 61(4): 431-7.
[] [PMID: 19298688]
Vejnovic I, Huonder C, Betz G. Permeation studies of novel terbinafine formulations containing hydrophobins through human nails in vitro. Int J Pharm 2010; 397(1-2): 67-76.
[] [PMID: 20620203]
Hui X, Chan TCK, Barbadillo S, Lee C, Maibach HI, Wester RC. Enhanced econazole penetration into human nail by 2-n-nonyl-1, 3-dioxolane. J Pharm Sci 2003; 92(1): 142-8.
[] [PMID: 12486690]
Repka MA, O’Haver J, See CH, Gutta K, Munjal M. Nail morphology studies as assessments for onychomycosis treatment modalities. Int J Pharm 2002; 245(1-2): 25-36.
[] [PMID: 12270239]
Mididoddi PK, Prodduturi S, Repka MA. Influence of tartaric acid on the bioadhesion and mechanical properties of hot-melt extruded hydroxypropyl cellulose films for the human nail. Drug Dev Ind Pharm 2006; 32(9): 1059-66.
[] [PMID: 17012118]
Swenholt KG. Nail fungus treatment and composition. US2016235847A1 (2016).
Inoue S, Abe S. Promotion of antifungal agent absorption. JP2010126532A (2010).
Johnson N. Fungal nail treatment composition. CN102844026A (2012).
Capriotti J, Capriotti K. Antifungal composition for treatment of skin and nail. JP2018048159A (2018).
Lindahl A. Novel antifungal composition. RU2013136147A 2015
Sekiya K, Morikane S, Morikane D, Kikuchi J, Yasuhara S. External preparation for treating ringworm and method for applying the same. JP2012162511A (2012)
Weijun L. Film coating agent for treating onychomycosis and preparation method thereof. CN102488702A (2012)
Rockhill T, Beeson WH. Excipient system for topical delivery of pharmaceutical agents. AU2017272269A1 (2018)
Willers C. Topical pharmaceutical compositions comprising terbinafide and urea. EP2664327A1 (2013)
Tausk F. Treatment of nail disorders. US2016008274A1 (2014).
Natori N, Takabe H, Ishimaru T, Iseki H, Karasawa K. External preparation for treating trichophytosis unguium. WO2019088005A1 (2019).
Zhong Y. Plant extraction formula applied to onychomycosis and tinea pedis. CN109303815A (2019)
Selner M. Penetrating carrier, anti-fungal composition using the same and method for treatment of dermatophyte. WO2010037089A1 (2010).
Nagpal S, Goyal A, Narang RK. Formulation and evaluation of itraconazole loaded niosomal gel for the treatment of onychomycosis. IN3107DE2013A (2015)
Kim N, Cho Y, Jeong S, Bae B, Lee J, Lee J. Nail lacquer composition containing ciclopirox. US2018104227A1 (2018).
Lu H. Pharmaceutical composition for treating leuconychia. CN105193726A (2015)
Niedermeyer WH. Nanoparticle compositions and methods for treating onychomycosis. US2017209490A1 (2017).
Krainbring VGA. G.A. Composition for treating onychomycosis. WO2019105793A1 (2019).
Touitou E, Barry BW. Enhancement in drug delivery. Boca Raton: CRC Press 2007.
Flores FC, Chiu WS, Beck RCR, da Silva CB, Delgado-Charro MB. Enhancement of tioconazole ungual delivery: Combining nanocapsule formulation and nail poration approaches. Int J Pharm 2018; 535(1-2): 237-44.
[] [PMID: 29126904]
Rocha KAD, Krawczyk-Santos AP, Andrade LM, et al. Voriconazole-loaded Nanostructured Lipid Carriers (NLC) for drug delivery in deeper regions of the nail plate. Int J Pharm 2017; 531(1): 292-8.
[] [PMID: 28859937]

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