Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Limitations and Opportunities in Topical Drug Delivery: Interaction Between Silica Nanoparticles and Skin Barrier

Author(s): Francisco Arriagada* and Javier Morales*

Volume 25 , Issue 4 , 2019

Page: [455 - 466] Pages: 12

DOI: 10.2174/1381612825666190404121507

Price: $65


The first limiting barrier for the transport in the skin is the stratum corneum; different strategies have been developed to overcome this barrier, including chemical enhancers. However, these penetration enhancers have limitations, including toxic adverse effects. In this context, research into nanomaterials has provided new tools to increase the residence time of drugs by generating a reservoir, increasing the specificity of drugs and reducing their adverse effects, and improving the penetration of drugs that are difficult to formulate. Silica nanoparticles have been proposed as suitable nanocarriers for skin delivery. Unfortunately, the mechanisms involved in the interaction, transport and fate of silica nanoparticles in the skin have not been fully investigated. This paper reviews significant findings about the interaction between silica-based nanocarriers and the skin. First, this review focuses on the properties and functions of the skin, the skin penetration properties of silica nanoparticles, their synthesis strategies and their toxicity. Finally, advances and evidence on the application of silica nanocarriers in skin drug delivery are provided, in which the use of nanoparticles increases the stability and solubility of the bioactive compound, enhancing its performance, act as penetrator enhancer and improving controlled release. Thus, improving the treatment of some skin disorders.

Keywords: Silica nanoparticles, skin delivery, topical delivery, nanomedicines, skin disorders, nanocarriers.

Roberts MS. Targeted drug delivery to the skin and deeper tissues: role of physiology, solute structure and disease. Clin Exp Pharmacol Physiol 1997; 24(11): 874-9.
Touitou E. Drug delivery across the skin. Expert Opin Biol Ther 2002; 2(7): 723-33.
Barry BW. Drug delivery routes in skin: a novel approach. Adv Drug Deliv Rev 2002; 54(Suppl. 1): S31-40.
Benson HAE. Transdermal drug delivery: penetration enhancement techniques. Curr Drug Deliv 2005; 2(1): 23-33.
Wiedersberg S, Guy RH. Transdermal drug delivery: 30+ years of war and still fighting! J Control Release 2014; 190: 150-6.
Pastore MN, Kalia YN, Horstmann M, Roberts MS. Transdermal patches: history, development and pharmacology. Br J Pharmacol 2015; 172(9): 2179-209.
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001; 46(1-3): 3-26.
Bos JD, Meinardi MM. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol 2000; 9(3): 165-9.
Prausnitz MR, Mitragotri S, Langer R. Current status and future potential of transdermal drug delivery. Nat Rev Drug Discov 2004; 3(2): 115-24.
Gilaberte Y, Prieto-Torres L, Pastushenko I, Juarranz Á. Chapter 1 - Anatomy and Function of the Skin. In: Hamblin MR, Avci P, Prow TW, ed.^eds., Nanoscience in Dermatology. Academic Press: Boston, 2016; pp. 1-14.
Alexander A, Dwivedi S. Ajazuddin , et al Approaches for breaking the barriers of drug permeation through transdermal drug delivery. J Control Release 2012; 164(1): 26-40.
Vitorino C, Sousa J, Pais A. Overcoming the skin permeation barrier: challenges and opportunities. Curr Pharm Des 2015; 21(20): 2698-712.
Patzelt A, Mak WC, Jung S, et al. Do nanoparticles have a future in dermal drug delivery? J Control Release 2017; 246: 174-82.
Cevc G, Vierl U. Nanotechnology and the transdermal route: A state of the art review and critical appraisal. J Control Release 2010; 141(3): 277-99.
Schneider M, Stracke F, Hansen S, Schaefer UF. Nanoparticles and their interactions with the dermal barrier. Dermatoendocrinol 2009; 1(4): 197-206.
Gupta M, Agrawal U, Vyas SP. Nanocarrier-based topical drug delivery for the treatment of skin diseases. Expert Opin Drug Deliv 2012; 9(7): 783-804.
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.
Lauterbach A, Müller-Goymann CC. Applications and limitations of lipid nanoparticles in dermal and transdermal drug delivery via the follicular route. Eur J Pharm Biopharm 2015; 97: 152-63.
DeLouise LA. Applications of nanotechnology in dermatology. J Invest Dermatol 2012; 132(3 Pt 2): 964-75.
Tang F, Li L, Chen D. Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery. Adv Mater 2012; 24(12): 1504-34.
Tang L, Cheng J. Nonporous silica nanoparticles for nanomedicine application. Nano Today 2013; 8(3): 290-312.
McGrath JA, Eady RAJ, Pope FM. Anatomy and organization of human skin Rook’s textbook of dermatology 2004; 3: 1-15
Ng KW, Lau WM. Human Skin Structure and Drug Penetration.In: Dragicevic N, Maibach HI, ed.Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement: Drug Manipulation Strategies and Vehicle Effects. Springer Berlin, Heidelberg: Berlin Heidelberg 2015; pp. 3-11.
Roberts MS, Cross SE, Pellett MA. Skin Transport 2002.
Deo PN, Deshmukh R. Pathophysiology of keratinization. J Oral Maxillofac Pathol 2018; 22(1): 86-91.
Prow TW, Grice JE, Lin LL, et al. Nanoparticles and microparticles for skin drug delivery. Adv Drug Deliv Rev 2011; 63(6): 470-91.
Benítez JM, Montáns FJ. The mechanical behavior of skin: Structures and models for the finite element analysis. Comput Struc 2017; 190: 75-107.
Nemes Z, Steinert PM. Bricks and mortar of the epidermal barrier. Exp Mol Med 1999; 31(1): 5-19.
Michaels AS, Chandrasekaran SK, Shaw JE. Drug permeation through human skin: Theory and in vitro experimental measurement. AIChE J 1975; 21: 985-96.
Tobin DJ. Biochemistry of human skin--our brain on the outside. Chem Soc Rev 2006; 35(1): 52-67.
Charalambopoulou GC, Karamertzanis P, Kikkinides ES, Stubos AK, Kanellopoulos NK, Papaioannou AT. A study on structural and diffusion properties of porcine stratum corneum based on very small angle neutron scattering data. Pharm Res 2000; 17(9): 1085-91.
Johnson ME, Blankschtein D, Langer R. Evaluation of solute permeation through the stratum corneum: lateral bilayer diffusion as the primary transport mechanism. J Pharm Sci 1997; 86(10): 1162-72.
Cevc G. Lipid vesicles and other colloids as drug carriers on the skin. Adv Drug Deliv Rev 2004; 56(5): 675-711.
Rawlings AV, Harding CR. Moisturization and skin barrier function. Dermatol Ther 2004; 17(Suppl. 1): 43-8.
Harding CR, Watkinson A, Rawlings AV, Scott IR. Dry skin, moisturization and corneodesmolysis. Int J Cosmet Sci 2000; 22(1): 21-52.
Verdier-Sévrain S, Bonté F. Skin hydration: a review on its molecular mechanisms. J Cosmet Dermatol 2007; 6(2): 75-82.
Langton AK, Halai P, Griffiths CE, Sherratt MJ, Watson RE. The impact of intrinsic ageing on the protein composition of the dermal-epidermal junction. Mech Ageing Dev 2016; 156: 14-6.
Burgeson RE, Christiano AM. The dermal-epidermal junction. Curr Opin Cell Biol 1997; 9(5): 651-8.
Trowbridge JM, Gallo RL. Dermatan sulfate: new functions from an old glycosaminoglycan. Glycobiology 2002; 12(9): 117R-25R.
Badylak SF, Freytes DO, Gilbert TW. Extracellular matrix as a biological scaffold material: Structure and function. Acta Biomater 2009; 5(1): 1-13.
Lapière CM. The ageing dermis: the main cause for the appearance of ‘old’ skin. Br J Dermatol 1990; 122(Suppl. 35): 5-11.
Farage MA, Miller KW, Elsner P, Maibach HI. Structural characteristics of the aging skin: a review. Cutan Ocul Toxicol 2007; 26(4): 343-57.
Bainbridge P. Wound healing and the role of fibroblasts. J Wound Care 2013; 22(8): 407-408, 410-412.
Unger K, Rupprecht H, Valentin B, Kircher W. The use of porous and surface modified silicas as drug delivery and stabilizing agents. Drug Dev Ind Pharm 1983; 9: 69-91.
Vallet-Regi M, Rámila A, del Real RP, Pérez-Pariente J. A New Property of MCM-41: Drug Delivery System. Chem Mater 2001; 13: 308-11.
Jadhav SA. Incredible pace of research on mesoporous silica nanoparticles. Inorg Chem Front 2014; 1: 735-9.
Vallet-Regí M, Colilla M, Izquierdo-Barba I, Manzano M. Mesoporous Silica Nanoparticles for Drug Delivery: Current Insights. Molecules 2017; 23(1): 23.
Torney F, Trewyn BG, Lin VSY, Wang K. Mesoporous silica nanoparticles deliver DNA and chemicals into plants. Nat Nanotechnol 2007; 2(5): 295-300.
Chen J-F, Ding H-M, Wang J-X, Shao L. Preparation and characterization of porous hollow silica nanoparticles for drug delivery application. Biomaterials 2004; 25(4): 723-7.
Zhou T, Wang B, Dong B, Li CY. Thermoresponsive Amphiphilic Janus Silica Nanoparticles via Combining “Polymer Single-Crystal Templating” and “Grafting-from”. Methods Macromolecules 2012; 45: 8780-9.
Bagwe RP, Hilliard LR, Tan W. Surface modification of silica nanoparticles to reduce aggregation and nonspecific binding. Langmuir 2006; 22(9): 4357-62.
Slowing I, Trewyn BG, Lin VS. Effect of surface functionalization of MCM-41-type mesoporous silica nanoparticles on the endocytosis by human cancer cells. J Am Chem Soc 2006; 128(46): 14792-3.
Graf C, Gao Q, Schütz I, et al. Surface functionalization of silica nanoparticles supports colloidal stability in physiological media and facilitates internalization in cells. Langmuir 2012; 28(20): 7598-613.
Park JH, Gu L, von Maltzahn G, Ruoslahti E, Bhatia SN, Sailor MJ. Biodegradable luminescent porous silicon nanoparticles for in vivo applications. Nat Mater 2009; 8(4): 331-6.
Shen D, Yang J, Li X, et al. Biphase stratification approach to three-dimensional dendritic biodegradable mesoporous silica nanospheres. Nano Lett 2014; 14(2): 923-32.
Phillips E, Penate-Medina O, Zanzonico PB, et al. Clinical translation of an ultrasmall inorganic optical-PET imaging nanoparticle probe. Sci Transl Med 2014; 6(260): 260ra149.
Stöber W, Fink A, Bohn E. Controlled growth of monodisperse silica spheres in the micron size range. J Colloid Interface Sci 1968; 26: 62-9.
Kumar D, Schumacher K, du Fresne von Hohenesche C, Grün M, Unger KK. MCM-41, MCM-48 and related mesoporous adsorbents: their synthesis and characterisation. Colloids Surf A Physicochem Eng Asp 2001; 187-188: 109-16.
Nooney RI, Thirunavukkarasu D, Chen Y, Josephs R, Ostafin AE. Synthesis of Nanoscale Mesoporous Silica Spheres with Controlled Particle Size. Chem Mater 2002; 14: 4721-8.
Caruso F, Caruso RA, Möhwald H. Nanoengineering of inorganic and hybrid hollow spheres by colloidal templating. Science 1998; 282(5391): 1111-4.
Khanal A, Inoue Y, Yada M, Nakashima K. Synthesis of silica hollow nanoparticles templated by polymeric micelle with core-shell-corona structure. J Am Chem Soc 2007; 129(6): 1534-5.
Chen F, Hong H, Shi S, et al. Engineering of hollow mesoporous silica nanoparticles for remarkably enhanced tumor active targeting efficacy. Sci Rep 2014; 4: 5080.
Li Y, Li N, Pan W, Yu Z, Yang L, Tang B. Hollow Mesoporous Silica Nanoparticles with Tunable Structures for Controlled Drug Delivery. ACS Appl Mater Interfaces 2017; 9(3): 2123-9.
Musso GE, Bottinelli E, Celi L, Magnacca G, Berlier G. Influence of surface functionalization on the hydrophilic character of mesoporous silica nanoparticles. Phys Chem Chem Phys 2015; 17(21): 13882-94.
Vallet-Regí M. Ordered mesoporous materials in the context of drug delivery systems and bone tissue engineering. Chemistry 2006; 12(23): 5934-43.
Rossi LM, Silva PR, Vono LLR, et al. Protoporphyrin IX nanoparticle carrier: preparation, optical properties, and singlet oxygen generation. Langmuir 2008; 24(21): 12534-8.
Ravera M, Perin E, Gabano E, et al. Functional fluorescent nonporous silica nanoparticles as carriers for Pt(IV) anticancer prodrugs. J Inorg Biochem 2015; 151: 132-42.
Teng Z, Han Y, Li J, Yan F, Yang W. Preparation of hollow mesoporous silica spheres by a sol–gel/emulsion approach. Microporous Mesoporous Mater 2010; 127: 67-72.
Labouta HI, Schneider M. Interaction of inorganic nanoparticles with the skin barrier: current status and critical review. Nanomedicine (Lond) 2013; 9(1): 39-54.
Gupta R, Rai B. In-silico design of nanoparticles for transdermal drug delivery application. Nanoscale 2018; 10(10): 4940-51.
Chen F, Hableel G, Zhao ER, Jokerst JV. Multifunctional nanomedicine with silica: Role of silica in nanoparticles for theranostic, imaging, and drug monitoring. J Colloid Interface Sci 2018; 521: 261-79.
Nafisi S, Schäfer-Korting M, Maibach HI. Perspectives on percutaneous penetration: Silica nanoparticles. Nanotoxicology 2015; 9(5): 643-57.
Sekkat N, Kalia YN, Guy RH. Biophysical study of porcine ear skin in vitro and its comparison to human skin in vivo. J Pharm Sci 2002; 91(11): 2376-81.
Meyer W. Comments on the suitability of swine skin as a biological model for human skin Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete 1996; 47: 182-312
Mangelsdorf S, Otberg N, Maibach HI, Sinkgraven R, Sterry W, Lademann J. Ethnic variation in vellus hair follicle size and distribution. Skin Pharmacol Physiol 2006; 19(3): 159-67.
Rancan F, Gao Q, Graf C, et al. Skin penetration and cellular uptake of amorphous silica nanoparticles with variable size, surface functionalization, and colloidal stability. ACS Nano 2012; 6(8): 6829-42.
Nabeshi H, Yoshikawa T, Matsuyama K, et al. Systemic distribution, nuclear entry and cytotoxicity of amorphous nanosilica following topical application. Biomaterials 2011; 32(11): 2713-24.
Hirai T, Yoshikawa T, Nabeshi H, et al. Dermal absorption of amorphous nanosilica particles after topical exposure for three days. Pharmazie 2012; 67(8): 742-3.
Boonen J, Baert B, Lambert J, De Spiegeleer B. Skin penetration of silica microparticles. Pharmazie 2011; 66(6): 463-4.
Michel K, Scheel J, Karsten S, Stelter N, Wind T. Risk assessment of amorphous silicon dioxide nanoparticles in a glass cleaner formulation. Nanotoxicology 2013; 7(5): 974-88.
Ostrowski A, Nordmeyer D, Mundhenk L, et al. AHAPS-functionalized silica nanoparticles do not modulate allergic contact dermatitis in mice. Nanoscale Res Lett 2014; 9(1): 524.
Brown MB, Martin GP, Jones SA, Akomeah FK. Dermal and transdermal drug delivery systems: current and future prospects. Drug Deliv 2006; 13(3): 175-87.
Ostrowski A, Nordmeyer D, Boreham A, et al. Skin barrier disruptions in tape stripped and allergic dermatitis models have no effect on dermal penetration and systemic distribution of AHAPS-functionalized silica nanoparticles. Nanomedicine (Lond) 2014; 10(7): 1571-81.
Nafisi S, Schäfer-Korting M, Maibach HI. Measuring Silica Nanoparticles in the Skin. In: ed.^eds., Agache’s Measuring the Skin. Springer, Cham, 2015; pp. 1-25.
Morilla MJ, Romero EL. Carrier Deformability in Drug Delivery. Curr Pharm Des 2016; 22(9): 1118-34.
Perez AP, Altube MJ, Schilrreff P, et al. Topical amphotericin B in ultradeformable liposomes: Formulation, skin penetration study, antifungal and antileishmanial activity in vitro. Colloids Surf B Biointerfaces 2016; 139: 190-8.
Baroli B. Penetration of nanoparticles and nanomaterials in the skin: fiction or reality? J Pharm Sci 2010; 99(1): 21-50.
Sapino S, Ugazio E, Gastaldi L, et al. Mesoporous silica as topical nanocarriers for quercetin: characterization and in vitro studies. Eur J Pharm Biopharm 2015; 89: 116-25.
Lademann J, Richter H, Teichmann A, et al. Nanoparticles--an efficient carrier for drug delivery into the hair follicles. Eur J Pharm Biopharm 2007; 66(2): 159-64.
Vogt A, Rancan F, Ahlberg S, et al. Interaction of dermatologically relevant nanoparticles with skin cells and skin. Beilstein J Nanotechnol 2014; 5: 2363-73.
Escobar-Chávez J, Díaz-Torres R, Rodríguez Cruz I, et al. Nanocarriers for transdermal drug delivery. Research and Reports in Transdermal Drug Delivery 2012; 2012: 1-3.
Neubert RHH. Potentials of new nanocarriers for dermal and transdermal drug delivery. Eur J Pharm Biopharm 2011; 77(1): 1-2.
Donnelly RF, Raj Singh TR, Woolfson AD. Microneedle-based drug delivery systems: microfabrication, drug delivery, and safety. Drug Deliv 2010; 17(4): 187-207.
Singh TRR, Dunne NJ, Cunningham E, Donnelly RF. Review of patents on microneedle applicators. Recent Pat Drug Deliv Formul 2011; 5(1): 11-23.
Donnelly R, Douroumis D. Microneedles for drug and vaccine delivery and patient monitoring. Drug Deliv Transl Res 2015; 5(4): 311-2.
Hamam F, Al-Remawi M. Novel delivery system of curcumin through transdermal route using sub-micronized particles composed of mesoporous silica and oleic acid. J Funct Foods 2014; 8: 87-99.
Tu J, Du G, Reza Nejadnik M, et al. Mesoporous Silica Nanoparticle-Coated Microneedle Arrays for Intradermal Antigen Delivery. Pharm Res 2017; 34(8): 1693-706.
Xu B, Jiang G, Yu W, et al. H2O2-Responsive mesoporous silica nanoparticles integrated with microneedle patches for the glucose-monitored transdermal delivery of insulin. J Mater Chem B Mater Biol Med 2017; 5: 8200-8.
Hirai T, Yoshikawa T, Nabeshi H, et al. Amorphous silica nanoparticles size-dependently aggravate atopic dermatitis-like skin lesions following an intradermal injection. Part Fibre Toxicol 2012; 9: 3.
J.A.C.C. Report. 51 - Synthetic Amorphous Silica. In: ed.^eds., Ecetoc
Mironava T, Hadjiargyrou M, Simon M, Jurukovski V, Rafailovich MH. Gold nanoparticles cellular toxicity and recovery: effect of size, concentration and exposure time. Nanotoxicology 2010; 4(1): 120-37.
Kiss B, Bíró T, Czifra G, et al. Investigation of micronized titanium dioxide penetration in human skin xenografts and its effect on cellular functions of human skin-derived cells. Exp Dermatol 2008; 17(8): 659-67.
Kim I-Y, Joachim E, Choi H, Kim K. Toxicity of silica nanoparticles depends on size, dose, and cell type. Nanomedicine (Lond) 2015; 11(6): 1407-16.
Ryu HJ, Seong NW, So BJ, et al. Evaluation of silica nanoparticle toxicity after topical exposure for 90 days. Int J Nanomedicine 2014; 9(Suppl. 2): 127-36.
Shim KH, Jeong KH, Bae SO, et al. Assessment of ZnO and SiO2 nanoparticle permeability through and toxicity to the blood-brain barrier using Evans blue and TEM. Int J Nanomedicine 2014; 9(Suppl. 2): 225-33.
Park Y-H, Kim JN, Jeong SH, et al. Assessment of dermal toxicity of nanosilica using cultured keratinocytes, a human skin equivalent model and an in vivo model. Toxicology 2010; 267(1-3): 178-81.
Park Y-H, Bae HC, Jang Y, et al. Effect of the size and surface charge of silica nanoparticles on cutaneous toxicity. Mol Cell Toxicol 2013; 9: 67-74.
Nabeshi H, Yoshikawa T, Matsuyama K, et al. Size-dependent cytotoxic effects of amorphous silica nanoparticles on Langerhans cells. Pharmazie 2010; 65(3): 199-201.
Ebabe Elle R, Rahmani S, Lauret C, et al. Functionalized Mesoporous Silica Nanoparticle with Antioxidants as a New Carrier That Generates Lower Oxidative Stress Impact on Cells. Mol Pharm 2016; 13(8): 2647-60.
Bradbury MS, Phillips E, Montero PH, et al. Clinically-translated silica nanoparticles as dual-modality cancer-targeted probes for image-guided surgery and interventions. Integr Biol 2013; 5(1): 74-86.
Benezra M, Penate-Medina O, Zanzonico PB, et al. Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma. J Clin Invest 2011; 121(7): 2768-80.
Yang J-H, Lee S-Y, Han Y-S, Park K-C, Choy J-H. Efficient Transdermal Penetration and Improved Stability of L-Ascorbic Acid Encapsulated in an Inorganic Nanocapsule. Bull Korean Chem Soc 2003; 24: 499-503.
Ghouchi Eskandar N, Simovic S, Prestidge CA. Nanoparticle coated submicron emulsions: sustained in vitro release and improved dermal delivery of all-trans-retinol. Pharm Res 2009; 26(7): 1764-75.
Scalia S, Franceschinis E, Bertelli D, Iannuccelli V. Comparative evaluation of the effect of permeation enhancers, lipid nanoparticles and colloidal silica on in vivo human skin penetration of quercetin. Skin Pharmacol Physiol 2013; 26(2): 57-67.
Heck R, Hermann S, Lunter DJ, Daniels R. Film-forming formulations containing porous silica for the sustained delivery of actives to the skin. Eur J Pharm Biopharm 2016; 108: 1-8.
Heck R, Lukić MZ, Savić SD, Daniels R, Lunter DJ. Ex vivo skin permeation and penetration of nonivamide from and in vivo skin tolerability of film-forming formulations containing porous silica. Eur J Pharm Sci 2017; 106: 34-40.
Cai XJ, Woods A, Mesquida P, Jones SA. Assessing the Potential for Drug-Nanoparticle Surface Interactions To Improve Drug Penetration into the Skin. Mol Pharm 2016; 13(4): 1375-84.
Tanabe M, Ito Y, Tokudome N, et al. Possible use of combination chemotherapy with mitomycin C and methotrexate for metastatic breast cancer pretreated with anthracycline and taxanes. Breast Cancer 2009; 16(4): 301-6.
De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/ carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol 2012; 30(2): 191-9.
Kalb RE, Strober B, Weinstein G, Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference. J Am Acad Dermatol 2009; 60(5): 824-37.
Raaby L, Zachariae C, Østensen M, et al. Methotrexate Use and Monitoring in Patients with Psoriasis: A Consensus Report Based on a Danish Expert Meeting. Acta Derm Venereol 2017; 97(4): 426-32.
Weinblatt ME, Kremer JM, Coblyn JS, et al. Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum 1999; 42(7): 1322-8.
Visser K, Katchamart W, Loza E, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis 2009; 68(7): 1086-93.
Yélamos O, Català A, Vilarrasa E, Roé E, Puig L. Acute severe methotrexate toxicity in patients with psoriasis: a case series and discussion. Dermatology (Basel) 2014; 229(4): 306-9.
Shen S, O’Brien T, Yap LM, Prince HM, McCormack CJ. The use of methotrexate in dermatology: a review. Australas J Dermatol 2012; 53(1): 1-18.
Ball MA, McCullough JL, Weinstein GD. Percutaneous absorption of methotrexate: effect on epidermal DNA synthesis in hairless mice. J Invest Dermatol 1982; 79(1): 7-10.
Bergstrom JS, Jaworsky C. Topical methotrexate for lymphomatoid papulosis. J Am Acad Dermatol 2003; 49(5): 937-9.
Sapino S, Oliaro-Bosso S, Zonari D, Zattoni A, Ugazio E. Mesoporous silica nanoparticles as a promising skin delivery system for methotrexate. Int J Pharm 2017; 530(1-2): 239-48.
Nafisi S, Samadi N, Houshiar M, Maibach HI. Mesoporous silica nanoparticles for enhanced lidocaine skin delivery. Int J Pharm 2018; 550(1-2): 325-32.
Mebert AM, Alvarez GS, Peroni R, et al. Collagen-silica nanocomposites as dermal dressings preventing infection in vivo. Mater Sci Eng C 2018; 93: 170-7.
Vasile A, Ignat M, Zaltariov MF, et al. Development of New Bexarotene-loaded Mesoporous Silica Systems for Topical Pharmaceutical Formulations. Acta Chim Slov 2018; 65(1): 97-107.
Berlier G, Gastaldi L, Sapino S, et al. MCM-41 as a useful vector for rutin topical formulations: synthesis, characterization and testing. Int J Pharm 2013; 457(1): 177-86.
Ugazio E, Gastaldi L, Brunella V, et al. Thermoresponsive mesoporous silica nanoparticles as a carrier for skin delivery of quercetin. Int J Pharm 2016; 511(1): 446-54.
Jadhav SA, Scalarone D, Brunella V, Ugazio E, Sapino S, Berlier G. Thermoresponsive copolymer-grafted SBA-15 porous silica particles for temperature-triggered topical delivery systems. Express Polym Lett 2017; 11: 96-105.
Chen-Yang YW, Chen YT, Li CC, et al. Preparation of UV-filter encapsulated mesoporous silica with high sunscreen ability. Mater Lett 2011; 65: 1060-2.
Li CC, Lin YT, Chen YT, Sie SF, Chen-Yang YW. Improvement in UV protection retention capability and reduction in skin penetration of benzophenone-3 with mesoporous silica as drug carrier by encapsulation. J Photochem Photobiol B 2015; 148: 277-83.
Niu X, Wang Z, Zhang L, Quan Y, Wei K. Experimental study of the protective effect of mesosilica-supported 5-hydroxymethyl-furfural on UV-induced aging of human dermal fibroblasts. RSC Advances 2018; 8: 25021-30.
Lin YC, Lin CF, Alalaiwe A, Wang PW, Fang YP, Fang JY. UV filter entrapment in mesoporous silica hydrogel for skin protection against UVA with minimization of percutaneous absorption. Eur J Pharm Sci 2018; 122: 185-94.
Cozzi AC, Perugini P, Gourion-Arsiquaud S. Comparative behavior between sunscreens based on free or encapsulated UV filters in term of skin penetration, retention and photo-stability. Eur J Pharm Sci 2018; 121: 309-18.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy