Login Register Cart 0
Generic placeholder image

Current Drug Delivery

Editor-in-Chief

ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Transdermal Delivery of Methotrexate Loaded in Chitosan Nanoparticles to Treat Rheumatoid Arthritis

Author(s): Nusaiba Al-Nemrawi*, Yazan Wahsheh and Karem H. Alzoubi

Volume 21, Issue 3, 2024

Published on: 15 May, 2023

Page: [451 - 460] Pages: 10

DOI: 10.2174/1567201820666230428124346

Price: $65

Abstract

Introduction: Methotrexate shows high efficiency in the treatment of Rheumatoid arthritis, but its adverse effects cannot be tolerated by many patients. Additionally, Methotrexate suffers from rapid clearance from blood. Polymeric nanoparticles were used to solve these problems including chitosan.

Methods: Herein, a new nanoparticulate system to deliver Methotrexate (MTX) using chitosan nanoparticles (CS NPs) was developed to be used transdermally. CS NPs were prepared and characterized. The drug release was studied in vitro and ex vivo using rat skin. The drug performance in vivo was investigated on rats. Formulations were applied topically once a day on the paws and knee joints of arthritis rats for 6 weeks. Paw thickness was measured and synovial fluid samples were collected.

Results: The results showed that CS NPs were monodispersed, and spherical with a size of 279.9 nm and a charge above ± 30mV. Further, 88.02% of MTX was entrapped in the NPs. CS NPs prolonged MTX release and enhanced its permeation (apparent permeability ⁓35.00cm/h) and retention (retention capacity ⁓12.01%) through rats’ skin. The transdermal delivery of MTX-CS NPs improves the progress of the disease compared to free MTX, as reflected by the lower arthritic index values, lower proinflammatory cytokines (TNF-α and IL-6), and higher anti-inflammatory cytokine (IL-10) in the synovial fluid. Further, the oxidative stress activities were significantly higher in the group treated with the MTX-CS NPs, as indicated by GSH. Finally, MTX-CS NPs were more effective in reducing lipid peroxidation in synovial fluid.

Conclusion: In conclusion, loading Methotrexate in chitosan nanoparticles controlled its release and enhance its effectiveness against rheumatoid when applied dermally.

« Previous Next »
Graphical Abstract

[1]
Guo, Q.; Wang, Y.; Xu, D.; Nossent, J.; Pavlos, N.J.; Xu, J. Rheumatoid arthritis: Pathological mechanisms and modern pharmacologic therapies. Bone Res., 2018, 6(1), 15.
[http://dx.doi.org/10.1038/s41413-018-0016-9] [PMID: 29736302]
[2]
McInnes, I.B.; Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med., 2011, 365(23), 2205-2219.
[http://dx.doi.org/10.1056/NEJMra1004965] [PMID: 22150039]
[3]
Burska, A.N.; Hunt, L.; Boissinot, M.; Strollo, R.; Ryan, B.J.; Vital, E.; Nissim, A.; Winyard, P.G.; Emery, P.; Ponchel, F. Autoantibodies to posttranslational modifications in rheumatoid arthritis. Mediators Inflamm., 2014, 2014, 1-19.
[http://dx.doi.org/10.1155/2014/492873] [PMID: 24782594]
[4]
Pal, R.; Chaudhary, M.J.; Tiwari, P.C.; Nath, R.; Pant, K.K. Pharmacological and biochemical studies on protective effects of mangiferin and its interaction with nitric oxide (NO) modulators in adjuvant-induced changes in arthritic parameters, inflammatory, and oxidative biomarkers in rats. Inflammopharmacology, 2018, 27, 291-299.
[PMID: 29934863]
[5]
Ostałowska, A.; Kasperczyk, S.; Kasperczyk, A.; Słowińska, L.; Marzec, M.; Stołtny, T.; Koczy, B.; Birkner, E. Oxidant and anti-oxidant systems of synovial fluid from patients with knee post-traumatic arthritis. J. Orthop. Res., 2007, 25(6), 804-812.
[http://dx.doi.org/10.1002/jor.20357] [PMID: 17318890]
[6]
Smolen, J.S.; Aletaha, D.; Koeller, M.; Weisman, M.H.; Emery, P. New therapies for treatment of rheumatoid arthritis. Lancet, 2007, 370(9602), 1861-1874.
[http://dx.doi.org/10.1016/S0140-6736(07)60784-3] [PMID: 17570481]
[7]
Abolmaali, S.S.; Tamaddon, A.M.; Dinarvand, R. A review of therapeutic challenges and achievements of methotrexate delivery systems for treatment of cancer and rheumatoid arthritis. Cancer Chemother. Pharmacol., 2013, 71(5), 1115-1130.
[http://dx.doi.org/10.1007/s00280-012-2062-0] [PMID: 23292116]
[8]
Shinde, C.G.; Venkatesh, M.P.; Kumar, T.M.P.; Shivakumar, H.G. Methotrexate: A gold standard for treatment of rheumatoid arthritis. J. Pain Palliat. Care Pharmacother., 2014, 28(4), 351-358.
[http://dx.doi.org/10.3109/15360288.2014.959238] [PMID: 25322199]
[9]
Drosos, A.A. Methotrexate intolerance in elderly patients with rheumatoid arthritis: What are the alternatives? Drugs Aging, 2003, 20(10), 723-736.
[http://dx.doi.org/10.2165/00002512-200320100-00002] [PMID: 12875609]
[10]
Qindeel, M.; Ullah, M.H. Fakhar-ud-Din; Ahmed, N.; Rehman, A. Recent trends, challenges and future outlook of transdermal drug delivery systems for rheumatoid arthritis therapy. J. Control. Release, 2020, 327, 595-615.
[http://dx.doi.org/10.1016/j.jconrel.2020.09.016] [PMID: 32920080]
[11]
Agboh, O.C.; Qin, Y. Chitin and chitosan fibers. Polym. Adv. Technol., 1997, 8(6), 355-365.
[http://dx.doi.org/10.1002/(SICI)1099-1581(199706)8:6<355:AID-PAT651>3.0.CO;2-T]
[12]
Ekinci, M.; Ilem-Ozdemir, D.; Gundogdu, E.; Asikoglu, M. Methotrexate loaded chitosan nanoparticles: Preparation, radiolabeling and in vitro evaluation for breast cancer diagnosis. J. Drug Deliv. Sci. Technol., 2015, 30, 107-113.
[http://dx.doi.org/10.1016/j.jddst.2015.10.004]
[13]
Al-Nemrawi, N.K.; Alsharif, S.S.M.; Alzoubi, K.H.; Alkhatib, R.Q. Preparation and characterization of insulin chitosan-nanoparticles loaded in buccal films. Pharm. Dev. Technol., 2019, 24(8), 967-974.
[http://dx.doi.org/10.1080/10837450.2019.1619183] [PMID: 31092092]
[14]
Rizvi, S.A.A.; Saleh, A.M. Applications of nanoparticle systems in drug delivery technology. Saudi Pharm. J., 2018, 26(1), 64-70.
[http://dx.doi.org/10.1016/j.jsps.2017.10.012] [PMID: 29379334]
[15]
Liu, Z.; Jiao, Y.; Wang, Y.; Zhou, C.; Zhang, Z. Polysaccharides-based nanoparticles as drug delivery systems. Adv. Drug Deliv. Rev., 2008, 60(15), 1650-1662.
[http://dx.doi.org/10.1016/j.addr.2008.09.001] [PMID: 18848591]
[16]
Hatem, S.; Elkheshen, S.A.; Kamel, A.O.; Nasr, M.; Moftah, N.H.; Ragai, M.H.; Elezaby, R.S.; El Hoffy, N.M. Functionalized chitosan nanoparticles for cutaneous delivery of a skin whitening agent: An approach to clinically augment the therapeutic efficacy for melasma treatment. Drug Deliv., 2022, 29(1), 1212-1231.
[http://dx.doi.org/10.1080/10717544.2022.2058652] [PMID: 35403519]
[17]
Sandri, G.; Bonferoni, M.C.; Ferrari, F.; Rossi, S.; Mori, M.; Caramella, C. Opportunities offered by chitosan-based nanotechnology in mucosal/skin drug delivery. Curr. Top. Med. Chem., 2015, 15(4), 401-412.
[http://dx.doi.org/10.2174/1568026615666150108124122] [PMID: 25579349]
[18]
Al-nemrawi, N.K.; Alsharif, S.S.M.; Dave, R.H. Preparation of chitosan-tpp nanoparticles: The influence of chitosan polymeric properties and formulation variables. Int. J App. Pharm., 2018, 10(5), 60.
[http://dx.doi.org/10.22159/ijap.2018v10i5.26375]
[19]
Al-nemrawi, N.K.; Alkhatib, R.Q.; Ayyad, H.; Alshraiedeh, N. Formulation and characterization of tobramycin-chitosan nanoparticles coated with zinc oxide nanoparticles. Saudi Pharm. J., 2022, 30(4), 454-461.
[20]
Garg, N.K.; Sharma, G.; Singh, B.; Nirbhavane, P.; Katare, O.P. Quality by Design (QbD)-based development and optimization of a simple, robust RP-HPLC method for the estimation of methotrexate. J. Liq. Chromatogr. Relat. Technol., 2015, 38(17), 1629-1637.
[http://dx.doi.org/10.1080/10826076.2015.1087409]
[21]
Al-Nemrawi, N.K.; Altawabeyeh, R.M.; Darweesh, R.S. Preparation and characterization of docetaxel-PLGA nanoparticles coated with folic acid-chitosan conjugate for cancer treatment. J. Pharm. Sci., 2021, 111(2), 485-494.
[PMID: 34728172]
[22]
Amarachinta, P.R.; Sharma, G.; Samed, N.; Chettupalli, A.K.; Alle, M.; Kim, J.C. Central composite design for the development of carvedilol-loaded transdermal ethosomal hydrogel for extended and enhanced anti-hypertensive effect. J. Nanobiotechnology, 2021, 19(1), 100.
[http://dx.doi.org/10.1186/s12951-021-00833-4] [PMID: 33836744]
[23]
Barbosa, A.I.; Costa Lima, S.A.; Reis, S. Development of methotrexate loaded fucoidan/chitosan nanoparticles with anti-inflammatory potential and enhanced skin permeation. Int. J. Biol. Macromol., 2019, 124, 1115-1122.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.12.014] [PMID: 30521895]
[24]
Garg, N.K.; Singh, B.; Tyagi, R.K.; Sharma, G.; Katare, O.P. Effective transdermal delivery of methotrexate through nanostructured lipid carriers in an experimentally induced arthritis model. Colloids Surf. B Biointerfaces, 2016, 147, 17-24.
[http://dx.doi.org/10.1016/j.colsurfb.2016.07.046] [PMID: 27478959]
[25]
Koyama, A.; Tanaka, A.; To, H. Daily oral administration of low-dose methotrexate has greater antirheumatic effects in collagen-induced arthritis rats. J. Pharm. Pharmacol., 2017, 69(9), 1145-1154.
[http://dx.doi.org/10.1111/jphp.12752] [PMID: 28560778]
[26]
Alzoubi, K.H.; Al-Jamal, F.F.; Mahasneh, A.F. Cerebrolysin prevents sleep deprivation induced memory impairment and oxidative stress. Physiol. Behav., 2020, 217, 112823.
[http://dx.doi.org/10.1016/j.physbeh.2020.112823] [PMID: 31987894]
[27]
Massadeh, A.M.; Alzoubi, K.H.; Milhem, A.M.; Rababa’h, A.M.; Khabour, O.F. Evaluating the effect of selenium on spatial memory impairment induced by sleep deprivation. Physiol. Behav., 2022, 244, 113669.
[http://dx.doi.org/10.1016/j.physbeh.2021.113669] [PMID: 34871651]
[28]
Nogueira, D.R.; Tavano, L.; Mitjans, M.; Pérez, L.; Infante, M.R.; Vinardell, M.P. In vitro antitumor activity of methotrexate via pH-sensitive chitosan nanoparticles. Biomaterials, 2013, 34(11), 2758-2772.
[http://dx.doi.org/10.1016/j.biomaterials.2013.01.005] [PMID: 23352041]
[29]
Howard, K.A.; Paludan, S.R.; Behlke, M.A.; Besenbacher, F.; Deleuran, B.; Kjems, J. Chitosan/siRNA nanoparticle-mediated TNF-α knockdown in peritoneal macrophages for anti-inflammatory treatment in a murine arthritis model. Mol. Ther., 2009, 17(1), 162-168.
[http://dx.doi.org/10.1038/mt.2008.220] [PMID: 18827803]
[30]
Al-Nemrawi, N.K.; Dave, R.H. Formulation and characterization of acetaminophen nanoparticles in orally disintegrating films. Drug Deliv., 2016, 23(2), 540-549.
[http://dx.doi.org/10.3109/10717544.2014.936987] [PMID: 25013958]
[31]
Infrared Spectroscopy Absorption Table Chemistry LibreTexts; , 2014. Available from : [https://chem.libretexts.org/Ancillary_Materials/Reference/Reference_Tables/Spectroscopic_Reference_Tables/Infrared_Spectroscopy_Absorption_Table
[32]
Al-Nemrawi, N.; Hameedat, F.; Al-Husein, B.; Nimrawi, S. Photolytic controlled release formulation of methotrexate loaded in chitosan/TiO2 nanoparticles for breast cancer. Pharmaceuticals, 2022, 15(2), 149.
[http://dx.doi.org/10.3390/ph15020149] [PMID: 35215259]
[33]
Teja, S.P.S.; Damodharan, N. 2 3 Full factorial model for particle size optimization of methotrexate loaded chitosan nanocarriers: A Design of Experiments (DoE) approach. BioMed Res. Int., 2018, 2018, 1-9.
[http://dx.doi.org/10.1155/2018/7834159] [PMID: 30356374]
[34]
Hasipoglu, H.N.; Yilmaz, E.; Yilmaz, O.; Caner, H. Preparation and characterization of maleic acid grafted chitosan. Int. J. Polym. Anal. Charact., 2005, 10(5-6), 313-327.
[http://dx.doi.org/10.1080/10236660500479478]
[35]
Pentak, D.; Kozik, V. Bąk, A.; Dybał P.; Sochanik, A.; Jampilek, J. Methotrexate and cytarabine—loaded nanocarriers for multidrug cancer therapy. Spectroscopic study. Molecules, 2016, 21(12), 1689.
[http://dx.doi.org/10.3390/molecules21121689] [PMID: 27941655]
[36]
Agrawal, Y.O.; Mahajan, U.B.; Mahajan, H.S.; Ojha, S. Methotrexate-Loaded nanostructured lipid carrier gel alleviates imiquimod-induced psoriasis by moderating inflammation: Formulation, optimization, characterization, in vitro and in vivo studies. Int. J. Nanomedicine, 2020, 15, 4763-4778.
[http://dx.doi.org/10.2147/IJN.S247007] [PMID: 32753865]
[37]
Yoksan, R.; Jirawutthiwongchai, J.; Arpo, K. Encapsulation of ascorbyl palmitate in chitosan nanoparticles by oil-in-water emulsion and ionic gelation processes. Colloids Surf. B Biointerfaces, 2010, 76(1), 292-297.
[http://dx.doi.org/10.1016/j.colsurfb.2009.11.007] [PMID: 20004558]
[38]
Aydın, A.S.T.; Pulat, M. 5-fluorouracil encapsulated chitosan nanoparticles for pH-stimulated drug delivery. J. Nanomater., 2012, 2012, 1-11.
[39]
Ahmed, A.B.; Konwar, R.; Sengupta, R. Atorvastatin calcium loaded chitosan nanoparticles: In vitro evaluation and in vivo pharmacokinetic studies in rabbits. Braz. J. Pharm. Sci., 2015, 51(2), 467-477.
[http://dx.doi.org/10.1590/S1984-82502015000200024]
[40]
Garg, U.; Chauhan, S.; Nagaich, U.; Jain, N. Current advances in chitosan nanoparticles based drug delivery and targeting. Adv. Pharm. Bull., 2019, 9(2), 195-204.
[http://dx.doi.org/10.15171/apb.2019.023] [PMID: 31380245]
[41]
Hasanovic, A.; Zehl, M.; Reznicek, G.; Valenta, C. Chitosan-tripolyphosphate nanoparticles as a possible skin drug delivery system for aciclovir with enhanced stability. J. Pharm. Pharmacol., 2010, 61(12), 1609-1616.
[http://dx.doi.org/10.1211/jpp.61.12.0004] [PMID: 19958582]
[42]
Al-Kassas, R.; Wen, J.; Cheng, A.E.M.; Kim, A.M.J.; Liu, S.S.M.; Yu, J. Transdermal delivery of propranolol hydrochloride through chitosan nanoparticles dispersed in mucoadhesive gel. Carbohydr. Polym., 2016, 153, 176-186.
[http://dx.doi.org/10.1016/j.carbpol.2016.06.096] [PMID: 27561485]
[43]
Owen, J.B.; Butterfield, D.A. Measurement of oxidized/reduced glutathione ratio. Methods Mol. Biol., 2010, 648, 269-277.
[http://dx.doi.org/10.1007/978-1-60761-756-3_18] [PMID: 20700719]
[44]
Dickinson, D.A.; Forman, H.J. Cellular glutathione and thiols metabolism. Biochem. Pharmacol., 2002, 64(5-6), 1019-1026.
[http://dx.doi.org/10.1016/S0006-2952(02)01172-3] [PMID: 12213601]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy