Methotrexate-Polymer Nanocomposites for Targeted Pulmonary Drug Delivery

Aseel Khaled Mohammad AL-Sarayrah(1), Samer Hasan Hussein-Al-Ali(2*), Mike Khalil Haddad(3), Dalia Kalil(4)

(1) Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Isra University, Amman 11622, Jordan
(2) Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Isra University, Amman 11622, Jordan; Department of Chemistry, Faculty of Sciences, Isra University, Amman 11622, Jordan
(3) Department of Renewable Energy Engineering, Faculty of Engineering, Isra University, Amman 11622, Jordan
(4) Department of Physiotherapy, Faculty of Allied Medical Sciences, Isra University, Amman 11622, Jordan
(*) Corresponding Author


Nanocomposite formulation is a suitable technology that enables the development of successful dry powder inhalers. The methotrexate (MTX) and polyamide-disulfide (polymer) were used as a model to form MTX-polymer nanocomposites. Different amounts of the independent variable, MTX (0.025 and 0.050 g), polymer (0.05 and 0.01 g), pH (6.7 and 11.3), and across-linker ferric chloride (FeCl3) (0.05 and 0.10 g) were used. The loading efficiency and particle size were dependent variables. The optimized formula can be obtained with the highest loading efficiency and optimum particle size. This formula can be collected by using 0.025 g of drug, 0.079 g of polymer, 0.050 g of FeCl3, and pH = 6.7. The release of MTX from the nanocomposites occurs in two release steps; the first release step starts from the beginning up to 60 min, followed by a continuous release phase within 60 min. The results of the NGI analysis demonstrated that 28.1% of the nominated dose in each puff reached the lower parts of the respiratory system, an indication that the nanocomposites can be used in the delivery of MTX as a respiratory system.


pulmonary drug delivery; methotrexate; nanocomposites

Full Text:

Full Text PDF


[1] Mims, J.W., 2015, Asthma: Definitions and pathophysiology, Int. Forum Allergy Rhinol., 5 (S1), S2–S6.

[2] Caramori, G., Nucera, F., Mumby, S., Lo Bello, F., and Adcock, I.M., 2022, Corticosteroid resistance in asthma: Cellular and molecular mechanisms, Mol. Aspects Med., 85, 100969.

[3] Pinnock, H., Epiphaniou, E., Pearce, G., Parke, H., Greenhalgh, T., Sheikh, A., Griffiths, C.J., and Taylor, S.J., 2015, Implementing supported self-management for asthma: A systematic review and suggested hierarchy of evidence of implementation studies, BMC Med., 13 (1), 127.

[4] Khosa, J.K., Louie, S., Lobo Moreno, P., Abramov, D., Rogstad, D.K., Alismail, A., Matus, M.J., and Tan, L.D., 2023, Asthma care in the elderly: Practical guidance and challenges for clinical management-a framework of 5 “Ps”, J. Asthma Allergy, 16, 33–43.

[5] Balde, A., Kim, S.K., Benjakul, S., and Nazeer, R.A., 2022, Pulmonary drug delivery applications of natural polysaccharide polymer derived nano/micro-carrier systems: A review, Int. J. Biol. Macromol., 220, 1464–1479.

[6] Kumar, R., Mehta, P., Shankar, K.R., Rajora, M.A., Mishra, Y.K., Mostafavi, E., and Kaushik, A., 2015, Nanotechnology-assisted metered-dose inhalers (MDIs) for high-performance pulmonary drug delivery applications, Pharm. Res., 39 (11), 2831–2855.

[7] Ibrahim, M., Verma, R., and Garcia-Contreras, L., 2015, Inhalation drug delivery devices: Technology update, Med. Devices: Evidence Res., 8, 131–139.

[8] Kumar, M., Hilles, A.R., Almurisi, S.H., Bhatia, A., and Mahmood, S., 2023, Micro and nano-carriers-based pulmonary drug delivery system: Their current updates, challenges, and limitations – A review, JCIS Open, 12, 100095.

[9] Shakeel, F., 2023, Editorial: Nanomedicine-based drug delivery systems: Recent developments and future prospects, Molecules, 28 (10), 4138.

[10] Mehta, P.P., and Dhapte-Pawar, V., 2023, “Multifunctional Cyclodextrins Carriers for Pulmonary Drug Delivery: Prospects and Potential” in Pulmonary Drug Delivery Systems: Material and Technological Advances, Springer Nature Singapore, Singapore, 247–279.

[11] Sanchis, J., Corrigan, C., Levy, M.L., and Viejo, J.L., 2013, Inhaler devices – From theory to practice, Respir. Med., 107 (4), 495–502.

[12] Siahaan, P., Mentari, N.C., Wiedyanto, U.O., Hudiyanti, D., Hildayani, S.Z., and Laksitorini, M.D., 2017, The optimum conditions of carboxymethyl chitosan synthesis on drug delivery application and its release of kinetics study, Indones. J. Chem., 17 (2), 291–300.

[13] Astuti, I.Y., Marchaban, M., Martien, R., and Nugroho, A.E., 2017, Design and optimization of self nano-emulsifying drug delivery system containing a new anti-inflammatory agent pentagamavunon-0, Indones. J. Chem., 17 (3), 365–375.

[14] Lestari, D., Nizardo, N.M., and Mulia, K., 2022, Enhanced drug release of poly (lactic-co-glycolic acid) nanoparticles modified with hydrophilic polymers: Chitosan and carboxymethyl chitosan, Indones. J. Chem., 22 (5), 1338–1347.

[15] Friedman, B., and Cronstein, B., 2019, Methotrexate mechanism in treatment of rheumatoid arthritis, Jt., Bone, Spine, 86 (3), 301–307.

[16] Sharma, M., and Chauhan, P.M.S., 2012, Dihydrofolate reductase as a therapeutic target for infectious diseases: Opportunities and challenges, Future Med. Chem., 4 (10), 1335–1365.

[17] Nalwa, H.S., Prasad, P., Ganguly, N.K., Chaturvedi, V., and Mittal, S.A., 2023, Methotrexate intolerance in Rheumatoid Arthritis, Transl. Med. Commun., 8 (1), 10.

[18] Gürler, M., Selcuk, E.B., Özerol, B.G., Tanbek, K., Taşlıdere, E., Yıldız, A., Yağın, F.H., and Gürel, E., 2023, Protective effect of dexpanthenol against methotrexate-induced liver oxidative toxicity in rats, Drug Chem. Toxicol., 46 (4), 708–716.

[19] Sandhu, J., Kumar, A., and Gupta, S.K., 2022, The therapeutic role of methotrexate in chronic urticaria: A systematic review, Indian J. Dermatol. Venereol. Leprol., 88 (3), 313–321.

[20] Song, G.G., and Lee, Y.H., 2021, Methotrexate for treating polymyalgia rheumatica: A meta-analysis of randomized controlled trials, Int. J. Clin. Pharmacol. Ther., 59 (5), 366–371.

[21] Alkurdi, N.M., Hussein-Al-Ali, S.H., Albalwi, A., Haddad, M.K., Aldalahmed, Y., and Ali, D.K., 2022, Development and evaluation of a novel polymer drug delivery system using cromolyn-polyamides-disulfide using response surface design, J. Chem., 2022, 7903310.

[22] Kourkoumelis, N., Zhang, X., Lin, Z., and Wang, J., 2019, Fourier transform infrared spectroscopy of bone tissue: Bone quality assessment in preclinical and clinical applications of osteoporosis and fragility fracture, Clin. Rev. Bone Miner. Metab., 17 (1), 24–39.

[23] Almahamid, Y.R., Hussein-Al-Ali, S.H., and Haddad, M.K., 2022, Application of factorial design and response surface methodology in the optimization of clindamycin nanocomposites, J. Nanomater., 2022, 1967606.

[24] Ahmed, Z.A.G., Hussein-Al-Ali, S.H., Ibrahim, I.A.A., Haddad, M.K., Ali, D.K., Hussein, A.M., and Abu Sharar, A.A., 2022, Development and evaluation of amlodipine-polymer nanocomposites using response surface methodology, Int. J. Polym. Sci., 2022, 3427400.

[25] Kahled, E., Fouad, M.F., Badawi, M.H., Abd El-Rahim, W.M., Shawky, H., and Moawad, H., 2022, Thermostable protease, amylase and lipase enzymes of thermophilic bacteria isolated from Egyptian hot springs, Egypt. J. Chem., 65 (10), 225–238.

[26] Hussein‐Al‐Ali, S.H., Kura, A., Hussein, M.Z., and Fakurazi, S., 2018, Preparation of chitosan nanoparticles as a drug delivery system for perindopril erbumine, Polym. Compos., 39 (2), 544–552.

[27] Aganovic, A., Cao G., Kurnitski, J., and Wargocki, P., 2023, New dose-response model and SARS-CoV-2 quanta emission rates for calculating the long-range airborne infection risk, Build Environ., 228, 109924.

[28] Labiris, N.R., and Dolovich, M.B., 2003, Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications, Br. J. Clin. Pharmacol., 56 (6), 588–599.

[29] Fuliaş, A., Popoiu, C., Vlase, G., Vlase, T., Oneţiu, D., Săvoiu, G., Simu, G., Pătruţescu, C., Ilia, G., and Ledeţi, I., 2014, Thermoanalytical and spectroscopic study on methotrexate – active substance and tablet, Dig. J. Nanomater. Biostruct., 9 (1), 93–98.

[30] Ali, D.K., Al-Zuheiri, A.M., and Sweileh, B.A., 2017, pH and reduction sensitive bio-based polyamides derived from renewable dicarboxylic acid monomers and cystine amino acid, Int. J. Polym. Anal. Charact., 22 (4), 361–373.


Article Metrics

Abstract views : 1896 | views : 769

Copyright (c) 2024 Indonesian Journal of Chemistry

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.


Indonesian Journal of Chemistry (ISSN 1411-9420 /e-ISSN 2460-1578) - Chemistry Department, Universitas Gadjah Mada, Indonesia.

Analytics View The Statistics of Indones. J. Chem.