Nashrieh Shimi va Mohandesi Shimi Iran

Nashrieh Shimi va Mohandesi Shimi Iran

Development of Dissolving Microneedles for local Methotrexate and lubricants Delivery: A Strategy for Improved Pain and Treatment Management of Rheumatoid Arthritis

Document Type : Research Article

Authors
1 Department of Bioscience Engineering, Interdisciplinary Colleges of Science and Technology, University of Tehran, Tehran, I.R. IRAN
2 Department of Petrochemistry, Faculty of Chemical, Oil and Gas Engineering, Iran University of Science and Technology, Tehran, I.R. IRAN
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease affecting the synovial membrane and disrupting the healthy production of synovial fluid, the natural lubricant of joints. Conventional treatments based on methotrexate (MTX), despite their widespread use, are associated with limitations such as low bioavailability, high systemic toxicity, and poor tissue penetration. Furthermore, these methods primarily focus on inflammation reduction, often necessitating the concurrent administration of analgesics for pain relief. In this study, a dissolving microneedle patch was designed to co-deliver MTX and two lubricants, hyaluronic acid (HA) and glycerol. Mechanical testing revealed that the fabricated patch could withstand a force of 0.11 N per microneedle and effectively penetrate the initial four layers of Parafilm®, indicating its potential to penetrate joint tissue without fracture. In vitro release studies using rat skin demonstrated localized drug delivery, with 48.46% of MTX remaining in the tissue after release. Glycerol, in addition to contributing to lubrication, could potentially enhance patch's flexibility, enabling conformal adaptation to joints with varying curvatures. The developed MN patch, with its potential for simultaneous treatment and pain alleviation, offers a promising avenue for improving rheumatoid arthritis therapies and presents a suitable alternative to existing market treatments.
Keywords
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[1] Rezaee M., Lotfi F., Gholami A., Azizpoor J., Aflaki E., Vazin A., Keshavarz K., Economic Burden of Rheumatoid Arthritis in Iran: A Societal Perspective Economic Burden of RA. (2022).
[2] Radu A. F., Bungau S.G., Management of Rheumatoid Arthritis: An Overview. Cells, 10(11): 2857 (2021).
[3] Weyand C.M., Goronzy J.J., The Immunology of Rheumatoid Arthritis. Nature immunology, 22(1): 10-18 (2021).
[4] Dahl L.B., Dahl I.M., Engström-Laurent A., Granath K., Concentration and Molecular Weight of Sodium Hyaluronate in Synovial Fluid from Patients with Rheumatoid Arthritis and Other Arthropathies, Annals of the rheumatic diseases, 44(12): 817-822 (1985).
[5] Kosinska M.K., Ludwig T.E., Liebisch G., Zhang R., Siebert H.C., Wilhelm J., Steinmeyer, J., Articular Joint Lubricants During Osteoarthritis and Rheumatoid Arthritis Display Altered Levels and Molecular Species. PloS one, 10(5): e0125192 (2015).
[6] Guo Q., Wang Y., Xu D., Nossent J., Pavlos N.J., Xu J., Rheumatoid Arthritis: Pathological Mechanisms and Modern Pharmacologic Therapies. Bone research, 6(1): 15 (2018).
[7] Zhang W., Yin G., Zhao H., Ling H., Xie Z., Xiao C., Chen Y., Lin Y., Jiang, T., Jin S., Wang J., Secreted KIAA1199 Promotes the Progression of Rheumatoid Arthritis by Mediating Hyaluronic Acid Degradation in an ANXA1-Dependent Manner. Cell death & disease, 12(1): 102 (2021).
[8] Seo J., Park S.H., Kim M.J., Ju H.J., Yin X.Y., Min B.H., Kim M.S., Injectable Click-Crosslinked Hyaluronic Acid Depot to Prolong Therapeutic Activity in Articular Joints Affected by Rheumatoid Arthritis. ACS applied materials & interfaces, 11(28): 24984-24998 (2019).
[9] Caporali R., Caprioli M., Bobbio-Pallavicini F., Montecucco C., DMARDS and Infections in Rheumatoid Arthritis. Autoimmunity reviews, 8(2): p. 139-143 (2008).
[10] Friedman B., Cronstein B., Methotrexate Mechanism in Treatment of Rheumatoid Arthritis, Joint bone spine, 86(3): 301-307 (2019).
[11] Wang W., Zhou H., Liu L., Side Effects of Methotrexate Therapy for Rheumatoid Arthritis: A Systematic Review. European journal of medicinal chemistry, 158: 502-516 (2018).
[12] Bianchi G., Caporali R., Todoerti M., Mattana P., Methotrexate and Rheumatoid Arthritis: Current Evidence Regarding Subcutaneous Versus Oral Routes of Administration. Advances in therapy, 33: 369-378 (2016).
[13] Gorantla S., Batra U., Samshritha R.N., Puppala E.R., Waghule,T., Naidu V.G.M., Singhvi G., Emerging Trends in Microneedle-Based Drug Delivery Strategies for the Treatment of Rheumatoid Arthritis. Expert Opinion on Drug Delivery, 19(4): 395-407 (2022).
[14] Rad Z.F., Prewett P.D., Davies G.J., An Overview of Microneedle Applications, Materials, and Fabrication Methods. Beilstein journal of nanotechnology, 12(11): 1034-1046 (2021).
[15] Teymoori M., Poorkhalil A., Farrokhzad H., Tabesh H., Glucose Responsive Microneedle Patch Using a Reversible and an Irreversible Crosslinking Agents. Results in Engineering, 106134 (2025).
[16] Vora D., Garimella H.T., German C.L., Banga A.K., Microneedle and Iontophoresis Mediated Delivery of Methotrexate Into and Across Healthy and Psoriatic Skin. International journal of pharmaceutics, 618: 121693 (2022).
[17] Tekko, I. A., Permana, A. D., Vora L., Hatahet T., McCarthy H.O., Donnelly R.F., Localised and Sustained Intradermal Delivery of Methotrexate using Nanocrystal-Loaded Microneedle Arrays: Potential for Enhanced Treatment of Psoriasis. European Journal of Pharmaceutical Sciences, 152: 105469 (2020).
[18] Tekko I.A., Chen G., Domínguez-Robles J., Thakur R.R.S., Hamdan I.M., Vora L., Larrañeta E., McElnay J.C., McCarthy H.O., Rooney M. Donnelly R.F., Development and Characterisation of Novel Poly (Vinyl Alcohol)/Poly (Vinyl Pyrrolidone)-Based Hydrogel-Forming Microneedle Arrays for Enhanced and Sustained Transdermal Delivery of Methotrexate. International journal of pharmaceutics, 586: 119580 (2020).
[19] Rajendran K., Pahal S., Badnikar K., Nayak M.M., Subramanyam D.N., Vemula P.K., Krishnan U.M., Methotrexate Delivering Microneedle Patches for Improved Therapeutic Efficacy in Treatment of Rheumatoid Arthritis. International Journal of Pharmaceutics, 642: 123184 (2023).
[20] Zhao W., Zheng L., Yang J., Ma Z., Tao X., Wang Q., Dissolving Microneedle Patch-Assisted Transdermal Delivery of Methotrexate Improve the Therapeutic Efficacy of Rheumatoid Arthritis. Drug Delivery, 30(1): 121-132 (2023).
[21] Orr C., Vieira-Sousa E., Boyle D.L., Buch M.H., Buckley C.D., Cañete J.D., Catrina A.I., Choy E.H., Emery P., Fearon U. Filer A., Synovial Tissue Research: A State-of-the-Art Review. Nature Reviews Rheumatology, 13(8): 463-475 (2017).
[22] Kim K.S., Park S.J., Yang J.A., Jeon J.H., Bhang S.H., Kim B.S., Hahn S.K., Injectable Hyaluronic Acid–Tyramine Hydrogels for the Treatment of Rheumatoid Arthritis. Acta biomaterialia, 7(2): 666-674 (2011).
[23] Chou C.L., Li H.W., Lee S.H., Tsai K.L., Ling H.Y., Effect of Intra-Articular Injection of Hyaluronic Acid in Rheumatoid Arthritis Patients with Knee Osteoarthritis. Journal of the Chinese Medical Association, 71(8): 411-415 (2008).
[24] Lu K.H., Lu P.W.A., Lin C.W., Lu E.W.H., Yang S.F., Different Molecular Weights of Hyaluronan Research in Knee Osteoarthritis: A State-of-the-Art Review. Matrix Biology, 117: 46-71 (2023).
[25] Mishra A., Pathak A., Plasticizers: A Vital Excipient in Novel Pharmaceutical Formulations. Current Research in Pharmaceutical Sciences, 1-10 (2017).
[26] Ananda P.W.R., Elim D., Zaman H.S., Muslimin W., Tunggeng M.G.R., Permana A.D., Combination of Transdermal Patches and Solid Microneedles for Improved Transdermal Delivery of Primaquine. International Journal of Pharmaceutics, 609: 121204 (2021).
[27] Kochhar J.S., Soon W.J., Choi J., Zou S., Kang L., Effect of Microneedle Geometry and Supporting Substrate on Microneedle Array Penetration into Skin. Journal of pharmaceutical sciences, 102(11): 4100-4108 (2013).
[28] Wu M., Xia T., Li Y., Wang T., Yang S., Yu J., Liang Q., Shen T., Yu M. Zhao B., Design and Fabrication of R-Hirudin Loaded Dissolving Microneedle Patch for Minimally Invasive and Long-Term Treatment of Thromboembolic Disease. Asian journal of pharmaceutical sciences, 17(2): 284-297 (2022).
[29] Cao J., Zhang, N., Wang Z., Su J., Yang J., Han J., Zhao Y., Microneedle-Assisted Transdermal Delivery of Etanercept for Rheumatoid Arthritis Treatment. Pharmaceutics. 11(5): 235 (2019).
[30] Lu Y., Xiao T., Lai R., Liu Z., Luo W., Wang Y., Fu S., Chai G., Jia J. Xu Y., Co-Delivery of Loxoprofen and Tofacitinib by Photothermal Microneedles for Rheumatoid Arthritis Treatment. Pharmaceutics, 15(5): 1500 (2023).
[31] Zhang D., Das D.B., Rielly C.D., Microneedle Assisted Micro-Particle Delivery from Gene Guns: Experiments using Skin-Mimicking Agarose Gel. Journal of Pharmaceutical Sciences, 103(2): 613-627 (2014).
[32] Wei H., Liu S., Tong Z., Chen T., Yang M., Guo Y., Sun H., Wu Y., Chu Y. Fan L., Hydrogel-Based Microneedles of Chitosan Derivatives for Drug Delivery. Reactive and Functional Polymers, 172: 105200 (2022).
[33] Oliveira C., Teixeira J.A., Oliveira N., Ferreira S., Botelho C.M., Microneedles’ Device: Design, Fabrication, and Applications. Macromol, 4(2): 320-355 (2024).
[34] Jeong J., Park J., Lee S., 3D Printing Fabrication Process for Fine Control of Microneedle Shape. Micro and Nano Systems Letters, 11(1): 1 (2023).
[35] Yang H.W., Ju S.P., Chen H.Y., Cheng Y.C., Hsu W.L., Ovalbumin-Loaded Gelation Microneedles Made of Predictive Formulation by Molecular Dynamics Simulation for Enhancement of Skin Immunization. ACS Biomaterials Science & Engineering, 5(11): 6012-6021 (2019).
[36] Larrañeta E., Moore J., Vicente-Pérez E.M., González-Vázquez P., Lutton R., Woolfson A.D., Donnelly R.F., A Proposed Model Membrane and Test Method for Microneedle Insertion Studies. International journal of pharmaceutics, 472(1-2): 65-73 (2014).
[37] Liu T., Fu J., Chen M., Wu Q., Quan G., Wu C., Pan X., In Situ Polymeric Nanomicelle-Generating Dissolving Microneedle Patch for Enhanced Transdermal Methotrexate Delivery in Rheumatoid Arthritis Treatment. European Polymer Journal, 210: 113008 (2024).
[38] Penn M.J., Hennessy M.G., Optimal Loading of Hydrogel-Based Drug-Delivery Systems. Applied Mathematical Modelling, 112: 649-668 (2022).
[39] Du H., Liu P., Zhu J., Lan J., Li Y., Zhang L., Zhu J. Tao J., Hyaluronic Acid-Based Dissolving Microneedle Patch Loaded with Methotrexate for Improved Treatment of Psoriasis. ACS applied materials & interfaces, 11(46): 43588-43598 (2019).
[40] Himawan A., Anjani Q.K., Detamornrat U., Vora L.K., Permana A.D., Ghanma R., Naser Y., Rahmawanty D., Scott C.J. Donnelly R.F., Multifunctional Low Temperature-Cured PVA/PVP/Citric Acid-Based Hydrogel Forming Microarray Patches: Physicochemical Characteristics and Hydrophilic Drug Interaction. European Polymer Journal, 186: 111836 (2023).
[41] Du H., Yang J., Li M., Xia Y., Li Y., Zhu J., Zhang L. Tao J., Microneedle-Assisted Percutaneous Delivery of Methotrexate-Loaded Nanoparticles Enabling Sustained Anti-Inflammatory Effects in Psoriasis Therapy. Journal of Materials Chemistry B, 12(10): 2618-2627 (2024).
[42] Evanich J.D., Evanich C.J., Wright M.B., Rydlewicz J.A., Efficacy of Intraarticular Hyaluronic Acid Injections in Knee Osteoarthritis. Clinical Orthopaedics and Related Research (1976-2007), 39: 173-181 (2001).
[43] Gigis I., Fotiadis E., Nenopoulos A., Tsitas K., Hatzokos I., Comparison of Two Different Molecular Weight Intra-Articular Injections of Hyaluronic Acid for the Treatment of Knee Osteoarthritis. Hippokratia, 20(1): 26 (2016).
[44] Saepang K., Buranrat B., Pitaksuteepong T., Boontha S., Effect of Polyvinyl Alcohol Concentrations on the Characteristics and in Vitro Skin Permeation of Rhein-Loaded Dissolving Microneedle Patches. Journal of Drug Delivery Science and Technology, 108: 106955 (2025).