Methotrexate Topical Cubosomes for Rheumatoid Arthritis.

  • Karishma Kapoor M. Pharm


Objective: Non Steroidal Anti-Inflammatory Drugs (NSAIDs) are essential part of the administration of Rheumatoid Arthritis (RA). Methotrexate (MTX) is effective for tumor necrosis factor alpha (TNF-a) biologic agents, indicated only in minority of patients suffering from severe RA. MTX remains the "anchor drug" in the treatment of RA. For delivery improvement, novel pharmaceutical drug delivery system i.e. MTX- Cubosomes were developed.

Methods: Poloxamer 407 and Glycerol monooleate (Monoelin, MO) used and the formulation were characterized as a sustained release drug delivery system for Methotrexate. Different ratios of Monolein, Poloxamer 407 and water were used to develop the different cubosomes using homogenization and emulsification method. Characterization of formulations for morphology was performed and also particle size distribution by Transmission Electron Microscopy (TEM).

Results: Formulation showed the internal cubic structures of the vesicles. The particle size of the formulation was found to be ranging from 53.21 to 185.32nm, zeta potential of the formulations varied from -18.20-36.10mV. The cubosomal formulation exhibited good entrapment efficiency along with high drug loading. Compatibility with the excipients was also established. An in-vitro release study was done using Franz Diffusion cell indicated sustained release of the formulation at a rate of 1.25%/h. Cubosomes proved to be reliable system for sustained transdermal drug delivery system.

Conclusion: Methotrexate cubosomes is a novel medication delivery framework and in this examination it has been developed and characterized. The formulations were found to be promising in terms of its characterization parameters like particle size, zeta potential,  entrapment efficiency, loading capacity,release kinetics, and stability, suitable for topical delivery.

Keywords: Rheumatoid arthritis, NSAIDs, Cubosomes, Methotrexate.


1. Shah JC, Sadhale Y, Chilukuri DM. Cubic phase gels as drug delivery systems. Adv Drug Deliv Rev. 2001;47(2-3):229-50
2. Cotran R, Kumar V, Collins T. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: W.B. Saunders Company, 1999.
3. Lineker S, Badley E, Charles C, Defining morning stiffness in rheumatoid arthritis. J Rheumatol, 1999; 26:1052-57.
4. Aida Turturro Brings RA Awareness Campaign to Philadelphia". Market Wire. 2005.
5. Lozada CJ, Firestein GS.. Management of osteoarthritis. Kelley's Textbook of Rheumatology. 8th ed., Vol. 2, Philadelphia: Saunders Elsevier; 2009. p 1563-77.
6. Firestein GS. Etiology and pathogenesis of rheumatoid arthritis. Kelley?s Textbook of rheumatology. 7th ed. Philadelphia: WB Saunders; 2005. p. 996–1042.
7. Rothschild BM, Rothschild C, Helbling M. Unified theory of the origins of erosive arthritis: conditioning as a protective/directing mechanism. J. Rheumatol, 2003; 30(10): 2095–102.
8. Spector TD. Rheumatoid Arthritis. Rheum Dis Clin North Am; 1990; 16:513-37.
9. Turesson C, O'Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann. Rheum. Di, 2003; 62(8): 722–7.
10. Goldring SR. A 55-year-old woman with rheumatoid arthritis. JAMA, 2005; 283: 524–531.
11. Rothschild BM, Turner KR, Deluca MA. Symmetrical erosive peripheral polyarthritis in the late Archaic period of Alabama. Science. 1998; 241:1498-1501.
12. Silman AJ, Macgregor AJ,Whiting S, ET AL. Twin concordance rates for rheumatoid arthritis: Results from a nationwide study. Br J Rheumatol. 1993; 32:903-7.
13. Lee KW, Nguyen TH, Hanley T, Boyd BJ. Nanostructure of liquid crystalline matrix determines in vitro sustained release and in vivo oral absorption kinetics for hydrophilic model drugs. Int J Pharm. 2009;365(1–2):190–199.
14. Caffrey M. A lipid’s eye view of membrane protein crystallization in mesophases. CurrOpin Struct Biol. 2000;10(4):486–497. 7(2–3):229–50.
15. Pan X, Han K, Peng X, et al. Nanostructured cubosomes as advanced drug delivery system. Curr Pharm Des. 2013;19(35):6290–97.
17. S. L. Morgan, R. A. Oster, J. Y. Lee, G. S. Alarc ´ on, and J. E. Baggott, “The effect of folic acid and folinic acid supplements on purine metabolism in methotrexate-treated rheumatoid arthritis,” Arthritis & Rheumatism,2004; vol. 50, no. 10, pp. 3104– 3111.
18. Trotta M, Peira E, Carlotti ME, Gallarate M. Deformable liposomes for dermal administration of methotrexate. Int J Pharm. 2004; 270:119–125.
19. Amidon GL, Lennern¨as H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995; 12:413–420.
20. Morsi NM, Abdelbary GA, Ahmed MA. (). Silver sulfadiazine based cubosome hydrogels for topical treatment of burns: development and in vitro/in vivo characterization. Eur J Pharm Biopharm. 2014; 86: 178–89.
21. Salwa Salah, Azza A. Mahmoud &Amany O. Kamel.. Etodolac transdermal cubosomes for the treatment of rheumatoid arthritis: ex vivo permeation and in vivo pharmacokinetic studies, Drug Delivery. 2017, 24:1, 846-856
22. O'dell JR, Leff R, Paulsen G..Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002; 46: 1164-70.
23. Alice R. Oliveira, Lilia B. Caland, Edilene G. Oliveira, Eryvaldo S. T. Egito, Matheus F. F. Pedrosa and Arnóbio A. Silva Júnior. HPLC-DAD and UV-Vis Spectrophotometric Methods for Methotrexate Assay in Different Biodegradable Microparticles. 2015; Vol. 26, No. 4, 649-s59.
24. Strom P., Anderson D. M. The cubic phase region in the system didodecyldimethyl-ammonium bromide-water-styrene, Langmuir, 8(2), 691—709 (1992).
25. Lynch M. L., Kochvar K. K., Burns J. L., Laughlin R. G., Langmuir. 2000;16:3537-42.
26. Engström S., Larsson K., Lindman B.Controlled Release Bioact. Mater.199815: 105-6.
27. Engström S., Lindahl L., Wallin R., Engblom J., Int. J. Pharm.,1992;86: 137—145
28. Boyle E., German J. B..Crit. Rev. Food Sci. Nutr 1996;36:785—805.
29. Drummond C. J., Fong C., Surfactant self-assembly objects as novel drug delivery vehicles. Curr. Opin.Colloid.Interface Sci;2000:4, 449-56.
30. Lee SJ, Kavanaugh A. Pharmacological treatment of established rheumatoid arthritis. Best Pract Res Cl Rh. 2003;17:811–29.
31. Cutolo M. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis,2001;60:729–35.
32. Lee DM, Weinblatt ME. Rheumatoid arthritis.Lancet. 2001;358:903–11.
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