Dermal drug delivery system that is required to localizes methotrexate (MTX) in the synovial joint is needed to treat inflammation in rheumatoid arthritis (RA). The present investigation aims at exploring the potential of fatty acid vesicles for the topical delivery of methotrexate. Vesicles were prepared by film hydration method using oleic acid as a fatty acid principal component. Developed vesicles were characterized for size, size distribution, shape, in vitro release, pH dependent, and storage stability. Interaction between MTX and oleic acid was investigated using differential scanning calorimetry. The MTX amount permeated through rat skin was three- to fourfold higher using oleic acid compared to those from plain drug solution or carbopol gel. At the end of the skin permeation assay using ufasomes, up to 50% of the administered dose was found in the skin. These results suggest that methotrexate encapsulated in oleic acid vesicles may be of value for the topical administration of MTX in the treatment of psoriasis. 1. Introduction Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology and complex multifactorial pathogenesis. It is characterized by progressive and irreversible damage of the synovial-lined joints, resulting in the loss of joint space, bone, and a decrease in joint function and deformity [1]. RA is usually treated first with a nonsteroidal antiinflammatory drug (NSAID). However, current RA treatment favors early use of slow acting disease modifying anti-rheumatic drugs (DMARDs) because DMARDs have the potential to prevent or reduce joint damage. Therefore, they are used early in the treatment of RA and usually no later than 3 months after the commencement of NSAID treatment [2, 3]. Methotrexate (MTX) is one of the most frequently used DMARDs in the treatment of RA. Although the exact mechanism of action is still unclear, the efficacy of MTX is related to its cytotoxic and anti-inflammatory effects [4]. When administered in low weekly oral doses, MTX effectively suppresses inflammation in RA [5]. However, systemic toxicity effects such as stomatitis, nausea, bone marrowdepression, and liver toxicity can limit the oral use of this drug [6]. To reduce these effects, clinical studies have been done with topical methotrexate [7, 8]. A major problem in topical administration of methotrexate is that the drug is hydrosoluble and is mostly in the dissociated form at physiological pH: its capacity for passive diffusion is thus limited. One of the possibilities for increasing the penetration of drugs through the skin is
References
[1]
W. Grassi, R. De Angelis, G. Lamanna, and C. Cervini, “The clinical features of rheumatoid arthritis,” European Journal of Radiology, vol. 27, no. 1, pp. S18–S24, 1998.
[2]
L. Ryan and P. Brooks, “Disease-modifying antirheumatic drugs,” Current Opinion in Rheumatology, vol. 11, no. 3, pp. 161–166, 1999.
[3]
T. Pincus, J. R. O'Dell, and J. M. Kremer, “Combination therapy with multiple disease-modifying antirheumatic drugs in rheumatoid arthritis: a preventive strategy,” Annals of Internal Medicine, vol. 131, no. 10, pp. 768–774, 1999.
[4]
B. N. Cronstein, “The mechanism of action of methotrexate,” Rheumatic Disease Clinics of North America, vol. 23, no. 4, pp. 739–755, 1997.
[5]
A. E. Van Ede, R. F. J. M. Laan, H. J. Blom, R. A. De Abreu, and L. B. A. Van de Putte, “Methotrexate in rheumatoid arthritis: an update with focus on mechanisms involved in toxicity,” Seminars in Arthritis and Rheumatism, vol. 27, no. 5, pp. 277–292, 1998.
[6]
J. R. O'Dell, “Methotrexate use in rheumatoid arthritis,” Rheumatic Disease Clinics of North America, vol. 23, no. 4, pp. 779–796, 1997.
[7]
P. T. Condit, “On the site of action of amethopterin,” Science, vol. 134, no. 3488, p. 1421, 1961.
[8]
G. C. Hwang, A. Y. Lin, W. Chen, and R. J. Sharpe, “Development and optimization of a methotrexate topical formulation,” Drug Development and Industrial Pharmacy, vol. 21, no. 17, pp. 1941–1952, 1995.
[9]
K. Egbaria and N. Weiner, “Liposomes as a topical drug delivery system,” Advanced Drug Delivery Reviews, vol. 5, no. 3, pp. 287–300, 1990.
[10]
A. Sharma, V. kumar, V. Dhillon, A. Gupta, and S. Arora, “Evaluation of transdermal permeability of zidovudine entrapped in oleic acid vesicles Indo-Global Research,” Journal of Pharmaceutical Sciences, vol. 1, pp. 21–35, 2011.
[11]
V. Dhillon, S. Sharma, S. Jain, A. Sharma, and S. Arora, “Formulation characterization and evaluation of new topical 5-fu by drug entrapment in oleic acid vesicles,” American Journal of PharmTech Research, vol. 1, pp. 1–16, 2011.
[12]
M. Murakami, H. Yoshikawa, K. Takada, and S. Muranishi, “Effect of oleic acid vesicles on intestinal absorption of carboxyfluorescein in rats,” Pharmaceutical Research, vol. 3, no. 1, pp. 35–41, 1986.
[13]
T. J. Franz, “Percutaneous absorption. On the relevance of in vitro data,” Journal of Investigative Dermatology, vol. 64, no. 3, pp. 190–195, 1975.
[14]
R. R. Warner, M. C. Myers, and D. A. Taylor, “Electron probe analysis of human skin: determination of the water concentration profile,” Journal of Investigative Dermatology, vol. 90, no. 2, pp. 218–224, 1988.
[15]
S. Jain, R. Sapre, A. K. Tiwary, and N. K. Jain, “Proultraflexible lipid vesicles for effective transdermal delivery of levonorgestrel: development, characterization, and performance evaluation.,” AAPS PharmSciTech, vol. 6, no. 3, pp. E513–E522, 2005.
[16]
R. N. Saha, C. Sajeev, P. R. Jadhav, S. P. Patil, and N. Srinivasan, “Determination of celecoxib in pharmaceutical formulations using UV spectrophotometry and liquid chromatography,” Journal of Pharmaceutical and Biomedical Analysis, vol. 28, no. 3-4, pp. 741–751, 2002.
[17]
G. D. Weinstein, J. L. McCullough, and E. Olsen, “Topical methotrexate therapy for psoriasis,” Archives of Dermatology, vol. 125, no. 2, pp. 227–230, 1989.
[18]
M. J. Alvarez-Figueroa and J. Blanco-Méndez, “Transdermal delivery of methotrexate: iontophoretic delivery from hydrogels and passive delivery from microemulsions,” International Journal of Pharmaceutics, vol. 215, no. 1-2, pp. 57–65, 2001.
[19]
M. Trotta, E. Peira, F. Debernardi, and M. Gallarate, “Elastic liposomes for skin delivery of dipotassium glycyrrhizinate,” International Journal of Pharmaceutics, vol. 241, no. 2, pp. 319–327, 2002.
[20]
M. J. Alvarez-Figueroa, M. B. Delgado-Charro, and J. Blanco-Méndez, “Passive and iontophoretic transdermal penetration of methotrexate,” International Journal of Pharmaceutics, vol. 212, no. 1, pp. 101–107, 2001.
[21]
A. Sharma, V. Dhillon, S. Sharma, S. Jain, and S. Arora, “Formulation characterization and evaluation of new topical 5-Fu by drug entrapment in oleic acid vesicles,” American Journal of PharmTech Research, vol. 1, no. 2, pp. 1–16, 2011.
[22]
P. Loan Honeywell-Nguyen, A. M. De Graaff, H. W. Wouter Groenink, and J. A. Bouwstra, “The in vivo and in vitro interactions of elastic and rigid vesicles with human skin,” Biochimica et Biophysica Acta, vol. 1573, no. 2, pp. 130–140, 2002.
[23]
B. A. I. Van Den Bergh, J. Vroom, H. Gerritsen, H. E. Junginger, and J. A. Bouwstra, “Interactions of elastic and rigid vesicles with human skin in vitro: electron microscopy and two-photon excitation microscopy,” Biochimica et Biophysica Acta, vol. 1461, no. 1, pp. 155–173, 1999.
[24]
W. R. Hargreaves, “Liposomes from ionic, single-chain amphiphiles,” Biochemistry, vol. 17, no. 18, pp. 3759–3767, 1978.
[25]
D. P. Cistola, J. A. Hamilton, D. Jackson, and D. M. Small, “lonization and phase behavior of fatty acids in water: application of the Gibbs phase rule,” Biochemistry, vol. 27, no. 6, pp. 1881–1888, 1988.
[26]
P. Walde, T. Namani, K. Morigaki, and H. Hauser, “Formation and properties of fatty acid vesicles (liposomes),” in Liposome Technology, G. Gregoriadis, Ed., pp. 1–20, Informa Healthcare, New York, NY, USA, 3rd edition, 2007.
[27]
C. L. Apel, D. W. Deamer, and M. N. Mautner, “Self-assembled vesicles of monocarboxylic acids and alcohols: conditions for stability and for the encapsulation of biopolymers,” Biochimica et Biophysica Acta, vol. 1559, no. 1, pp. 1–9, 2002.
[28]
M. B. Dowling, J. H. Lee, and S. R. Raghavan, “pH-responsive jello: gelatin gels containing fatty acid vesicles,” Langmuir, vol. 25, no. 15, pp. 8519–8525, 2009.
[29]
J. M. Gebicki and M. Hicks, “Ufasomes are stable particles surrounded by unsaturated fatty acid membranes,” Nature, vol. 243, no. 5404, pp. 232–234, 1973.
[30]
P. L. Luisi, P. Walde, M. Blocher, and E. Blochliger, “Matrix effect in the size distribution of fatty acid vesicles,” The Journal of Physical Chemistry B, vol. 102, pp. 10383–10390, 1998.
