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Current Drug Delivery

Editor-in-Chief

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

General Research Article

Betulinic Acid Nanogels: Rheological, Microstructural Characterization and Evaluation of their Anti-inflammatory Activity

Author(s): Dalis S. Sosa-Gutierrez, Jorge F. Toro-Vazquez, Cynthia Cano-Sarmiento, Peter Grube-Pagola, Alejandro Aparicio-Saguilan, Cristobal Torres-Palacios, Andres A. Acosta-Osorio* and Hugo S. Garcia*

Volume 18, Issue 2, 2021

Published on: 17 August, 2020

Page: [212 - 223] Pages: 12

DOI: 10.2174/1567201817999200817154003

Price: $65

Abstract

Background: Betulinic Acid (BA) is a lipophilic compound with proven beneficial results in topical inflammation. Nanogels (NG) are carriers of bioactive compounds with properties that make them good candidates to treat skin diseases.

Objective: The objective of this study was to evaluate the anti-inflammatory activity of BA carried in NG.

Methods: NG were composed of a nanoemulsion and a crosslinking agent (Carbopol 940®) applied at three concentrations (0.5, 1, and 1.5 %) and three activation times (6, 12 and 24 h). In order to select the optimal formulation, the NG were characterized mechanically and micro-structurally followed by evaluation of the BA anti-inflammatory activity in an in vivo model of auricular edema. We determined the edema inhibition activity as percent weight. Additionally, the anti-inflammatory activity of NG was validated through histological analysis.

Results: The formulation with the best viscoelastic properties was the one prepared with 0.5% carbopol and 6 h of activation. Microstructural examination of this formulation showed mostly spherical structures with a mean diameter of 65 nm. From the evaluation of edema and the histological analyses, we established that the NG of BA produced 52% inhibition. In contrast, a conventional gel and free BA produced 28% and 19% inhibition, respectively.

Conclusion: The NG of BA were found to be good vehicles to treat skin inflammation.

Keywords: Nanogel, betulinic acid, inflammation, auricular edema, skin, microspheres.

Graphical Abstract

[1]
Recio, M.C.; Giner, R.M.; Máñez, S.; Gueho, J.; Julien, H.R.; Hostettmann, K.; Ríos, J.L. Investigations on the steroidal anti-inflammatory activity of triterpenoids from Diospyros leucomelas. Planta Med., 1995, 61(1), 9-12.
[http://dx.doi.org/10.1055/s-2006-957988] [PMID: 7701004]
[2]
Ciurlea, S.A.; Dehelean, C.A.; Ionescu, D.; Berko, S.; Csanyi, E.; Hadaruga, D.I.; Ganta, S.; Amiji, M.M. A comparative study regarding melanoma activity of Betulinic acid on topical ointment vs. systemic nanoemulsion delivery systems. J. Agroaliment. Process. Technol., 2010, 16, 420-426.
[3]
Kumar, R.; Katare, O.P. Lecithin organogels as a potential phospholipid-structured system for topical drug delivery: A review. AAPS PharmSciTech, 2005, 6(2), E298-E310.
[http://dx.doi.org/10.1208/pt060240] [PMID: 16353989]
[4]
Carter, P.; Narasimhan, B.; Wang, Q. Biocompatible nanoparticles and vesicular systems in transdermal drug delivery for various skin diseases. Int. J. Pharm., 2019, 555, 49-62.
[http://dx.doi.org/10.1016/j.ijpharm.2018.11.032] [PMID: 30448309]
[5]
Rai, V.K.; Mishra, N.; Yadav, K.S.; Yadav, N.P. Nanoemulsion as pharmaceutical carrier for dermal and transdermal drug delivery: formulation development, stability issues, basic considerations and applications. J. Control. Release, 2018, 270, 203-225.
[http://dx.doi.org/10.1016/j.jconrel.2017.11.049] [PMID: 29199062]
[6]
Kathe, K.; Kathpalia, H. Film forming systems for topical and transdermal drug delivery. Asian J. Pharm. Sci., 2017, 12(6), 487-497.
[http://dx.doi.org/10.1016/j.ajps.2017.07.004] [PMID: 32104362]
[7]
Mendes, I.T.; Ruela, A.L.M.; Carvalho, F.C.; Freitas, J.T.J.; Bonfilio, R.; Pereira, G.R. Development and characterization of nanostructured lipid carrier-based gels for the transdermal delivery of donepezil. Colloids Surf. B Biointerfaces, 2019, 177, 274-281.
[http://dx.doi.org/10.1016/j.colsurfb.2019.02.007] [PMID: 30763792]
[8]
Zhang, J.; Michniak-Kohn, B.B. Investigation of microemulsion and microemulsion gel formulations for dermal delivery of clotrimazole. Int. J. Pharm., 2018, 536(1), 345-352.
[http://dx.doi.org/10.1016/j.ijpharm.2017.11.041] [PMID: 29170117]
[9]
Aranaz, I.; Harris, R.; Navarro-García, F.; Heras, A.; Acosta, N. Chitosan based films as supports for dual antimicrobial release. Carbohydr. Polym., 2016, 146, 402-410.
[http://dx.doi.org/10.1016/j.carbpol.2016.03.064] [PMID: 27112890]
[10]
Alenezi, H.; Emin, M.; Edirisinghe, M. Experimental and theoretical investigation of the fluid behavior during polymeric fiber formation with and without pressure. Appl. Phys. Rev., 2019, 6e041401
[http://dx.doi.org/10.1063/1.5110965]
[11]
Caló, E.; Khutoryansky, V.V. Biomedical applications of hydrogels: a review of patents and commercial products. Eur. Polym. J., 2015, 65, 252-267.
[http://dx.doi.org/10.1016/j.eurpolymj.2014.11.024]
[12]
Ramirez, A.; Benítez, J.L.; Rojas de Astudillo, L.; Rojas de Gáscue, B. Materiales polímeros de tipo hidrogeles: Revisión sobre su caracterización mediante FTIR, DSC, MEB, MET. Rev. Latinoam. Metal. Mater., 2016, 36(2), 108-130.
[13]
Maya, S.; Sarmento, B.; Nair, A.; Rejinold, N.S.; Nair, S.V.; Jayakumar, R. Smart stimuli sensitive nanogels in cancer drug delivery and imaging: A review. Curr. Pharm. Des., 2013, 19(41), 7203-7218.
[http://dx.doi.org/10.2174/138161281941131219124142] [PMID: 23489200]
[14]
Zha, L.; Banik, B.; Alexis, F. Stimulus responsive nanogels for drug delivery. Soft Matter, 2011, 7, 5908-5916.
[http://dx.doi.org/10.1039/c0sm01307b]
[15]
Shen, C.Y.; Xu, P.H.; Shen, B.; Min, H.Y.; Li, X.R.; Han, J.; Yuan, H.L. Nanogel for dermal application of the triterpenoids isolated from Ganoderma lucidum (GLT) for frostbite treatment. Drug Deliv., 2014, 7544, 1-9.
[http://dx.doi.org/10.3109/10717544.2014.929756] [PMID: 24963753]
[16]
Yuan, Y.Y.; Du, J.Z.; Song, W.J.; Wang, F.; Yang, X.Z.; Xiong, M.H.; Wang, J. Biocompatible and functionalizable polyphosphate nanogel with a branched structure. J. Mater. Chem., 2012, 22, 9322-9329.
[http://dx.doi.org/10.1039/c2jm30663h]
[17]
Cavazos-Garduño, A.; Ochoa-Flores, A.A.; Serrano-Niño, J.C.; Beristain, C.I.; García, H.S. Operating and compositional variables for preparation of betulinic acid nanoemulsions. Rev. Mex. Ing. Quim., 2014, 13, 689-703.
[18]
de Vargas, B.A.; Bidone, J.; Oliveira, L.K.; Koester, L.S.; Bassani, V.L.; Teixeira, H.F. Development of topical hydrogels containing genistein-loaded nanoemulsions. J. Biomed. Nanotechnol., 2012, 8(2), 330-336.
[http://dx.doi.org/10.1166/jbn.2012.1386] [PMID: 22515085]
[19]
Stanley, P.L.; Steiner, S.; Havens, M.; Tramposch, K.M. Mouse skin inflammation induced by multiple topical applications of 12-O-tetradecanoylphorbol-13-acetate. Skin Pharmacol., 1991, 4(4), 262-271.
[http://dx.doi.org/10.1159/000210960] [PMID: 1789987]
[20]
McClements, D.J.; Rao, J. Food-grade nanoemulsions: formulation, fabrication, properties, performance, biological fate, and potential toxicity. Crit. Rev. Food Sci. Nutr., 2011, 51(4), 285-330.
[http://dx.doi.org/10.1080/10408398.2011.559558] [PMID: 21432697]
[21]
Yuan, Y.; Gao, Y.; Mao, L. Characterization and stability evaluation of β-carotene nanoemulsions prepared by high pressure homogenization under various emulsifying conditions. Food Res. Int., 2008, 41, 61-68.
[http://dx.doi.org/10.1016/j.foodres.2007.09.006]
[22]
Islam, M.T.; Rodríguez-Hornedo, N.; Ciotti, S.; Ackermann, C. Rheological characterization of topical carbomer gels neutralized to different pH. Pharm. Res., 2004, 21(7), 1192-1199.
[http://dx.doi.org/10.1023/B:PHAM.0000033006.11619.07] [PMID: 15290859]
[23]
Menger, F.M.; Caran, K.L. Anatomy of a gel. Amino acid derivatives that rigidify water at submillimolar concentrations. J. Am. Chem. Soc., 2000, 122, 11679-11691.
[http://dx.doi.org/10.1021/ja0016811]
[24]
Naé, H.N.; Reichert, W.W. Rheological properties of lightly cross linked carboxy copolymers in aqueous solutions. Rheol. Acta, 1992, 31, 351-360.
[http://dx.doi.org/10.1007/BF00418332]
[25]
Todica, M.; Pop, C.V.; Udrescu, L.; Pop, M. Rheological behavior of some aqueous gels of carbopol with pharmaceutical applications. Chinese Phys. Soc., 2010, 27, 18301.
[http://dx.doi.org/10.1088/0256-307X/27/1/018301]
[26]
Lefrançois, P.; Ibarboure, E.; Payré, B.; Gontier, E.; Le Meins, J-F.; Schatz, C. Insights into carbopol gel formulations: Microscopy analysis of the microstructure and the influence of polyol additives. J. Appl. Polym. Sci., 2015, 132(46), 42761.
[http://dx.doi.org/10.1002/app.42761]
[27]
Lee, D.; Gutowski, I.A.; Bailey, A.E.; Rubatat, L.; de Bruyn, J.R.; Frisken, B.J. Investigating the microstructure of a yield-stress fluid by light scattering. Phys. Rev. E Stat. Nonlin. Soft Matter Phys., 2011, 83(3 Pt 1), 031401-031408.
[http://dx.doi.org/10.1103/PhysRevE.83.031401] [PMID: 21517498]
[28]
De Young, L.M.; Kheifets, J.B.; Ballaron, S.J.; Young, J.M. Edema and cell infiltration in the phorbol ester-treated mouse ear are temporally separate and can be differentially modulated by pharmacologic agents. Agents Actions, 1989, 26(3-4), 335-341.
[http://dx.doi.org/10.1007/BF01967298] [PMID: 2567568]
[29]
Batlouni, M. Nonsteroidal antiinflammatory drugs: Gastrointestinal and cardiovascular and renal safety. Arq. Bras. Cardiol., 2009, 94, 538-546.
[30]
McGettigan, P.; Henry, D. Cardiovascular risk and inhibition of cyclooxygenase: A systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA, 2006, 296(13), 1633-1644.
[http://dx.doi.org/10.1001/jama.296.13.jrv60011] [PMID: 16968831]
[31]
Ferrán, C-L. Aine y riesgo cardiovascular: los menos posibles, a la menor dosis posible y durante el menor tiempo posible. Rev. Med. Clin. Las Condes, 2014, 25, 850-851.
[http://dx.doi.org/10.1016/S0716-8640(14)70116-6]
[32]
Tejada, F. Hepatotoxicity due to drugs. Family Med. Clin. Magaz., 2010, 3, 177-191.
[33]
Kienzler, J.L.; Gold, M.; Nollevaux, F. Systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers. J. Clin. Pharmacol., 2010, 50(1), 50-61.
[http://dx.doi.org/10.1177/0091270009336234] [PMID: 19841157]
[34]
Yadav, H.K.S.; Anwar, N.; Halabi, A.; Alsalloum, G.A. Nanogels as novel drug delivery systems - a review. Insights Pharma Res., 2017, 1(1), 5.
[35]
Escalona, O.; Quintanar, D. Nanogeles poliméricos: una nueva alternativa para la administración de fármacos. Rev. Mex. Cienc. Farm., 2014, 45, 17-38.
[36]
Yogeeswari, P.; Sriram, D. Betulinic acid and its derivatives: a review on their biological properties. Curr. Med. Chem., 2005, 12(6), 657-666.
[http://dx.doi.org/10.2174/0929867053202214] [PMID: 15790304]
[37]
Máñez, S.; Recio, M.C.; Giner, R.M.; Ríos, J-L. Effect of selected triterpenoids on chronic dermal inflammation. Eur. J. Pharmacol., 1997, 334(1), 103-105.
[http://dx.doi.org/10.1016/S0014-2999(97)01187-4] [PMID: 9346335]
[38]
Huguet, A.; del Carmen Recio, M.; Máñez, S.; Giner, R.; Ríos, J. Effect of triterpenoids on the inflammation induced by protein kinase C activators, neuronally acting irritants and other agents. Eur. J. Pharmacol., 2000, 410(1), 69-81.
[http://dx.doi.org/10.1016/S0014-2999(00)00860-8] [PMID: 11134658]
[39]
Tseng, H.C.; Liu, Y.C. Immobilized betulinic acid column and its interactions with phospholipase A2 and snake venom proteins. J. Sep. Sci., 2004, 27(14), 1215-1220.
[http://dx.doi.org/10.1002/jssc.200401752] [PMID: 15537079]
[40]
Steffe, J.F. Rheological methods in food process engineering, 2nd ed; Dept. of Agricultural Engineering, Michigan State University, 1996.
[41]
National Research Council. Guide for the care and use of laboratory animals, 8th ed; Washington (DC): National Academies Press (US), 2011.

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