Generic placeholder image

Current Drug Delivery

Editor-in-Chief

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

Research Article

Formulation and Evaluation of Resveratrol Loaded Cubosomal Nanoformulation for Topical Delivery

Author(s): Bhaskar Kurangi, Sunil Jalalpure* and Satveer Jagwani

Volume 18, Issue 5, 2021

Published on: 02 September, 2020

Page: [607 - 619] Pages: 13

DOI: 10.2174/1567201817666200902150646

Price: $65

Abstract

Aim: The aim of the study was to formulate, characterize, and evaluate the Resveratrol- loaded Cubosomes (RC) for topical application.

Background: Resveratrol (RV) is a nutraceutical compound with exciting pharmacological potential in different diseases, including cancers. Many studies on resveratrol have been reported for anti- melanoma activity. Due to its low bioavailability, the therapeutic activities of resveratrol are strongly limited. Hence, an approach with nanotechnology has been made to increase its activity through transdermal drug delivery.

Objective: To formulate, characterize, and evaluate the resveratrol-loaded cubosomes (RC). To evaluate Resveratrol-loaded Cubosomal Gel (RC-Gel) for its topical application. Methods: RC was formulated by homogenization technique and optimized using a 2-factor 3-level factorial design. Formulated RCs were characterized for particle size, zeta potential, and entrapment efficiency. Optimized RC was evaluated for in vitro release and stability study. Optimized RC was further formulated into cubosomal gel (RC-Gel) using carbopol and evaluated for drug permeation and deposition. Furthermore, developed RC-Gel was evaluated for its topical application using skin irritancy, toxicity, and in vivo local bioavailability studies.

Results: The optimized RC indicated cubic-shaped structure with mean particle size, entrapment efficiency, and zeta potential were 113±2.36 nm, 85.07 ± 0.91%, and -27.40 ± 1.40 mV, respectively. In vitro drug release of optimized RC demonstrated biphasic drug release with the diffusion-controlled release of resveratrol (RV) (87.20 ± 3.91%). The RC-Gel demonstrated better drug permeation and deposition in mice skin layers. The composition of RC-Gel has been proved non-irritant to mice skin. In vivo local bioavailability study depicted the good potential of RC-Gel for skin localization.

Conclusion: The RC nanoformulation proposes a promising drug delivery system for melanoma treatment simply through topical application.

Keywords: Melanoma, cubosome, resveratrol, factorial design, cubosomal gel, local bioavailability.

Graphical Abstract
[1]
Gladfelter, P.; Darwish, N.H.E.; Mousa, S.A. Current status and future direction in the management of malignant melanoma. Melanoma Res., 2017, 27(5), 403-410.
[http://dx.doi.org/10.1097/CMR.0000000000000379] [PMID: 28800028]
[2]
Garbe, C.; Peris, K.; Hauschild, A.; Saiag, P.; Middleton, M.; Spatz, A.; Grob, J-J.; Malvehy, J.; Newton-Bishop, J.; Stratigos, A.; Pehamberger, H.; Eggermont, A. Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline. Eur. J. Cancer, 2010, 46(2), 270-283.
[http://dx.doi.org/10.1016/j.ejca.2009.10.032] [PMID: 19959353]
[3]
Braithwaite, D. Demb, J.; Henderson, L. M. American Cancer Society: Cancer Facts and Figures 2016; GA Am. Cancer Soc.: Atlanta, 2016.
[4]
Batra, P.; Sharma, A. K. Anti-cancer potential of flavonoids: recent trends and future perspectives. 3 Biotech, 2013, 3(6), 439-459.
[5]
Kuttan, G.; Pratheeshkumar, P.; Manu, K.A.; Kuttan, R. Inhibition of tumor progression by naturally occurring terpenoids. Pharm. Biol., 2011, 49(10), 995-1007.
[http://dx.doi.org/10.3109/13880209.2011.559476] [PMID: 21936626]
[6]
Steinmetz, K.A.; Potter, J.D. Vegetables, fruit, and cancer. II. Mechanisms. Cancer Causes Control, 1991, 2(6), 427-442.
[http://dx.doi.org/10.1007/BF00054304] [PMID: 1764568]
[7]
Kurangi, B.K.; Jalalpure, S.S. Review of selected herbal phytoconstituents for potential melanoma treatment. Indian J. Health. Sci. Biomed. Res., 2018, 11(1), 3-11.
[8]
Gatouillat, G.; Balasse, E.; Joseph-Pietras, D.; Morjani, H.; Madoulet, C. Resveratrol induces cell-cycle disruption and apoptosis in chemoresistant B16 melanoma. J. Cell. Biochem., 2010, 110(4), 893-902.
[http://dx.doi.org/10.1002/jcb.22601] [PMID: 20564188]
[9]
Osmond, G.W.; Augustine, C.K.; Zipfel, P.A.; Padussis, J.; Tyler, D.S. Enhancing melanoma treatment with resveratrol. J. Surg. Res., 2012, 172(1), 109-115.
[http://dx.doi.org/10.1016/j.jss.2010.07.033] [PMID: 20855085]
[10]
Fang, Y.; Bradley, M.J.; Cook, K.M.; Herrick, E.J.; Nicholl, M.B. A potential role for resveratrol as a radiation sensitizer for melanoma treatment. J. Surg. Res., 2013, 183(2), 645-653.
[http://dx.doi.org/10.1016/j.jss.2013.02.037] [PMID: 23522452]
[11]
Niles, R.M.; McFarland, M.; Weimer, M.B.; Redkar, A.; Fu, Y.M.; Meadows, G.G. Resveratrol is a potent inducer of apoptosis in human melanoma cells. Cancer Lett., 2003, 190(2), 157-163.
[http://dx.doi.org/10.1016/S0304-3835(02)00676-6] [PMID: 12565170]
[12]
Asensi, M.; Medina, I.; Ortega, A.; Carretero, J.; Baño, M.C.; Obrador, E.; Estrela, J.M. Inhibition of cancer growth by resveratrol is related to its low bioavailability. Free Radic. Biol. Med., 2002, 33(3), 387-398.
[http://dx.doi.org/10.1016/S0891-5849(02)00911-5] [PMID: 12126761]
[13]
Karami, Z.; Hamidi, M. Cubosomes: remarkable drug delivery potential. Drug Discov. Today, 2016, 21(5), 789-801.
[http://dx.doi.org/10.1016/j.drudis.2016.01.004] [PMID: 26780385]
[14]
Malmsten, M. Soft drug delivery systems. Soft Matter, 2006, 2(9), 760-769.
[http://dx.doi.org/10.1039/b608348j] [PMID: 32680216]
[15]
Ibrahim, H.K.; El-Leithy, I.S.; Makky, A.A. Mucoadhesive nanoparticles as carrier systems for prolonged ocular delivery of gatifloxacin/prednisolone bitherapy. Mol. Pharm., 2010, 7(2), 576-585.
[http://dx.doi.org/10.1021/mp900279c] [PMID: 20163167]
[16]
Larsson, K. Cubic lipid-water phases: structures and biomembrane Aspects. J. Phys. Chem., 1989, 93(21), 7304-7314.
[http://dx.doi.org/10.1021/j100358a010]
[17]
Tavano, L.; Muzzalupo, R.; Picci, N.; de Cindio, B. Co-encapsulation of lipophilic antioxidants into niosomal carriers: percutaneous permeation studies for cosmeceutical applications. Colloids Surf. B Biointerfaces, 2014, 114, 144-149.
[http://dx.doi.org/10.1016/j.colsurfb.2013.09.055] [PMID: 24176892]
[18]
Teskac, K.; Kristl, J. Teskaˇ. The evidence for solid lipid nanoparticles mediated cell uptake of resveratrol. Int. J. Pharm., 2010, 390(1), 61-69.
[http://dx.doi.org/10.1016/j.ijpharm.2009.10.011] [PMID: 19833178]
[19]
Sanna, V.; Roggio, A.M.; Siliani, S.; Piccinini, M.; Marceddu, S.; Mariani, A.; Sechi, M. Development of novel cationic chitosan-and anionic alginate-coated poly(D, L-lactide-co-glycolide) nanoparticles for controlled release and light protection of resveratrol. Int. J. Nanomedicine, 2012, 7, 5501-5516.
[http://dx.doi.org/10.2147/IJN.S36684] [PMID: 23093904]
[20]
Carlotti, M.E.; Sapino, S.; Ugazio, E.; Gallarate, M.; Morel, S. Resveratrol in solid lipid nanoparticles. J. Dispers. Sci. Technol., 2012, 33(4), 465-471.
[http://dx.doi.org/10.1080/01932691.2010.548274]
[21]
Abdel-Bar, H.M.; El Basset Sanad, R.A. Endocytic pathways of optimized resveratrol cubosomes capturing into human hepatoma cells. Biomed. Pharmacother., 2017, 93, 561-569.
[http://dx.doi.org/10.1016/j.biopha.2017.06.093] [PMID: 28686970]
[22]
Badie, H.; Abbas, H. Novel small self-assembled resveratrol-bearing cubosomes and hexosomes: preparation, charachterization, and ex vivo permeation. Drug Dev. Ind. Pharm., 2018, 44(12), 2013-2025.
[http://dx.doi.org/10.1080/03639045.2018.1508220] [PMID: 30095009]
[23]
Elnaggar, Y.S.R.; Etman, S.M.; Abdelmonsif, D.A.; Abdallah, O.Y. Novel piperine-loaded Tween-integrated monoolein cubosomes as brain-targeted oral nanomedicine in Alzheimer’s disease: pharmaceutical, biological, and toxicological studies. Int. J. Nanomedicine, 2015, 10, 5459-5473.
[http://dx.doi.org/10.2147/IJN.S87336] [PMID: 26346130]
[24]
Ahirrao, M.; Shrotriya, S. In vitro and in vivo evaluation of cubosomal in situ nasal gel containing resveratrol for brain targeting. Drug Dev. Ind. Pharm., 2017, 43(10), 1686-1693.
[http://dx.doi.org/10.1080/03639045.2017.1338721] [PMID: 28574732]
[25]
Esposito, E.; Mariani, P.; Ravani, L.; Contado, C.; Volta, M.; Bido, S.; Drechsler, M.; Mazzoni, S.; Menegatti, E.; Morari, M.; Cortesi, R. Nanoparticulate lipid dispersions for bromocriptine delivery: characterization and in vivo study. Eur. J. Pharm. Biopharm., 2012, 80(2), 306-314.
[http://dx.doi.org/10.1016/j.ejpb.2011.10.015] [PMID: 22061262]
[26]
Dhamecha, D.; Movsas, R.; Sano, U.; Menon, J.U. Applications of alginate microspheres in therapeutics delivery and cell culture: Past, present and future. Int. J. Pharm., 2019, 569(August), 118627.
[http://dx.doi.org/10.1016/j.ijpharm.2019.118627] [PMID: 31421199]
[27]
Kurangi, B.; Jalalpure, S.; Jagwani, S. A validated stability-indicating HPLC method for simultaneous estimation of resveratrol and piperine in cubosome and human plasma. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2019, 1122-1123(May), 39-48.
[http://dx.doi.org/10.1016/j.jchromb.2019.05.017] [PMID: 31150952]
[28]
Dhamecha, D.; Jalalpure, S.; Jadhav, K.; Sajjan, D. Green synthesis of gold nanoparticles using pterocarpus marsupium: characterization and biocompatibility studies. Particul. Sci. Technol., 2016, 34(2), 156-164.
[http://dx.doi.org/10.1080/02726351.2015.1054972]
[29]
Dhamecha, D.; Jalalpure, S.; Jadhav, K. Doxorubicin functionalized gold nanoparticles: characterization and activity against human cancer cell lines. Process Biochem., 2015, 50(12), 2298-2306.
[http://dx.doi.org/10.1016/j.procbio.2015.10.007]
[30]
Jin, X.; Zhang, Z.H.; Li, S.L.; Sun, E.; Tan, X.B.; Song, J.; Jia, X.B. A nanostructured liquid crystalline formulation of 20(S)-protopanaxadiol with improved oral absorption. Fitoterapia, 2013, 84(1), 64-71.
[http://dx.doi.org/10.1016/j.fitote.2012.09.013] [PMID: 23006538]
[31]
Morsi, N.M.; Abdelbary, G.A.; Ahmed, M.A. Silver sulfadiazine based cubosome hydrogels for topical treatment of burns: development and in vitro/in vivo characterization. Eur. J. Pharm. Biopharm., 2014, 86(2), 178-189.
[http://dx.doi.org/10.1016/j.ejpb.2013.04.018] [PMID: 23688805]
[32]
Fule, R.; Dhamecha, D.; Maniruzzaman, M.; Khale, A.; Amin, P. Development of hot melt co-formulated antimalarial solid dispersion system in fixed dose form (ARLUMELT): Evaluating amorphous state and in vivo performance. Int. J. Pharm., 2015, 496(1), 137-156.
[http://dx.doi.org/10.1016/j.ijpharm.2015.09.069] [PMID: 26471056]
[33]
Salah, S.; Mahmoud, A.A.; Kamel, A.O. Etodolac transdermal cubosomes for the treatment of rheumatoid arthritis: ex vivo permeation and in vivo pharmacokinetic studies. Drug Deliv., 2017, 24(1), 846-856.
[http://dx.doi.org/10.1080/10717544.2017.1326539] [PMID: 28535740]
[34]
Jadhav, K.; Hr, R.; Deshpande, S.; Jagwani, S.; Dhamecha, D.; Jalalpure, S.; Subburayan, K.; Baheti, D. Phytosynthesis of gold nanoparticles: Characterization, biocompatibility, and evaluation of its osteoinductive potential for application in implant dentistry. Mater. Sci. Eng. C, 2018, 93, 664-670.
[http://dx.doi.org/10.1016/j.msec.2018.08.028] [PMID: 30274099]
[35]
Luo, Q.; Lin, T.; Zhang, C.Y.; Zhu, T.; Wang, L.; Ji, Z.; Jia, B.; Ge, T.; Peng, D.; Chen, W. A novel glyceryl monoolein-bearing cubosomes for gambogenic acid: Preparation, cytotoxicity and intracellular uptake. Int. J. Pharm., 2015, 493(1-2), 30-39.
[http://dx.doi.org/10.1016/j.ijpharm.2015.07.036] [PMID: 26209071]
[36]
Qian, S.; Wong, Y.C.; Zuo, Z. Development, characterization and application of in situ gel systems for intranasal delivery of tacrine. Int. J. Pharm., 2014, 468(1-2), 272-282.
[http://dx.doi.org/10.1016/j.ijpharm.2014.04.015] [PMID: 24709220]
[37]
Nasr, M.; Ghorab, M.K.; Abdelazem, A. In vitro and in vivo evaluation of cubosomes containing 5-fluorouracil for liver targeting. Acta Pharm. Sin. B, 2015, 5(1), 79-88.
[http://dx.doi.org/10.1016/j.apsb.2014.12.001] [PMID: 26579429]
[38]
Peram, M.R.; Jalalpure, S.; Kumbar, V.; Patil, S.; Joshi, S.; Bhat, K.; Diwan, P. Factorial design based curcumin ethosomal nanocarriers for the skin cancer delivery: in vitro evaluation. J. Liposome Res., 2019, 29(3), 291-311.
[http://dx.doi.org/10.1080/08982104.2018.1556292] [PMID: 30526186]
[39]
Mitkari, B.V.; Korde, S.A.; Mahadik, K.R.; Kokare, C.R. Formulation and evaluation of topical liposomal gel for fluconazole. Indian J Pharm Educ Res, 2010, 44(4), 324-333.
[40]
Shelke, S.; Shahi, S.; Jadhav, K.; Dhamecha, D.; Tiwari, R.; Patil, H. Thermoreversible nanoethosomal gel for the intranasal delivery of Eletriptan hydrobromide. J. Mater. Sci. Mater. Med., 2016, 27(6), 103.
[http://dx.doi.org/10.1007/s10856-016-5713-6] [PMID: 27091045]
[41]
Esposito, E.; Ravani, L.; Mariani, P.; Contado, C.; Drechsler, M.; Puglia, C.; Cortesi, R. Curcumin containing monoolein aqueous dispersions: a preformulative study. Mater. Sci. Eng. C, 2013, 33(8), 4923-4934.
[http://dx.doi.org/10.1016/j.msec.2013.08.017] [PMID: 24094206]
[42]
Ahad, A.; Al-Saleh, A.A.; Al-Mohizea, A.M.; Al-Jenoobi, F.I.; Raish, M.; Yassin, A.E.B.; Alam, M.A. Pharmacodynamic study of eprosartan mesylate-loaded transfersomes Carbopol® gel under Dermaroller® on rats with methyl prednisolone acetate-induced hypertension. Biomed. Pharmacother., 2017, 89, 177-184.
[http://dx.doi.org/10.1016/j.biopha.2017.01.164] [PMID: 28237913]
[43]
Khan, M.A.; Pandit, J.; Sultana, Y.; Sultana, S.; Ali, A.; Aqil, M.; Chauhan, M. Novel carbopol-based transfersomal gel of 5-fluorouracil for skin cancer treatment: in vitro characterization and in vivo study. Drug Deliv., 2015, 22(6), 795-802.
[http://dx.doi.org/10.3109/10717544.2014.902146] [PMID: 24735246]
[44]
Uttley, M.; Van Abbe, N.J. Primary irritation of the skin: mouse ear test and human patch test procedures. J. Soc. Cosmet. Chem., 1973, 24(4), 217-227.
[45]
Draize, J.H.; Woodard, G.; Calvery, H.O. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J. Pharmacol. Exp. Ther., 1944, 82(3), 377-390.
[46]
Sahu, P.; Kashaw, S.K.; Sau, S.; Kushwah, V.; Jain, S.; Agrawal, R.K.; Iyer, A.K. pH responsive 5-fluorouracil loaded biocompatible nanogels for topical chemotherapy of aggressive melanoma. Colloids Surf. B Biointerfaces, 2019, 174, 232-245.
[http://dx.doi.org/10.1016/j.colsurfb.2018.11.018] [PMID: 30465998]
[47]
Singh, H.P.; Tiwary, A.K.; Jain, S. Preparation and in vitro, in vivo characterization of elastic liposomes encapsulating cyclodextrin-colchicine complexes for topical delivery of colchicine. Yakugaku Zasshi, 2010, 130(3), 397-407.
[PMID: 20190524]
[48]
Italia, J.L.; Singh, D.; Ravi Kumar, M.N. High-performance liquid chromatographic analysis of amphotericin B in rat plasma using α-naphthol as an internal standard. Anal. Chim. Acta, 2009, 634(1), 110-114.
[http://dx.doi.org/10.1016/j.aca.2008.12.006] [PMID: 19154818]
[49]
Kaur, L.; Jain, S.K.; Manhas, R.K.; Sharma, D. Nanoethosomal formulation for skin targeting of amphotericin B: an in vitro and in vivo assessment. J. Liposome Res., 2015, 25(4), 294-307.
[http://dx.doi.org/10.3109/08982104.2014.995670] [PMID: 25547800]
[50]
Kurangi, B.; Shah, R.; Kemkar, V.; Honarao, U.; Mahajan, S. Formulation, evaluation and optimization of time and enzyme dependent polymers matrix based tablet for colon targeted drug delivery. IJPRS, 2014, 3(1), 524-534.
[51]
Zhai, Y.; Xu, R.; Wang, Y.; Liu, J.; Wang, Z.; Zhai, G. Ethosomes for skin delivery of ropivacaine: preparation, characterization and ex vivo penetration properties. J. Liposome Res., 2015, 25(4), 316-324.
[http://dx.doi.org/10.3109/08982104.2014.999686] [PMID: 25625544]
[52]
Mainardes, R.M.; Evangelista, R.C. PLGA nanoparticles containing praziquantel: effect of formulation variables on size distribution. Int. J. Pharm., 2005, 290(1-2), 137-144.
[http://dx.doi.org/10.1016/j.ijpharm.2004.11.027] [PMID: 15664139]
[53]
Pal, S.L.; Jana, U.; Manna, P.K.; Mohanta, G.P.; Manavalan, R. Nanoparticle: an overview of preparation and characterization. J. Appl. Pharm. Sci., 2011, 1(6), 228-234.
[54]
Hundekar, Y.R.; Saboji, J.K.; Patil, S.M.; Nanjwade, B.K. Preparation and evaluation of diclofenac sodium cubosomes for percutaneous administration. World J. Pharm. Pharm. Sci., 2014, 3(5), 523-539.
[55]
Rizwan, S.B.; Hanley, T.; Boyd, B.J.; Rades, T.; Hook, S. Liquid crystalline systems of phytantriol and glyceryl monooleate containing a hydrophilic protein: Characterisation, swelling and release kinetics. J. Pharm. Sci., 2009, 98(11), 4191-4204.
[http://dx.doi.org/10.1002/jps.21724] [PMID: 19340889]
[56]
Kohli, A.K.; Alpar, H.O. Potential use of nanoparticles for transcutaneous vaccine delivery: effect of particle size and charge. Int. J. Pharm., 2004, 275(1-2), 13-17.
[http://dx.doi.org/10.1016/j.ijpharm.2003.10.038] [PMID: 15081134]
[57]
Barry, B.W.; B.W, B. Dermatological formulations: percutaneous absorption. J. Pharm. Sci., 1983, 73(4), 573.
[58]
Hadgraft, J. Skin, the final frontier. Int. J. Pharm., 2001, 224(1-2), 1-18.
[http://dx.doi.org/10.1016/S0378-5173(01)00731-1] [PMID: 11512545]
[59]
Freag, M.S.; Elnaggar, Y.S.R.; Abdelmonsif, D.A.; Abdallah, O.Y. Stealth, biocompatible monoolein-based lyotropic liquid crystalline nanoparticles for enhanced aloe-emodin delivery to breast cancer cells: in vitro and in vivo studies. Int. J. Nanomedicine, 2016, 11, 4799-4818.
[http://dx.doi.org/10.2147/IJN.S111736] [PMID: 27703348]
[60]
Kwon, T.K.; Kim, J-C. Preparation and in vitro skin permeation of cubosomes containing hinokitiol. J. Dispers. Sci. Technol., 2010, 31(7), 1004-1009.
[61]
Smith, E.W.; Maibach, H.I. Percutaneous Penetration Enhancers; CRC Press, 1995.
[62]
Norlén, L.; Al-Amoudi, A. Stratum corneum keratin structure, function, and formation: the cubic rod-packing and membrane templating model. J. Invest. Dermatol., 2004, 123(4), 715-732.
[http://dx.doi.org/10.1111/j.0022-202X.2004.23213.x] [PMID: 15373777]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy