Generic placeholder image

Nanoscience & Nanotechnology-Asia

Editor-in-Chief

ISSN (Print): 2210-6812
ISSN (Online): 2210-6820

Research Article

Dermal Delivery of Meloxicam Nanosuspensions based Gel: Optimization with Box Behnken Design Experiment Approach: Ex Vivo and In Vivo Study

Author(s): Inayat B. Pathan*, Mahesh Sakhare, Wahid Ambekar and Chitral M. Setty

Volume 10, Issue 6, 2020

Page: [766 - 777] Pages: 12

DOI: 10.2174/2210681209666190809103155

Price: $65

Abstract

Background: Transdermal delivery of meloxicam is advantageous than the oral route in the treatment of pain management.

Objective: The goal of the present study is to formulate and evaluate meloxicam (MX) loaded nanosuspensions based gel for transdermal application.

Methods: The formulation parameters were optimized using Box Behnken design (BBD) taking three independent variables and three responses. Formulations were evaluated for particle size (nm), polydispersity index (PDI), zeta potential (mV), ex vivo permeation, in vivo study, morphology, FTIR, skin irritation and, stability study. Optimized formulation having Poloxamer 188 (0.4 mg), PVP K30 (0.5 mg) and sonication time (60 min.) demonstrated smaller particle size (159.2 ± 3.5 nm), low PDI (0.120 ± 0.01) and higher zeta potential value (-29 ± 4mV).

Results: In the ex vivo study, MX-NG showed a significant increase (p<0.05) in the flux (24.40 ± 2.6 μg/cm2/h) of meloxicam through the human cadaver skin as compared to other formulations. In the in- vivo study, MX-NG showed a significant (p<0.05) increase in anti-inflammatory activity as compared to marketed gel.

Conclusion: Thus, it is concluded that the developed meloxicam loaded nanosuspensions based gel showed maximum therapeutic effects in rats.

Keywords: Meloxicam, nanosuspensions based gel, anti-inflammatory activity, NSAID, cancer, pain management.

Graphical Abstract
[1]
Davies, N.M.; Skjodt, N.M. Clinical pharmacokinetics of meloxicam. A cyclo-oxygenase-2 preferential nonsteroidal anti-inflammatory drug. Clin. Pharmacokinet., 1999, 36(2), 115-126.
[http://dx.doi.org/10.2165/00003088-199936020-00003] [PMID: 10092958]
[2]
Goldman, A.P.; Williams, C.S.; Sheng, H.; Lamps, L.W.; Williams, V.P.; Pairet, M.; Morrow, J.D.; DuBois, R.N. Meloxicam inhibits the growth of colorectal cancer cells. Carcinogenesis, 1998, 19(12), 2195-2199.
[http://dx.doi.org/10.1093/carcin/19.12.2195] [PMID: 9886578]
[3]
Tsubouchi, Y.; Mukai, S.; Kawahito, Y.; Yamada, R.; Kohno, M.; Inoue, K.; Sano, H. Meloxicam inhibits the growth of non-small cell lung cancer. Anticancer Res., 2000, 20(5A), 2867-2872.
[PMID: 11062695]
[4]
Chen, J.; Gao, Y. Strategies for meloxicam delivery to and across the skin: A review. Drug Deliv., 2016, 23(8), 3146-3156.
[http://dx.doi.org/10.3109/10717544.2016.1157839] [PMID: 26956920]
[5]
Distel, M.; Mueller, C.; Bluhmki, E.; Fries, J. Safety of Meloxicam: A global analysis of clinical trials. Br. J. Rheumatol., 1996, 35, 68-77.
[http://dx.doi.org/10.1093/rheumatology/35.suppl_1.68]
[6]
Lanes, S.F.; Rodrígeuz, L.A.; Hwangg, E. Baseline risk of gastrointestinal disorders among new users of meloxicam, ibuprofen, diclofenac, naproxen and indomethacin. Pharmacoepidemiol. Drug Saf., 2000, 9(2), 113-117.
[http://dx.doi.org/10.1002/(SICI)1099-1557(200003/04)9:2<113:AID-PDS478>3.0.CO;2-2] [PMID: 19025810]
[7]
Tina, R.; Alenka, N.S.; Jerin, A.; Butinar, J.; Silvestra, K. Effect of meloxicam and meloxicam with misoprostol on serum prostaglandins and gastrointestinal permeability in healthy beagle dogs. Acta Vet. Brno, 2011, 61(1), 33-47.
[http://dx.doi.org/10.2298/AVB1101033R]
[8]
Luger, P.; Daneck, K.; Engel, W.; Trummlitz, G.; Wagner, K. Structure and physicochemical properties of meloxicam, a new NSAID. Eur. J. Pharm. Sci., , 1996, 4(3), 175-187.
[http://dx.doi.org/10.1016/0928-0987(95)00046-1]
[9]
Prausnitz, M.R.; Mitragotri, S.; Langer, R. Current status and future potential of transdermal drug delivery. Nat. Rev. Drug Discov., 2004, 3(2), 115-124.
[http://dx.doi.org/10.1038/nrd1304] [PMID: 15040576]
[10]
Yu, Q.; Wu, X.; Zhu, Q.; Wu, W.; Chen, Z.; Li, Y.; Lu, Y. Enhanced transdermal delivery of meloxicam by nanocrystals: Preparation, in vitro and in vivo evaluation. Asian J. Pharmaceut. Sci., 2018, 13(6), 518-526.
[11]
Duangjit, S.; Obata, Y.; Sano, H.; Onuki, Y.; Opanasopit, P.; Ngawhirunpat, T.; Miyoshi, T.; Kato, S.; Takayama, K. Comparative study of novel ultradeformable liposomes: Menthosomes, transfersomes and liposomes for enhancing skin permeation of meloxicam. Biol. Pharm. Bull., 2014, 37(2), 239-247.
[http://dx.doi.org/10.1248/bpb.b13-00576] [PMID: 24225259]
[12]
Yuan, Y.; Li, S.M.; Mo, F.K.; Zhong, D.F. Investigation of microemulsion system for transdermal delivery of meloxicam. Int. J. Pharm., 2006, 321(1-2), 117-123.
[http://dx.doi.org/10.1016/j.ijpharm.2006.06.021] [PMID: 16876972]
[13]
Ahad, A.; Raish, M.; Al-Mohizea, A.M.; Al-Jenoobi, F.I.; Alam, M.A. Enhanced anti-inflammatory activity of carbopol loaded meloxicam nanoethosomes gel. Int. J. Biol. Macromol., 2014, 67, 99-104.
[http://dx.doi.org/10.1016/j.ijbiomac.2014.03.011] [PMID: 24657163]
[14]
Pathan, I.; Mangle, M.; Bairagi, S. Design and characterization of nanoemulsion for transdermal delivery of meloxicam. Anal. Chem. Lett., 2016, 6(3), 286-295.
[http://dx.doi.org/10.1080/22297928.2016.1209126]
[15]
Drais, H.K.; Hussein, A.A. formulation characterization and evaluation of meloxicam nanoemulgel to be used topically. Iraqi J. Pharm Sci., 2017, 26(1), 9-16.
[16]
Fetih, G. Meloxicam formulations for transdermal delivery: Hydrogels versus organogels. J. Drug Deliv. Sci. Technol., 2010, 20(6), 451-456.
[http://dx.doi.org/10.1016/S1773-2247(10)50078-9]
[17]
Kumar, M.; Chauhan, A.K.; Kumar, S.; Kumar, A.; Malik, S. Design and evaluation of pectin based metrics for transdermal patches of meloxicam. J. Pharm. Res. Heal. Care, 2010, 2, 244-247.
[18]
El-Badry, M.; Fetih, G.; Fathalla, D.; Shakeel, F. Transdermal delivery of meloxicam using niosomal hydrogels: In vitro and pharmacodynamic evaluation. Pharm. Dev. Technol., 2015, 20(7), 820-826.
[http://dx.doi.org/10.3109/10837450.2014.926919] [PMID: 24909736]
[19]
Park, K. Nanotechnology: What it can do for drug delivery. J. Control. Release, 2007, 120(1-2), 1-3.
[http://dx.doi.org/10.1016/j.jconrel.2007.05.003] [PMID: 17532520]
[20]
Hatahet, T.; Morille, M.; Hommoss, A.; Dorandeu, C.; Müller, R.H.; Bégu, S. Dermal quercetin smartCrystals®: Formulation development, antioxidant activity and cellular safety. Eur. J. Pharm. Biopharm., 2016, 102, 51-63.
[http://dx.doi.org/10.1016/j.ejpb.2016.03.004] [PMID: 26948977]
[21]
Patel, V.R.; Agrawal, Y.K. Nanosuspension: An approach to enhance solubility of drugs. J. Adv. Pharm. Technol. Res., 2011, 2(2), 81-87.
[http://dx.doi.org/10.4103/2231-4040.82950] [PMID: 22171298]
[22]
Liversidge, G.G.; Cundy, K.C.; Bishop, J.F.; Czekai, D.A. Surface modified drug nanoparticles. US Pat. 1992, 5(145) 684
[23]
Merisko-Liversidge, E.; Liversidge, G.G.; Cooper, E.R. Nanosizing: A formulation approach for poorly-water-soluble compounds. Eur. J. Pharm. Sci., 2003, 18(2), 113-120.
[http://dx.doi.org/10.1016/S0928-0987(02)00251-8] [PMID: 12594003]
[24]
Kesisoglou, F.; Panmai, S.; Wu, Y. Nanosizing--oral formulation development and biopharmaceutical evaluation. Adv. Drug Deliv. Rev., 2007, 59(7), 631-644.
[http://dx.doi.org/10.1016/j.addr.2007.05.003] [PMID: 17601629]
[25]
Chavhan, S.S.; Petkar, K.C.; Sawant, K.K. Nanosuspensions in drug delivery: Recent advances, patent scenarios, and commercialization aspects. Crit. Rev. Ther. Drug Carrier Syst., 2011, 28(5), 447-488.
[http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.v28.i5.20] [PMID: 22077201]
[26]
Li, Q.; Chen, F.; Liu, Y.; Yu, S.; Gai, X.; Ye, M.; Yang, X.; Pan, W. A novel albumin wrapped nanosuspension of meloxicam to improve inflammation-targeting effects. Int. J. Nanomedicine, 2018, 13, 4711-4725.
[http://dx.doi.org/10.2147/IJN.S160714] [PMID: 30154656]
[27]
Çelebi, N.; Ermiş, S.; Özkan, S. Development of topical hydrogels of terbinafine hydrochloride and evaluation of their antifungal activity. Drug Dev. Ind. Pharm., 2015, 41(4), 631-639.
[http://dx.doi.org/10.3109/03639045.2014.891129] [PMID: 24576265]
[28]
Chaudhary, H.; Kohli, K.; Amin, S.; Rathee, P.; Kumar, V. Optimization and formulation design of gels of Diclofenac and Curcumin for transdermal drug delivery by Box-Behnken statistical design. J. Pharm. Sci., 2011, 100(2), 580-593.
[http://dx.doi.org/10.1002/jps.22292] [PMID: 20669331]
[29]
Beg, S.; Swain, S.; Singh, H.P.; Patra, ChN.; Rao, M.E.B. Development, optimization, and characterization of solid self-nano-emulsifying drug delivery systems of valsartan using porous carriers. AAPS PharmSciTech, 2012, 13(4), 1416-1427.
[http://dx.doi.org/10.1208/s12249-012-9865-5] [PMID: 23070560]
[30]
Kocbek, P.; Baumgartner, S.; Kristl, J. Preparation and evaluation of nanosuspensions for enhancing the dissolution of poorly soluble drugs. Int. J. Pharm., 2006, 312(1-2), 179-186.
[http://dx.doi.org/10.1016/j.ijpharm.2006.01.008] [PMID: 16469459]
[31]
Shen, C.; Shen, B.; Liu, X.; Yuan, H. Nanosuspensions based gel as delivery system of nitrofurazone for enhanced dermal bioavailability. J. Drug Deliv. Sci. Technol., 2018, 43, 1-11.
[http://dx.doi.org/10.1016/j.jddst.2017.09.012]
[32]
Barot, B.S.; Parejiya, P.B.; Patel, H.K.; Gohel, M.C.; Shelat, P.K. Microemulsion-based gel of terbinafine for the treatment of onychomycosis: Optimization of formulation using D-optimal design. AAPS PharmSciTech, 2012, 13(1), 184-192.
[http://dx.doi.org/10.1208/s12249-011-9742-7] [PMID: 22187363]
[33]
Fang, J.Y.; Sung, K.C.; Lin, H.H.; Fang, C.L. Transdermal iontophoretic delivery of diclofenac sodium from various polymer formulations: In vitro and in vivo studies. Int. J. Pharm., 1999, 178(1), 83-92.
[http://dx.doi.org/10.1016/S0378-5173(98)00361-5] [PMID: 10205628]
[34]
Zuo, J.; Du, L.; Li, M.; Liu, B.; Zhu, W.; Jin, Y. Transdermal enhancement effect and mechanism of iontophoresis for non-steroidal anti-inflammatory drugs. Int. J. Pharm., 2014, 466(1-2), 76-82.
[http://dx.doi.org/10.1016/j.ijpharm.2014.03.013] [PMID: 24607207]
[35]
Winter, C.A.; Risley, E.A.; Nuss, G.W. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc. Soc. Exp. Biol. Med.,, 1962, 111(3), 544-547.
[http://dx.doi.org/10.3181/00379727-111-27849] [PMID: 14001233]
[36]
Busch, U.; Schmid, J.; Heinzel, G.; Schmaus, H.; Baierl, J.; Huber, C.; Roth, W. Pharmacokinetics of meloxicam in animals and the relevance to humans. Drug Metab. Dispos., 1998, 26(6), 576-584.
[PMID: 9616195]
[37]
Arora, P.; Mukherjee, B. Design, development, physicochemical, and in vitro and in vivo evaluation of transdermal patches containing diclofenac diethylammonium salt. J. Pharm. Sci., 2002, 91(9), 2076-2089.
[http://dx.doi.org/10.1002/jps.10200] [PMID: 12210054]
[38]
Pople, P.V.; Singh, K.K. Development and evaluation of topical formulation containing solid lipid nanoparticles of vitamin A. AAPS PharmSciTech, 2006, 7(4), 91.
[http://dx.doi.org/10.1208/pt070491] [PMID: 17285742]
[39]
Mutalik, S.; Udupa, N. Glibenclamide transdermal patches: Physicochemical, pharmacodynamic, and pharmacokinetic evaluations. J. Pharm. Sci., 2004, 93(6), 1577-1594.
[http://dx.doi.org/10.1002/jps.20058] [PMID: 15124215]
[40]
Ali, H.S.M.; York, P.; Ali, A.M.A.; Blagden, N. Hydrocortisone nanosuspensions for ophthalmic delivery: A comparative study between microfluidic nanoprecipitation and wet milling. J. Control. Release, 2011, 149(2), 175-181.
[http://dx.doi.org/10.1016/j.jconrel.2010.10.007] [PMID: 20946923]
[41]
Lindfors, L.; Skantze, P.; Skantze, U.; Rasmusson, M.; Zackrisson, A.; Olsson, U. Amorphous drug nanosuspensions. Inhibition of Ostwald ripening. Langmuir, 2006, 22(3), 906-910.
[http://dx.doi.org/10.1021/la0523661] [PMID: 16430247]
[42]
Wu, L.; Zhang, J.; Watanabe, W. Physical and chemical stability of drug nanoparticles. Adv. Drug Deliv. Rev., 2011, 63(6), 456-469.
[http://dx.doi.org/10.1016/j.addr.2011.02.001] [PMID: 21315781]
[43]
Romero, G.B.; Keck, C.M.; Müller, R.H. Simple low-cost miniaturization approach for pharmaceutical nanocrystals production. Int. J. Pharm., 2016, 501(1-2), 236-244.
[http://dx.doi.org/10.1016/j.ijpharm.2015.11.047] [PMID: 26642945]
[44]
Yang, H.; Teng, F.; Wang, P.; Tian, B.; Lin, X.; Hu, X.; Zhang, L.; Zhang, K.; Zhang, Y.; Tang, X. Investigation of a nanosuspension stabilized by Soluplus® to improve bioavailability. Int. J. Pharm., 2014, 477(1-2), 88-95.
[http://dx.doi.org/10.1016/j.ijpharm.2014.10.025] [PMID: 25455766]
[45]
Ghosh, I.; Schenck, D.; Bose, S.; Ruegger, C. Optimization of formulation and process parameters for the production of nanosuspension by wet media milling technique: Effect of Vitamin E TPGS and nanocrystal particle size on oral absorption. Eur. J. Pharm. Sci., 2012, 47(4), 718-728.
[http://dx.doi.org/10.1016/j.ejps.2012.08.011] [PMID: 22940548]
[46]
Danaei, M.; Dehghankhold, M.; Ataei, S.; Hasanzadeh Davarani, F.; Javanmard, R.; Dokhani, A.; Khorasani, S.; Mozafari, M.R. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics, 2018, 10(2)E57
[http://dx.doi.org/10.3390/pharmaceutics10020057] [PMID: 29783687]
[47]
Ahuja, B.K.; Jena, S.K.; Paidi, S.K.; Bagri, S.; Suresh, S. Formulation, optimization and in vitro-in vivo evaluation of febuxostat nanosuspension. Int. J. Pharm., 2015, 478(2), 540-552.
[http://dx.doi.org/10.1016/j.ijpharm.2014.12.003] [PMID: 25490182]
[48]
Singare, D.S.; Marella, S.; Gowthamrajan, K.; Kulkarni, G.T.; Vooturi, R.; Rao, P.S. Optimization of formulation and process variable of nanosuspension: An industrial perspective. Int. J. Pharm., 2010, 402(1-2), 213-220.
[http://dx.doi.org/10.1016/j.ijpharm.2010.09.041] [PMID: 20933066]
[49]
Lee, J.; Choi, J.Y.; Park, C.H. Characteristics of polymers enabling nano-comminution of water-insoluble drugs. Int. J. Pharm., 2008, 355(1-2), 328-336.
[http://dx.doi.org/10.1016/j.ijpharm.2007.12.032] [PMID: 18261866]
[50]
Lee, M.K.; Kim, S.; Ahn, C.H.; Lee, J. Hydrophilic and hydrophobic amino acid copolymers for nano-comminution of poorly soluble drugs. Int. J. Pharm., 2010, 384(1-2), 173-180.
[http://dx.doi.org/10.1016/j.ijpharm.2009.09.041] [PMID: 19788919]
[51]
Hong, C.; Dang, Y.; Lin, G.; Yao, Y.; Li, G.; Ji, G.; Shen, H.; Xie, Y. Effects of stabilizing agents on the development of myricetin nanosuspension and its characterization: An in vitro and in vivo evaluation. Int. J. Pharm., 2014, 477(1-2), 251-260.
[http://dx.doi.org/10.1016/j.ijpharm.2014.10.044] [PMID: 25445518]
[52]
Franco, F.; Pérez-Maqueda, L.A.; Pérez-Rodríguez, J.L. The effect of ultrasound on the particle size and structural disorder of a well-ordered kaolinite. J. Colloid Interface Sci., 2004, 274(1), 107-117.
[http://dx.doi.org/10.1016/j.jcis.2003.12.003] [PMID: 15120284]
[53]
Muller, R.H.; Keck, C.M. Challenges and solutions for the delivery of biotech drugs--a review of drug nanocrystal technology and lipid nanoparticles. J. Biotechnol., 2004, 113(1-3), 151-170.
[http://dx.doi.org/10.1016/j.jbiotec.2004.06.007] [PMID: 15380654]
[54]
Rabinow, B.E. Nanosuspensions in drug delivery. Nat. Rev. Drug Discov., 2004, 3(9), 785-796.
[http://dx.doi.org/10.1038/nrd1494] [PMID: 15340388]
[55]
Riddick, T.M. Control of colloid stability through zeta potential. Blood, 1968, 1(10), 1.
[56]
Inamdar, N.; Bhise, K.; Memon, S. Solubility enhancement and development of dispersible tablet of meloxicam. Asian J. Pharm., 2008, 2(2), 128.
[http://dx.doi.org/10.4103/0973-8398.42502]
[57]
Paudel, K.S.; Milewski, M.; Swadley, C.L.; Brogden, N.K.; Ghosh, P.; Stinchcomb, A.L. Challenges and opportunities in dermal/transdermal delivery. Ther. Deliv., 2010, 1(1), 109-131.
[http://dx.doi.org/10.4155/tde.10.16] [PMID: 21132122]
[58]
Müller, R.H.; Gohla, S.; Keck, C.M. State of the art of nanocrystals--special features, production, nanotoxicology aspects and intracellular delivery. Eur. J. Pharm. Biopharm., 2011, 78(1), 1-9.
[http://dx.doi.org/10.1016/j.ejpb.2011.01.007] [PMID: 21266197]
[59]
Kumbhar, D.; Wavikar, P.; Vavia, P. Niosomal gel of lornoxicam for topical delivery: In vitro assessment and pharmacodynamic activity. AAPS PharmSciTech, 2013, 14(3), 1072-1082.
[http://dx.doi.org/10.1208/s12249-013-9986-5] [PMID: 23818079]
[60]
Biruss, B.; Valenta, C. The advantage of polymer addition to a non-ionic oil in water microemulsion for the dermal delivery of progesterone. Int. J. Pharm., 2008, 349(1-2), 269-273.
[http://dx.doi.org/10.1016/j.ijpharm.2007.08.003] [PMID: 17869457]
[61]
Kantarci, G.; Ozgüney, I.; Karasulu, H.Y.; Arzik, S.; Güneri, T. Comparison of different water/oil microemulsions containing diclofenac sodium: preparation, characterization, release rate, and skin irritation studies. AAPS PharmSciTech, 2007, 8(4) E91
[http://dx.doi.org/10.1208/pt0804091] [PMID: 18181551]
[62]
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, 377-390.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy