Login Register Cart 0
Generic placeholder image

Current Drug Delivery

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Iontophoretic Mediated Intraarticular Delivery of Deformable Liposomes of Diclofenac Sodium

Author(s): Kenchappa Vanaja*, Salwa S., S. Narasimha Murthy and H.N. Shivakumar

Volume 18, Issue 4, 2021

Published on: 14 October, 2020

Page: [421 - 432] Pages: 12

DOI: 10.2174/1567201817666201014144708

Price: $65

Abstract

Background and Objective: Topical therapy is ineffective in the case of Musculoskeletal Disorders (MSD) as it is not able to maintain therapeutic levels of the drug in the affected joint due to its inability to surpass the dermal circulation and penetrate into deeper tissues. One of the approaches to enhance deep tissue penetration of drugs is to increase drug delivery much above the dermal clearance. The objective of the present work was to formulate negatively charged Deformable Liposomes (DL) of Diclofenac Sodium (DS) using biosurfactants and target the same to the synovial fluid by application of iontophoresis.

Methods: Deformable liposomes loaded with diclofenac sodium were formulated and characterized for surface morphology, particle size distribution, zeta potential and entrapment efficiency. In vitro permeation of the diclofenac from aqueous solution, conventional liposomes, and deformable liposomes under iontophoresis was performed using Franz diffusion cells and compared to passive control. Intraarticular microdialysis was carried out to determine the time course of drug concentration in the synovial fluid at the knee-joint region of the hind limb in Sprague Dawley rats.

Results: The vesicles were found to display a high entrapment (> 60%) and possess a negative zeta potential lower than -30 mV. The size of the vesicles was varied from 112.41 ± 1.42 nm and 154.6 ± 3.22 nm, demonstrated good stability on the application of iontophoresis. The iontophoretic flux values for the DS aqueous solution, conventional liposomes and deformable liposomal formulation were found to be 7.55 ± 0.42, 16.75±1.77and 44.01 ± 3.47 μg/ cm2 h-1, respectively. Deformable liposomes were found to display an enhancement of 5.83 fold compared to passive control. Iontophoresis was found to enhance the availability of DS deformable liposomes (0.56 ± 0.08 μg.h/ml) in the synovial fluid by nearly 2-fold over passive delivery (0.29 ± 0.05 μg.h/ml).

Conclusion: Results obtained indicate that iontophoretic mediated transport of deformable liposomes could improve the regional bioavailability of diclofenac sodium to the synovial joints, an efficient mode for treating MSD in the elderly.

Keywords: Iontophoresis, liposome(s), intraarticular, deformable, microdialysis, NSAID, transdermal.

« Previous Next »
Graphical Abstract

[1]
Woolf, A.D.; Pfleger, B. Burden of major musculoskeletal conditions. Bull. World Health Organ., 2003, 81(9), 646-656.
[PMID: 14710506]
[2]
Nair, B.; Taylor-Gjevre, R. A review of topical diclofenac use in musculoskeletal disease. Pharmaceuticals (Basel), 2010, 3(6), 1892-1908.
[http://dx.doi.org/10.3390/ph3061892] [PMID: 27713334]
[3]
Ricciotti, E.; FitzGerald, G.A. Prostaglandins and inflammation. Arterioscler. Thromb. Vasc. Biol., 2011, 31(5), 986-1000.
[http://dx.doi.org/10.1161/ATVBAHA.110.207449] [PMID: 21508345]
[4]
Riess, W.; Schmid, K.; Botta, L.; Kobayashi, K.; Moppert, J.; Schneider, W.; Sioufi, A.; Strusberg, A.; Tomasi, M. The percutaneous absorption of diclofenac. Arzneimittelforschung, 1986, 36(7), 1092-1096.
[PMID: 3768079]
[5]
Ghanbarzadeh, S.; Arami, S. Enhanced transdermal delivery of diclofenac sodium via conventional liposomes, ethosomes, and transfersomes. BioMed. Res. Int., 2013, 2013, 616810.
[http://dx.doi.org/10.1155/2013/616810] [PMID: 23936825]
[6]
Sharma, G.; Goyal, H.; Thakur, K.; Raza, K.; Katare, O.P. Novel Elastic Membrane Vesicles (EMVs) and ethosomes-mediated effective topical delivery of aceclofenac: a new therapeutic approach for pain and inflammation. Drug Deliv., 2016, 23(8), 3135-3145.
[http://dx.doi.org/10.3109/10717544.2016.1155244] [PMID: 26960815]
[7]
Cevc, G.; Blume, G. New, highly efficient formulation of diclofenac for the topical, transdermal administration in ultradeformable drug carriers, transfersomes. Biochim. Biophys. Acta, 2001, 1514(2), 191-205.
[http://dx.doi.org/10.1016/S0005-2736(01)00369-8] [PMID: 11557020]
[8]
Cevc, G. Self-regulating “smart carriers” for non-invasive and targeted drug delivery. Cell. Mol. Biol. Lett., 2002, 7(2), 224-225.
[PMID: 12097924]
[9]
Hui, X.; Anigbogu, A.; Singh, P.; Xiong, G.; Poblete, N.; Liu, P.; Maibach, H.I. Pharmacokinetic and local tissue disposition of [14C]sodium diclofenac following iontophoresis and systemic administration in rabbits. J. Pharm. Sci., 2001, 90(9), 1269-1276.
[http://dx.doi.org/10.1002/jps.1079] [PMID: 11745779]
[10]
Butoescu, N.; Seemayer, C.A.; Palmer, G.; Guerne, P.A.; Gabay, C.; Doelker, E.; Jordan, O. Magnetically retainable microparticles for drug delivery to the joint: efficacy studies in an antigen-induced arthritis model in mice. Arthritis Res. Ther., 2009, 11(3), R72.
[http://dx.doi.org/10.1186/ar2701] [PMID: 19454011]
[11]
Türker, S.; Erdoğan, S.; Ozer, Y.A.; Bilgili, H.; Deveci, S. Enhanced efficacy of diclofenac sodium-loaded lipogelosome formulation in intra-articular treatment of rheumatoid arthritis. J. Drug Target., 2008, 16(1), 51-57.
[http://dx.doi.org/10.1080/10611860701725191] [PMID: 18172820]
[12]
Sammeta, S.M.; Murthy, S.N. “ChilDrive”: a technique of combining regional cutaneous hypothermia with iontophoresis for the delivery of drugs to synovial fluid. Pharm. Res., 2009, 26(11), 2535-2540.
[http://dx.doi.org/10.1007/s11095-009-9977-0] [PMID: 19774343]
[13]
Vanaja, K.; Wahl, M.A.; Bukarica, L.; Heinle, H. Liposomes as carriers of the lipid soluble antioxidant resveratrol: evaluation of amelioration of oxidative stress by additional antioxidant vitamin. Life Sci., 2013, 93(24), 917-923.
[http://dx.doi.org/10.1016/j.lfs.2013.10.019] [PMID: 24177602]
[14]
Zeb, A.; Qureshi, O.S.; Kim, H.S.; Cha, J.H.; Kim, H.S.; Kim, J.K. Improved skin permeation of methotrexate via nanosized ultradeformable liposomes. Int. J. Nanomedicine, 2016, 11, 3813-3824.
[http://dx.doi.org/10.2147/IJN.S109565] [PMID: 27540293]
[15]
Zhao, X.Y.; Guo, C.L.; Yao, W.T.; Cai, Q.Q.; Wang, Y.S.; Wang, J.Q. Vitamin E TPGS based liposomal delivery of doxorubicin in osteosarcoma cancer cells. Biomed. Res., 2017, 28(3), 1344-1349.
[16]
Sammeta, S.M.; Vaka, S.R.K.; Murthy, S.N. Dermal drug levels of antibiotic (cephalexin) determined by electroporation and transcutaneous sampling (ETS) technique. J. Pharm. Sci., 2009, 98(8), 2677-2685.
[http://dx.doi.org/10.1002/jps.21642] [PMID: 19067398]
[17]
Souza, J.G.; Dias, K.; Pereira, T.A.; Bernardi, D.S.; Lopez, R.F. Topical delivery of ocular therapeutics: carrier systems and physical methods. J. Pharm. Pharmacol., 2014, 66(4), 507-530.
[http://dx.doi.org/10.1111/jphp.12132] [PMID: 24635555]
[18]
Cevc, G.; Blume, G. Hydrocortisone and dexamethasone in very deformable drug carriers have increased biological potency, prolonged effect, and reduced therapeutic dosage. Biochim. Biophys. Acta, 2004, 1663(1-2), 61-73.
[http://dx.doi.org/10.1016/j.bbamem.2004.01.006] [PMID: 15157608]
[19]
Cevc, G.; Gebauer, D. Hydration-driven transport of deformable lipid vesicles through fine pores and the skin barrier. Biophys. J., 2003, 84(2 Pt 1), 1010-1024.
[http://dx.doi.org/10.1016/S0006-3495(03)74917-0] [PMID: 12547782]
[20]
Cevc, G.; Blume, G. Biological activity and characteristics of triamcinolone-acetonide formulated with the self-regulating drug carriers, transfersomes. Biochim. Biophys. Acta, 2003, 1614(2), 156-164.
[http://dx.doi.org/10.1016/S0005-2736(03)00172-X] [PMID: 12896808]
[21]
Cevc, G.; Schätzlein, A.; Richardsen, H. Ultradeformable lipid vesicles can penetrate the skin and other semi-permeable barriers unfragmented. Evidence from double label CLSM experiments and direct size measurements. Biochim. Biophys. Acta, 2002, 1564(1), 21-30.
[http://dx.doi.org/10.1016/S0005-2736(02)00401-7] [PMID: 12100992]
[22]
Roberts, M.S. Targeted drug delivery to the skin and deeper tissues: role of physiology, solute structure and disease. Clin. Exp. Pharmacol. Physiol., 1997, 24(11), 874-879.
[http://dx.doi.org/10.1111/j.1440-1681.1997.tb02708.x] [PMID: 9363373]
[23]
van den Bergh, B.A.; Wertz, P.W.; Junginger, H.E.; Bouwstra, J.A. Elasticity of vesicles assessed by electron spin resonance, electron microscopy and extrusion measurements. Int. J. Pharm., 2001, 217(1-2), 13-24.
[http://dx.doi.org/10.1016/S0378-5173(01)00576-2] [PMID: 11292538]
[24]
El Zaafarany, G.M.; Awad, G.A.S.; Holayel, S.M.; Mortada, N.D. Role of edge activators and surface charge in developing ultradeformable vesicles with enhanced skin delivery. Int. J. Pharm., 2010, 397(1-2), 164-172.
[http://dx.doi.org/10.1016/j.ijpharm.2010.06.034] [PMID: 20599487]
[25]
Gregoriadis, G. Overview of liposomes. J. Antimicrobial Chemotherapy, 1991, 28(Suppl B), 39-48.
[http://dx.doi.org/10.1093/jac/28.suppl_B.39]
[26]
Vanaja, K.; Shobha Rani, R.H.; Sacchidananda, S. Formulation and clinical evaluation of ultradeformable liposomes in the topical treatment of psoriasis. Clin. Res. Regul. Aff., 2008, 25(1), 41-52.
[http://dx.doi.org/10.1080/10601330701885116]
[27]
Shrestha, H.; Bala, R.; Arora, S. Lipid-based drug delivery systems. J. Pharm. (Cairo), 2014, 2014, 801820.
[http://dx.doi.org/10.1155/2014/801820] [PMID: 26556202]
[28]
Daraee, H.; Etemadi, A.; Kouhi, M.; Alimirzalu, S.; Akbarzadeh, A. Application of liposomes in medicine and drug delivery. Artif. Cells Nanomed. Biotechnol., 2016, 44(1), 381-391.
[http://dx.doi.org/10.3109/21691401.2014.953633] [PMID: 25222036]
[29]
Abd El-Alim, S.H.; Kassem, A.A.; Basha, M.; Salama, A. Comparative study of liposomes, ethosomes and transfersomes as carriers for enhancing the transdermal delivery of diflunisal: in vitro and in vivo evaluation. Int. J. Pharm., 2019, 563, 293-303.
[http://dx.doi.org/10.1016/j.ijpharm.2019.04.001] [PMID: 30951860]
[30]
Yang, C.; Dai, X.; Yang, S.; Ma, L.; Chen, L.; Gao, R.; Wu, X.; Shi, X. Coarse-grained molecular dynamics simulations of the effect of edge activators on the skin permeation behavior of transfersomes. Colloids Surf. B Biointerfaces, 2019, 183, 110462.
[http://dx.doi.org/10.1016/j.colsurfb.2019.110462] [PMID: 31479973]
[31]
Malinovskaja-Gomez, K.; Espuelas, S.; Garrido, M. J.; Hirvonen, J.; Laaksonen, T. Comparison of liposomal drug formulations for transdermal iontophoretic drug delivery. Euro. J. Pharmaceut. Sci., 2017, 106, 294-301.
[http://dx.doi.org/10.1016/j.ejps.2017.06.025]
[32]
Al-Mahallawi, A.M.; Khowessah, O.M.; Shoukri, R.A. Nano- transfersomal ciprofloxacin loaded vesicles for non-invasive trans-tympanic ototopical delivery: in-vitro optimization, ex-vivo permeation studies, and in-vivo assessment. Int. J. Pharm., 2014, 472(1-2), 304-314.
[http://dx.doi.org/10.1016/j.ijpharm.2014.06.041] [PMID: 24971692]
[33]
Aboud, H.M.; Ali, A.A.; El-Menshawe, S.F.; Elbary, A.A. Nanotransfersomes of carvedilol for intranasal delivery: formulation, characterization and in vivo evaluation. Drug Deliv., 2016, 23(7), 2471-2481.
[http://dx.doi.org/10.3109/10717544.2015.1013587] [PMID: 25715807]
[34]
Manrique-Moreno, M.; Garidel, P.; Suwalsky, M.; Howe, J.; Brandenburg, K. The membrane-activity of ibuprofen, diclofenac, and naproxen: a physico-chemical study with lecithin phospholipids. Biochim. Biophys. Acta, 2009, 1788(6), 1296-1303.
[http://dx.doi.org/10.1016/j.bbamem.2009.01.016] [PMID: 19366589]
[35]
Lopes, L.B.; Scarpa, M.V.; Silva, G.V.; Rodrigues, D.C.; Santilli, C.V.; Oliveira, A.G. Studies on the encapsulation of diclofenac in small unilamellar liposomes of soya phosphatidylcholine. Colloids Surf. B Biointerfaces, 2004, 39(4), 151-158.
[http://dx.doi.org/10.1016/j.colsurfb.2004.09.004] [PMID: 15555896]
[36]
Hussain, A.; Singh, S.; Sharma, D.; Webster, T.J.; Shafaat, K.; Faruk, A. Elastic liposomes as novel carriers: recent advances in drug delivery. Int. J. Nanomedicine, 2017, 12, 5087-5108.
[http://dx.doi.org/10.2147/IJN.S138267] [PMID: 28761343]
[37]
Dar, M.J.; Din, F.U.; Khan, G.M. Sodium stibogluconate loaded nano-deformable liposomes for topical treatment of leishmaniasis: macrophage as a target cell. Drug Deliv., 2018, 25(1), 1595-1606.
[http://dx.doi.org/10.1080/10717544.2018.1494222] [PMID: 30105918]
[38]
Hodge, R.E.; Webster, J.D. Formulations of deoxycholic acid and salts thereof. US Patent US8101593B2, Feb. 5;2013
[39]
Shivakumar, H.N. Hand Book on non-invasive drug delivery systems; Elsevier Inc: Bulington, MA, USA, 2010, p. 328.
[40]
Hadgraft, J.; W. D., G.; Allan., G. Azone pharmaceutical skin penetration enhancement: effect of different vehicles on hydrocortisone acetate skin permeation and retention. J. Controlled Release, 1993, , 147-154.
[41]
Arunkumar, S.; Ashok, P.; Desai, B.G.; Shivakumar, H.N. Effect of chemical penetration enhancer on transdermal iontophoretic delivery of diclofenac sodium under constant voltage. J. Drug Deliv. Sci. Technol., 2015, 30, 171-179.
[http://dx.doi.org/10.1016/j.jddst.2015.10.007]
[42]
Takahashi, K.; Tamagawa, S.; Katagi, T.; Yoshitomi, H.; Kamada, A.; Rytting, J.H.; Nishihata, T.; Mizuno, N. In vitro transport of sodium diclofenac across rat abdominal skin: effect of selection of oleaginous component and the addition of alcohols to the vehicle. Chem. Pharm. Bull. (Tokyo), 1991, 39(1), 154-158.
[http://dx.doi.org/10.1248/cpb.39.154] [PMID: 2049800]
[43]
Fang, J.; Wang, R.; Huang, Y.; Wu, P.C.; Tsai, Y. Passive and iontophoretic delivery of three diclofenac salts across various skin types. Biol. Pharm. Bull., 2000, 23(11), 1357-1362.
[http://dx.doi.org/10.1248/bpb.23.1357] [PMID: 11085366]
[44]
Nishihata, T.; Kotera, K.; Nakano, Y.; Yamazaki, M. Rat percutaneous transport of diclofenac and influence of hydrogenated soya phospholipids. Chem. Pharm. Bull. (Tokyo), 1987, 35(9), 3807-3812.
[http://dx.doi.org/10.1248/cpb.35.3807] [PMID: 3435976]
[45]
Li, L.; Hoffman, R.M. Topical liposome delivery of molecules to hair follicles in mice. J. Dermatol. Sci., 1997, 14(2), 101-108.
[http://dx.doi.org/10.1016/S0923-1811(96)00557-9] [PMID: 9039973]
[46]
de Leeuw, J.; de Vijlder, H.C.; Bjerring, P.; Neumann, H.A. Liposomes in dermatology today. J. Eur. Acad. Dermatol. Venereol., 2009, 23(5), 505-516.
[http://dx.doi.org/10.1111/j.1468-3083.2009.03100.x] [PMID: 19175703]
[47]
Modepalli, N.; Shivakumar, H.N.; McCrudden, M.T.; Donnelly, R.F.; Banga, A.; Murthy, S.N. Transdermal Delivery of iron using soluble microneedles: dermal kinetics and safety. J. Pharm. Sci., 2016, 105(3), 1196-1200.
[http://dx.doi.org/10.1016/j.xphs.2015.12.008] [PMID: 26928401]
[48]
Lee, R.D.; White, H.S.; Scott, E.R. Visualization of iontophoretic transport paths in cultured and animal skin models. J. Pharm. Sci., 1996, 85(11), 1186-1190.
[http://dx.doi.org/10.1021/js960106l] [PMID: 8923323]
[49]
Hagen, M.; Baker, M. Skin penetration and tissue permeation after topical administration of diclofenac. Curr. Med. Res. Opin., 2017, 33(9), 1623-1634.
[http://dx.doi.org/10.1080/03007995.2017.1352497] [PMID: 28681621]
[50]
Maurya, A.; Murthy, S.N. Pretreatment with skin permeability enhancers: importance of duration and composition on the delivery of diclofenac sodium. J. Pharm. Sci., 2014, 103(5), 1497-1503.
[http://dx.doi.org/10.1002/jps.23938] [PMID: 24644068]
[51]
Benveniste, H.; Hüttemeier, P.C. Microdialysis-theory and application. Prog. Neurobiol., 1990, 35(3), 195-215.
[http://dx.doi.org/10.1016/0301-0082(90)90027-E] [PMID: 2236577]
[52]
Qian, M.; West, W.; Wu, J.T.; Lu, B.; Christ, D.D. Development of a dog microdialysis model for determining synovial fluid pharmacokinetics of anti-arthritis compounds exemplified by methotrexate. Pharm. Res., 2003, 20(4), 605-610.
[http://dx.doi.org/10.1023/A:1023246832321] [PMID: 12739768]
[53]
Benfeldt, E.; Hansen, S.H.; Vølund, A.; Menné, T.; Shah, V.P. Bioequivalence of topical formulations in humans: evaluation by dermal microdialysis sampling and the dermatopharmacokinetic method. J. Invest. Dermatol., 2007, 127(1), 170-178.
[http://dx.doi.org/10.1038/sj.jid.5700495] [PMID: 16874309]
[54]
Radermacher, J.; Jentsch, D.; Scholl, M.A.; Lustinetz, T.; Frölich, J.C. Diclofenac concentrations in synovial fluid and plasma after cutaneous application in inflammatory and degenerative joint disease. Br. J. Clin. Pharmacol., 1991, 31(5), 537-541.
[http://dx.doi.org/10.1111/j.1365-2125.1991.tb05576.x] [PMID: 1888621]
[55]
Liauw, H.L.; Ku, E.; Brandt, K.D.; Benson, M.D.; Aldo-Benson, M.A.; Waiter, S.L.; Lee, W.; Chan, K.; Vyas, K. Effects of voltaren on arachidonic acid metabolism in arthritis patients. Agents Actions Suppl., 1985, 17, 195-199.
[http://dx.doi.org/10.1007/978-3-0348-7720-6_24] [PMID: 3937448]
[56]
Wagner, J.S.M. Bindung von diclofenac-Na (Voltareng) an serumproteine verschiedener spezies und interaktionen mit anderen pharmaka. Akt. Rheumatol., 1979, 4, 153-162.

Rights & Permissions Print Cite
Article Metrics
27
1
© 2024 Bentham Science Publishers | Privacy Policy