FORMULATION AND EVALUATION OF ETODOLAC AND TRIAMCINOLONE ACETONIDE LOADED NANO LIPID CARRIER GELS FOR THE THERAPEUTIC MANAGEMENT OF OSTEOARTHRITIS PAIN THROUGH TOPICAL ADMINISTRATION: A COMPARATIVE STUDY

SOUVIK CHAKRABORTY; N. VISHAL GUPTA; VIKAS JAIN; BALAMURALIDHARA V.

doi:10.22159/ijap.2024v16i5.51326

Authors

SOUVIK CHAKRABORTY Department of Pharmaceutics, Eminent College of Pharmaceutical Technology, Mos pukur, Barbaria, Paschim Khilkapur, Barasat, Jagannathpur, West Bengal-700126, India
N. VISHAL GUPTA Department of Pharmaceutics, JSS College of Pharmacy, Sri Shivarathreeshwara Nagara, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru-570015, Karnataka, India
VIKAS JAIN Department of Pharmaceutics, JSS College of Pharmacy, Sri Shivarathreeshwara Nagara, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru-570015, Karnataka, India
BALAMURALIDHARA V. Department of Pharmaceutics, JSS College of Pharmacy, Sri Shivarathreeshwara Nagara, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru-570015, Karnataka, India

DOI:

https://doi.org/10.22159/ijap.2024v16i5.51326

Keywords:

EDT, TCA, OAOA, NLCs, Hydrogels

Abstract

Objective: The present study aims to prepare carbopol-based hydrogels loaded with Etodolac (EDT), and Triamcinolone Acetonide (TCA) incorporated Nanolipid Carriers (NLCs) (EDTg and TCAg) to compare the efficacy and potency of both drugs for Osteoarthritis (OA) pain management.

Methods: EDT-NLCs and TCA-NLCs were prepared with the help of the solvent evaporation method after screening the lipids, and the NLCs were optimized. The optimized NLC formulations EDT-NLC and TCA-NLCs were examined for particle size, PDI, zeta otential, Differential Scanning Calorimetry (DSC), Powder X-ray Diffraction (PXRD), Transmission Electron Mcroscopy (TEM) and in vitro release. The prepared EDTg and TCAg have been evaluated with in vitro drug release, ex-vivo skin permeation, and in vivo pharmacokinetic and pharmacodynamic parameters.

Results: DSC and PXRD graphs showed a decrease in melting point and the amorphous form of the optimized NLC formulation. Different evaluation tests revealed that the EDT-NLCs and TCA-NLCshad particle size of 161±0.0021 nm and 167.4±0.0010 nm, PDI of 0.148±0.023 and 0.130±0.01, and zeta potential of-14 mV and-15 mV respectively, indicating their distinct nature. In vitro drug release study, ETDg showed 89.84±1.71 % release, while TCAg released 94.75±1.79 % after 24 h of application. ETDg permeated 86.5±1.68% of EDT-NLCs through the dorsal skin, compared to TCA-NLCs 76.5±1.13 %in an ex vivo skin permeation investigation. A pharmacokinetic study identified 76.3±1.98 % of EDT-NLCs and 63.25±2.003 of TCA-NLCs in drug plasma. Pharmacodynamic characteristics like X-ray analysis, Immuno Histochemistry (IHC), and histopathology indicated that EDTg and TCAg managed OA pain. All evaluation tests carried out in this research showed that formulated hydrogels could manage OA.

Conclusion: The results suggested in this research prove EDTg to have a higher potentiality than TCAg for the management of OA pain

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References

Anandacoomarasamy A, March L. Current evidence for osteoarthritis treatments. Ther Adv Musculoskelet Dis. 2010 Feb;2(1):17-28. doi: 10.1177/1759720X09359889, PMID 22870434.

Boer CG, Hatzikotoulas K, Southam L, Stefansdottir L, Zhang Y, Coutinho de Almeida R. Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations. Cell. 2021;184(18):4784-818.e17. doi: 10.1016/j.cell.2021.07.038.

Wieland HA, Michaelis M, Kirschbaum BJ, Rudolphi KA. Osteoarthritis-an untreatable disease? Nat Rev Drug Discov. 2005;4(4):331-44. doi: 10.1038/nrd1693, PMID 15803196.

Bannuru RR, Osani MC, Vaysbrot EE, Arden NK, Bennell K, Bierma Zeinstra SM. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019;27(11):1578-89. doi: 10.1016/j.joca.2019.06.011, PMID 31278997.

Kolasinski SL, Neogi T, Hochberg MC, Oatis C, Guyatt G, Block J. American college of rheumatology/arthritis foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Rheumatol. 2020;72(2):220-33. doi: 10.1002/art.41142, PMID 31908163.

Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J. American college of rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64(4):465-74. doi: 10.1002/acr.21596, PMID 22563589.

Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P. Eular recommendations 2003: an evidence-based approach to the management of knee osteoarthritis: report of a task force of the standing committee for international clinical studies including therapeutic trials (ESCISIT). Ann Rheum Dis. 2003;62(12):1145-55. doi: 10.1136/ard.2003.011742, PMID 14644851.

McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014;22(3):363-88. doi: 10.1016/j.joca.2014.01.003, PMID 24462672.

Da Costa BR, Pereira TV, Saadat P, Rudnicki M, Iskander SM, Bodmer NS. Effectiveness and safety of non-steroidal anti-inflammatory drugs and opioid treatment for knee and hip osteoarthritis: network meta-analysis. BMJ. 2021;375:n2321. doi: 10.1136/bmj.n2321, PMID 34642179.

Scarpignato C, Lanas A, Blandizzi C, Lems WF, Hermann M, Hunt RH. Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis-an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks. BMC Med. 2015;13:55. doi: 10.1186/s12916-015-0285-8, PMID 25857826.

Zeng C, Wei J, Persson MS, Sarmanova A, Doherty M, Xie D. Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies. Br J Sports Med. 2018;52(10):642-50. doi: 10.1136/bjsports-2017-098043, PMID 29436380.

Hochberg MC, Altman RD, Brandt KD, Clark BM, Dieppe PA, Griffin MR. Guidelines for the medical management of osteoarthritis. Part II. Osteoarthritis of the knee. American College of Rheumatology. Arthritis Rheum. 1995;38(11):1541-6. doi: 10.1002/art.1780381104, PMID 7488273.

Zhang Y, Cun D, Kong X, Fang L. Design and evaluation of a novel transdermal patch containing diclofenac and teriflunomide for rheumatoid arthritis therapy. Asian J Pharm Sci. 2014;9(5):251-9. doi: 10.1016/j.ajps.2014.07.007.

Von Heideken J, Chowdhry S, Borg J, James K, Iversen MD. Reporting of harm in randomized controlled trials of therapeutic exercise for knee osteoarthritis: a systematic review. Phys Ther. 2021;101(10):161. doi: 10.1093/ptj/pzab161, PMID 34180534.

Abdellatif AA, El-Telbany DF, Zayed G, Al-Sawahli MM. Hydrogel containing PEG-coated fluconazole nanoparticles with enhanced solubility and antifungal activity. J Pharm Innov. 2019;14(2):112-22. doi: 10.1007/s12247-018-9335-z.

Karadzovska D, Brooks JD, Riviere JE. Modeling the effect of experimental variables on the in vitro permeation of six model compounds across porcine skin. Int J Pharm. 2013;443(1-2):58-67. doi: 10.1016/j.ijpharm.2013.01.002, PMID 23313919.

Kurakula M, Ahmed OA, Fahmy UA, Ahmed TA. Solid lipid nanoparticles for transdermal delivery of avanafil: optimization, formulation, in vitro and ex-vivo studies. J Liposome Res. 2016;26(4):288-96. doi: 10.3109/08982104.2015.1117490, PMID 26784833.

Schnitzer TJ, Ballard IM, Constantine G, McDonald P. Double-blind, placebo-controlled comparison of the safety and efficacy of orally administered etodolac and nabumetone in patients with active osteoarthritis of the knee. Clin Ther. 1995;17(4):602-12. doi: 10.1016/0149-2918(95)80037-9, PMID 8565024.

Van Middelkoop M, Arden NK, Atchia I, Birrell F, Chao J, Rezende MU. The OA Trial bank: a meta-analysis of individual patient data from knee and hip osteoarthritis trials show that patients with severe pain exhibit greater benefit from intra-articular glucocorticoids. Osteoarthritis Cartilage. 2016;24(7):1143-52. doi: 10.1016/j.joca.2016.01.983, PMID 26836288.

Xing D, Yang Y, Ma X, Ma J, Ma B, Chen Y. Dose intraarticular steroid injection increase the rate of infection in subsequent arthroplasty: grading the evidence through a meta-analysis. J Orthop Surg Res. 2014;9:107. doi: 10.1186/s13018-014-0107-2, PMID 25391629.

Mohammadi M, Pezeshki A, Mesgari Abbasi M, Ghanbarzadeh B, Hamishehkar H. Vitamin D3-loaded nanostructured lipid carriers as a potential approach for fortifying food beverages; in vitro and in vivo evaluation. Adv Pharm Bull. 2017;7(1):61-71. doi: 10.15171/apb.2017.008, PMID 28507938.

Radha GV, Sastri KT, Prathyusha P, Bhanu P, Rajkumar J. Formulation and evaluation of aceclofenac proniosome loaded orabase for management of dental pain. Int J App Pharm. 2018;10(6):204-10. doi: 10.22159/ijap.2018v10i6.29143.

Kumar G, Sushma B, Jeyaprakash M. LC-MS/MS-based quantitative profiling of papain enzyme in carica papaya L.: method development and validation. Int J Appl Pharm. 2024;16(2):86-91.

Iqbal B, Ali J, Baboota S. Silymarin loaded nanostructured lipid carrier: from design and dermatokinetic study to mechanistic analysis of epidermal drug deposition enhancement. J Mol Liq. 2018;255:513-29. doi: 10.1016/j.molliq.2018.01.141.

Patel DK, Kesharwani R, Kumar V. Etodolac loaded solid lipid nanoparticle-based topical gel for enhanced skin delivery. Biocatal Agric Biotechnol. 2020;29:101810. doi: 10.1016/j.bcab.2020.101810.

Kawadkar J, Pathak A, Kishore R, Chauhan MK. Formulation, characterization and in vitro–in vivo evaluation of flurbiprofen-loaded nanostructured lipid carriers for transdermal delivery. Drug Dev Ind Pharm. 2013;39(4):569-78. doi: 10.3109/03639045.2012.686509, PMID 22639934.

Chand P, Kumar H, Badduri N, Gupta NV, Bettada VG, Madhunapantula SV. Design and evaluation of cabazitaxel-loaded NLCs against breast cancer cell lines. Colloids Surf B Biointerfaces. 2021;199:111535. doi: 10.1016/j.colsurfb.2020.111535, PMID 33360926.

Mohammadi Samani S, Zojaji S, Entezar Almahdi E. Piroxicam loaded solid lipid nanoparticles for topical delivery: preparation, characterization and in vitro permeation assessment. J Drug Deliv Sci Technol. 2018;47:427-33. doi: 10.1016/j.jddst.2018.07.015.

Jain K, Sood S, Gowthamarajan K. Optimization of artemether-loaded NLC for intranasal delivery using central composite design. Drug Deliv. 2015;22(7):940-54. doi: 10.3109/10717544.2014.885999, PMID 24512368.

Patel S, Shah UH. Synthesis of flavones from 2-hydroxy acetophenone and aromatic aldehyde derivatives by conventional methods and green chemistry approach. Asian J Pharm Clin Res 2017;10(2):403-6. doi: 10.22159/ajpcr.2017.v10i2.15928.

Hu FQ, Jiang SP, Du YZ, Yuan H, Ye YQ, Zeng S. Preparation and characterization of stearic acid nanostructured lipid carriers by solvent diffusion method in an aqueous system. Colloids Surf B Biointerfaces. 2005;45(3-4):167-73. doi: 10.1016/j.colsurfb.2005.08.005, PMID 16198092.

Wamorkar V, Varma MM, Manjunath SY. Formulation and evaluation of stomach-specific in-situ gel of metoclopramide using natural, bio-degradable polymers. Int J. Biomed Sci. 2011;2:193-201.

Zhuang CY, Li N, Wang M, Zhang XN, Pan WS, Peng JJ. Preparation and characterization of vinpocetine-loaded nanostructured lipid carriers (NLC) for improved oral bioavailability. Int J Pharm. 2010;394(1-2):179-85. doi: 10.1016/j.ijpharm.2010.05.005, PMID 20471464.

Luo Q, Zhao J, Zhang X, Pan W. Nanostructured lipid carrier (NLC) coated with chitosan oligosaccharides and its potential use in ocular drug delivery system. Int J Pharm. 2011;403(1-2):185-91. doi: 10.1016/j.ijpharm.2010.10.013, PMID 20951778.

Shah NV, Seth AK, Balaraman R, Aundhia CJ, Maheshwari RA, Parmar GR. Nanostructured lipid carriers for oral bioavailability enhancement of raloxifene: design and in vivo study. J Adv Res. 2016;7(3):423-34. doi: 10.1016/j.jare.2016.03.002, PMID 27222747.

He Y, Majid K, Maqbool M, Hussain T, Yousaf AM, Khan IU. Formulation and characterization of lornoxicam-loaded cellulosic-microsponge gel for possible applications in arthritis. Saudi Pharm J. 2020;28(8):994-1003. doi: 10.1016/j.jsps.2020.06.021, PMID 32792844.

Souto EB, Wissing SA, Barbosa CM, Müller RH. Evaluation of the physical stability of SLN and NLC before and after incorporation into hydrogel formulations. Eur J Pharm Biopharm. 2004;58(1):83-90. doi: 10.1016/j.ejpb.2004.02.015, PMID 15207541.

Bove SE, Calcaterra SL, Brooker RM, Huber CM, Guzman RE, Juneau PL. Weight-bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. Osteoarthritis Cartilage. 2003;11(11):821-30. doi: 10.1016/s1063-4584(03)00163-8, PMID 14609535.

Patel KN, Patel HK, Patel VA. Formulation and characterization of drug in adhesive transdermal patches of diclofenac acid. Int J Pharm Pharm Sci. 2012;4:296-9.

Vashisth I, Ahad A, Aqil M, Agarwal SP. Investigating the potential of essential oils as penetration enhancer for transdermal losartan delivery: effectiveness and mechanism of action. Asian J Pharm Sci. 2014;9(5):260-7. doi: 10.1016/j.ajps.2014.06.007.

Danafar H, Hamidi M. Simple and sensitive high-performance liquid chromatography (HPLC) method with UV detection for mycophenolic acid assay in human plasma. Application to a bioequivalence study. Adv Pharm Bull. 2015;5(4):563-8. doi: 10.15171/apb.2015.076, PMID 26819930.

Liu SC, Lee HP, Hung CY, Tsai CH, Li TM, Tang CH. Berberine attenuates CCN2-induced IL-1β expression and prevents cartilage degradation in a rat model of osteoarthritis. Toxicol Appl Pharmacol. 2015;289(1):20-9. doi: 10.1016/j.taap.2015.08.020, PMID 26344001.

Bhalekar MR. Solid lipid nanoparticles incorporated transdermal patch for improving the permeation of piroxicam. Asian J Pharm. 2016;10(1):45-50.

Ah YC, Choi JK, Choi YK, Ki HM, Bae JH. A novel transdermal patch incorporating meloxicam: in vitro and in vivo characterization. Int J Pharm. 2010;385(1-2):12-9. doi: 10.1016/j.ijpharm.2009.10.013, PMID 19833177.

Sun L, Cun D, Yuan BO, Cui H, Xi H, Mu L. Formulation and in vitro/in vivo correlation of a drug‐in‐adhesive transdermal patch containing azasetron. J Pharm Sci. 2012;101(12):4540-8. doi: 10.1002/jps.23317, PMID 22972714.

Sastri KT, Gupta NV, Kannan A, Balamuralidhara V, Ramkishan A. Potential nanocarrier-mediated miRNA-based therapy approaches for multiple sclerosis. Drug Discov Today. 2022;27:103357.

C Juneja S, Ventura M. A less invasive approach of medial meniscectomy in rat: a model to target early or less severe human osteoarthritis. J Arthritis. 2016;05(2):1-17. doi: 10.4172/2167-7921.1000193.

Mishra N, Mishra M, Padh H. Formulation development and optimization of efavirenz loaded SLNs and NLCs using placket-burman design and its statistical elucidation. Int J Pharm R H Sci. 2018;6:2379-88.

Gonullu U, Uner M, Yener G, Karaman EF, Aydogmuş Z. Formulation and characterization of solid lipid nanoparticles, nanostructured lipid carriers and nanoemulsion of lornoxicam for transdermal delivery. Acta Pharm. 2015;65(1):1-13. doi: 10.1515/acph-2015-0009, PMID 25781700.

Li X, Nie SF, Kong J, Li N, Ju CY, Pan WS. A controlled-release ocular delivery system for ibuprofen based on nanostructured lipid carriers. Int J Pharm. 2008;363(1-2):177-82. doi: 10.1016/j.ijpharm.2008.07.017, PMID 18706987.

Unger WW, van Beelen AJ, Bruijns SC, Joshi M, Fehres CM, van Bloois L. Glycan-modified liposomes boost CD4+ and CD8+ T-cell responses by targeting DC-SIGN on dendritic cells. J Control Release. 2012;160(1):88-95. doi: 10.1016/j.jconrel.2012.02.007, PMID 22366522.

Jain V, Kumar H, Chand P, Jain S. Lipid‐based nanocarriers as drug delivery system and its applications. Nanopharmaceutical Adv Deliv Syst. 2021:1-29.

Dandagi PM, Dessai GA, Gadad AP, Desai VB. Formulation and evaluation of nanostructured lipid carrier (NLC) of lornoxicam. Int J Pharm Pharm Sci. 2014;6(2):73-7.

Kumar RM, Kumar H, Bhatt T, Jain R, Panchal K, Chaurasiya A. Fisetin in cancer: attributes, developmental aspects, and nanotherapeutics. Pharmaceuticals (Basel). 2023;16(2):196. doi: 10.3390/ph16020196, PMID 37259344.

Bhattacharya SA, Prajapati BG. Formulation and optimization of celecoxib nanoemulgel. Asian J Pharm Clin Res. 2017;10(8):353-65. doi: 10.22159/ajpcr.2017.v10i8.19510.

Gaba B, Fazil M, Khan S, Ali A, Baboota S, Ali J. Nanostructured lipid carrier system for topical delivery of terbinafine hydrochloride. Bull Fac Pharm Cairo Univ. 2015;53(2):147-59. doi: 10.1016/j.bfopcu.2015.10.001.

Kumar H, Chand P, Pachal S, Mallick S, Jain R, Madhunapantula SV. Fisetin-loaded nanostructured lipid carriers: formulation and evaluations against advanced and metastatic melanoma. Mol Pharm. 2023;20(12):6035-55. doi: 10.1021/acs.molpharmaceut.3c00309, PMID 37906601.

Shah JI, Patel SH, Bhairy SR, Hirlekar RA. Formulation optimization, characterization and in vitro anti-cancer activity of curcumin loaded nanostructured lipid carriers. Int J Curr Pharm Sci. 2022;14(1):31-43. doi: 10.22159/ijcpr.2022v14i1.44110.

Abdelbary G, Haider M. In vitro characterization and growth inhibition effect of nanostructured lipid carriers for controlled delivery of methotrexate. Pharm Dev Technol. 2013;18(5):1159-68. doi: 10.3109/10837450.2011.614251, PMID 21958084.

Chakraborty S, Gupta NV, Sastri KT, MS, Chand P, Kumar H. Current progressions in transdermal drug delivery systems for management of rheumatoid and osteoarthritis: a comprehensive review. J Drug Deliv Sci Technol. 2022;73:103476. doi: 10.1016/j.jddst.2022.103476.