Pain Management with Topical Aceclofenac Nanosuspension In-Vitro/In-
Vivo and Proof of Concept Studies

Shaina      Nagpal; Parina      Kumari; Komal      Saini; Vandita      Kakkar

doi:10.2174/1574885517666220518094723

Abstract

Introduction: Pain is one of the most common medical conditions and affects more than diabetes, heart disease, and cancer combined. Current pain treatments mainly rely on NSAID analgesics and remain unsatisfactory. Due to associated adverse effects such as gastrointestinal ulcers and bleeding, low solubility limits its use.

Objective: The present research focuses on advances in the field of pain treatment by topical delivery of NSAIDs (aceclofenac) drugs via enhancing its solubility and diminishing related side effects.

Materials and Methods: ACE-nanosuspension (ACE-NS) prepared by anti-solvent precipitation technique was characterized for particle size, PDI, zeta-potential, total drug content, DSC, FTIR, P-XRD and FESEM. Furthermore, spreadability, ex-vivo occlusivity, in-vitro release, ex-vivo skin permeation and retention and stability studies were performed. Dermal irritation and histopathological examinations were conducted in accordance with OECD guidelines. Proof of concept studies was accomplished using radiant tail-flick and paw-licking animal models.

Results: ACE-NS showed particle size of 148 ± 15 nm with PDI: 0.170, zeta potential: 21.2 mV and total drug content of 86 ± 0.23%, respectively. DSC, FT-IR, P-XRD and FESEM studies revealed the thermal behavior, compatibility, solid-state characterization and morphology of ACE-NS. ACE-NSloaded ointment showed a spreadability ratio of 0.23 and a drug content of 84 ± 1.15%. In-vitro release of ACE from nano-ACE-ointment (88.07%) was higher than the marketed formulation (70.55%) and free drug ointment (70.45%) after 24 hours. Release profile of nano-ACE-ointment fitted best for Higuchi model with r2 = 0.94 and n = 0.45 and its permeation flux was 9.2312 ± 0.8430 mg/cm2/h, which was significantly higher (p ≤0.05) than ACE marketed gel (2.6158 ± 0.4352 mg/cm2/h). Cutaneous irritation and histological studies revealed no inflammatory skin lesions post-treatment with ACE-NS. Furthermore, ACE-NS-ointment showed a better analgesic effect than the marketed formulation in both the radiant tail-flick model (2.87 times) and paw-licking (2.73 times) animal model.

Conclusion: Studies highlighted the potential of topical nano-ACE-ointment for pain management.

Keywords: Nanosuspension, pain, aceclofenac, histopathology, dermal irritation, analgesic studies, in vitro, in vivo.

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[1] 
Aditya NP, Yang H, Kim S, Ko S. Fabrication of amorphous curcumin nanosuspensions using β-lactoglobulin to enhance solubility, stability, and bioavailability. Colloids Surf B Biointerfaces 2015; 127: 114-21.
        
[http://dx.doi.org/10.1016/j.colsurfb.2015.01.027] [PMID: 25660094] 
[2] 
Agarwal V, Bajpai M. Preparation and optimization of esomeprazole nanosuspension using evaporative precipitation–ultrasonication. Trop J Pharm Res 2014; 13(4): 497-503.
        
[http://dx.doi.org/10.4314/tjpr.v13i4.2] 
[3] 
Akimoto H, Yamazaki R, Hashimoto S, Sato T, Ito A. 4′-Hydroxy aceclofenac suppresses the interleukin-1-induced production of promatrix metalloproteinases and release of sulfated-glycosaminoglycans from rabbit articular chondrocytes. Eur J Pharmacol 2000; 401(3): 429-36.
        
[http://dx.doi.org/10.1016/S0014-2999(00)00472-6] [PMID: 10936503] 
[4] 
Humphries TJ, Kessler CM. Managing chronic pain in adults with haemophilia: Current status and call to action. Haemophilia 2015; 21(1): 41-51.
        
[http://dx.doi.org/10.1111/hae.12526] [PMID: 25274075] 
[5] 
Zinellu A, Carru C, Sotgia S, Porqueddu E, Enrico P, Deiana L. Separation of aceclofenac and diclofenac in human plasma by free zone capillary electrophoresis using N-methyl-D-glucamine as an effective electrolyte additive. Eur J Pharm Sci 2005; 24(4): 375-80.
        
[http://dx.doi.org/10.1016/j.ejps.2004.12.003] [PMID: 15734304] 
[6] 
Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol 2008; 26(11): 1261-8.
        
[http://dx.doi.org/10.1038/nbt.1504] [PMID: 18997767] 
[7] 
Wang R, Wang X, Jia X, Wang H, Li W, Li J. Impacts of particle size on the cytotoxicity, cellular internalization, pharmacokinetics and biodistribution of betulinic acid nanosuspensions in combined chemotherapy. Int J Pharm 2020; 588: 119799.
        
[http://dx.doi.org/10.1016/j.ijpharm.2020.119799] [PMID: 32828973] 
[8] 
Oktay AN, Karakucuk A, Ilbasmis-Tamer S, Celebi N. Dermal flurbiprofen nanosuspensions: Optimization with design of experiment approach and in vitro evaluation. Eur J Pharm Sci 2018; 122: 254-63.
        
[http://dx.doi.org/10.1016/j.ejps.2018.07.009] [PMID: 29981401] 
[9] 
Geetha G, Poojitha U, Khan KA. Various techniques for preparation of nanosuspension-A review. Int J Pharma Sci 2014; 3(9): 30-7.
[10] 
Ghosh I, Michniak-Kohn B. Influence of critical parameters of nanosuspension formulation on the permeability of a poorly soluble drug through the skin--A case study. AAPS PharmSciTech 2013; 14(3): 1108-17.
        
[http://dx.doi.org/10.1208/s12249-013-9995-4] [PMID: 23824877] 
[11] 
Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: The answer to solubility-limited oral bioavailability? J Pharm Sci 2009; 98(8): 2549-72.
        
[http://dx.doi.org/10.1002/jps.21650] [PMID: 19373886] 
[12] 
Lai F, Pireddu R, Corrias F, et al. Nanosuspension improves tretinoin photostability and delivery to the skin. Int J Pharm 2013; 458(1): 104-9.
        
[http://dx.doi.org/10.1016/j.ijpharm.2013.10.007] [PMID: 24135683] 
[13] 
Masilamani k, Ravichandiran V. Effect of formulation and process variables on particle size of aceclofenac nanosuspension. J Pharm Res 2012; 5(1): 715-8.
[14] 
Jorvekar P, Pathak AA, Chaudhari PD. Formulation development of aceclofenac loaded nanosuspension by three square (32) factorial design. Int J Pharm Sci Nanotechnol 2012; 4: 1575-82.
[15] 
Prabu SL, Sharavanan S, Govindaraju S, Suriyaprakash T. Formulation development of aceclofenac nanosuspension as an alternative approach for improving drug delivery of poorly soluble drugs. Int J Pharm Sci Nanotechnol 2013; 6(3): 2145-53.
        
[http://dx.doi.org/10.37285/ijpsn.2013.6.3.6] 
[16] 
Thakkar HP, Patel BV, Thakkar SP. Development and characterization of nanosuspensions of olmesartan medoxomil for bioavailability enhancement. J Pharm Bioallied Sci 2011; 3(3): 426-34.
        
[http://dx.doi.org/10.4103/0975-7406.84459] [PMID: 21966165] 
[17] 
Subash K, Nina M, Rao P, Chakraborty J. Aceclofenac nanosuspension: Formulation and evaluation. Uni J Pharm Bio Sci 2016; 04(02): 11-9.
[18] 
Rahim H, Sadiq A, Khan S, et al. Aceclofenac nanocrystals with enhanced in vitro, in vivo performance: Formulation optimization, characterization, analgesic and acute toxicity studies. Drug Des Devel Ther 2017; 11: 2443-52.
        
[http://dx.doi.org/10.2147/DDDT.S140626] [PMID: 28860715] 
[19] 
Patel HM, Patel UB, Shah C, Akbari B. Formulation and development of nanosuspension as an alternative approach for solubility and dissolution enhancement of aceclofenac. Int J Adv Pharm 2018; 7(5): 33-47.
[20] 
Bhargavi R. A technical review of nanosuspensions. Int J Pharm Technol 2011; 3(3): 1503-11.
[21] 
Carvalho BM, Pellá MCG, Hardt JC, et al. Ecovio®-based nanofibers as a potential fast transdermal releaser of aceclofenac. J Mol Liq 2021; 325: 115206.
        
[http://dx.doi.org/10.1016/j.molliq.2020.115206] 
[22] 
Kakkar V, Kaur IP, Kaur AP, Saini K, Singh KK. Topical delivery of tetrahydrocurcumin lipid nanoparticles effectively inhibits skin inflammation: In vitro and in vivo study. Drug Dev Ind Pharm 2018; 44(10): 1701-12.
        
[http://dx.doi.org/10.1080/03639045.2018.1492607] [PMID: 29938544] 
[23] 
Ganesh M, Jeon UJ, Ubaidulla U, et al. Chitosan cocrystals embedded alginate beads for enhancing the solubility and bioavailability of aceclofenac. Int J Biol Macromol 2015; 74: 310-7.
        
[http://dx.doi.org/10.1016/j.ijbiomac.2014.12.038] [PMID: 25557368] 
[24] 
Xie Y, Chen Z, Su R, et al. Preparation and optimization of amorphous ursodeoxycholic acid nano-suspensions by nanoprecipitation based on acid-base neutralization for enhanced dissolution. Curr Drug Deliv 2017; 14(4): 483-91.
        
[http://dx.doi.org/10.2174/1567201813666160902152122] [PMID: 27593183] 
[25] 
Md S, Kit BCM, Jagdish S, David DJP, Pandey M, Chatterjee LA. Development and in vitro evaluation of a zerumbone loaded nanosuspension drug delivery system. Crystals (Basel) 2018; 8(7): 286.
        
[http://dx.doi.org/10.3390/cryst8070286] 
[26] 
Sharma S, Issarani R, Nagori BP. Development of aceclofenac nanosuspension stabilized by poly vinyl alcohol and sodium dodecyl sulphate. Res J Pharm Techn 2015; 8(3): 235-41.
        
[http://dx.doi.org/10.5958/0974-360X.2015.00027.X] 
[27] 
Dantas MG, Reis SA, Damasceno CM, et al. Development and evaluation of stability of a gel formulation containing the monoterpene borneol. ScientificWorldJournal 2016; 2016: 7394685.
        
[http://dx.doi.org/10.1155/2016/7394685] [PMID: 27247965] 
[28] 
Amarji B, Garg NK, Singh B, Katare OP. Microemulsions mediated effective delivery of methotrexate hydrogel: More than a tour de force in psoriasis therapeutics. J Drug Target 2016; 24(2): 147-60.
        
[http://dx.doi.org/10.3109/1061186X.2015.1058804] [PMID: 26204326] 
[29] 
Khan MA, Pandit J, Sultana Y, et al. 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] 
[30] 
Shrotriya S, Ranpise N, Satpute P, Vidhate B. Skin targeting of curcumin solid lipid nanoparticles-engrossed topical gel for the treatment of pigmentation and irritant contact dermatitis. Artif Cells Nanomed Biotechnol 2018; 46(7): 1471-82.
        
[http://dx.doi.org/10.1080/21691401.2017.1373659] [PMID: 28884598] 
[31] 
Rapalli VK, Sharma S, Roy A, Alexander A, Singhvi G. Solid lipid nanocarriers embedded hydrogel for topical delivery of apremilast: In-vitro, ex-vivo, dermatopharmacokinetic and anti-psoriatic evaluation. J Drug Deliv Sci Technol 2021; 63: 102442.
        
[http://dx.doi.org/10.1016/j.jddst.2021.102442] 
[32] 
Park JJ, Meghani N, Choi JS, Lee BJ. Development and evaluation of decorated aceclofenac nanocrystals. Colloids Surf B Biointerfaces 2016; 143: 206-12.
        
[http://dx.doi.org/10.1016/j.colsurfb.2016.03.022] [PMID: 27011350] 
[33] 
Kopečná M, Kováčik A, Novák P, Boncheva Bettex M, Vávrová K. Transdermal permeation and skin retention of diclofenac and etofenamate/flufenamic acid from over-the-counter pain relief products. J Pharm Sci 2021; 110(6): 2517-23.
        
[http://dx.doi.org/10.1016/j.xphs.2021.01.022] [PMID: 33508308] 
[34] 
Theochari I, Ilic T, Nicolic I, et al. Biological evaluation of oil-in-water microemulsions as carriers of benzothiophene analogues for dermal applications. Biomimetics (Basel) 2021; 6(1): 10.
        
[http://dx.doi.org/10.3390/biomimetics6010010] [PMID: 33514031] 
[35] 
Jacob S, Nair AB, Shah J. Emerging role of nanosuspensions in drug delivery systems. Biomark Res 2020; 24(1): 3.
        
[http://dx.doi.org/10.1186/s40824-020-0184-8] [PMID: 31969986] 
[36] 
Iqbal B, Ali J, Baboota S. Recent advances and development in epidermal and dermal drug deposition enhancement technology. Int J Dermatol 2018; 57(6): 646-60.
        
[http://dx.doi.org/10.1111/ijd.13902] [PMID: 29430629] 
[37] 
Fuhr LM, Marok FZ, Hanke N, Selzer D, Lehr T. Pharmacokinetics of the CYP3A4 and CYP2B6 inducer carbamazepine and its drug-drug interaction potential: A physiologically based pharmacokinetic modeling approach. Pharmaceutics 2021; 13(2): 270.
        
[http://dx.doi.org/10.3390/pharmaceutics13020270] [PMID: 33671323] 
[38] 
OECD guideline for testing of chemicals 404 2002.
[39] 
Singh H, Kaur J, Arora R, et al. Ameliorative potential of Argyreia speciosa against CCI-induced neuropathic pain in rats: Biochemical and histopathological studies. J Ethnopharmacol 2020; 249: 112399.
        
[http://dx.doi.org/10.1016/j.jep.2019.112399] [PMID: 31733307] 
[40] 
Deuis JR, Dvorakova LS, Vetter I. Methods used to evaluate pain behaviors in rodents. Front Mol Neurosci 2017; 6(10): 284.
        
[http://dx.doi.org/10.3389/fnmol.2017.00284] 
[41] 
Santenna C, Kumar S, Balakrishnan S, Jhaj R, Ahmed SN. A comparative experimental study of analgesic activity of a novel non-steroidal anti-inflammatory molecule - zaltoprofen, and a standard drug - piroxicam, using murine models. J Exp Pharmacol 2019; 11: 85-91.
        
[http://dx.doi.org/10.2147/JEP.S212988] [PMID: 31447593] 
[42] 
Lai SC, Peng WH, Huang SC, et al. Analgesic and anti-inflammatory activities of methanol extract from Desmodium triflorum DC in mice. Am J Chin Med 2009; 37(3): 573-88.
        
[http://dx.doi.org/10.1142/S0192415X09007065] [PMID: 19606516] 
[43] 
Garg AK, Negi LM, Chauhan M. Gel containing ethosomal vesicles for transdermal delivery of aceclofenac. Int J Pharm Pharm Sci 2010; (2): 102-8.
[44] 
Kalvakuntla S, Deshpande M, Attari Z, Kunnatur BK. Preparation and characterization of nanosuspension of aprepitant by H96 process. Adv Pharm Bull 2016; 6(1): 83-90.
        
[http://dx.doi.org/10.15171/apb.2016.013] [PMID: 27123422] 
[45] 
Phan HT, Haes AJ. What does nanoparticle stability mean? J Phys Chem C 2019; 123(27): 16495-507.
        
[http://dx.doi.org/10.1021/acs.jpcc.9b00913] [PMID: 31844485] 
[46] 
Liu X, Gan H, Hu C, et al. Silver sulfadiazine nanosuspension-loaded thermosensitive hydrogel as a topical antibacterial agent. Int J Nanomedicine 2018; 14: 289-300.
        
[http://dx.doi.org/10.2147/IJN.S187918] [PMID: 30643407] 
[47] 
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] 
[48] 
Mishra RK, Datt M, Pal K, Banthia AK. Preparation and characterization of amidated pectin based hydrogels for drug delivery system. J Mater Sci Mater Med 2008; 19(6): 2275-80.
        
[http://dx.doi.org/10.1007/s10856-007-3310-4] [PMID: 18058200] 
[49] 
Rahim H, Sadiq A, Ullah R, et al. Formulation of aceclofenac tablets using nanosuspension as granulating agent: An attempt to enhance dissolution rate and oral bioavailability. Int J Nanomedicine 2020; 15: 8999-9009.
        
[http://dx.doi.org/10.2147/IJN.S270746] [PMID: 33235448] 
[50] 
Meenakshi B, Parina K. Preparation, characterization and evaluation of pectin-curcumin nanosuspension. Inventi Impact Pharm Process Develop 2016; (4): 177-85.
[51] 
Aiyalu R, Govindarjan A, Ramasamy A. Formulation and evaluation of topical herbal gel for the treatment of arthritis in animal model. Braz J Pharm Sci 2016; 52: 493-507.
        
[http://dx.doi.org/10.1590/s1984-82502016000300015] 
[52] 
Lambers H, Piessens S, Bloem A, Pronk H, Finkel P. Natural skin surface pH is on average below 5, which is beneficial for its resident flora. Int J Cosmet Sci 2006; 28(5): 359-70.
        
[http://dx.doi.org/10.1111/j.1467-2494.2006.00344.x] [PMID: 18489300] 
[53] 
Jenning V, Gysler A, Schäfer-Korting M, Gohla SH. Vitamin A loaded solid lipid nanoparticles for topical use: Occlusive properties and drug targeting to the upper skin. Eur J Pharm Biopharm 2000; 49(3): 211-8.
        
[http://dx.doi.org/10.1016/S0939-6411(99)00075-2] [PMID: 10799811] 
[54] 
Hamishehkar H, Same S, Adibkia K, et al. A comparative histological study on the skin occlusion performance of a cream made of solid lipid nanoparticles and Vaseline. Res Pharm Sci 2015; 10(5): 378-87.
        
[PMID: 26752986] 
[55] 
Xia D, Cui F, Piao H, Cun D, Piao H. Effect of crystal size on the in vitro dissolution and oral absorption of nitrendipine in rats. Pharm Res 2010; 27: 1965-76.
[56] 
Hatahet T, Morille M, Hommoss A, Dorandeu C, Müller R, Begu S. Dermal quercetin smartCrystals®: Formulation development, antioxidant activity and cellular safety. Eur J Pharm Biopharm 2016; 102: 51-63.
[57] 
Romero G, Arntjen A, Keck C, Müller R. Amorphous cyclosporin A nanoparticles for enhanced dermal bioavailability. Int J Pharm 2016; 498: 217-24.
[58] 
Kumbhar D, Wavikar P, Vavia P. Niosomal gel of lornoxicam for topical delivery: In vitro assessment and pharmacodynamic activity. AAPS PharmSciTech 2013; 14: 1072-82.
        
[http://dx.doi.org/10.1208/s12249-013-9986-5] 
[59] 
Palmer BC, DeLouise LA. Nanoparticle-enabled transdermal drug delivery systems for enhanced dose control and tissue targeting. Molecules 2016; 21(12): 1719.
        
[http://dx.doi.org/10.3390/molecules21121719] [PMID: 27983701] 
[60] 
Argenziano M, Haimhoffer A, Bastiancich C, et al. In vitro enhanced skin permeation and retention of imiquimod loaded in β-cyclodextrin nanosponge hydrogel. Pharmaceutics 2019; 11(3): 138.
        
[http://dx.doi.org/10.3390/pharmaceutics11030138] [PMID: 30897794] 
[61] 
Permana AD, McCrudden MTC, Donnelly RF. Enhanced intradermal delivery of nanosuspensions of antifilariasis drugs using dissolving microneedles: A proof of concept study. Pharmaceutics 2019; 11(7): 346.
        
[http://dx.doi.org/10.3390/pharmaceutics11070346] [PMID: 31319602] 
[62] 
Shakeel F, Ramadan W, Shafiq S. Solubility and dissolution improvement of aceclofenac using different nanocarriers. J Bioequivalence Bioavailab 2009; 1(02): 39-43.
        
[http://dx.doi.org/10.4172/jbb.1000007] 
[63] 
Wang J, Li Z, Sun F, et al. Evaluation of dermal irritation and skin sensitization due to vitacoxib. Toxicol Rep 2017; 4: 287-90.
        
[http://dx.doi.org/10.1016/j.toxrep.2017.06.003] [PMID: 28959651] 
[64] 
Somagoni J, Boakye CH, Godugu C, et al. Nanomiemgel--a novel drug delivery system for topical application-in vitro and in vivo evaluation. PLoS One 2014; 9(12): e115952.
        
[http://dx.doi.org/10.1371/journal.pone.0115952] [PMID: 25546392] 
[65] 
Fischer AH, Jacobson KA, Rose J, Zeller R. Hematoxylin and eosin staining of tissue and cell sections. CSH Protoc 2008; 2008 pdb.prot4986
        
[http://dx.doi.org/10.1101/pdb.prot4986] 
[66] 
Sharma G, Saini MK, Thakur K, et al. Aceclofenac cocrystal nanoliposomes for rheumatoid arthritis with better dermatokinetic attributes: A preclinical study. Nanomedicine (Lond) 2017; 12(6): 615-38.
        
[http://dx.doi.org/10.2217/nnm-2016-0405] [PMID: 28186461] 
[67] 
Mahnashi MH, Alyami BA, Alqahtani YS, et al. Phytochemical profiling of bioactive compounds, anti-inflammatory and analgesic potentials of Habenaria digitata Lindl.: Molecular docking based synergistic effect of the identified compounds. J Ethnopharmacol 2021; 273: 113976.
        
[http://dx.doi.org/10.1016/j.jep.2021.113976] [PMID: 33647424] 
[68] 
Paliwal S, Tilak A, Sharma J, et al. Flurbiprofen loaded ethosomes-transdermal delivery of anti-inflammatory effect in rat model. Lipids Health Dis 2019; 18(1): 1-5.
        
[http://dx.doi.org/10.1186/s12944-019-1064-x] [PMID: 30611256] 

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DOI https://dx.doi.org/10.2174/1574885517666220518094723	Print ISSN 1574-8855
Publisher Name Bentham Science Publisher	Online ISSN 2212-3903

Current Drug Therapy

Pain Management with Topical Aceclofenac Nanosuspension In-Vitro/In- Vivo and Proof of Concept Studies

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