Curcuminoids, piperine, microemulsion, polyherbal, RAW 264.7, CFA


Objective: Observations from traditional medicine and findings of modern science recommend use of curcuminoids and piperine in inflammatory ailments such as rheumatoid arthritis. Therapeutic potential of these phytoconstituents cannot be exploited to the maximum extent because of poor solubility and low bioavailability. The objective of this study was to overcome these challenges and harness the potential of these phytoconstituents by developing lipid and surfactant-based formulation.

Methods: A microemulsion was prepared by selecting lipids, surfactants and cosurfactants on the basis of solubility and stability of phytoconstituents. It was further converted into transparent gel for topical application. The phytoformulation was characterized by physicochemical tests. Its hemocompatibility and irritation potential was determined. Further phytoformulation was studied in RAW 264.7 cells for cell internalization and antiarthritic potential was investigated in Complete Freund’s Adjuvant (CFA) induced arthritic rats. The disease progression was recorded. At the end of the study hematological, biochemical and oxidative stress parameters were measured.

Results: A stable phytoformulation containing 0.75% w/w curcuminoids and 0.25% w/w piperine was developed. At the end of 24 hours, the amount of curcuminoids and piperine permeated through the skin from phytoformulation was 4.38 and 1.38 times that of the oil. It had a good hemocompatibility and poor irritation potential. Internalization of phytoformulation in RAW 264.7 cells was concentration dependent. There were significant changes in rats due to disease induction by CFA and results indicated regression of the disease progress due to phytoformulation.

Conclusion: Lipid and surfactant-based formulation improved solubility and permeability of phytoconstituents. The developed phytoformulation could recover inflammatory changes in rats and it can be further studied in human beings.


Download data is not yet available.


. Wang K, Chen Y, Zhang P, Lin P, Xie N, Wu M. Protective features of autophagy in pulmonary infection and inflammatory diseases. Cells. 2019 Feb 3;8(2):123. doi: 10.3390/cells8020123.

. Liu FT, Yang RY, Hsu DK. Galectins in acute and chronic inflammation. Ann N Y Acad Sci. 2012 Apr;1253(1):80-91. doi:10.1111/j.1749-6632.2011.06386.x.

. Hall CJ, Sanderson LE, Lawrence LM, Pool B, Van Der Kroef M, Ashimbayeva E, Britto D, Harper JL, Lieschke GJ, Astin JW, Crosier KE. Blocking fatty acid–fueled mROS production within macrophages alleviates acute gouty inflammation. J Clin Invest. 2018 May 1;128(5):1752-71. doi: 10.1172/JCI94584.

. Chen B, Li H, Ou G, Ren L, Yang X, Zeng M. Curcumin attenuates MSU crystal-induced inflammation by inhibiting the degradation of IκBα and blocking mitochondrial damage. Arthritis Res Ther. 2019 Dec;21(1):1-5. doi: 10.1186/s13075-019-1974-z.

. Kanai M. Therapeutic applications of curcumin for patients with pancreatic cancer. World J. Gastroenterol. 2014 Jul 7;20(28):9384. doi:10.3748/wjg.v20.i28.9384.

. Peng Y, Ao M, Dong B, Jiang Y, Yu L, Chen Z, Hu C, Xu R. Anti-inflammatory effects of curcumin in the inflammatory diseases: Status, limitations and countermeasures. Drug Des Devel Ther. 2021;15:4503. doi: 10.2147/DDDT.S327378.

. Nadkarni AK. Indian Materia Medica. Bombay: Popular Prakashan PVP; 1976, 969-972.

. Umar S, Sarwar AH, Umar K, Ahmad N, Sajad M, Ahmad S, Katiyar CK, Khan HA. Piperine ameliorates oxidative stress, inflammation and histological outcome in collagen induced arthritis. Cell Immunol. 2013 Jul 1;284(1-2):51-9. doi: 10.1016/j.cellimm.2013.07.004 .

. Bang JS, Oh DH, Choi HM, Sur BJ, Lim SJ, Kim JY, Yang HI, Yoo MC, Hahm DH, Kim KS. Anti-inflammatory and antiarthritic effects of piperine in human interleukin 1β-stimulated fibroblast-like synoviocytes and in rat arthritis models. Arthritis Res Ther. 2009 Apr;11(2):1-9. doi: 10.1186/ar2662.

. Kumar S, Malhotra S, Prasad AK, Van der Eycken EV, Bracke ME, Stetler-Stevenson WG et al. Anti-inflammatory and antioxidant properties of Piper species: a perspective from screening to molecular mechanisms. Curr Top Med Chem. 2015;15(9):886-93. doi: 10.2174/1568026615666150220120651.

. R David S, Akmar Binti Anwar N, Yian KR, Mai CW, Das SK, Rajabalaya R. Development and evaluation of curcumin liquid crystal systems for cervical cancer. Sci Pharm. 2020;88(1):15. doi: 10.3390/scipharm88010015.

. Zheng B, McClements DJ. Formulation of more efficacious curcumin delivery systems using colloid science: enhanced solubility, stability, and bioavailability. Molecules. 2020 Jun 17;25(12):2791. doi:10.3390/molecules25122791.

. Prasad S, Tyagi AK, Aggarwal BB. Recent developments in delivery, bioavailability, absorption and metabolism of curcumin: the golden pigment from golden spice. Cancer Res Treat. 2014 Jan 15;46(1):2-18. doi: 10.4143/crt.2014.46.1.2.

. Bhalekar MR, Madgulkar AR, Desale PS, Marium G. Formulation of piperine solid lipid nanoparticles (SLN) for treatment of rheumatoid arthritis. DDIP. 2017 Jun 3;43(6):1003-10. doi: 10.1080/03639045.2017.1291666.

. Zafar A, Imam SS, Alruwaili NK, Alsaidan OA, Elkomy MH, Ghoneim MM, Alshehri S, Ali AM, Alharbi KS, Yasir M, Noorulla KM. Development of piperine-loaded solid self-nanoemulsifying drug delivery system: optimization, in-vitro, ex-vivo, and in-vivo evaluation. Nanomaterials. 2021 Oct 31;11(11):2920. doi: 10.3390/nano11112920.

. Imam SS, Alshehri S, Altamimi MA, Hussain A, Qamar W, Gilani SJ, Zafar A, Alruwaili NK, Alanazi S, Almutairy BK. Formulation of piperine–chitosan-coated liposomes: Characterization and in vitro cytotoxic evaluation. Molecules. 2021 May 29;26(11):3281. doi: 10.3390/molecules26113281.

. Reddy KR, Faruqui AA. Efficacy and tolerability of fixed dose combination of curcumin and piperine in Indian osteoarthritic patients. Int J of Orthop Sci. 2016;2(4):445-9. doi:10.1186/s12906-017-2062-z.

. Tu Y, Sun D, Zeng X, Yao N, Huang X, Huang D, Chen Y. Piperine potentiates the hypocholesterolemic effect of curcumin in rats fed on a high fat diet. Exp Ther Med. 2014;8(1):260-6. doi:10.3892/etm.2014.1717.

. Sehgal A, Kumar M, Jain M, Dhawan DK. Combined effects of curcumin and piperine in ameliorating benzo (a) pyrene induced DNA damage. Food Chem Toxicol. 2011;49(11):3002-6. doi:10.1016/j.fct.2011.07.058.

. Chakraborty M, Bhattacharjee A, Kamath JV. Cardioprotective effect of curcumin and piperine combination against cyclophosphamide-induced cardiotoxicity. Indian J Pharmacol. 2017;49(1):65. doi:10.4103/0253-7613.201015.

. Badawi AA, Abd el-aziz N, Amin MM, Sheta NM. Topical Benzophenone-3 microemulsion-based gels: preparation, evaluation and determination of microbiological UV blocking activity. Int J Pharm Shota Sci. 2014;6(8):562-70.

. Subongkot T, Ngawhirunpat T. Development of a novel microemulsion for oral absorption enhancement of all-trans retinoic acid. International Journal of Nanomedicine. 2017;12:5585. doi: 10.2147/IJN.S142503

Reddy ASK., Matte KV, Kosuru R. (2021). Formulation, optimization, and in vitro characterization of dasatinib loaded polymeric nanocarriers to extend the release of the model drug. Int J Appl Pharm. .2021;13(5), 318–330. doi: 10.22159/ijap.2021v13i5.41995’

. Olsen DS, Lee M, Turley AP. Assessment of test method variables for in vitro skin irritation testing of medical device extracts. Toxicol in Vitro. 2018 Aug 1; 50:426-32. doi: 10.1016/j.tiv.2017.11.012.

. Köllner S, Nardin I, Markt R, Griesser J, Prüfert F, Bernkop-Schnürch A. Self-emulsifying drug delivery systems: Design of a novel vaginal delivery system for curcumin. Eur J Pharm Biopharm. 2017 Jun 1; 115:268-75. doi: 10.1016/j.ejpb.2017.03.012.

. Blake-Haskins JC, Scala D, Rhein LD, Robbins CR. Predicting surfactant irritation from the swelling response of a collagen film. J Soc Cosmet Chem. 1986;37(4):199-210.

. Sharma, C, Thakur N, Kaur B, Goswami M. Investigating effects of permeation enhancers on percutaneous absorption of loxapine succinate. Int J Appl Pharm 2022;14(4), 158–162. doi: 10.22159/ijap.2022v14i4.44896

. Kelchen MN, Brogden NK. In vitro skin retention and drug permeation through intact and microneedle pretreated skin after application of propranolol loaded microemulsions. Pharm Res. 2018 Dec;35(12):1-2. doi: 10.1007/s11095-018-2495-1

. Synmon B, Roy S, Majee SB, Paul M, Dasgupta S. Erdosteine: an effective antioxidant for protecting complete freund’s adjuvant induced arthritis in rats. Asian J Pharm Clin Res. 2021;14(10):71-5. doi: 0.22159/ajpcr.2021.v14i10.42365

. Date AA, Patravale VB. Microemulsions: applications in transdermal and dermal delivery. Crit Rev Ther Drug Carrier Syst. 2007;24(6) 547–596. doi: 10.1615/critrevtherdrugcarriersyst.v24.i6.20.

. Baum L, Ng A. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models. J Alzheimers Dis. 2004 Jan 1;6(4):367-77. doi: 10.3233/jad-2004-6403.

. Chen X, Zou LQ, Niu J, Liu W, Peng SF, Liu CM. The stability, sustained release and cellular antioxidant activity of curcumin nanoliposomes. Molecules. 2015 Aug 5;20(8):14293-311. doi: 10.3390/molecules200814293.

. Arianto A, Amelia R, Bangun H. The effect of tween 80, palm kernel oil, and its conversion product on in vitro penetration enhancement of indomethacin through rabbit skin. Asian J Pharm Clin Res.10 (7), 2017 July, 284-8. doi: 10.22159/ajpcr.2017.v10i7.18608.

. Yemparala V, Damre AA, Manohar V, Singh KS, Mahajan GB, Sawant SN, Deokule T, Sivaramakrishnan H. Effect of the excipient concentration on the pharmacokinetics of PM181104, a novel antimicrobial thiazolyl cyclic peptide antibiotic, following intravenous administration to mice. Results Pharma Sci. 2014 Jan 1; 4:34-41. doi: 10.1016/j.rinphs.2014.09.001.

. Kronberg B, Dahlman A, Carlfors J, Karlsson J, Artursson P. Preparation and evaluation of sterically stabilized liposomes: colloidal stability, serum stability, macrophage uptake, and toxicity. J Pharm Sci. 1990 Aug 1;79(8):667-71. doi: 10.1002/jps.2600790803.

. Oliveira MB, Calixto G, Graminha M, Cerecetto H, González M, Chorilli M. Development, characterization, and in vitro biological performance of fluconazole-loaded microemulsions for the topical treatment of cutaneous leishmaniasis. Biomed Res. Int. 2015 Jan 12;2015. doi: 10.1155/2015/396894.

. Date AA, Nagarsenker MS. Design and evaluation of microemulsions for improved parenteral delivery of propofol. AAPS Pharm SciTech. 2008 Mar;9(1):138-45. doi: 10.1208/s12249-007-9023-7.

. Rogiers V, Balls M, Basketter D, Berardesca E, Edwards C, Elsner P, Ennen J, Lévêque JL, Lóden M, Masson P, Parra J. The Potential Use of Non-invasive Methods in the Safety Assessment of Cosmetic Products: The Report and Recommendations of an ECVAM/EEMCO Workshop (ECVAM Workshop 36)–. Alternatives to Laboratory Animals. 1999 Jul;27(4):515-37.

. Morrison Jr BM, Paye M. A comparison of three in vitro screening tests with an in vivo clinical test to evaluate the irritation potential of. J. Soc. Cosmet. Chem. 1995 Nov;46:291-9.

. Herkenne C, Naik A, Kalia YN, Hadgraft J, Guy RH. Pig ear skin ex vivo as a model for in vivo dermatopharmacokinetic studies in man. Pharm Res. 2006 Aug;23(8):1850-6. doi:10.1007/s11095-006-9011-8.

. Jacobi U, Kaiser M, Toll R, Mangelsdorf S, Audring H, Otberg N, Sterry W, Lademann J. Porcine ear skin: an in vitro model for human skin. Skin Res Technol. 2007 Feb;13(1):19-24. doi: 10.1111/j.1600-0846.2006.00179.x.

. Martins CA, Leyhausen G, Volk J, Geurtsen W. Curcumin in combination with piperine suppresses osteoclastogenesis in vitro. J Endod. 2015 Oct 1;41(10):1638-45.

. Hu G, Guo M, Xu J, Wu F, Fan J, Huang Q, Yang G, Lv Z, Wang X, Jin Y. Nanoparticles targeting macrophages as potential clinical therapeutic agents against cancer and inflammation. Front immunol. 2019 Aug 21;10:1998. doi: 10.3389/fimmu.2019.01998.

. Song Y, Huang Y, Zhou F, Ding J, Zhou W. Macrophage-targeted nanomedicine for chronic diseases immunotherapy. Chin Chem Lett. 2021 Aug 22. doi: 10.1016/j.cclet.2021.08.090.

. Zhang Z, Feng SS. The drug encapsulation efficiency, in vitro drug release, cellular uptake and cytotoxicity of paclitaxel-loaded poly (lactide)–tocopheryl polyethylene glycol succinate nanoparticles. Biomaterials. 2006 Jul 1;27(21):4025-33. doi: 10.1016/j.biomaterials.2006.03.006.

. Li B, Hu Y, Zhao Y, Cheng M, Qin H, Cheng T, Wang Q, Peng X, Zhang X. Curcumin attenuates titanium particle-induced inflammation by regulating macrophage polarization in vitro and in vivo. Front immunol. 2017 Jan 31;8:55. doi: 10.3389/fimmu.2017.00055.

. Pearson CM, Wood FD. Studies of polyarthritis and other lesions induced in rats by injection of mycobacterial adjuvant. I. General clinical and pathologic characteristics and some modifying factors. Arthritis Rheum. 1959 Oct;2(5):440-59.

. Mowat AG. Hematologic abnormalities in rheumatoid arthritis. Semin Arthritis Rheum. 1972 Dec 1 (Vol. 1, No. 3, pp. 195-219). WB Saunders. doi: 10.1016/0049-0172(72)90001-7.

. Niino-Nanke Y, Akama H, Hara M, Kashiwazaki S. Alkaline phosphatase (ALP) activity in rheumatoid arthritis (RA): its clinical significance and synthesis of ALP in RA synovium. Ryumachi. 1998 Aug 1;38(4):581-8.

. Tawfeeq HR, Ali J. Assessment of Liver Enzymes Activity in Patients with Rheumatoid Arthritis in Nineveh province. Tikrit J. Pharmaceut. Sci. 2012;8:138-44.

. Barik A, Mishra B, Shen L, Mohan H, Kadam RM, Dutta S, Zhang HY, Priyadarsini KI. Evaluation of a new copper (II)-curcumin complex as superoxide dismutase mimic and its free radical reactions. Free Radic Biol Med. 2005;39(6):811–822. doi: 10.1016/j.freeradbiomed.2005.05.005.

. Banford JC, Brown DH, Hazelton RA, McNeil CJ, Sturrock RD, Smith WE. Serum copper and erythrocyte superoxide dismutase in rheumatoid arthritis. Ann Rheum Dis. 1982 Oct 1;41(5):458-62. doi: 10.1136/ard.41.5.458.

. Henrotin Y, Kurz B. Antioxidant to treat osteoarthritis: dream or reality? Curr Drug Targets. 2007 Feb 1;8(2):347-57. doi: 10.1016/j.joen.2015.05.009.



How to Cite




Original Article(s)