ADVANCES IN AMELIORATING RHEUMATOID ARTHRITIS BY ANDROGRAPHOLIDE ETHOSOME-BASED GEL: PHARMACOKINETIC AND ACTIVITY STUDY IN RATS

Authors

  • KARTIKA FIDI ASTUTI Laboratory of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Indonesia, Depok, West Java, 16424, Indonesia https://orcid.org/0000-0001-8151-7252
  • SILVIA SURINI Laboratory of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Indonesia, Depok, West Java, 16424, Indonesia https://orcid.org/0000-0003-1211-9706
  • ANTON BAHTIAR Laboratory of Pharmacology and Toxicology, Faculty of Pharmacy, Universitas Indonesia, Depok, West Java, 16424, Indonesia

DOI:

https://doi.org/10.22159/ijap.2023v15i1.46350

Keywords:

Andrographolide, ethosomes, transdermal, pharmacokinetic study, rheumatoid arthritis

Abstract

Objective: Andrographolide is the primary active constituent that was isolated from Andrographis paniculata and has been adopted to treat rheumatoid arthritis. Several studies revealed that it has poor oral bioavailability and skin penetration, which can be solved through the transdermal delivery of ethosomes. Therefore, this study aims to determine the pharmacokinetic profiles, relative bioavailability, and efficacy of andrographolide in the form of transdermal ethosomal gel in rheumatoid arthritis (RA) animal models.

Methods: Andrographolide was processed into ethosomes using the thin layer hydration-sonication technique. Its physical properties were then characterized, including particle size, polydispersity index, zeta potential, and entrapment efficiency, before it was incorporated into a gel dosage form. An in vivo study was also carried out on male Sprague Dawley rats. Subsequently, two gels, namely ethosomal and non-ethosomal, as well as an oral solution were prepared for the pharmacokinetic study. For the anti-rheumatic activity, thirty-six male rats were divided into three controls as well as three treatment groups, which were treated with 25, 50, and 100 mg/kg of andrographolide. During the induction and post-treatment phases, clinical manifestations of arthritis were thoroughly monitored.

Results: The andrographolide ethosomes were successfully prepared with particle sizes of 76.35±0.74 nm and entrapment efficiency of 97.87±0.23%. Based on the pharmacokinetic studies, the Cmax obtained for ethosomal and non-ethosomal gel, as well as oral suspension, were 53.07±4.73, 27.34±1.48, and 11.72±0.74 μg/mL with AUC0-∞ of 152.10±16.53, 77.15±12.28, and 23.20±3.46 μg.h/mL, respectively. Furthermore, the relative bioavailability recorded for the preparations was 655.60%. Anti-rheumatic activity investigations revealed that the 50 and 100 mg/kg ethosomal gels reduced oedema volume closely with 0.135 mg methotrexate subcutaneously.

Conclusions: The ethosomal gel enhanced Cmax, AUC0-∞, and the relative bioavailability of andrographolide. Furthermore, it reduced oedema volume, ankle joint diameter, and arthritic scores in RA rats.

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References

. Pawar A, Rajalakshmi S, Mehta P, Shaikh K, Bothiraja C. Strategies for formulation development of andrographolide. RSC Adv. 2016;6(73):69282–300.

. Tan WSD, Liao W, Zhou S, Wong WSF. Is there a future for andrographolide to be an anti-inflammatory drug? Deciphering its major mechanisms of action. Biochem. Pharmacol. [Internet]. 2017 [cited 2021 Jun 7];139:71–81. Available from: http://dx.doi.org/10.1016/j.bcp.2017.03.024

. Burgos RA, Hancke JL, Bertoglio JC, Aguirre V, Arriagada S, Calvo M, et al. Efficacy of an Andrographis paniculata composition for the relief of rheumatoid arthritis symptoms: A prospective randomized placebo-controlled trial. Clin. Rheumatol. 2009;28(8):931–46.

. Li Z zhong, Tan J peng, Wang L li, Li Q hua. Andrographolide Benefits Rheumatoid Arthritis via Inhibiting MAPK Pathways. Inflammation. 2017;40(5):1599–605.

. Yan J, Chen Y, He C, Yang ZZ, Lü C, Chen XS. Andrographolide induces cell cycle arrest and apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes. Cell. Biol. Toxicol. 2012; 28(1):47–56.

. Chellampillai B, Pawar AP. Improved bioavailability of orally administered andrographolide from pH-sensitive nanoparticles. Eur. J. Drug. Metab. Pharmacokinet. 2011;35(3–4):123–9.

. Ye L, Wang T, Tang L, Liu W, Yang Z, Zhou J et al. Poor Oral Bioavailability of a Promising Anticancer Agent Andrographolide is Due to Extensive Metabolism and Efflux by P-Glycoprotein. J. Pharm. Sci. [Internet]. 2011 [cited 2021 May 24];17:100–5007. Available from: http://onlinelibrary.wiley.com/doi/10.1002/jps.22007/full%5Cnhttp://www.ncbi.nlm.nih.gov/pubmed/19967780

. Ramadani AP, Syukri Y, Hasanah E, Syahyeri AW. Acute oral toxicity evaluation of andrographolide self-nanoemulsifying drug delivery system (SNEDDS) formulation. J. Pharm. Bioallied. Sci. 2021;13(2):199–204.

. Surini S, Nastiti PD, Putri AR, Putri KSS. Formulation of andrographolide transfersomes gel for transdermal delivery: A preliminary study. Int. J. Appl. Pharm. 2020 Mar 1;12(Special Issue 1):187–91.

. Mohammed Magdy I, Makky Amna MA, Abdellatif Menna M. Formulation and characterization of ethosomes bearing vancomycin hydrochloride for transdermal delivery. Int. J. Pharm. Pharm. Sci. 2014;6(11):190–194.

. Hashimoto N, Nakamichi N, Yamazaki E, Oikawa M, Masuo Y, Schinkel AH, et al. P-Glycoprotein in skin contributes to transdermal absorption of topical corticosteroids. Int. J. Pharm. [Internet]. 2017 [cited 2021 Apr 2];521(1–2):365–73. Available from: http://dx.doi.org/10.1016/j.ijpharm.2017.02.064

. Yan N, Tang Z, Xu Y, Li X, Wang Q. Pharmacokinetic Study of Ferulic Acid Following Transdermal or Intragastric Administration in Rats. AAPS PharmSciTech. 2020;21(5):1–7.

. Barry BW. Novel mechanisms and devices to enable successful transdermal drug delivery. Eur. J. Pharm. Sci. 2001;14(2):101–14.

. Leonyza A, Surini S. Optimization of sodium deoxycholate-based transfersomes for percutaneous delivery of peptides and proteins. Int. J. Appl. Pharm. 2019;11(5):329–332.

. Jalajakshi MN, Chandrakala V, Srinivasan S. An overview : recent development in transdermal drug delivery. Int. J. Pharm. Pharm. Sci. 2022;14(10):1–9.

. Touitou E, Dayan N, Bergelson L, Godin B, Eliaz M. Ethosomes — novel vesicular carriers for enhanced delivery: characterization and skin penetration properties. J. Controlled Release. [Internet]. 2000 [cited 2021 May 1];65(3):403–18. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0168365999002229

. Martihandini N, Surini S, Bahtiar A. Andrographolide-loaded ethosomal gel for transdermal application: Formulation and in vitro penetration study. Pharm. Sci. 2021;28(3).

. Syukri Y, Widarno I. S, Adewiyah A, Wibowo A, Martien R, Lukitaningsih E, et al. Development and Validation of a Simple HPLC-UV Method for The Quantification of Andrographolide In Rabbit Plasma. Drug Delivery Technol. [Internet]. 2017 [cited 2021 Apr 2];7(1):22–6. Available from: https://ijddt.com/index.php/IJDDT/article/view/87.

. Panossian A, Hovhannisyan A, Mamikonyan G, Abrahamian H, Hambardzumyan E, Gabrielian E, et al. Pharmacokinetic and oral bioavailability of andrographolide from Andrographis paniculata fixed combination Kan Jang in rats and human. Phytomedicine. 2000;7(5):351–64.

. Li X, Yuan K, Zhu Q, Lu Q, Jiang H, Zhu M, et al. Andrographolide ameliorates rheumatoid arthritis by regulating the apoptosis–NETosis balance of neutrophils. Int. J. Mol. Sci. 2019;20(20).

. Gupta S, Mishra KP, Kumar B, Singh SB, Ganju L. Andrographolide attenuates complete freund’s adjuvant induced arthritis via suppression of inflammatory mediators and pro-inflammatory cytokines. J. Ethnopharmacol. [Internet]. 2020 [cited 2021 May 4];261:113022. Available from: https://doi.org/10.1016/j.jep.2020.113022

. Smit HF, Labadie RP, Dijk H van. Picrorhiza scrophulariiflora, from traditional use to immunomodulatory activity. Universiteit Utrecht, Faculteit Farmacie [Internet]. 2000 [cited 2021 Jun 2];(July). Available from: https://dspace.library.uu.nl/bitstream/handle/1874/321/chapter1.pdf;jsessionid=8858577B55CE7052C0F1775466F087FA?sequence=23

. Chourasia MK, Kang L, Chan SY. Nanosized ethosomes bearing ketoprofen for improved transdermal delivery. Results Pharma Sci. 2011;1(1):60–7.

. Malvern. Zetasizer Nano User Manual. Worcestershire, UK: Malvern Instruments Ltd.; 2013. 250 p.

. Pathan IB, Jaware BP, Shelke S, Ambekar W. Curcumin loaded ethosomes for transdermal application: Formulation, optimization, in-vitro and in-vivo study. J. Drug. Deliv. Sci. Technol. [Internet]. 2018 [cited 2021 May 5];44:49–57. Available from: https://doi.org/10.1016/j.jddst.2017.11.005.

. Surini S, Arnedy AR, Iswandana R. Development of ethosome containing bitter melon (Momordica charantia Linn.) fruit fraction and in vitro skin penetration. Pharmacogn J.2019;11(6):1242-1251.

. Surini S, Leonyza A, Suh CW. Formulation and in vitro penetration of recombinant human epidermal growth factor-loaded transfersomal emulgel. Adv. Pharm. Bull. 2020;10(4):586-594.

. Oktay AN, Ilbasmis-Tamer S, Han S, Uludag O, Celebi N. Preparation and in vitro / in vivo evaluation of flurbiprofen nanosuspension-based gel for dermal application. Eur. J. Pharm. Sci. 2020;155:105548.

. Bast Jr R, Corce C, Hait W, Hong W, et al. Holland-Frei Cancer Medicine 9th Edition [Preprint]. 2016 [cited 2021 May 2]. Available from: http://support.wiley.com

. Katzung BG, Masters SB, Trevor AJ. Basic & clinical pharmacology. McGraw-Hill Medical; 2009. 1218 p.

. Pirvu C, Hlevca C, Ortan A, Prisada R. Elastic vesicles as drug carriers through the skin View project [Internet]. Farmacia. 2010 [cited 2021 May 4];58(2):128-135. Available from: https://www.researchgate.net/publication/268350119.

. Morsi NM, Aboelwafa AA, Dawoud MHS. Improved bioavailability of timolol maleate via transdermal transfersomal gel: Statistical optimization, characterization, and pharmacokinetic assessment. J. Adv. Res. 2016;7(5):691–701.

. Fan J, de Lannoy IAM. Pharmacokinetics. Biochem. Pharmacol. 2014;87(1):93–120.

. Sou K. Electrostatics of carboxylated anionic vesicles for improving entrapment capacity. Chem. Phys. Lipids. 2011;164(3):211–5.

. Padmasri B, Nagaraju R. Formulation and Evaluation of Novel In-Situ Gel System in The Management of Rheumatoid Arthritis. Int. J. Appl. Pharm. 2022 Sep 1;14(5):62–8.

. Patil R, Jain V. Andrographolide: A review of analytical methods. J. Chromatogr. Sci. 2021;59(2):191–203.

. Xia YF, Ye BQ, Li YD, Wang JG, He XJ, Lin X, et al. Andrographolide Attenuates Inflammation by Inhibition of NF-κB Activation through Covalent Modification of Reduced Cysteine 62 of p50. J. Immunol. 2004;173(6):4207–17.

. Schinnerling K, Rosas C, Soto L, Thomas R, Aguillón JC. Humanized mouse models of rheumatoid arthritis for studies on immunopathogenesis and preclinical testing of cell-based therapies. Front. Immunol. 2019;203(10).

. Pal R, Chaudhary MJ, Tiwari PC, Nath R, Pant KK. Pharmacological and biochemical studies on protective effects of mangiferin and its interaction with nitric oxide (NO) modulators in adjuvant-induced changes in arthritic parameters, inflammatory, and oxidative biomarkers in rats. Inflammopharmacology. 2018;27(2):291–9.

Published

21-11-2022

How to Cite

ASTUTI, K. F., SURINI, S., & BAHTIAR, A. (2022). ADVANCES IN AMELIORATING RHEUMATOID ARTHRITIS BY ANDROGRAPHOLIDE ETHOSOME-BASED GEL: PHARMACOKINETIC AND ACTIVITY STUDY IN RATS. International Journal of Applied Pharmaceutics, 15(1). https://doi.org/10.22159/ijap.2023v15i1.46350

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