TRANSETHOSOMES FOR ENHANCED TRANSDERMAL DELIVERY OF METHOTREXATE AGAINST RHEUMATOID ARTHRITIS: FORMULATION, OPTIMISATION AND CHARACTERISATION

POOJARI PRATIKSHA N.; SNEH PRIYA; SANJANA; PRASANNA SHAMA KHANDIGE

doi:10.22159/ijap.2024v16i6.51772

Authors

POOJARI PRATIKSHA N. Nitte (Deemed to be University), NGSM Institute of Pharmaceutical Sciences (NGSMIPS), Department of Pharmaceutics, Mangalore, India https://orcid.org/0009-0005-7714-7072
SNEH PRIYA Nitte (Deemed to be University), NGSM Institute of Pharmaceutical Sciences (NGSMIPS), Department of Pharmaceutics, Mangalore, India https://orcid.org/0000-0002-4110-8726
SANJANA Nitte (Deemed to be University), NGSM Institute of Pharmaceutical Sciences (NGSMIPS), Department of Pharmaceutics, Mangalore, India
PRASANNA SHAMA KHANDIGE Nitte (Deemed to be University), NGSM Institute of Pharmaceutical Sciences (NGSMIPS), Department of Pharmaceutics, Mangalore, India https://orcid.org/0000-0002-4698-9761

DOI:

https://doi.org/10.22159/ijap.2024v16i6.51772

Keywords:

Methotrexate, Rheumatoid arthritis, Transethosomes, Box behnken design, Film-forming gel

Abstract

Objective: The study aimed to develop and optimise Methotrexate (MTX)-loaded Transethosomal Film-Forming Gel (TE FFG) for transdermal delivery to treat rheumatoid arthritis while alleviating the side associated with oral administration.

Methods: The Transethosomes (TE) were prepared using the thin film hydration technique and incorporated into an FFG using chitosan. The Box-Behnken Design method was used to analyse the influence of independent variables such as the concentration of soya lecithin, surfactant, and ethanol on parameters including vesicle size, PDI (Polydispersity Index), zeta potential, and entrapment efficiency. The optimised transethosomal suspension was incorporated into the FFG using 3% chitosan and other excipients. In vitro drug release and ex vivo skin permeation of FFG were performed using Franz diffusion cells.

Results: The vesicle size, PDI, zeta potential and entrapment efficiency of the optimised formulation of TE were 110.3 nm, 0.352, -14.4 mV and 49.36%, respectively. The Transmission Electron Microscopy (TEM) image showed that the vesicles were uniform and spherical. The in vitro drug release study was higher for Conventional (CL) FFG) than TE FFG and the drug release mechanism was fitted into the Higuchi model. The permeation was higher for TE FFG, with the steady-state flux being 1.55 times greater than the CL FFG. The skin irritation test on Wistar rats revealed no indication of irritation on the skin. The histopathology examination showed a significant reduction in the inflammatory cells in the treated group

Conclusion: Therefore, the results concluded that the formulated MTX-loaded TE FFG could be a potentially promising substitute for the oral delivery of methotrexate

Downloads

Download data is not yet available.

References

Radu AF, Bungau SG. Management of rheumatoid arthritis: an overview. Cells. 2021 Oct 23;10(11):2857.

Ahuja NK, Rajawat JS. Novel nano therapeutic materials for the effective treatment of rheumatoid arthritis-recent insights. Int J App Pharm. 2021;13(6):31-40. https://doi.org/10.22159/ijap.2021v13i6.42912

Zhao Z, Hua Z, Luo X, Li Y, Yu L, Li M, et al. Application and pharmacological mechanism of methotrexate in rheumatoid arthritis. Biomed. Pharmacother. 2022 Jun 1;150:113074.

Vezmar S, Becker A, Bode U, Jaehde U. Biochemical and clinical aspects of methotrexate neurotoxicity. Chemotherapy. 2003 May 7;49(1-2):92-104.

Murakami T, Mori N. Involvement of multiple transporters-mediated transports in mizoribine and methotrexate pharmacokinetics. Pharmaceuticals. 2012 Aug 10;5(8):802-36.

Wang X, Yan H. Methotrexate-loaded porous polymeric adsorbents as oral sustained release formulations. Mater. Sci.Eng.C. 2017 Sep 1;78:598–602.

Saheli D, Sharadha M, Venkatesh MP, Subhashree S, Tripathy J, Dv Gowda. Formulation and evaluation of topical nanoemulgel of methotrexate for rheumatoid arthritis. Int J App Pharm. 2021;13(5):351-7. https://doi.org/10.22159/ijap.2021v13i5.41026

Mazzaferro S, Bouchemal K, Ponchel G. Oral delivery of anticancer drugs I: General considerations. Drug Discov. Today. 2013 Jan 1;18(1-2):25-34.

Prasad R, Koul V. Transdermal delivery of methotrexate: Past, present and future prospects. Vol. 3, Ther. Deliv. 2012 Mar;3(3):315-25.

Jalajakshi MN, Chandrakala V, Srinivasan S. An overview: recent development in transdermal drug delivery. Int. J. Pharm. Pharm. Sci. 2022;14(10):1–9. Available from: http://dx.doi.org/10.22159/ijpps.2022v14i10.45471

Srinivas PS, Babu DR. Formulation and evaluation of parenteral methotrexate nanoliposomes. Int. J. Pharm. Pharm. Sci. 2014;6:295-300.

Ferrara F, Benedusi M, Cervellati F, Sguizzato M, Montesi L, Bondi A, et al. Dimethyl Fumarate-Loaded Transethosomes: A Formulative Study and Preliminary Ex Vivo and In Vivo Evaluation. Int J Mol Sci. 2022 Aug 6;23(15):8756.

Abdallah MH, Elghamry HA, Khalifa NE, Khojali WMA, Khafagy ES, Shawky S, et al. Development and Optimisation of Erythromycin Loaded Transethosomes Cinnamon Oil Based Emulgel for Antimicrobial Efficiency. Gels. 2023 Feb 6;9(2):137.

Albash R, Abdelbary AA, Refai H, El-Nabarawi MA. Use of transethosomes for enhancing the transdermal delivery of olmesartan medoxomil: In vitro, ex vivo, and in vivo evaluation. Int J Nanomedicine. 2019;15:1953–68.

Kaur PR, Garg VA, Bawa PA, Sharma RO, Singh SK, Kumar BI, Gulati MO, Pandey NK, Narang RA, Wadhwa SH, MOHANTA S. Formulation, systematic optimisation, in vitro, ex vivo and stability assessment of transethosome based gel of curcumin. Asian J Pharm Clin Res. 2018;11(2):41-7. https://doi.org/10.22159/ajpcr.2018.v11s2.28563

Aprianti I, Iskandarsyah, Setiawan H. Diflunisal transethosomes for transdermal delivery: formulation and characterisation. Int J App Pharm. 2023;15(3):61–66. https://doi.org/10.22159/ijap.2023v15i3.47691

Ascenso A, Raposo S, Batista C, Cardoso P, Mendes T, Praça FG, et al. Development, characterisation, and skin delivery studies of related ultradeformable vesicles: Transfersomes, ethosomes, and transethosomes. Int J Nanomedicine. 2015 Sep 18;10:5837–51.

Politis SN, Colombo P, Colombo G, Rekkas DM. Design of experiments (DoE) in pharmaceutical development. Drug Dev.Ind.Pharm. 2017 Jun 3;43(6):889-901.

Vanaja K, Rani RHS. Design of experiments: Concept and applications of plackett burman design. Clin.Res.Regul.Aff. 2007 Jan 1;24(1):1-23.

Decaestecker TN, Lambert WE, Van Peteghem CH, Deforce D, Van Bocxlaer JF. Optimisation of solid-phase extraction for a liquid chromatographic-tandem mass spectrometric general unknown screening procedure by means of computational techniques. J.Chromatogr.A. 2004 Nov 12;1056(1-2):57-65

Fukuda IM, Pinto CFF, Moreira CDS, Saviano AM, Lourenço FR. Design of experiments (DoE) applied to pharmaceutical and analytical quality by design (QbD). Braz.J.Pharm.Sci. 2018 Nov 8;54.

Zeb A, Qureshi OS, Kim HS, Cha JH, Kim HS, Kim JK. Improved skin permeation of methotrexate via nanosized ultradeformable liposomes. Int J Nanomedicine. 2016 Aug 8;11:3813–24.

Nayak D, Tawale RM, Aranjani JM, Tippavajhala VK. Formulation, Optimisation and Evaluation of Novel Ultra-deformable Vesicular Drug Delivery System for an Anti-fungal Drug. AAPS PharmSciTech. 2020 Jul 1;21(5).

Guimarães D, Noro J, Loureiro A, Lager F, Renault G, Cavaco-Paulo A, et al. Increased encapsulation efficiency of methotrexate in liposomes for rheumatoid arthritis therapy. Biomedicines. 2020 Dec 1;8(12):1–15.

Habib BA, Sayed S, Elsayed GM. Enhanced transdermal delivery of ondansetron using nanovesicular systems: Fabrication, characterisation, optimisation and ex-vivo permeation study-Box-Cox transformation practical example. Eur.J.Pharma.Sci. 2018 Mar 30;115:352–61.

Hassan AS, Hofni A, Abourehab MAS, Abdel-Rahman IAM. Ginger Extract–Loaded Transethosomes for Effective Transdermal Permeation and Anti-Inflammation in Rat Model. Int J Nanomedicine. 2023;18:1259–80.

Rady M, Gomaa I, Afifi N, Abdel-Kader M. Dermal delivery of Fe-chlorophyllin via ultradeformable nanovesicles for photodynamic therapy in melanoma animal model. Int J Pharm. 2018 Sep 5;548(1):480–90.

Khasraghi AH, Vartanian L, Thomas LM. Preparation and evaluation of lornoxicam film-forming gel. Drug Invention Today. 2019 Aug 1;11(8):1906-13.

Shetty S, Jose J, Kumar L, Charyulu RN. Novel ethosomal gel of clove oil for the treatment of cutaneous candidiasis. J Cosmet Dermatol. 2019 Jun 1;18(3):862–9.

Hegdekar NY, Priya S, Shetty SS, Jyothi D. Formulation and Evaluation of Niosomal Gel Loaded with Asparagus racemosus Extract for Anti-inflammatory Activity. Indian J.Pharm.Educ. 2023 Jan 1;57(1):s63–74.

Avasatthi V, Pawar H, Dora CP, Bansod P, Gill MS, Suresh S. A novel nanogel formulation of methotrexate for topical treatment of psoriasis: optimisation, in vitro and in vivo evaluation. Pharm Dev Technol. 2016 Jul 3;21(5):554–62

Maru AD, Lahoti SR. Formulation and evaluation of moisturising cream containing sunflower wax. Int J Pharm Pharm Sci. 2018 Nov 1;10(11):54-9.

Raychaudhuri R, Pandey A, Das S, Nannuri SH, Joseph A, George SD, et al. Nanoparticle impregnated self-supporting protein gel for enhanced reduction in oxidative stress: A molecular dynamics insight for lactoferrin-polyphenol interaction. Int J Biol Macromol. 2021 Oct 31;189:100–13.

Jain A, Jain SK. In vitro release kinetics model fitting of liposomes: An insight. Chem.Phys.Lipids. 2016 Dec 1;201:28-40.

Kotian V, Koland M, Mutalik S. Nanocrystal-Based Topical Gels for Improving Wound Healing Efficacy of Curcumin. Crystals. 2022 Nov 1;12(11):1565

Parhi R, Panchamukhi T. RSM-Based Design and Optimization of Transdermal Film of Ondansetron HCl. J Pharm Innov. 2020 Mar 1;15(1):94–109.

Ghosh S, Mukherjee B, Chaudhuri S, Roy T, Mukherjee A, Sengupta S. Methotrexate Aspasomes Against Rheumatoid Arthritis: Optimised Hydrogel Loaded Liposomal Formulation with In Vivo Evaluation in Wistar Rats. AAPS PharmSciTech. 2018 Apr 1;19(3):1320–36.

Subongkot T, Duangjit S, Rojanarata T, Opanasopit P, Ngawhirunpat T. Ultradeformable liposomes with terpenes for delivery of hydrophilic compound. J Liposome Res. 2012 Sep;22(3):254–62.

Zafar A, Alruwaili NK, Imam SS, Yasir M, Alsaidan OA, Alquraini A, et al. Development and Optimisation of Nanolipid-Based Formulation of Diclofenac Sodium: In Vitro Characterization and Preclinical Evaluation. Pharmaceutics. 2022 Mar 1;14(3).

Zhao L, Temelli F, Curtis JM, Chen L. Preparation of liposomes using supercritical carbon dioxide technology: Effects of phospholipids and sterols. Food Res.Int. 2015 Nov 1;77:63–72.

Khalid H, Batool S, Din F ud, Khan S, Khan GM. Macrophage targeting of nitazoxanide-loaded transethosomal gel in cutaneous leishmaniasis. R Soc Open Sci. 2022 Oct 5;9(10).

El-Menshawe SF, Ali AA, Halawa AA, Srag El-Din ASG. A novel transdermal nanoethosomal gel of betahistine dihydrochloride for weight gain control: In-vitro and in-vivo characterisation. Drug Des Devel Ther. 2017 Nov 28;11:3377–88.