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Formulation, Characterization, and Optimization of Transethosomes for Enhanced Transdermal Delivery of Methotrexate

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Abstract

Purpose

Methotrexate (MTX) is an antineoplastic drug used in the treatment of rheumatoid arthritis (RA). Given that it is a class IV drug with low permeability and solubility, this study aims to improve MTX skin permeation by loading it in transethosomes (TEs) and casting a transethosomal patch that allows for dose quantification to mitigate toxicity.

Methods

To accomplish this goal, MTX transethosomes (TEs) were developed using the thin film hydration technique and optimized using the Box-Behnken design (BBD) with soya phosphatidylcholine 50, Tween 80, and ethanol as independent variables using the desirability function. Furthermore, zeta potential (ZP) analysis and high-resolution transmission electron microscopy (HR-TEM) were used to confirm the stability and surface morphology of TEs. A transdermal patch was also designed and evaluated from the optimized TE (OPTZ TEs) batch using a solvent casting method with hydroxypropyl methylcellulose (HPMC) as the polymer, dimethyl sulfoxide (DMSO) as a permeation enhancer, and polyethylene glycol (PEG 400) as the plasticizer. Furthermore, ex vivo skin permeation and deposition through rat skin proved that the TE patch had better drug permeation and retention within the skin layers.

Results

The highest desirability batch had 92.19 ± 3.826 nm vesicle size, 0.35 ± 0.062 PDI, 74.05 ± 5.157% EE and 62.75 ± 4.448% Q8h which were within the predicted results. Furthermore, ZP was found to be more than − 30 mV, and HR-TEM results proved that the TE vesicles were spherical. The results of the evaluation parameters such as weight variation, folding endurance, and thickness were 0.07 ± 0.01 g, 82.3 ± 1.52 folds, and 0.93 ± 0.01, respectively, and were well within the limits. The TE patch incorporated more than 90% of the drug confirmed by the drug content analysis which allowed ex vivo permeation for almost 24 h providing a sustained release action with a permeation flux of 19 ± 1.08 and an enhancement ratio of 3.68 when compared to the MTX solution.

Conclusion

This study suggests that MTX-loaded transethosomal patch not only enhanced the skin permeation but also provided a 24-h release profile and reduced its toxicity.

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Abbreviations

MTX:

Methotrexate

RA:

Rheumatoid arthritis

HLA:

Human leucocyte antigen

TDDS:

Transdermal delivery system

TEs:

Transethosome

SPC 50:

Soya phosphatidylcholine 50

BBD:

Box-Behnken design

FTIR:

Fourier transform infrared spectroscopy

ZP:

Zeta potential

% EE:

% Entrapment efficiency

PDI:

Polydispersity index

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Acknowledgements

We gratefully acknowledge Neon Pharmaceuticals Mumbai and Lipidome Lifesciences, Ahmedabad for providing gift samples of MTX and SPC 50, respectively. We would also like to acknowledge IIT Bombay for performing the HR-TEM analysis of the sample along with Dr. Prabhakar Kore Basic Science Research Center (BSRC) and Department of Pharmaceutical Quality Assurance, KLE College of Pharmacy, KLE Academy of Higher Education and Research (KAHER), and Belagavi for providing the facility to perform the research study. We would also like to extend our acknowledgment to Mr. Mote G.D from Annasaheb Dange College of Pharmacy, and Ashta for helping in FTIR and particle size analysis along with Dr. U.B. Bolmal from Rani Channamma University, for his invaluable guidance and help in major aspects of this research.

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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  1. Department of Pharmaceutical Quality Assurance, KLE College of Pharmacy, KLE Academy of Higher Education and Research (KAHER), Belagavi, 590010, Karnataka, India

    Priyanka J. Veer & Vinayak S. Mastiholimath

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  1. Priyanka J. Veer
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PJV: conceptualization, visualization, data curation, formal analysis, investigation, writing-original draft. VM: supervision, guidance, mentoring, and review.

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Correspondence to Priyanka J. Veer.

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Veer, P.J., Mastiholimath, V.S. Formulation, Characterization, and Optimization of Transethosomes for Enhanced Transdermal Delivery of Methotrexate. J Pharm Innov 18, 2385–2401 (2023). https://doi.org/10.1007/s12247-023-09799-2

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