Metformin HCl-loaded transethosomal gel; development, characterization, and antidiabetic potential evaluation in the diabetes-induced rat model

Abstract

Herein we designed, optimized, and characterized the Metformin Hydrochloride Transethosomes (MTF-TES) and incorporate them into Chitosan gel to develop Metformin Hydrochloride loaded Transethosomal gel (MTF-TES gel) that provides a sustained release, improved transdermal flux and improved antidiabetic response of MTF. Design Expert® software (Ver. 12, Stat-Ease, USA) was applied for the statistical optimization of MTF-TES. The formulation with Mean Particle Size Distribution (MPSD) of 165.4 ± 2.3 nm, Zeta Potential (ZP) of −21.2 ± 1.9 mV, Polydispersity Index (PDI) of 0.169 ± 0.033, and MTF percent Entrapment Efficiency (%EE) of 89.76 ± 4.12 was considered to be optimized. To check the chemical incompatibility among the MTF and other formulation components, Fourier Transform Infrared (FTIR) spectroscopy was performed and demonstrated with no chemical interaction. Surface morphology, uniformity, and segregation were evaluated through Transmission Electron Microscopy (TEM). It was revealed that the nanoparticles were spherical and round in form with intact borders. The fabricated MTF-TES has shown sustained release followed by a more pronounced effect in MTF-TES gel as compared to the plain MTF solution (MTFS) at a pH of 7.4. The MTF-TES has shown enhanced permeation followed by MTF-TES gel as compared to the MTFS at a pH of 7.4. In vivo antidiabetic assay was performed and results have shown improved antidiabetic potential of the MTF-TES gel, in contrast to MTF-gel. Conclusively, MTF-TES is a promising anti-diabetic candidate for transdermal drug delivery that can provide sustained MTF release and enhanced antidiabetic effect.

Keywords:

• Transethosomes
• antidiabetic effect
• nanoparticle
• metformin hydrochloride transethosomes
• statistical optimization

Acknowledgement

The authors are thankful to the Higher Education Commission of Pakistan, National institute of Health Islamabad Pakistan and Department of Pharmacy, Quaid-i-Azam University Islamabad Pakistan for their facilitation in conducting this research.

Author contributions

Kainat Nousheen, Humzah Jamshaid: Conception, design, investigation and drafting. Rabia Afza, Saif Ullah Khan, Maimoona Malik: Design, analysis and interpretation of the data, intellectual content evaluation. Zakir Ali, Sibgha Batool, Alam Zeb: Design approval, drafting of the paper, visualization, approval of the draft. Abid Mehmood Yousaf, Saud Alqahtani: Methodology, software, validation, revision of the manuscript critically for intellectual content. Salman Khan, Gul Majid Khan: Design, validation, resources, final approval of the version to be published. Fakhar ud Din, Ali H Almari: Conception, design, supervision, funding, final approval for submission. Moreover, all the authors agree to be accountable for all aspects of the work.

Ethical approval

The animal study was performed as per the Guide for the Care and Use of Laboratory Animals (8^th Edition) and ARRIVE (Version 2) guidelines, after the approval of Quaid-i-Azam University ethical committee via approval number (BEC-FBS-QAU-2022-385). Further information on animal use is provided in Sections 2.3, 2.13 and 2.14.

Justification for use of animals

The cellular and molecular effects of a therapeutic agent could be predicted using in vitro systems and the usefulness cannot be underemphasized as it allows high throughput rapid screening of candidate compounds. However, a proper understanding of the complex physiological response needs a whole organism that could exhibit the signs and symptoms of diseases. Thus, animal studies have been introduced as a subset of test systems employed at the preclinical stage of drug development for the prediction of clinical effectiveness in humans. This has been possible due to the ability to correlate data generated from animal studies to humans.

Rodents (mice and rats) were used in this study, as they are the most commonly used animal models due to their short lifecycle and lifespan. These offer complementary benefits of cost and time savings as they can reproduce quickly, yielding faster results. Moreover, they have been reported to have 90-95% resemblance with human anatomy. As discussed earlier (Sections 2.3, 2.13 and 2.14) standard operating procedures were adopted to perform animal studies, including the use of minimal number with marginal pain and discomfort.

Disclosure statement

The authors declare no potential competing interest.

Data availability statement

The data that support the findings of this study are available from the corresponding author, [Fakhar Ud Din], upon reasonable request.

Additional information

Funding

The authors are thankful to the Higher Education Commission of Pakistan for funding this research work through its grant No: 20-14604/NRPU/R&D/HEC/2021. Moreover, the authors are grateful to the Deanship of Scientific Research at King Khalid University for funding this study through the Research Group Project, under grant number RGP2/436/44.