Fabrication and Characterization of Metforminium Gallate Gel for the Treatment of Diabetic Foot Ulcer in Rat Model
DOI:
https://doi.org/10.61919/07af1p54Keywords:
: metforminium gallate; diabetic foot ulcer; ion-pair salt; transdermal delivery; wound healing.Abstract
Background: Diabetic foot ulcers (DFUs) are chronic wounds that persist due to hyperglycemia-induced oxidative stress and inflammation, often leading to delayed healing and risk of infection. While metformin promotes tissue regeneration and gallic acid offers antioxidant and anti-inflammatory properties, both compounds have limited dermal penetration when used alone. Objective: This study aimed to synthesize and characterize an ion-paired salt, metforminium gallate, combining metformin and gallic acid to enhance transdermal delivery and evaluate its wound-healing efficacy in a diabetic rat model. Methods: Metforminium gallate was synthesized via metathesis and characterized using FTIR, confirming salt formation through loss of the gallic acid carbonyl band and split COO⁻ signals, and TGA/DSC, which demonstrated a single high-temperature transition indicative of a stable ionic complex. Ex vivo skin permeation studies were performed using Franz diffusion cells, while in vivo wound-healing efficacy was assessed in streptozotocin-induced diabetic rats with full-thickness dorsal wounds treated topically for 11 days. Results: Metforminium gallate exhibited ~71% cumulative permeation at 24 h, significantly higher than metformin (~67%) and gallic acid (~6%). Wound closure on day 11 reached ~92% for metforminium gallate versus 78%, 71%, and 39% for metformin, gallic acid, and control groups, respectively. Histopathological scores supported enhanced re-epithelialization and granulation (5.3 ± 0.4, p < 0.001). Conclusion: Ion-pairing metformin with gallic acid yielded a thermally robust salt with superior dermal penetration and wound-repair efficacy, offering a promising dual-action therapeutic approach for diabetic foot ulcers
References
1. Dilshad, R., et al., Comprehensive chemical profiling with UHPLC-MS, in-vitro, in-silico, and in-vivo antidiabetic potential of Typha domingensis Pers; A novel source of bioactive compounds. South African Journal of Botany, 2024. 171: p. 185-198.
2. Akhlaq, M., et al., Antioxidant, Immunomodulatory and Fungicidal Potential of Different Extracts of Raphanus Raphanistrum L. Var. Caudatus. Journal of Health and Rehabilitation Research, 2024. 4(1): p. 646-651.
3. Khan, F., et al., Phytochemical profiling and therapeutic potential of Ficus benjamina L.: Insights into anticancer and anti-inflammatory activities. Journal of Health and Rehabilitation Research, 2024. 4(2): p. 270-275.
4. Azeem, M., et al., An overview of anticancer, anti-inflammatory, antioxidant, antimicrobial, cardioprotective, and neuroprotective effects of rutin. Currents in Pharmaceutical Research, 2024. 2(2): p. 119-155.
5. Zahra, S., et al., Comparative efficacy of Aloe vera gel versus normal saline in accelerating episiotomy wound healing: A randomized controlled trial. Journal of Health and Rehabilitation Research, 2024. 4(2): p. 949-956.
6. Abid, H.M.U., et al., Global prevalence and mortality of type-2 diabetes from 1990 to 2019, with future projections to 2023 and 2050: a systematic review. Global Drug Design & Development Review, 2024. 9(1): p. 1-10.
7. Zulfiqar, M., et al., BIOCHEMICAL AND PHARMACOLOGICAL EVALUATION OF QUERCETIN POWDER AND ITS NANOPARTICLES.
8. Rizwan, M., et al., COMPARATIVE EFFICACY OF ALOE VERA (ALOBARBADENSIS) AND TURMERIC (CURCUMA LONGA) ON BURN WOUND HEALING IN RABBIT MODEL. Journal of Population Therapeutics and Clinical Pharmacology, 2024. 31(2): p. 526-34.
9. Sajawal, H.M., et al., Evaluating the healing properties of quercetin-enhanced nanoparticle ointments in diabetic rats. Journal of Health and Rehabilitation Research, 2024. 4(3): p. 1-7.
10. Hanif, M., et al., Hybrid halloysite nanotubes and their role as nanocontainers for biomedical applications, in Smart Halloysite Nanotubes. 2026, Elsevier. p. 233-252.
11. Abid, H.M.U., et al., Wound-healing and antibacterial activity of the quercetin–4-formyl phenyl boronic acid complex against bacterial pathogens of diabetic foot ulcer. ACS omega, 2022. 7(28): p. 24415-24422.
12. Usman Abid, H.M., et al., Exploring the potent combination of quercetin–boronic acid, epalrestat, and urea containing nanoethosomal keratolytic gel for the treatment of diabetic neuropathic pain: In vitro and in vivo studies. Molecular Pharmaceutics, 2023. 20(7): p. 3623-3631.
13. Zou, H., et al., Versatile carrier-free binary nanodrug based on metformin/epigallocatechin gallate nanoparticles: exploring its properties and potential in cancer treatment. Biomaterials Science, 2025. 13(3): p. 731-742.
14. Badran, I., et al., Kinetic study of the thermo-oxidative decomposition of metformin by isoconversional and theoretical methods. Thermochimica Acta, 2020. 694: p. 178797.
15. Moshikur, R.M., et al., Recent advances in biocompatible ionic liquids in drug formulation and delivery. Pharmaceutics, 2023. 15(4): p. 1179.
16. Hong, Y., et al., Gallic acid improves the metformin effects on diabetic kidney disease in mice. Renal Failure, 2023. 45(1): p. 2183726.
17. Thomas, J.R., Effects of age and diet on rat skin histology. The Laryngoscope, 2005. 115(3): p. 405-411.
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Copyright (c) 2025 Sobia Abid, Aasma Akram, Muhammad Hasnat Akhtar, Mubashir Ali Khalique, Muhammad Hassan, Farzana Khan, Muhammad Kashif Shabbir, Abdul Aziz, Hafiz Muhammad Usman Abid (Author)
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