Development and pharmacotechnological studies of transdermal patches with trans-resveratrol

Introduction. Due to its broad spectrum of biological activity, trans-resveratrol is a promising candidate for the development of pharmaceuticals. However, its low aqueous solubility and chemical instability when administered orally limit its clinical use. Therefore, alternative delivery methods that limit the first-pass effect through the liver are promising.

Aim. Development and pharmacotechnological evaluation of resveratrol transdermal patches.

Materials and methods. The object of the study was the substance trans-resveratrol (DSM, Switzerland). Polyvinylpyrrolidone (PVP) of various molecular weights (K-17, K-30, K-90, USP, Dalian Sinobio Chemistry Co., Ltd., China) and a copolymer of methacrylic acid and ethyl acrylate (BASF, Germany) were considered as carrier polymers that ensured the adhesion of the patches. Polyethyleneglycol-400 (PEG-400) (LLC GC "Ruskhim", Russia) served as a plasticizer. Sodium metabisulfite (Yantai Sodium Metabisulfite Co., Ltd, China) was used as an antioxidant, and ethyl alcohol 95 % (Pharmacopoeial Monograph 2.1.0036, Р N003960/01, ROSBIO LLC, Russia) served as a solvent for the matrix components. A 20-μm-thick polyethylene terephthalate film formed the outer coating layer (backing), and anti-adhesive siliconized paper protected the matrices. Patches were prepared using the casting method and dried in an HPP110 climatic chamber (Memmert, Germany). As part of the quality control of the finished TTS, shear resistance was assessed in accordance with the requirements of the FTM 8 methodology of the FINAT International Association Guidelines, and adhesion was assessed in accordance with the "Methods of Adhesion Testing" monograph of the 18th edition of the Japanese Pharmacopoeia. The Nicorette® transdermal patch (LTS Lohmann Therapy-Systems AG, Germany) served as the reference drug. An ERWEKA DT 626 dissolution tester (ERWEKA GmbH, Germany) with a holder disk was used to study the biopharmaceutical properties of the developed formulations. The hygroscopicity of the matrices was assessed using a BINDER FED 53 drying oven (BINDER GmbH, Germany). The test results were processed using elementary statistical methods in accordance with the requirements of the State Pharmacopoeia of the Russian Federation. To compare adhesion indices between groups, a one-way analysis of variance was performed (One-way ANOVA, GraphPad Prism 8.0.2, USA) at p < 0,0001.

Results and discussion. A comparative assessment of shear strength revealed that increasing matrix thickness leads to an increase in the number of shear layers, which reduces its cohesive strength. The introduction of high-molecular-weight PVP K-30 and K-90 into the PVP K-17 formulation provides a concentration-dependent increase in the composition's internal strength and enhances its resistance to shear deformations, but has a negative impact on the release of the active ingredient from the polymer matrix. The composition, based on a copolymer of methacrylic acid and ethyl acrylate, demonstrates an optimal combination of adhesive and biopharmaceutical properties.

Conclusion. The study confirms that developing a TTS is a complex, multi-step process that requires a balanced approach to formulation optimization. A critical aspect is the need for a comprehensive assessment of several key quality indicators, as modifying the formulation to improve some characteristics may degrade others. For further development of resveratrol patches, it is promising to use a matrix based on a copolymer of methacrylic acid and ethyl acrylate, and to consider optimizing the PVP K-17-based formulation to improve its adhesion properties.

1. Arefyev A. S., Zhukova I. V. Transdermal therapeutic systems, their types and advantages. Innovative scientific research. 2022;1–3(15):13–20. (In Russ.) DOI: 10.5281/zenodo.6368638.

2. Marchenkova L. A., Kotenko N. V., Kareva E. N. Alternative therapy of menopausal syndrome from the perspective of comprehensive aging prevention. Doctor.Ru. 2025;24(5):101–109. (In Russ.) DOI: 10.31550/1727-2378-2025-24-5-101-109.

3. Sokurenko M. S., Krechetov S. P., Olifer S. A., Krasnyuk I. I., Solovyova N. L., Makarenko M. A., Demina N. B. Development of composition and technology of resveratrol capsules. Drug development & registration. 2019;8(4):16–19. (In Russ.) DOI: 10.33380/2305-2066-2019-8-4-16-19.

4. Krechetov S. P., Maslennikova M. S., Kuksin A. Yu., Malinkin A. D., Solovieva N. L., Krasnyuk I. I. Preparation and investigation of properties of resveratrol and solubilizers compositions. Russian Journal of Biotherapy. 2023;22(2):65–73. (In Russ.) DOI: 10.17650/1726-9784-2023-22-2-65-73.

5. Dołowacka-Jóźwiak A., Nawrot-Hadzik I., Matkowski A., Ciecieląg T., Gawin-Mikołajewicz A., Dudek-Wicher R., Karolewicz B. L. Mucoadhesive PVA Film for Sustained Resveratrol Delivery: Formulation, Characterization, and Release Profile. Molecules. 2025;30(12):2642. DOI: 10.3390/molecules30122642.

6. Riccio B. V. F., Soares do Nascimento A. L. C., Bagliotti Meneguin A., Rodero C. F., Santos K. P., Sábio R. M., de Annunzio S. R., Fontana C. R., da Silva Barud H., Colerato Ferrari P., Chorilli M. Solid dispersions incorporated into PVP films for the controlled release of trans-resveratrol: development, physicochemical and in vitro characterizations and in vivo cutaneous anti-inflammatory evaluation. Pharmaceutics. 2022;14(6):1149. DOI: 10.3390/pharmaceutics14061149.

7. Choy Y. B., Prausnitz M. R. The rule of five for non-oral routes of drug delivery: ophthalmic, inhalation and transdermal. Pharmaceutical research. 2011;28(5):943–948. DOI: 10.1007/s11095-010-0292-6.

8. Sivadasan D., Madkhali O. A. The Design Features, Quality by Design Approach, Characterization, Therapeutic Applications, and Clinical Considerations of Transdermal Drug Delivery Systems-A Comprehensive Review. Pharmaceuticals (Basel). 2024;17(10):1346. DOI: 10.3390/ph17101346.

9. Vaseem R. S., D’cruz A., Shetty S., Hafsa, Vardhan A., Shenoy R. S., Marques S. M., Kumar L., Verma R. Transdermal Drug Delivery Systems: A Focused Review of the Physical Methods of Permeation Enhancement. Advanced Pharmaceutical Bulletin. 2024;14(1):67–85. DOI: 10.34172/apb.2024.018.

10. Zhang L., Dong Z., Liu W., Wu X., He H., Lu Y., Wu W., Qi J. Novel Pharmaceutical Strategies for Enhancing Skin Penetration of Biomacromolecules. Pharmaceuticals (Basel). 2022;15(7):877. DOI: 10.3390/ph15070877.

11. Ribeiro A., Pereira-Leite C., Rosado C., Aruci E., Colley H. E., Krohn I. K., Baldea I., Pantelić I., Fluhr J. W., Simões S. I., Savić S., Costa Lima S. A. Enhancing Transcutaneous Drug Delivery: Advanced Perspectives on Skin Models. JID Innovations. 2024;5(2):100340. DOI: 10.1016/j.xjidi.2024.100340.

12. Cheng T., Tai Z., Shen M., Li Y., Yu J., Wang J., Zhu Q., Chen Z. Advance and Challenges in the Treatment of Skin Diseases with the Transdermal Drug Delivery System. Pharmaceutics. 2023;15(8):2165. DOI: 10.3390/pharmaceutics15082165.

13. Agbadua O. G., Kúsz N., Berkecz R., Vass E., Csámpai A., Tóth G., Balogh G. T., Marcourt L., Wolfender J.-L., Ferreira Queiroz E., Hunyadi A. New Insights into the French Paradox: Free Radical Scavenging by Resveratrol Yields Cardiovascular Protective Metabolites. Journal of Medicinal Chemistry. 2025;68(10):10031–10047. DOI: 10.1021/acs.jmedchem.4c03061.

14. Grau L., Soucek R., Pujol M. D. Resveratrol derivatives: Synthesis and their biological activities. European Journal of Medicinal Chemistry. 2023;246:114962. DOI: 10.1016/j.ejmech.2022.114962.

15. Mitrović D., Pavlović N. In silico approach in the development of structural analogues of resveratrol with improved distribution in the central nervous system. Kragujevac Journal of Science. 2024;46:59–71. DOI: 10.5937/KgJSci2400000M.

16. Gironde C., Rigal M., Dufour C., Furger C. AOP1, a New Live Cell Assay for the Direct and Quantitative Measure of Intracellular Antioxidant Effects. Antioxidants (Basel). 2020;9(6):471. DOI: 10.3390/antiox9060471.

17. Gadag S., Narayan R., Nayak Y., Garg S., Nayak U. Y. Design, development and evaluation of Resveratrol transdermal patches for breast cancer therapy. International Journal of Pharmaceutics. 2023;632:122558. DOI: 10.1016/j.ijpharm.2022.122558.

18. Kalita B., Das M. K., Sarma M., Deka A. Sustained Anti-inflammatory Effect of Resveratrol-Phospholipid Complex Embedded Polymeric Patch. AAPS PharmSciTech. 2017;18(3):629–645. DOI: 10.1208/s12249-016-0542-y.

19. Bandiwadekar A., Jose J., Gopan G., Augustin V., Ashtekar H., Khot K. B. Transdermal delivery of resveratrol loaded solid lipid nanoparticle as a microneedle patch: a novel approach for the treatment of Parkinson’s disease. Drug Delivery and Translational Research. 2025;15(3):1043–1073. DOI: 10.1007/s13346-024-01656-0.

20. Diao N., Liu Y., Wang W., Cao M., Liu X., Yang W., Cao Y., Sun T., Pei H., Guo C., Chen D. Resveratrol nanocrystals based dissolving microneedles with highly efficient for rheumatoid arthritis. Drug Delivery and Translational Research. 2025;15(1):203–215. DOI: 10.1007/s13346-024-01581-2.

21. Wu W., Meng T., Jin F., Li J., Huang J., Guo Z., Yu M., Zhou Y. Effects of resveratrol on postmenopausal women: a systematic review and meta-analysis. Frontiers in Pharmacology. 2025;16:1588284. DOI: 10.3389/fphar.2025.1588284.

22. Montoya-Estrada A., García-Cortés A. Y., Romo-Yañez J., Ortiz-Luna G. F., Arellano-Eguiluz A., Belmont-Gómez A., Lopéz-Ugalde V., León-Reyes G., Flores-Pliego A., Espejel-Nuñez A., Solis-Paredes J. M., Reyes-Muñoz E. The Administration of Resveratrol and Vitamin C Reduces Oxidative Stress in Postmenopausal Women-A Pilot Randomized Clinical Trial. Nutrients. 2024;16(21):3775. DOI: 10.3390/nu16213775.

23. Rodrigues Uggioni M. L., Ronsani L., Motta S., Denoni Júnior J. C., Marçal F., Dagostin Ferraz S., Rosa M. I., Colonetti T. Effects of resveratrol on the lipid profile of post-menopause women: Systematic review and meta-analysis. Nutrition, Metabolism and Cardiovascular Diseases. 2025;35(4):103827. DOI: 10.1016/j.numecd.2024.103827.

24. Menegas S., Keller G. S., Possamai-Della T., Aguiar-Geraldo J. M., Quevedo J., Valvassori S. S. Potential mechanisms of action of resveratrol in prevention and therapy for mental disorders. The Journal of Nutritional Biochemistry. 2023;121:109435. DOI: 10.1016/j.jnutbio.2023.109435.

25. Al-Smadi K., Ali M., Zhu J., Abdoh A., Phan K., Mohammed Y. Advances in Characterization of Transdermal and Topical Products using Texture Analyzer Systems. AAPS PharmSciTech. 2025;26(5):157. DOI: 10.1208/s12249-025-03148-x.

26. Minghetti P., Cilurzo F., Montanari L. Evaluation of adhesive properties of patches based on acrylic matrices. Drug Development and Industrial Pharmacy. 1999;25(1):1–6. DOI: 10.1081/ddc-100102135.

27. Aung N. N., Ngawhirunpat T., Rojanarata T., Patrojanasophon P., Opanasopit P., Pamornpathomkul B. Enhancement of transdermal delivery of resveratrol using Eudragit and polyvinyl pyrrolidone-based dissolving microneedle patches. Journal of Drug Delivery Science and Technology. 2021;61:102284. DOI: 10.1016/j.jddst.2020.102284.

28. Sidelkovskaya F. A. Chemistry of N-vinylpyrrolidone and its polymers. Moscow: Nauka; 1970. 150 p. (In Russ.)

29. Oikonomou P., Sanopoulou M., Papadokostaki K. G. Blends of poly (vinyl alcohol) and poly (vinyl pyrrolidone): Interrelation between the degree of hydration and thermal and mechanical properties. Industrial & Engineering Chemistry Research. 2021;60(39):14203–14212. DOI: 10.1021/acs.iecr.1c02650.

30. Stepanova E. F., Losenkova S. O., Morozov Yu. A. Creation and pharmacotechnological investigations of innovative dosage forms of Mexidol. Drug development & registration. 2018;(4):37–43. (In Russ.)