Evaluation of combination patch of vetel leaf extract (Piper sp.) - ultrasonic assisted extraction (UAE) as a transdermal delivery system on fibroblast cell formation and collagen density
Abstract
The combination of red betel (Piper crocatum) and green betel (Piper betle L.) leaves is believed to act synergistically in enhancing wound healing. Transdermal patches offer advantages over conventional topical forms due to their sustained drug release, ease of application, and prolonged therapeutic effect. This study evaluated the histopathological effects of a combination patch containing betel leaf extracts for incision wound treatment in Wistar rats. The studies used an true experimental post-test-only control group design, five groups were tested: a blank patch (K−), a povidone-iodine patch (K+), and combination extract patches at concentrations of 7.5% (K1), 15% (K2), and 30% (K3), applied over 14 days with six animals per group. Patch characteristics were assessed through organoleptic tests, thickness, weight uniformity, folding endurance, and pH, while wound healing was evaluated through histological analysis of fibroblast cell counts and collagen density. Statistical analysis was conducted using the Kruskal-Wallis test followed by Mann-Whitney post-hoc tests. The 30% combination patch (K3) showed the most significant healing effect, with fibroblast counts exceeding 50 cells and dense collagen formation scoring +3. These results indicate that a transdermal patch combining Piper crocatum and Piper betle extracts effectively promotes wound healing by enhancing fibroblast proliferation and collagen synthesis.
References
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[38] Nikita, S., Meera, B. “Tannin Extracted from Punica granatum,“ Int. J. Engin. Res. Tech., 3(7), 479–81, 2014.
[39] Rohmah, S.N., Fuadah, D.Z., Girianto, W.R. “Efektivitas Daun Petai Cina (Leucaena leucocephala) dan Daun Jarak Pagar (Jatropha cucas) terhadap Proses Penyembuhan Luka Bakar Grade II pada Tikus Putih (Rattus norvegicus),“ J Ilmu Keperawatan, p20-33, 2016.
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[42] E. F. Palumpun, A. A. G. P. Wiraguna, and W. Pangkahila, “Pemberian ekstrak daun sirih (Piper betle) secara topikal meningkatkan ketebalan epidermis, jumlah fibroblas, dan jumlah kolagen dalam proses penyembuhan luka pada tikus jantan galur Wistar (Rattus norvegicus),” J. e-Biomedik, vol. 5, no. 1, 2017, doi: 10.35790/ebm.5.1.2017.15037.
[2] B. P. Statistik, “Profil Statistik Kesehatan 2023,” Badan Pus. Stat., vol. 7, no. 2598–5655, 2023.
[3] F. F. Balqis U, Masyitha D, “Proses Penyembuhan Luka Bakar dengan Gerusan Daun Kedondong (Spondias dulcis) dan Vaselin pada Tikus Putih (Rattus norvegicus) Secara Histopatologis,” J Med Veterania, pp. 8(01):9– 14., 2014.
[4] S. S. Piraino F, “A Current View of Functional Biomaterials for Wound Care, Molecular and Cellular Therapies,” Biomed Res Int, pp. 12–14, 2015.
[5] P. J. Widyawati R, Kasy F, Yunani R, “Efektivitas Salep Ekstrak Daun Sirih Merah (Piper crocatum) terhadap Luka Insisi pada Tikus Putih (Rattus norvegicus),” VITEK Bid. Kedokt. Hewan, pp. 11(2):39–46, 2021.
[6] S. R. I. Ditha Kusumawardhani A, Kalsum U, “Pengaruh Sediaan Salep Ekstrak Daun Sirih (Piper betle Linn.) terhadap Jumlah Fibroblas Luka Bakar Derajat IIA pada Tikus Putih (Rattus norvegicus) Galur Wistar,” Maj. Kesehat. FKUB, p. 2(1), 2015.
[7] Setyawati A, Wahyuningsih MSH, Nugrahaningsih DAA, Effendy C, Fneish F, Fortwengel G. “Piper crocatum Ruiz & Pav. ameliorates wound healing through p53, E-cadherin, and SOD1 pathways on wounded hyperglycemia fibroblasts,“ Saudi J Biol Sci. 2021 Dec;28(12):7257-7268. doi: 10.1016/j.sjbs.2021.08.039. Epub 2021 Aug 19. PMID: 34867030; PMCID: PMC8626332.
[8] Ghazali NA, Elmy A, Yuen LC, Sani NZ, Das S, Suhaimi F, Yusof R, Yusoff NH, Thent ZC. “Piper betel leaves induce wound healing activity via proliferation of fibroblasts and reducing 11β 11β-hydroxysteroid dehydrogenase-1 expression in diabetic rats,“ J Ayurveda Integr Med. 2016 Oct-Dec;7(4):198-208. doi: 10.1016/j.jaim.2016.08.008. Epub 2016 Nov 23. PMID: 27889427; PMCID: PMC5192284.
[9] R. Dalia, T. Elsa, P. Rian Ka, F.Agnes, W. Ratna. “Efektivitas Penyembuhan Luka Sediaan Patch Kombinasi Beberapa Spesies Sirih Secara in Vivo,“ JECP, 2024.
[10] D. A. Hutasuhut, D. Aspriyanto, I. W. A. Krishnawan Firdaus, “Uji Fitokimia Kualitatif Dan Kuantitatif Ekstrak Kulit Buah Rambai (Baccaurea motleyana) Konsentrasi 100%,” Dentin, vol. 6, no. 2, pp. 97–102, 2022, doi: 10.20527/dentin.v6i2.6394.
[11] Siregar Y, Lubis R, Irianti E. “Gel Daun Sirih Merah (Piper crocatum Ruiz &Pav) 15% Efektif dalam Mempercepat Penyembuhan Luka Perineum pada Tikus Putih Betina (Rattus norvegicus) Galur Wistar “. J Penelit Kesehat Suara Forikes. 2022;13(3):835–8. 25.
[12] Januarti IB, Waluyo K, Ningsih W, Sholeh AB, “Uji Aktivitas Sediaan Gel Ekstrak Daun Sirih (Piper betle L.) Terhadap Penyembuhan Luka Sayat Pada Kelinci (Oryctolagus cuniculus) “Medical Sains : Jurnal Ilmiah Kefarmasian Vol. 8 No. 1, Januari - Maret 2023, Hal. 229-240
[13] N. N. IS, “Pengembangan dan Evaluasi Formula Sediaan Patch Ekstrak Daun Binahong (Anredera cordifolia (Tenore) Steenis),” J Pharmacopolium, vol. 4, no. 2, pp. 81–90, 2021.
[14] T. L. Mark S. G, “Surgical Wound Healing and Management,” London, CRC Press, 2007.
[15] M. Y, “Studi Formulasi Dan Efektivitas Gel Ekstrak Etanol Daun Sirih (Piper betle L.) Terhadap Penyembuhan Luka Bakar Pada Kelinci (Oryctolagus cuniculus),” J Dunia Farm, 2019.
[16] S. E. Alphama R, “Perbandingan Efektivitas Povidone Iodine Dengan Kopi Robusta Terhadap Penyembuhan Luka Sayat Pada Mencit (Mus musculus),” J Ilm Simantek, vol. 3, no. 2, pp. 58–66, 2019.
[17] L. O. A. Rasydy, J. Supriyanta, and D. Novita, “Formulasi Ekstrak Etanol 96% Daun Sirih Hijau (Piper betle L.) Dalam Bedak Tabur Anti Jerawat Dan Uji Aktivitas Antiacne Terhadap Staphylococcus aureus,” J. Farmagazine, vol. 6, no. 2, p. 18, 2019, doi: 10.47653/farm.v6i2.142.
[18] A. Ardiansyah and A. T. Wicaksono, “Variasi Konsentrasi Senyawa Fitokimia Sirih Merah Dan Pelarut Heksana Menggunakan Gas Chromatography – Mass Spectrometry,” Al Kawnu Sci. Local Wisdom J., vol. 3, no. 2, pp. 36–43, 2024, doi: 10.18592/ak.v3i2.11752.
[19] Lee DH, Lim S, Kwak SS, Kim J. Advancements in Skin-Mediated Drug Delivery: Mechanisms, Techniques, and Applications. Adv Healthc Mater. 2023;2302375.
[20] Suliantari, Jenie BSL, Apriyantono MTS. Aktivitas Antibakteri Ekstrak Sirih Hijau terhadap Bakteri Patogen Pangan. Teknol dan Ind Pangan. 2008;19(1):1–7.
[21] Ulfa M, Fatmawaty A, Dambur AMR. Anti-Acne Patch Formulation Silkworm Cocoon Waste With HPMC and PVP Variations. Indones J Pharm Sci Technol. 2023;10(3):147.
[22] Latif MS, Azad AK, Nawaz A, Rashid SA, Rahman MH, Al Omar SY, et al. Ethyl Cellulose and Hydroxypropyl Methyl Cellulose Blended Methotrexate- Loaded Transdermal Patches: In Vitro and Ex Vivo. Polymers (Basel). 2021 Oct;13(20).
[23] Setyawan EI, Wijayanti NLPD, Samirana, PO, Sarasmitha MA, Warditiani NK, Padmanaba IG. Optimasi Mentol dan Polietilenglikol Pada Formulasi Patch Ekstrak Daun Sirih (Piper Betle L.). J Farm Udayana. 2016;5(1):1689– 99.
[24] Hamzah S, Yanti NI, Isnaini N, Rahmi N. Uji Stabilitas Fisik Formulasi Sediaan Patch Antiacne Kombinasi Ekstrak Etanol Buah Kurma Sukkari (Phoenix dactylifera) dan Madu Murni (Honey bee). Med Sains J Ilm Kefarmasian. 2023;8(3):901–10.
[25] S. Rahman VR, Bratadiredja MA, “Potensi Kolagen sebagai Bahan Aktif Sediaan Farmasi,” Maj Wong, W. F., Ang, K. P., Sethi, G., & Looi, C. Y. (2023). Recent Advancement of Medical Patch for Transdermal Drug Delivery. Medicina (Kaunas, Lithuania), 59(4), 778. https://doi.org/10.3390/medicina59040778
[26] S. Rahman VR, Bratadiredja MA, “Potensi Kolagen sebagai Bahan Aktif Sediaan Farmasi,” Maj Iversen M., Monisha M., Agarwala S. Flexible, Wearable and Fully-printed Smart Patch for pH and Hydration Sensing in Wounds. Int. J. Bioprinting. 2022;8:447. doi: 10.18063/ijb.v8i1.447. [DOI] [PMC free article] [PubMed] [Google Scholar]
[27] S. Rahman VR, Bratadiredja MA, “Potensi Kolagen sebagai Bahan Aktif Sediaan Farmasi,” Maj Farmasetika, p. 6(3):253, 2021.
[28] M. M. Cialdai F, Risaliti C, “Role Of Fibroblasts In Wound Healing And Tissue Remodeling On Earth And In Space,” Front Bioeng Biotechnol, p. 10:958381, 2022.
[29] V.-P. K. Benchaprathanphorn K, Sakulaue P, Siriwatwechakul W, Muangman P, Chinaroonchai K, Namviriyachote N, “Expansion of fibroblast cell sheets using a modified MEEK micrografting technique for wound healing applications,” Sci Rep, p. 3;12(1):18541, 2022.
[30] Y. Rangga, T. Nusdianto, S. Amung L., S. Budi, Y. Aditya and A. Bodhi. “Efek Ekstrak Metanol Daun Ketapang (Terminalia catappa L.) Terhadap Kepadatan Kolagen dalam Penyembuhan Luka Bakar Derajat II pada Tikus Putih (Rattus norvegicus)". J Med Vet, 3(1):82-88, 2020.
[31] Yensuari & Andriani. “Effectiveness of Red Betel Leaf Ointment (Piper Crocatum, Ruiz & Pav) On Slash Wounds In White Mice,“ Int J Health Pharm. 2024;4(2):253-259. doi: 10.51601/ijhp.v4i2.247.
[32] Zar’ah, Nurul & Syachruddin, Syachruddin & Kusmiyati, Kusmiyati. “The Effect of Green Betel Leaves (Piper betle L.) Extract on Wound Healing in Mice (Mus musculus L.),“J Biol Trop. 2021;21(1):103. doi: 10.29303/jbt.v21i1.2282.
[33] Micozzi, M.S. “Fundamentals of Complementary and Alternative Medicine,“ Saunders, Elsevier; Amsterdam, The Netherlands: 2011.
[34] Ganora L. “Herbal Constituents: Foundations of Phytochemistry,“ 1st ed. Lisa Ganora; Louisville, KY, USA: 2009.
[35] Elliot, J., Woodward, J., Umarji, A., Mei, Y., and Tona, A. “The effect of surface chemistry on the formation of thin films of native fibrillar collagen,“ Biomat., 28(4), 576- 585, 2007.
[36] Purnama, M.T.E., Rahmaningtyas, I.H., Pratama, A.R., Prastika, Z., Kartikasari, A.M., Cahyo, N.P.D. “Tadpole serum activity (Rana catesbeiana) in caspase-3 as a marker of the role of apoptosis and total cytotoxic T lymphocytes in albino rats’ epithelial cells induced by neoplasia,“ Vet. World, 12(1), 63, 2019.
[37] Lim, H., Kim, H. “Inhibition of mammalian collagenase, matrix metalloproteinase-1, by naturally-occurring flavonoids,“ Planta Med., 73(12), 1267–1274, 2007.
[38] Nikita, S., Meera, B. “Tannin Extracted from Punica granatum,“ Int. J. Engin. Res. Tech., 3(7), 479–81, 2014.
[39] Rohmah, S.N., Fuadah, D.Z., Girianto, W.R. “Efektivitas Daun Petai Cina (Leucaena leucocephala) dan Daun Jarak Pagar (Jatropha cucas) terhadap Proses Penyembuhan Luka Bakar Grade II pada Tikus Putih (Rattus norvegicus),“ J Ilmu Keperawatan, p20-33, 2016.
[40] Manoi., F. “Binahong (Anredera cordifolia) Sebagai Obat,“ Badan Penelitian dan Pengembangan Pertanian. 15, 2009.
[41] Lais C. Agra, Jamylle N. S. Ferro, Fabiano T. Barbosa, and Emiliano B. “Triterpenes with healing activity: A systematic review,“ J Dermatolog Treat, 26(5): 465–470, 2015.
[42] E. F. Palumpun, A. A. G. P. Wiraguna, and W. Pangkahila, “Pemberian ekstrak daun sirih (Piper betle) secara topikal meningkatkan ketebalan epidermis, jumlah fibroblas, dan jumlah kolagen dalam proses penyembuhan luka pada tikus jantan galur Wistar (Rattus norvegicus),” J. e-Biomedik, vol. 5, no. 1, 2017, doi: 10.35790/ebm.5.1.2017.15037.
Published
2025-04-30
How to Cite
TRINOVITA, Elsa et al.
Evaluation of combination patch of vetel leaf extract (Piper sp.) - ultrasonic assisted extraction (UAE) as a transdermal delivery system on fibroblast cell formation and collagen density.
JURNAL ILMU KEFARMASIAN INDONESIA, [S.l.], v. 23, n. 1, p. 198-210, apr. 2025.
ISSN 2614-6495.
Available at: <http://jifi.farmasi.univpancasila.ac.id/index.php/jifi/article/view/1687>. Date accessed: 14 may 2025.
doi: https://doi.org/10.35814/jifi.v23i2.1687.
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