Abstract
Aldara™ (5% w/w imiquimod) topical cream is approved by the US FDA for the treatment of superficial basal cell carcinoma. However, the cream formulation suffers from dose variability, low drug availability due to the incomplete release, and poor patient compliance. To achieve sustained and complete release of imiquimod, chitosan films were prepared by casting using propylene glycol as a plasticizer. Chitosan films had appropriate physicochemical characteristics for wound dressing and excellent content uniformity and maintained the original physical form of imiquimod. Films were capable of releasing a defined dose of imiquimod over a period of 7 days. The bioactivity of imiquimod was not affected by its entrapment in chitosan matrix as indicated by the results of in vitro growth inhibition assay. In addition, the film formulation showed significantly (p ˂ 0.05) higher drug accumulation in the skin when compared to commercial cream formulation.
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References
Urosevic M, Dummer R. Immunotherapy for nonmelanoma skin cancer: does it have a future? Cancer. 2002;94(2):477–85. https://doi.org/10.1002/cncr.10178.
Sauder DN. Immunomodulatory and pharmacologic properties of imiquimod. J Am Acad Dermatol. 2000;43(1 Pt 2):S6–11.
Schon MP, Schon M. Imiquimod: mode of action. Br J Dermatol. 2007;157(Suppl 2):8–13. https://doi.org/10.1111/j.1365-2133.2007.08265.x.
Vidal D, Matias-Guiu X, Alomar A. Efficacy of imiquimod for the expression of Bcl-2, Ki67, p53 and basal cell carcinoma apoptosis. Br J Dermatol. 2004;151(3):656–62. https://doi.org/10.1111/j.1365-2133.2004.06094.x.
Bubna AK. Imiquimod—its role in the treatment of cutaneous malignancies. Indian J Pharmacol. 2015;47(4):354–9. https://doi.org/10.4103/0253-7613.161249.
Davis ME, Chen ZG, Shin DM. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov. 2008;7(9):771–82. https://doi.org/10.1038/nrd2614.
Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986;46(12 Pt 1):6387–92.
Berman B, Ricotti CA Jr, Cazzaniga A, Davis SC. Determination of the area of skin capable of being covered by the application of 250 mg of 5% imiquimod cream. Dermatol Surg. 2004;30(5):784–6. https://doi.org/10.1111/j.1524-4725.2004.30217.x.
Kathe K, Kathpalia H. Film forming systems for topical and transdermal drug delivery. Asian J Pharm Sci. 2017;12(6):487–97. https://doi.org/10.1016/j.ajps.2017.07.004.
Donnelly RF, McCarron PA, Zawislak AA, Woolfson AD. Design and physicochemical characterisation of a bioadhesive patch for dose-controlled topical delivery of imiquimod. Int J Pharm. 2006;307(2):318–25. https://doi.org/10.1016/j.ijpharm.2005.10.023.
Lalani R, Misra A, Amrutiya J, Patel H, Bhatt P, Patel V. Challenges in dermal delivery of therapeutic antimicrobial protein and peptides. Curr Drug Metab. 2017;18(5):426–36. https://doi.org/10.2174/1389200218666170222151217.
Campos M. Chitosan cross-linked films for drug delivery applications. Macromol Symp. 2009;279:169–74.
Kumar MNVR, Muzzarelli RAA, Muzzarelli C, Sashiwa H, Domb AJ. Chitosan chemistry and pharmaceutical perspectives. Chem Rev. 2004;104(12):6017–84. https://doi.org/10.1021/cr030441b.
Layek B, Singh J. 8 - Chitosan for DNA and gene therapy A2 - Jennings, J. Amber. In: Bumgardner JD, editor. Chitosan Based Biomaterials Volume 2: Woodhead Publishing; 2017. p. 209–44.
Muzzarelli RAA. Chitins and chitosans for the repair of wounded skin, nerve, cartilage and bone. Carbohydr Polym. 2009;76(2):167–82. https://doi.org/10.1016/j.carbpol.2008.11.002.
Pellá MCG, Lima-Tenório MK, Tenório-Neto ET, Guilherme MR, Muniz EC, Rubira AF. Chitosan-based hydrogels: from preparation to biomedical applications. Carbohydr Polym. 2018;196:233–45. https://doi.org/10.1016/j.carbpol.2018.05.033.
Rinaudo M. Chitin and chitosan: properties and applications. Prog Polym Sci. 2006;31(7):603–32. https://doi.org/10.1016/j.progpolymsci.2006.06.001.
Berger J, Reist M, Mayer JM, Felt O, Peppas NA, Gurny R. Structure and interactions in covalently and ionically crosslinked chitosan hydrogels for biomedical applications. Eur J Pharm Biopharm. 2004;57(1):19–34. https://doi.org/10.1016/S0939-6411(03)00161-9.
Peh K, Khan T, Ch’ng H. Mechanical, bioadhesive strength and biological evaluations of chitosan films for wound dressing. J Pharm Pharm Sci. 2000;3(3):303–11.
Rhim J-W, Hong S-I, Park H-M, Ng PKW. Preparation and characterization of chitosan-based nanocomposite films with antimicrobial activity. J Agric Food Chem. 2006;54(16):5814–22. https://doi.org/10.1021/jf060658h.
Singh S, Jain S, Muthu MS, Tiwari S, Tilak R. Preparation and evaluation of buccal bioadhesive films containing clotrimazole. AAPS PharmSciTech. 2008;9(2):660–7. https://doi.org/10.1208/s12249-008-9083-3.
Córdoba-Díaz M, Nova M, Elorza B, Córdoba-Díaz D, Chantres JR, Córdoba-Borrego M. Validation protocol of an automated in-line flow-through diffusion equipment for in vitro permeation studies. J Control Release. 2000;69(3):357–67. https://doi.org/10.1016/S0168-3659(00)00306-0.
Layek B, Sadhukha T, Prabha S. Glycoengineered mesenchymal stem cells as an enabling platform for two-step targeting of solid tumors. Biomaterials. 2016;88:97–109. https://doi.org/10.1016/j.biomaterials.2016.02.024.
Sadhukha T, Layek B, Prabha S. Incorporation of lipolysis in monolayer permeability studies of lipid-based oral drug delivery systems. Drug Deliv Transl Res. 2018;8(2):375–86. https://doi.org/10.1007/s13346-017-0383-6.
Chollet JL, Jozwiakowski MJ, Phares KR, Reiter MJ, Roddy PJ, Schultz HJ, et al. Development of a topically active imiquimod formulation. Pharm Dev Technol. 1999;4(1):35–43. https://doi.org/10.1080/10837459908984222.
Preis M, Knop K, Breitkreutz J. Mechanical strength test for orodispersible and buccal films. Int J Pharm. 2014;461(1):22–9. https://doi.org/10.1016/j.ijpharm.2013.11.033.
Sasikala L, Durai B, Rathinamoorthy R. Manuka honey loaded chitosan hydrogel films for wound dressing applications. 2013.
Preis M, Woertz C, Kleinebudde P, Breitkreutz J. Oromucosal film preparations: classification and characterization methods. Expert Opin Drug Deliv. 2013;10(9):1303–17. https://doi.org/10.1517/17425247.2013.804058.
Peh KK, Wong CF. Polymeric films as vehicle for buccal delivery: swelling, mechanical, and bioadhesive properties. J Pharm Pharm Sci. 1999;2(2):53–61.
Mi F-L, Shyu S-S, Wu Y-B, Lee S-T, Shyong J-Y, Huang R-N. Fabrication and characterization of a sponge-like asymmetric chitosan membrane as a wound dressing. Biomaterials. 2001;22(2):165–73. https://doi.org/10.1016/S0142-9612(00)00167-8.
Allegrini P, Razzetti G, Bologna A, Magrone D, Ventimiglia G. A process for the purification of imiquimod. Google Patents; 2007.
Chen H, Hu X, Chen E, Wu S, McClements DJ, Liu S, et al. Preparation, characterization, and properties of chitosan films with cinnamaldehyde nanoemulsions. Food Hydrocoll. 2016;61:662–71. https://doi.org/10.1016/j.foodhyd.2016.06.034.
Wiedmann TS, Naqwi A. Pharmaceutical salts: theory, use in solid dosage forms and in situ preparation in an aerosol. Asian J Pharm Sci. 2016. https://doi.org/10.1016/j.ajps.2016.07.002.
Barnes L. The management of basal cell carcinomas. Ir Med J. 2006;99(6):179–81.
Szeimies RM, Karrer S, Radakovic-Fijan S, Tanew A, Calzavara-Pinton PG, Zane C, et al. Photodynamic therapy using topical methyl 5-aminolevulinate compared with cryotherapy for actinic keratosis: a prospective, randomized study. J Am Acad Dermatol. 2002;47(2):258–62.
Salasche S, Shumack S. A review of imiquimod 5% cream for the treatment of various dermatological conditions. Clin Exp Dermatol. 2003;28(Suppl 1):1–3.
Morales JO, McConville JT. Manufacture and characterization of mucoadhesive buccal films. Eur J Pharm Biopharm. 2011;77(2):187–99. https://doi.org/10.1016/j.ejpb.2010.11.023.
Kouchak M, Handali S, Naseri Boroujeni B. Evaluation of the mechanical properties and drug permeability of chitosan/Eudragit RL composite film. Osong Public Health Res Perspect. 2015;6(1):14–9. https://doi.org/10.1016/j.phrp.2014.12.001.
Wei H, Li-Fang F, Bai X, Chun-Lei L, Qing D, Yong-Zhen C, et al. An investigation into the characteristics of chitosan/Kollicoat SR30D free films for colonic drug delivery. Eur J Pharm Biopharm. 2009;72(1):266–74. https://doi.org/10.1016/j.ejpb.2008.10.017.
S-h H, Whu SW, Tsai C-L, Wu Y-H, Chen H-W, Hsieh K-H. Chitosan as scaffold materials: effects of molecular weight and degree of deacetylation. J Polym Res. 2004;11(2):141–7. https://doi.org/10.1023/B:JPOL.0000031080.70010.0b.
Stein P, Gogoll K, Tenzer S, Schild H, Stevanovic S, Langguth P, et al. Efficacy of Imiquimod-based transcutaneous immunization using a nano-dispersed emulsion gel formulation. PLoS One. 2014;9(7):e102664. https://doi.org/10.1371/journal.pone.0102664.
Lemmer HJ, Hamman JH. Paracellular drug absorption enhancement through tight junction modulation. Expert Opin Drug Deliv. 2013;10(1):103–14. https://doi.org/10.1517/17425247.2013.745509.
Kowapradit J, Opanasopit P, Ngawhiranpat T, Apirakaramwong A, Rojanarata T, Ruktanonchai U, et al. Methylated N-(4-N,N-dimethylaminobenzyl) chitosan, a novel chitosan derivative, enhances paracellular permeability across intestinal epithelial cells (Caco-2). AAPS PharmSciTech. 2008;9(4):1143–52. https://doi.org/10.1208/s12249-008-9160-7.
Ramineni SK, Dziubla TD, Cunningham LL Jr, Puleo DA. Local delivery of imiquimod in hamsters using mucoadhesive films and their residence time in human patients. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;118(6):665–73. https://doi.org/10.1016/j.oooo.2014.08.015.
Acknowledgements
The authors would like to thank Hanna Iaizzo and Mamta Kapoor for conducting the preliminary studies. The mechanical tests were performed at the Characterization Facility, University of Minnesota, Minneapolis, MN.
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Guest Editors: Mahavir Bhupal Chougule, Vijaykumar B. Sutariya and Sudip K. Das
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Layek, B., Rahman Nirzhor, S.S., Rathi, S. et al. Design, Development, and Characterization of Imiquimod-Loaded Chitosan Films for Topical Delivery. AAPS PharmSciTech 20, 58 (2019). https://doi.org/10.1208/s12249-018-1288-5
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DOI: https://doi.org/10.1208/s12249-018-1288-5