Advertisement

AAPS PharmSciTech

, 20:58 | Cite as

Design, Development, and Characterization of Imiquimod-Loaded Chitosan Films for Topical Delivery

  • Buddhadev Layek
  • Saif S. Rahman Nirzhor
  • Sneha Rathi
  • Karunya K. Kandimalla
  • Timothy S. Wiedmann
  • Swayam PrabhaEmail author
Research Article Theme: Translational Multi-Disciplinary Approach for the Drug and Gene Delivery Systems
Part of the following topical collections:
  1. Theme: Translational Multi-Disciplinary Approach for the Drug and Gene Delivery Systems

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.

Key Words

chitosan imiquimod basal cell carcinoma film formulation topical drug delivery 

Notes

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.

References

  1. 1.
    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.CrossRefPubMedGoogle Scholar
  2. 2.
    Sauder DN. Immunomodulatory and pharmacologic properties of imiquimod. J Am Acad Dermatol. 2000;43(1 Pt 2):S6–11.CrossRefGoogle Scholar
  3. 3.
    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.CrossRefPubMedGoogle Scholar
  4. 4.
    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.CrossRefPubMedGoogle Scholar
  5. 5.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    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.CrossRefPubMedGoogle Scholar
  7. 7.
    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.PubMedGoogle Scholar
  8. 8.
    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.CrossRefPubMedGoogle Scholar
  9. 9.
    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.CrossRefGoogle Scholar
  10. 10.
    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.CrossRefPubMedGoogle Scholar
  11. 11.
    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.CrossRefPubMedGoogle Scholar
  12. 12.
    Campos M. Chitosan cross-linked films for drug delivery applications. Macromol Symp. 2009;279:169–74.CrossRefGoogle Scholar
  13. 13.
    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.CrossRefPubMedGoogle Scholar
  14. 14.
    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.Google Scholar
  15. 15.
    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.CrossRefGoogle Scholar
  16. 16.
    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.CrossRefPubMedGoogle Scholar
  17. 17.
    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.CrossRefGoogle Scholar
  18. 18.
    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.CrossRefPubMedGoogle Scholar
  19. 19.
    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.PubMedGoogle Scholar
  20. 20.
    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.CrossRefPubMedGoogle Scholar
  21. 21.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    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.CrossRefPubMedGoogle Scholar
  23. 23.
    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.CrossRefPubMedGoogle Scholar
  24. 24.
    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.CrossRefPubMedGoogle Scholar
  25. 25.
    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.CrossRefPubMedGoogle Scholar
  26. 26.
    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.CrossRefPubMedGoogle Scholar
  27. 27.
    Sasikala L, Durai B, Rathinamoorthy R. Manuka honey loaded chitosan hydrogel films for wound dressing applications. 2013.Google Scholar
  28. 28.
    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.CrossRefPubMedGoogle Scholar
  29. 29.
    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.PubMedGoogle Scholar
  30. 30.
    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.CrossRefPubMedGoogle Scholar
  31. 31.
    Allegrini P, Razzetti G, Bologna A, Magrone D, Ventimiglia G. A process for the purification of imiquimod. Google Patents; 2007.Google Scholar
  32. 32.
    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.CrossRefGoogle Scholar
  33. 33.
    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.
  34. 34.
    Barnes L. The management of basal cell carcinomas. Ir Med J. 2006;99(6):179–81.PubMedGoogle Scholar
  35. 35.
    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.CrossRefGoogle Scholar
  36. 36.
    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.CrossRefGoogle Scholar
  37. 37.
    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.CrossRefPubMedGoogle Scholar
  38. 38.
    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.CrossRefPubMedGoogle Scholar
  39. 39.
    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.CrossRefPubMedGoogle Scholar
  40. 40.
    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.CrossRefGoogle Scholar
  41. 41.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    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.CrossRefPubMedGoogle Scholar
  43. 43.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    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.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Buddhadev Layek
    • 1
  • Saif S. Rahman Nirzhor
    • 2
  • Sneha Rathi
    • 2
  • Karunya K. Kandimalla
    • 2
  • Timothy S. Wiedmann
    • 2
  • Swayam Prabha
    • 1
    • 2
    Email author
  1. 1.Department of Experimental and Clinical Pharmacology, College of PharmacyUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of Pharmaceutics, College of PharmacyUniversity of MinnesotaMinneapolisUSA

Personalised recommendations