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AAPS PharmSciTech

, Volume 18, Issue 5, pp 1617–1623 | Cite as

Evaluation of the Safety, Cell Migration, and Mucoadhesive Properties of a Mucoadhesive Polymer Blend in Human Oral Mucosa

  • Guiyun Song
  • Daniel Banov
  • August S. Bassani
  • Benigno C. Valdez
Research Article
First Online:
Received:
Accepted:

Abstract

The efficacy of active pharmaceutical ingredients (API) in compounded medications for oral mucosa greatly depends on the composition of the base. Here, we assessed the safety, facilitation of cell migration, and mucoadhesive properties of a newly developed mucoadhesive polymer blend (MPB) which contains pullulan, tamarindus indica polysaccharide, and sodium hyaluronate. No cell death was observed when human oral keratinocyte (HOK) and fibroblast (HOrF) cells were exposed to 1% MPB for 24 h. Epithelial cells in a 3D buccal tissue model (EpiOral) were unaffected when exposed to 50% MPB for 20 h whereas 1% Triton X-100 killed 93% cells after 4.5 h. The expressions of cytokines IL1α and IL1β and cell proliferation markers PCNA, CYCLIN A, and CYCLIN D1 in EpiOral tissue did not increase suggesting that MPB is neither an irritant nor a mitogen. Markers of apoptosis such as cleavage of CASPASES 8/9, upregulation of pro-apoptosis NOXA protein, and downregulation of anti-apoptosis XIAP protein were observed in Triton X-100-treated cells but not in cells exposed to MPB. The migration of HOK and HOrF cells was stimulated by MPB, and the expression of E-CADHERIN in the EpiOral tissues was unaffected. Moreover, MPB showed stronger mucoadhesion on the human EpiOral tissue model compared with a reference product. We conclude that MPB can safely deliver API within the oral mucosa, facilitate cell migration, and may increase drug efficacy through its strong mucoadhesive property.

KEY WORDS

cell migration compounded medication mucoadhesive polymer blend oral mucosa 
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REFERENCES

  1. 1.
    Ahuja A, Khar RK, Ali J. Mucoadhesive drug delivery systems. Drug Dev Ind Pharm. 1997;23:489–515.CrossRefGoogle Scholar
  2. 2.
    Bruschi M, Freitas O. Oral bioadhesive drug delivery system. Drug Dev Ind Pharm. 2005;31:293–310.CrossRefPubMedGoogle Scholar
  3. 3.
    Boddupalli BM, Mohammed ZNK, Nath RA, Banji D. Mucoadhesive drug delivery system: An overview. J Adv Pharm Technol Res. 2010;2:381–7.CrossRefGoogle Scholar
  4. 4.
    Giannola LI, Caro VD, Giandalia G, et al. A. Current status in buccal drug delivery. Pharm Technol Eur. 2008;20:32-6–8–9.Google Scholar
  5. 5.
    Hao J, Heng P. Buccal delivery systems. Drug Dev Ind Pharm. 2003;29:821–32.CrossRefPubMedGoogle Scholar
  6. 6.
    Salamat N, Chittchang M, Johnston T. The use of mucoadhesive polymers in buccal drug delivery. Adv Drug Deliv Rev. 2005;57:1666–91.CrossRefGoogle Scholar
  7. 7.
    Shojaei AH. Buccal mucosa as a route for systemic drug delivery: A review. J Pharm Pharm Sci. 1998;1:15–30.PubMedGoogle Scholar
  8. 8.
    Koschier F, Kostrubsky V, Toole C, Galio MA. In vitro effects of ethanol and mouthrinse on permeability in an oral buccal mucosa tissue construct. Food Chem Toxicol. 2011;49:2524–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55–63.CrossRefPubMedGoogle Scholar
  10. 10.
    Klausner M, Ayehunie S, Breyfogle BA, Wertz PW, Bacca L, Kubilus J. Organotypic human oral tissue models for toxicological studies. Toxicol in Vitro. 2007;21:938–49.CrossRefPubMedGoogle Scholar
  11. 11.
    Moharamzadeh K, Franklin KL, Brook IM, van Noort R. Biologic assessment of antiseptic mouthwashes using a three-dimensional human oral mucosal model. J Periodontol. 2009;80:769–75.CrossRefPubMedGoogle Scholar
  12. 12.
    Valdez BC, Li Y, Murray D, Champlin RE, Andersson BS. The synergistic cytotoxicity of clofarabine, fludarabine and busulfan in AML cells involves ATM pathway activation and chromatin remodeling. Biochem Pharmacol. 2011;81:222–32.CrossRefPubMedGoogle Scholar
  13. 13.
    Gough W, Hulkower KI, Lynch R, McGlynn P, Uhlik M, Yan L, et al. A quantitative, facile, and highthroughput image-based cell migration method is a robust alternative to the scratch assay. J Biomol Screen. 2011;16:155–63.CrossRefPubMedGoogle Scholar
  14. 14.
    Cohen GM. Caspases: the executioners of apoptosis. Biochem J. 1997;326:1–16.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature. 1997;388:300–4.CrossRefPubMedGoogle Scholar
  16. 16.
    Ploner C, Kofler R, Villunger A. Noxa: at the tip of the balance between life and death. Oncogene. 2008;27:S84–92.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 1998;273:5858–68.CrossRefPubMedGoogle Scholar
  18. 18.
    Maga G, Hubscher U. Proliferating cell nuclear antigen (PCNA): a dancer with many partners. J Cell Sci. 2003;116:3051–60.CrossRefPubMedGoogle Scholar
  19. 19.
    Lukas J, Bartkova J, Bartek J. Convergence of mitogenic signaling cascades from diverse classes of receptors at the cyclin D-cyclin-dependent kinase-pRb-controlled G1 checkpoint. Mol Cell Biol. 1996;16:6917–25.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Roguet R. Use of skin cell cultures for in vitro assessment of corrosion and cutaneous irritancy. Cell Biol Toxicol. 1999;15:63–75.CrossRefPubMedGoogle Scholar
  21. 21.
    Warren R, Schwartz J, Sanders L, Juneja P. Attenuation of surfactant-induced interleukin 1α and expression by zinc pyrithione. Exog Dermatol. 2003;2:23–7.CrossRefGoogle Scholar
  22. 22.
    Thakur RA, Michniak BB, Meidan VM. Transdermal and buccal delivery of methylxanthines through human tissue in vitro. Drug Dev Ind Pharm. 2007;33:513–21.CrossRefPubMedGoogle Scholar
  23. 23.
    Lambros MP, Parsa C, Mulamalla HC, et al. Identifying cell and molecular stress after radiation in a three-dimensional (3-d) model of oral mucositis. Biochem Biophys Res Commun. 2011;405:102–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Yadev NP, Murdoch C, Saville SP, Thornhill MH. Evaluation of tissue engineered models of the oral mucosa to investigate oral candidiasis. Microb Pathog. 2011;50:278–85.CrossRefPubMedGoogle Scholar
  25. 25.
    Sridevi U, Jain A, Nagalaxmi V, Kumar UV, Goyal S. Expression of E-cadherin in normal oral mucosa, in oral precancerous lesions and in oral carcinomas. Eur J Dent. 2015;9:364–72.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kumar D, Saimi N, Pandit V, Ali S. An insight to pullulan: a biopolymer in pharmaceutical approaches. Int J Basic Appl Sci. 2012;1:202–19.Google Scholar
  27. 27.
    Xi K, Tabat Y, Uno K, Yoshimoto M, Kishida T, Sokawa Y, et al. Liver targeting of interferon through pullulan conjugation. Pharm Res. 1996;13:1846–50.CrossRefPubMedGoogle Scholar
  28. 28.
    Scomparin A, Salmaso S, Bersani S, Satchi-Fainaro R, Caliceti P. Novel folated and non-folated pullulan bioconjugates for anti-cancer drug delivery. Eur J Pharm Sci. 2011;42:547–58.CrossRefPubMedGoogle Scholar
  29. 29.
    Takahashi Y, Takeda C, Seto I, Kawano G, Machida Y. Formulation and evaluation of lactoferrin bioadhesive tablets. Int J Pharm. 2007;3:220–7.CrossRefGoogle Scholar
  30. 30.
    Law CH, Li JM, Cho HC, Chen YH, Chan HL. Hyaluronic acid-dependent protection in H9C2 cardiomyocytes; a cell model of heart ischemia-reperfusion injury and treatment. Toxicology. 2013;303:54–71.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2016

Authors and Affiliations

  1. 1.Professional Compounding Centers of AmericaHoustonUSA
  2. 2.Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer CenterUniversity of TexasHoustonUSA

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