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Mucoadhesive Polymeric Films to Enhance Barbaloin Penetration Into Buccal Mucosa: a Novel Approach to Chemoprevention

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Abstract

Nowadays, chemoprevention by administering natural supplements is considered an attractive strategy to reverse, suppress, or prevent the evolution of premalignant oral lesions. In particular, Barbaloin exhibits anti-proliferative, anti-inflammatory, and anti-cancer properties, and it results useful in multi-therapy with classic chemotherapeutics. Therefore, in this work, mucoadhesive buccal films, as locoregional drug delivery system able to provide a targeted and efficient therapeutic delivery of Barbaloin, are proposed. Thus, Aloin extract-loaded Eudragit® RL100 or Eudragit® RS100-based buccal films were designed in order to obtain an easily self-administrable formulation capable of promoting Barbaloin penetration into buccal mucosa and assuring high patient compliance. Large amounts of extract (44%) were loaded into the polymer matrix and six formulations were prepared varying polymers and plasticizers ratios. For all formulations, physical form (thermogravimetric analysis-differential scanning calorimetry, TGA-DSC), swelling degree, mucoadhesiveness, drug release, and ability to promote drug penetration in mucosa have been investigated. After a sequential selection process, Eudragit RS 100-based film, with low PVP and high plasticizers amounts, emerged as the most promising. It results appropriately flexible, uniform in terms of weight, thickness and drug content, as well as characterized by suitable surface pH, good mucoadhesiveness, and low swelling degree. It displays a Higuchian drug release behavior up to 89% of Barbaloin released, thus demonstrating that diffusion through the matrix is the main release mechanism. Remarkable penetration enhancer properties of film were demonstrated by evidence of Barbaloin accumulation into buccal mucosa up to 10-fold higher than those obtained following administration of Aloin solution.

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References

  1. Nguyen S, Hiorth M. Advanced drug delivery systems for local treatment of the oral cavity. Ther Deliv. 2015;6(5):595–608.

    Article  CAS  Google Scholar 

  2. Sankar V, Hearnden V, Hull K, Juras DV, Greenberg M, Kerr A et al. Local drug delivery for oral mucosal diseases: challenges and opportunities. Oral Dis. 17(s1):73–84.

  3. van der Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management. Oral Oncol. 2009;45(4–5):317–23.

    Article  Google Scholar 

  4. Johnson JJ, Miller DL, Jiang R, Liu Y, Shi Z, Tarwater L et al.. Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB activation suppresses inflammation-associated tumor suppressor MicroRNAs in oral squamous cell carcinoma. J Biol Chem. 2016;291(13):6936–45.

    Article  CAS  Google Scholar 

  5. Goodson ML, Sloan P, Robinson CM, Cocks K, Thomson PJ. Oral precursor lesions and malignant transformation—who, where, what, and when? Br J Oral Maxillofac Surg. 2015;53(9):831–5.

    Article  CAS  Google Scholar 

  6. Coppen C, de Wilde PCM, Pop LA, van den Hoogen FJA, Merkx MAW. Treatment results of patients with a squamous cell carcinoma of the buccal mucosa. Oral Oncol. 2006;42(8):795–9.

    Article  Google Scholar 

  7. Mallery S, Desai K-G, Holpuch A, Schwendeman S. Optimizing therapeutic efficacy of chemopreventive agents: a critical review of delivery strategies in oral cancer chemoprevention clinical trials. J Carcinog. 2011;10(1):23.

    Article  Google Scholar 

  8. Fotedar V, Fotedar S, Seam RK, Gupta MK. Oral cancer and chemoprevention. Int J Pharm Sci Inv. 2013;2(2):16–20.

    Google Scholar 

  9. Ramshankar V, Krishnamurthy A. Chemoprevention of oral cancer: green tea experience. J Nat Sci Biol Med. 2014;5(1):3–7.

    Article  Google Scholar 

  10. Adeeb S, Fazli W, Sup LY. Curcumin in cancer chemoprevention: molecular targets, pharmacokinetics, bioavailability, and clinical trials. Arch Pharm (Weinheim). 343(9):489–99.

  11. Harlev E, Nevo E, Lansky EP, Ofir R, Bishayee A. Anticancer potential of aloes: antioxidant, antiproliferative, and immunostimulatory attributes. Planta Med. 2012;78(9):843–52.

    Article  CAS  Google Scholar 

  12. Choi S, Chung M-H. A review on the relationship between aloe vera components and their biologic effects. Semin Integr Med. 2003;1(1):53–62.

    Article  Google Scholar 

  13. Zhong J, Huang Y, Ding W, Wu X, Wan J, Luo H. Chemical constituents of Aloe barbadensis Miller and their inhibitory effects on phosphodiesterase-4D. Fitoterapia. 2013;91:159–65.

    Article  CAS  Google Scholar 

  14. Esmat AY, Said MM, Khalil SA. Aloin: a natural antitumor anthraquinone glycoside with iron chelating and non-atherogenic activities. Pharm Biol. 2015;53(1):138–46.

    Article  CAS  Google Scholar 

  15. Liu FW, Liu FC, Wang YR, Tsai HI, Yu HP. Aloin protects skin fibroblasts from heat stress-induced oxidative stress damage by regulating the oxidative defense system. PLoS One. 2015;10(12):1–14.

    Google Scholar 

  16. Niciforovic A, Adzic M, Zaric BRM. Adjuvant antiproliferative and cytotoxic effect of aloin in irradiated HeLaS3 cells. Russ J Phys Chem. 2007;9(81):1463–6.

    Article  Google Scholar 

  17. Park MY, Kwon HJ, Sung MK. Dietary aloin, aloesin, or aloe-gel exerts anti-inflammatory activity in a rat colitis model. Life Sci. 2011;88(11–12):486–92.

    Article  CAS  Google Scholar 

  18. Lucini L, Pellizzoni M, Pellegrino R, Pietro MG, Colla G. Phytochemical constituents and in vitro radical scavenging activity of different Aloe species. Food Chem. 2015;170:501–7.

    Article  CAS  Google Scholar 

  19. Kumar S, Matharasi DP, Gopi S, Sivakumar SNS. Synthesis of cytotoxic and antioxidant Schiff’s base analogs of aloin. J Asian Nat Prod Res. 2010;5(12):360–70.

    Article  Google Scholar 

  20. Tabolacci C, Rossi S, Lentini A, Provenzano B, Turcano L, Facchiano F et al. Aloin enhances cisplatin antineoplastic activity in B16-F10 melanoma cells by transglutaminase-induced differentiation. Amino Acids. 2013;44(1):293–300.

    Article  CAS  Google Scholar 

  21. Hamiza OO, Rehman MUKR. Chemopreventive effects of aloin against 1,2-dimethylhydrazine-induced preneoplastic lesions in the colon of Wistar rats. Hum Exp Toxicol. 2014;33:148–63.

    Article  CAS  Google Scholar 

  22. Salamat-Miller N, Chittchang M, Johnston T. The use of mucoadhesive polymers in buccal drug delivery. Adv Drug Deliv Rev. 2005;57(11):1666–91.

    Article  CAS  Google Scholar 

  23. Dixit RP, Puthli SP. Oral strip technology: overview and future potential. J Control Release. 2009;139(2):94–107.

    Article  CAS  Google Scholar 

  24. Gal JY, Fovet Y, Adib-Yadzi M. About a synthetic saliva for in vitro studies. Talanta. 2001;53(6):1103–15.

    Article  CAS  Google Scholar 

  25. Scaturro AL, De Caro V, Campisi G, Giannola LI. Potential transbuccal delivery of l-DOPA methylester prodrug: stability in the environment of the oral cavity and ability to cross the mucosal tissue. Drug Deliv. 2016;23(7):2355–62.

    CAS  PubMed  Google Scholar 

  26. Mahesh A, Shastri N, Sadanandam M. Development of taste masked fast disintegrating films of levocetirizine dihydrochloride for oral use. Curr Drug Deliv. 2010;7(1):21–7.

    Article  CAS  Google Scholar 

  27. Irfan M, Rabel S, Bukhtar Q, Qadir MI, Jabeen F, Khan A. Orally disintegrating films: a modern expansion in drug delivery system. Saudi Pharm J. 2016;24(5):537–46.

    Article  Google Scholar 

  28. Senthilkumar K, Vijaya C. Formulation development of mouth dissolving film of Etoricoxib for pain management. Adv Pharm. 2015;2015:1–11.

    Google Scholar 

  29. Kassem MA, Elmeshad AN, Fares AR. Enhanced bioavailability of buspirone hydrochloride via cup and core buccal tablets: formulation and in vitro/in vivo evaluation. Int J Pharm. 2014;463(1):68–80.

    Article  CAS  Google Scholar 

  30. Semalty M, Semalty A, Kumar G. Formulation and characterization of mucoadhesive buccal films of glipizide. Indian J Pharm Sci. 2008;70(1):43–8.

    Article  Google Scholar 

  31. Giannola LI, De Caro V, Giandalia G, Siragusa MG, D’Angelo M, Lo Muzio L et al. Transbuccal tablets of carbamazepine: formulation, release and absorption pattern. Int J Immunopathol Pharmacol. 2005;18(3 Suppl):21–31.

    CAS  PubMed  Google Scholar 

  32. Siepmann J, Siepmann F. Mathematical modeling of drug delivery. Int J Pharm. 2008;364(2):328–43.

    Article  CAS  Google Scholar 

  33. Frenning G. Modelling drug release from inert matrix systems: from moving-boundary to continuous-field descriptions. Int J Pharm. 2011;418(1):88–99.

    Article  CAS  Google Scholar 

  34. Siepmann J, Peppas NA. Higuchi equation: derivation, applications, use and misuse. Int J Pharm. 2011;418(1):6–12.

    Article  CAS  Google Scholar 

  35. De Caro V, Giandalia G, Siragusa MG, Sutera FM, Giannola LI. New prospective in treatment of Parkinson’s disease: studies on permeation of ropinirole through buccal mucosa. Int J Pharm. 2012.

  36. Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm. 2010;67(3):217–23.

    CAS  PubMed  Google Scholar 

  37. Sudhakar Y, Kuotsu K, Bandyopadhyay AK. Buccal bioadhesive drug delivery—a promising option for orally less efficient drugs. J Control Release. 2006;114(1):15–40.

    Article  CAS  Google Scholar 

  38. Mura P, Cirri M, Mennini N, Casella G, Maestrelli F. Polymeric mucoadhesive tablets for topical or systemic buccal delivery of clonazepam: effect of cyclodextrin complexation. Carbohydr Polym. 2016;152:755–63.

    Article  CAS  Google Scholar 

  39. Joshi M. Role of Eudragit in targeted drug delivery. Int J Curr Pharm Res. 2013;5(2):58–62.

    CAS  Google Scholar 

  40. Bravo-Osuna I, Vauthier C, Farabollini A, Palmieri GF, Ponchel G. Mucoadhesion mechanism of chitosan and thiolated chitosan-poly(isobutyl cyanoacrylate) core-shell nanoparticles. Biomaterials. 2007;28(13):2233–43.

    Article  CAS  Google Scholar 

  41. Sfondrini MF, Fraticelli D, Barbati M, Scribante A, Gandini P. Effects of a new pharmaceutical preparation on the soft tissues healing after apthous lesions in pediatric patients. Dent Cadmos. 2012;80(6):334–9.

    Article  Google Scholar 

  42. Mennella JA, Beauchamp GK. Optimizing oral medications for children. Clin Ther. 2008;30(11):2120–32.

    Article  Google Scholar 

  43. Hutteau F, Mathlouthi M, Portmann MO, Kilcast D. Physicochemical and psychophysical characteristics of binary mixtures of bulk and intense sweeteners. Food Chem. 1998;63(1):9–16.

    Article  CAS  Google Scholar 

  44. De Caro V, Giandalia G, Siragusa MG, Giannola LI. Buccal delivery of Methimazole as an alternative means for improvement of drug bioavailability: permeation studies and matrix system design. Curr Pharm Des. 2012;18(34):5405–10.

    Article  Google Scholar 

  45. Sarı A, Biçer A, Karaipekli A. Synthesis, characterization, thermal properties of a series of stearic acid esters as novel solid–liquid phase change materials. Mater Lett. 2009;63(13):1213–6.

    Article  Google Scholar 

  46. Sax G, Winter G. Mechanistic studies on the release of lysozyme from twin-screw extruded lipid implants. J Control Release. 2012;163(2):187–94.

    Article  CAS  Google Scholar 

  47. Nair AB, Kumria R, Harsha S, Attimarad M, Al-Dhubiab BE, Alhaider IA. In vitro techniques to evaluate buccal films. J Control Release. 2013;166(1):10–21.

    Article  CAS  Google Scholar 

  48. Andrews GP, Laverty TP, Jones DS. Mucoadhesive polymeric platforms for controlled drug delivery. Eur J Pharm Biopharm. 2009;71(3):505–18.

    Article  CAS  Google Scholar 

  49. De Caro V, Ajovalasit A, Sutera FM, Murgia D, Sabatino MA, Dispenza C. Development and characterization of an amorphous solid dispersion of furosemide in the form of a sublingual bioadhesive film to enhance bioavailability. Pharmaceutics. 2017;9(3).

  50. Pan Q, Pan H, Lou H, Xu Y, Tian L. Inhibition of the angiogenesis and growth of Aloin in human colorectal cancer in vitro and in vivo. Cancer Cell Int. 2013;13:69.

    Article  CAS  Google Scholar 

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Acknowledgments

Authors are thankful to Dr. Francesco Carfì Pavia and ATeN Center of Palermo for technical support for DSC analyses.

Funding

Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research) MFAG 2017 Id.19982.

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Authors and Affiliations

  1. Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Via Ugo La Malfa 153, 90146, Palermo, Italy

    Giulia Di Prima

  2. Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi, 32, 90123, Palermo, Italy

    Giulia Di Prima & Viviana De Caro

  3. Dipartimento di Biopatologia e Biotecnologie Mediche (DIBIMED), Università degli Studi di Palermo, Via Divisi 83, 90133, Palermo, Italy

    Alice Conigliaro

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  1. Giulia Di Prima
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Correspondence to Viviana De Caro.

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Di Prima, G., Conigliaro, A. & De Caro, V. Mucoadhesive Polymeric Films to Enhance Barbaloin Penetration Into Buccal Mucosa: a Novel Approach to Chemoprevention. AAPS PharmSciTech 20, 18 (2019). https://doi.org/10.1208/s12249-018-1202-1

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