Journal of Pharmaceutical Innovation

, Volume 14, Issue 1, pp 15–27 | Cite as

Preparation and Evaluation of a Bio-Erodible Bio-Adhesive Drug Delivery System Designed for Intraoral Extended Release of Flurbiprofen: In Vitro and In Vivo Assessments

  • Adel PenhasiEmail author
  • Albert Reuveni
Original Article



Site-specific drug delivery for the local treatment of the diseases in the oral cavity is far superior to the systemic administration, for both safety and efficacy reasons. This study presents the design and development of an innovative bio-adhesive delivery system (BDS) based on a bio-erodible semi-interpenetrating polymeric network (semi-IPN) for intraoral extended release of flurbiprofen (FBP).


A unique combination of hydrolyzed gelatin (HG) cross-linked by tannic acid (TA) and Eudragit S, as the linear polymer, was used to compose the structure of the semi-IPN. The effect of structural factors, associated with the composition of the semi-IPN, on the release profile of FBP from the system was assessed using an in vitro dissolution method. The release rate of the drug in the oral cavity of healthy volunteers was also studied.


The degree of cross-linking of HG and the weight ratio between the cross-linked polymer and the linear polymer were found to be crucial factors affecting the release profile of FBP from the system. Likewise, the presence of a high concentration of plasticizer was essential for achieving a proper flexibility of the system as proved by a DSC method. The in vivo tests demonstrated a disparity between the volunteers in the FBP concentration found in the saliva, especially after 120 min post-administration of BDS. Both f1 and f2 tests indicated that the packaged BDS can be absolutely stable for at least 6 months at 30 °C.


Site-specific drug delivery Semi-interpenetrating polymeric network (semi-IPN) Topical treatment Dissolution test Hydrolyzed gelatin Tannic acid Eudragit S 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Danckwerts MP. Intraoral drug delivery—a comparative review. Am J Drug Deliv. 2003;1:171–86.CrossRefGoogle Scholar
  2. 2.
    Paderni C, Compilato D, Giannola LI, Campisi G. Oral local drug delivery and new perspectives in oral drug formulation. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114:e25–34.CrossRefGoogle Scholar
  3. 3.
    Nguyen S, Hiorth M. Advanced drug delivery systems for local treatment of the oral cavity. Ther Deliv. 2015;6:595–608.CrossRefGoogle Scholar
  4. 4.
    Amin WM, al-Ali MH, Salim NA, al-Tarawneh SK. A new form of intraoral delivery of antifungal drugs for the treatment of denture-induced oral candidosis. Eur J Dent. 2009;3:257–66.Google Scholar
  5. 5.
    Li B, Robinson JR. Preclinical assessment of oral mucosal drug delivery systems. In: Ghosh TK, Pfister WR, editors. Drug delivery to the oral cavity—molecules to market. Boca Raton: CRC Press, Taylor & Francis Group; 2005. p. 42–60.Google Scholar
  6. 6.
    Desai KGH. Polymeric drug delivery systems for intraoral site-specific chemoprevention of oral cancer. J Biomed Mater Res B Appl Biomater. 2017;106:1383–413. Scholar
  7. 7.
    Aksungur P, Sungur A, Ünal S, İskit AB, Squier CA, Şenel S. Chitosan delivery systems for the treatment of oral mucositis: in vitro and in vivo studies. J Control Release. 2004;98:269–79.CrossRefGoogle Scholar
  8. 8.
    Seals RR Jr, Aufdemorte TB, Cortes AL, Parel SM. An intraoral drug delivery system. J Prosthet Dent. 1989;61:239–42.Google Scholar
  9. 9.
    Neppelenbroek KH. Sustained drug-delivery system: a promising therapy for denture stomatitis? J Appl Oral Sci. 2016;24:420–2. Scholar
  10. 10.
    Li YJ, Lu CC, Tsai WL, Tai MH. An intra-oral drug delivery system design for painless, long-term and continuous drug release. Sensors Actuators B Chem. 2016;227:573–82.CrossRefGoogle Scholar
  11. 11.
    Yum SI, Yum E. Drug delivery systems for the treatment of periodontal and dental diseases. In: Ghosh TK, Pfister WR, editors. Drug delivery to the oral cavity—molecules to market. Boca Raton: CRC Press, Taylor & Francis Group; 2005. p. 211–33.CrossRefGoogle Scholar
  12. 12.
    Sipos T. Intraoral medicament-releasing device. 1995; United States Patent: 5,433,952.Google Scholar
  13. 13.
    NH004—Treatment for sialorrhea. In: Neurohealing Pharmaceuticals Inc. 2016. Accessed 01 Nov 2016.
  14. 14.
    Davidson RS. Edible film for relief of cough or symptoms associated with pharyngitis. 2004; WO 2004045537 A2.Google Scholar
  15. 15.
    Pfister WR, systems GTKI d. An overview, current status, and future trends. In: Ghosh TK, Pfister WR, editors. Drug delivery to the oral cavity—molecules to market. Boca Raton: CRC Press, Taylor & Francis Group; 2005. p. 2–31.Google Scholar
  16. 16.
    Patel VF, Liu F, Brown MB. Advances in oral transmucosal drug delivery. J Control Release. 2011;153:106–16.CrossRefGoogle Scholar
  17. 17.
    Kaur N, Kokate A, Li X, Jasti B. Transmucosal drug delivery. In: Mitra AK, Kwatra D, Vadlapudi AD, editors. Drug delivery. Burlington: Jones & Bartlett Learning; 2014. p. 264–79.Google Scholar
  18. 18.
    Chaudhary SA, Shahiwala AF. Medicated chewing gum—a potential drug delivery system. Expert Opin Drug Deliv. 2010;7:871–85.CrossRefGoogle Scholar
  19. 19.
    Hoffmann EM, Breitenbach A, Breitkreutz J. Advances in orodispersible films for drug delivery. Expert Opin Drug Deliv. 2011;8:299–316.CrossRefGoogle Scholar
  20. 20.
    Priyanka Nagar P, et al. Orally disintegrating tablets: formulation, preparation techniques and evaluation. J Appl Pharm Sci. 2011;1:35–45.Google Scholar
  21. 21.
    Garg D, Aggarwal G, Harikumar SL. Fast dissolving drug delivery systems. World. J Pharm Pharm Sci. 2016;5:833–49.Google Scholar
  22. 22.
    Bircher AJ, Howald H, Rufli TH. Adverse skin reactions to nicotine in a transdermal therapeutic system. Contact Dermatitis. 1991;25:230–6.CrossRefGoogle Scholar
  23. 23.
    Sentrakul P, Chompootaweep S, Sintupak S, Tasanapradit P, Tunsaringkarn K, Dusitsin N. Adverse skin reactions to transdermal oestradiol in tropical climate. A comparative study of skin tolerance after using oestradiol patch and gel in Thai postmenopausal women. Maturitas. 1991;13:151–4.CrossRefGoogle Scholar
  24. 24.
    Jain N, Kumar Sharma P, Banik A, Gupta A, Bhardwaj V. Pharmaceutical and biomedical applications of interpenetrating polymer network. Curr Drug Ther. 2011;6:263–70.CrossRefGoogle Scholar
  25. 25.
    Lohani A, Singh G, Bhattacharya SS, Verma A. Interpenetrating polymer networks as innovative drug delivery systems. J Drug Deliv. 2014;583612:1–11.Google Scholar
  26. 26.
    Roland CM. Interpenetrating Polymer Networks (IPN): structure and mechanical behavior. In: Kobayashi S, Müllen K, editors. Encyclopedia of polymeric nanomaterials. Berlin Heidelberg: Springer-Verlag; 2013. p. 1–10. Scholar
  27. 27.
    Zhang X, Do MD, Casey P, Sulistio A, Qiao GG, Lundin L, et al. Chemical modification of gelatin by a natural phenolic cross-linker, tannic acid. J Agric Food Chem. 2010b;58:6809–15.CrossRefGoogle Scholar
  28. 28.
    Stewart M. Flurbiprofen tablets for pain and inflammation. Patient making lives better. 2017. Accessed 15 Nov 2017.
  29. 29.
    Stokman MA, Spijkervet FKL, Burlage FR, Roodenburg JLN. Clinical effects of flurbiprofen tooth patch on radiation-induced oral mucositis. A pilot study. Support Care Cancer. 2005;13:42–8.CrossRefGoogle Scholar
  30. 30.
    Russo M, Bloch M, de Looze F, Morris C, Shephard A. Flurbiprofen microgranules for relief of sore throat: a randomized, double-blind trial. Br J Gen Pract. 2013;63:e149–55.CrossRefGoogle Scholar
  31. 31.
    Machtei EE, Hirsh I, Falah M, Shoshani E, Avramoff A, Penhasi A. Multiple applications of flurbiprofen and chlorhexidine chips in patients with chronic periodontitis: a randomized, double blind, parallel, 2-arms clinical trial. J Clin Periodontol. 2011;38:1037–43.CrossRefGoogle Scholar
  32. 32.
    International Council for Harmonisation (ICH) guidelines for validation of analytical procedures, Q2B. Methodology 1996.Google Scholar
  33. 33.
    Tammineni N, Rasco B, Powers J, Nindo C, Ünlü G. Bovine and fish gelatin coatings incorporating tannins: effect on physical properties and oxidative stability of salmon fillets. J Food Chem Nutr. 2014;02:93–102.Google Scholar
  34. 34.
    Patra CN, et al. Pharmaceutical significance of Eudragit: a review. Future J Pharm Sci. 2017;3:33–45.CrossRefGoogle Scholar
  35. 35.
    Kshirsagar SJ, Bhalekar MR, Umap RR. In vitro in vivo comparison of two pH sensitive Eudragit polymers for colon specific drug delivery. J Pharm Sci Res. 2009;1:61–70.Google Scholar
  36. 36.
    Smart JD. The basics and underlying mechanisms of mucoadhesion. Adv Drug Deliv Rev. 2005;57:1556–68.CrossRefGoogle Scholar
  37. 37.
    Gedde UW. Polymer physics. 1st ed. London: Kluwer Academic Publishers; 1999.CrossRefGoogle Scholar
  38. 38.
    Jadhav NR, Gaikwad VL, Nair KJ, Kadam HM. Glass transition temperature: basics and application in pharmaceutical sector. Asian J Pharm. 2009;3:82–9.CrossRefGoogle Scholar
  39. 39.
    Zaman HU, Khan MA, Khan RA. Studies on the thermo-mechanical properties of gelatin based films using 2-hydroxyethyl methacrylate by gamma radiation. Open J Compos Mater. 2012;2:15–21.CrossRefGoogle Scholar
  40. 40.
    Chuaynukul K, Prodpran T, Benjakul S. Preparation, thermal properties and characteristics of gelatin molding compound resin. Res J Chem Environ Sci. 2014;2:1–9.Google Scholar
  41. 41.
    Shehap AM, Mahmoud KhH, Abd El-Kader MFH, El-Basheer TM. Preparation and thermal properties of gelatin/TGS composite films. Middle East J Appl Sci. 2015;5:157–70.Google Scholar
  42. 42.
    Fadda HM, Khanna M, Santos JC, Osman D, Gaisford S, Basit AW. The use of dynamic mechanical analysis (DMA) to evaluate plasticization of acrylic polymer films under simulated gastrointestinal conditions. Eur J Pharm Biopharm. 2010;76:493–7.CrossRefGoogle Scholar
  43. 43.
    Babkina NV, Lipatov YS, Alekseeva TT, Sorochinskaya LA, Datsyuk YI. Effect of spatial constraints on phase separation during polymerization in sequential semi-interpenetrating polymer networks. Polym Sci Ser A. 2008;50:798–807.CrossRefGoogle Scholar
  44. 44.
    Bauer BJ, Briber RM, Han CC. Small-angle neutron scattering studies of compatible blends of linear poly(vinyl methyl ether) and cross-linked deuterated polystyrene. Macromolecules. 1989;22:940–8.CrossRefGoogle Scholar
  45. 45.
    Snejdrova E, Dittrich M. Pharmaceutically used plasticizers. In: Luqman M, editor. Recent advances in plasticizers. InTech; 2012. p. 45–68. ISBN: 978-953-51-0363-9, Accessed 15 Nov 2017.
  46. 46.
    Marques RCM, Loebenberg R, Almukainzi M. Simulated biological fluids with possible application in dissolution testing. Dissolution Technol. 2011;18:15–28.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Research and DevelopmentPolyCaps Ltd.Tel AvivIsrael
  2. 2.Department of Pharmaceutical EngineeringThe Azrieli Jerusalem College of EngineeringJerusalemIsrael

Personalised recommendations