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Development and In Vitro-In Vivo Evaluation of Fenretinide-Loaded Oral Mucoadhesive Patches for Site-Specific Chemoprevention of Oral Cancer

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ABSTRACT

Purpose

To develop fenretinide oral mucoadhesive patch formulations and evaluate their in vitro and in vivo release performance for future site-specific chemoprevention of oral cancer.

Methods

Solubilization of fenretinide in simulated saliva (SS) was studied by incorporating nonionic surfactants (Tween® 20 and 80, and Brij® 35 and 98), bile salts (sodium salt of cholic, taurocholic, glycocholic, and deoxycholic acids), phospholipid (lecithin), and novel polymeric solubilizer (Souplus®). Adhesive (polycarbophil: hydroxypropyl methylcellulose 4KM) and drug release (Fenretinide/Eudragit® RL PO with or without solubilizers) layers were prepared by solvent casting. Oral mucoadhesive patches were formed by attaching drug and adhesive layers onto backing layer (Tegaderm™ film). Physical state of drug in Eudragit® films was examined by X-ray diffraction (XRD). Evaluation of in vitro and in vivo fenretinide release from the patch was conducted in SS containing 5%w/v sodium deoxycholate and rabbits, respectively. Fenretinide was quantified by HPLC.

Results

Tween® 20 and 80, Brij® 98, and sodium deoxycholate exhibited the highest fenretinide solubilization potential among the solubilizers. Drug loading efficiency in Eudragit® films was 90%–97%. XRD suggested fenretinide was amorphous in solubilizer-free and solubilizer-loaded films. Solubilizer-free patch exhibited poor in vitro and in vivo controlled drug release behavior. Increases in drug loading (5–10 wt%) or changes in polymeric matrix permeability did not provide continuous drug release. Co-incorporation of either single or mixed solubilizers in fenretinide/Eudragit® patches, (20 wt% Tween® 20, Tween® 80 and sodium deoxycholate or 20 wt% Tween® 80 + 40 wt% sodium deoxycholate solubilizers) led to significantly improved continuous in vitro/in vivo fenretinide release.

Conclusion

Fenretinide/Eudragit® RL PO patches with 20 wt% Tween® 80 + 40 wt% sodium deoxycholate solubilizers exhibit excellent release behavior for further preclinical and/or clinical evaluation in oral cancer chemoprevention.

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REFERENCES

  1. http://seer.cancer.gov/statfacts/html/oralcav.html.

  2. Lefebvre JL. Current clinical outcomes demand new treatment options for SCCHN. Ann Oncol. 2005;16:VI7–VI12.

    Article  PubMed  Google Scholar 

  3. Choi S, Myers JN. Molecular pathogenesis of oral squamous cell carcinoma: implications for therapy. J Dent Res. 2008;87:14–32.

    Article  PubMed  CAS  Google Scholar 

  4. Chen SY, Samuel W, Fariss RN, Duncan T, Kutty RK, Wiggert B. Differentiation of human retinal pigment epithelial cells into neuronal phenotype by N-(4-hydroxyphenyl)retinamide. J Neurochem. 2003;84:972–81.

    Article  PubMed  CAS  Google Scholar 

  5. Hail N, Kim HJ, Lotan R. Mechanisms of fenretinide-induced apoptosis. Apoptosis. 2006;11:1677–94.

    Article  PubMed  CAS  Google Scholar 

  6. Lippman SM, Lee JJ, Martin JW, El-Naggar AK, Xu XC, Shin DM, et al. Fenretinide activity in retinoid-resistant oral leukoplakia. Clin Cancer Res. 2006;12:3109–14.

    Article  PubMed  CAS  Google Scholar 

  7. Chiesa F, Tradati N, Grigolato R, Boracchi P, Biganzoli E, Crose N, et al. Randomized trial of fenretinide (4-HPR) to prevent recurrences, new localizations and carcinomas in patients operated on for oral leukoplakia: long-term results. Int J Cancer. 2005;115:625–9.

    Article  PubMed  CAS  Google Scholar 

  8. Okuda T, Kawakami S, Higuchi Y, Satoh T, Oka Y, Yokoyama M, et al. Enhanced in vivo antitumor efficacy of fenretinide encapsulated in polymeric micelles. Int J Pharm. 2009;373:100–6.

    Article  PubMed  CAS  Google Scholar 

  9. Kokate A, Li XL, Jasti B. Transport of a novel anti-cancer agent, fenretinide across Caco-2 monolayers. Invest New Drug. 2007;25:197–203.

    Article  CAS  Google Scholar 

  10. William WN, Lee JJ, Lippman SM, Martin JW, Chakravarti N, Tran HT, et al. High-dose fenretinide in oral leukoplakia. Cancer Prev Res. 2009;2:22–6.

    Article  CAS  Google Scholar 

  11. Conley B, O’Shaughnessy J, Prindiville S, Lawrence J, Chow C, Jones E, et al. Pilot trial of the safety, tolerability, and retinoid levels of N-(4-hydroxyphenyl) retinamide in combination with tamoxifen in patients at high risk for developing invasive breast cancer. J Clin Oncol. 2000;18:275–83.

    PubMed  CAS  Google Scholar 

  12. Reddy LH. Drug delivery to tumours: recent strategies. J Pharm Pharmacol. 2005;57:1231–42.

    Article  PubMed  CAS  Google Scholar 

  13. GuhaSarkar S, Banerjee R. Intravesical drug delivery: challenges, current status, opportunities and novel strategies. J Control Release. 2010;148:147–59.

    Article  PubMed  CAS  Google Scholar 

  14. Weinberg BD, Ai H, Blanco E, Anderson JM, Gao JM. Antitumor efficacy and local distribution of doxorubicin via intratumoral delivery from polymer millirods. J Biomed Mater Res A. 2007;81A:161–70.

    Article  CAS  Google Scholar 

  15. Zhang L, Russell D, Conway BR, Batchelor H. Strategies and therapeutic opportunities for the delivery of drugs to the esophagus. Crit Rev Ther Drug. 2008;25:259–304.

    Google Scholar 

  16. Mallery SR, Zwick JC, Pei P, Tong M, Larsen PE, Shumway BS, et al. Topical application of a bioadhesive black raspberry gel modulates gene expression and reduces cyclooxygenase 2 protein in human premalignant oral lesions. Cancer Res. 2008;68:4945–57.

    Article  PubMed  CAS  Google Scholar 

  17. Ugalde CM, Liu ZF, Ren C, Chan KK, Rodrigo KA, Ling Y, et al. Distribution of anthocyanins delivered from a bioadhesive black raspberry gel following topical intraoral application in normal healthy volunteers. Pharm Res. 2009;26:977–86.

    Article  PubMed  CAS  Google Scholar 

  18. Shumway BS, Kresty LA, Larsen PE, Zwick JC, Lu B, Field HW, et al. Effects of a topically applied bioadhesive berry gel on loss of heterozygosity indices in premalignant oral lesions. Clin Cancer Res. 2008;14:2421–30.

    Article  PubMed  Google Scholar 

  19. Holpuch AS, Hummel GJ, Tong M, Seghi GA, Pei P, Ma P, et al. Nanoparticles for local drug delivery to the oral mucosa: proof of principle studies. Pharm Res. 2010;27:1224–36.

    Article  PubMed  CAS  Google Scholar 

  20. Wischke C, Zhang Y, Mittal S, Schwendeman SP. Development of PLGA-based injectable delivery systems for hydrophobic fenretinide. Pharm Res. 2010;27:2063–74.

    Article  PubMed  CAS  Google Scholar 

  21. Dittgen M, Durrani M, Lehmann K. Acrylic polymers—a review of pharmaceutical applications. STP Pharm Sci. 1997;7:403–37.

    CAS  Google Scholar 

  22. Hombreiro-Perez M, Siepmann J, Zinutti C, Lamprecht A, Ubrich N, Hoffman M, et al. Non-degradable microparticles containing a hydrophilic and/or a lipophilic drug: preparation, characterization and drug release modeling. J Control Release. 2003;88:413–28.

    Article  PubMed  CAS  Google Scholar 

  23. Perioli L, Ambrogi A, Angelici F, Ricci M, Giovagnoli S, Capuccella M, et al. Development of mucoadhesive patches for buccal administration of ibuprofen. J Control Release. 2004;99:73–82.

    Article  PubMed  CAS  Google Scholar 

  24. Wong CF, Yuen KH, Peh KK. An in-vitro method for buccal adhesion studies: importance of instrument variables. Int J Pharm. 1999;180:47–57.

    Article  PubMed  CAS  Google Scholar 

  25. Formelli F, Cavadini E, Luksch R, Garaventa A, Villani MG, Appierto V, et al. Pharmacokinetics of oral fenretinide in neuroblastoma patients: indications for optimal dose and dosing schedule also with respect to the active metabolite 4-oxo-fenretinide. Cancer Chemother Pharmacol. 2008;62:655–65.

    Article  PubMed  CAS  Google Scholar 

  26. Formelli F, Luksch R, Cavadini E, Ponzoni M, Montaldo PG, Fossati Bellani F, et al. Phase I and pharmacokinetic evaluation of fenretinide in children with advanced neuroblastoma. Proc Am Assoc Cancer Res. 1998;39:322.

    Google Scholar 

  27. Garaventa A, Luksch R, Lo Piccolo MS, Cavadini E, Montaldo PG, Pizzitola MR, et al. Phase I trial and pharmacokinetics of fenretinide in children with neuroblastoma. Clin Cancer Res. 2003;9:2032–9.

    PubMed  CAS  Google Scholar 

  28. Arai T, Benny O, Joki T, Menon LG, Machluf M, Abe T, et al. Novel local drug delivery system using thermoreversible gel in combination with polymeric microspheres or liposomes. Anticancer Res. 2010;30:1057–64.

    PubMed  CAS  Google Scholar 

  29. Petelin M, Sentjurc M, Stolic Z, Skaleric U. EPR study of mucoadhesive ointments for delivery of liposomes into the oral mucosa. Int J Pharm. 1998;173:193–202.

    Article  CAS  Google Scholar 

  30. Shemer A, Amichai B, Trau H, Nathansohn N, Mizrahi B, Domb AJ. Efficacy of a mucoadhesive patch compared with an oral solution for treatment of aphthous stomatitis. Drugs R&D. 2008;9:29–35.

    Article  CAS  Google Scholar 

  31. Thakkar AL. Solubilization of some steroid hormones in aqueous solutions of bile salts. J Pharm Sci. 1970;59:1499–501.

    Article  PubMed  CAS  Google Scholar 

  32. Mithani SD, Bakatselou V, TenHoor CN, Dressman JB. Estimation of the increase in solubility of drugs as a function of bile salt concentration. Pharm Res. 1996;13:163–7.

    Article  PubMed  CAS  Google Scholar 

  33. Wiedmann TS, Kamel L. Examination of the solubilization of drugs by bile salt micelles. J Pharm Sci. 2002;91:1743–64.

    Article  PubMed  CAS  Google Scholar 

  34. Samaha MW, Naggar VF. Micellar properties of non-ionic surfactants in relation to their solubility parameters. Int J Pharm. 1988;42:1–9.

    Article  CAS  Google Scholar 

  35. Dutt GB. Rotational diffusion of hydrophobic probes in Brij-35 micelles: effect of temperature on micellar internal environment. J Phys Chem B. 2003;107:10546–51.

    Article  CAS  Google Scholar 

  36. Magee GA, French J, Gibbon B, Luscombe C. Bile salt/lecithin mixed micelles optimized for the solubilization of a poorly soluble steroid molecule using statistical experimental design. Drug Dev Ind Pharm. 2003;29:441–50.

    Article  PubMed  CAS  Google Scholar 

  37. Torchilin VP. Structure and design of polymeric surfactant-based drug delivery systems. J Control Release. 2001;73:137–72.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  39. Smart JD. Drug delivery using buccal-adhesive systems. Adv Drug Deliv Rev. 1993;11:253–70.

    Article  CAS  Google Scholar 

  40. De Araujo DR, Padula C, Cereda CMS, Tofoli GR, Brito RB, De Paula E, et al. Bioadhesive films containing benzocaine: correlation between in vitro permeation and in vivo local anesthetic effect. Pharm Res. 2010;27:1677–86.

    Article  PubMed  Google Scholar 

  41. Desai KGH, Kumar TMP. Preparation and evaluation of a novel buccal adhesive system. AAPS PharmSciTech. 2004;5:9.

    Article  Google Scholar 

  42. Siepmann J, Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Deliv Rev. 2001;48:139–57.

    Article  PubMed  CAS  Google Scholar 

  43. Jain V, Jain D, Singh R. Factors effecting the morphology of eudragit S-100 based microsponges bearing dicyclomine for colonic delivery. J Pharm Sci. 2011;100:1545–52.

    Article  CAS  Google Scholar 

  44. Zhu Y, Mehta KA, McGinity JW. Influence of plasticizer level on the drug release from sustained release film coated and hot-melt extruded dosage forms. Pharm Dev Technol. 2006;11:285–94.

    Article  PubMed  CAS  Google Scholar 

  45. Sawant PD, Luu D, Ye R, Buchta R. Drug release from hydroethanolic gels. Effect of drug’s lipophilicity (log P), polymer-drug interactions and solvent lipophilicity. Int J Pharm. 2010;396:45–52.

    Article  PubMed  CAS  Google Scholar 

  46. Acartürk F, Encan A. Investigation of the effect of different adjuvants on felodipine release kinetics from sustained release monolithic films. Int J Pharm. 1996;131:183–9.

    Article  Google Scholar 

  47. Li CY, Zimmerman CL, Wiedmann TS. Solubilization of retinoids by bile salt/phospholipid aggregates. Pharm Res. 1996;13:907–13.

    Article  PubMed  CAS  Google Scholar 

  48. Cussler EL. Diffusion: mass transfer in fluid systems. Cambridge: Cambridge University Press; 2009.

    Google Scholar 

  49. Shin SC, Kim JY. Enhanced permeation of triamcinolone acetonide through the buccal mucosa. Eur J Pharm Biopharm. 2000;50:217–20.

    Article  PubMed  CAS  Google Scholar 

  50. Nicolazzo JA, Reed BL, Finnin BC. Buccal penetration enhancers—how do they really work? J Control Release. 2005;105:1–15.

    Article  PubMed  CAS  Google Scholar 

  51. Nicolazzo JA, Reed BL, Finnin BC. Enhanced buccal mucosal retention and reduced buccal permeability of estradiol in the presence of padimate O and Azone®: a mechanistic study. J Pharm Sci. 2005;94:873–82.

    Article  PubMed  CAS  Google Scholar 

  52. Junginger HE, Hoogstraate JA, Verhoef JC. Recent advances in buccal drug delivery and absorption—in vitro and in vivo studies. J Control Release. 1999;62:149–59.

    Article  PubMed  CAS  Google Scholar 

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ACKNOWLEDGMENTS & DISCLOSURES

This study was supported by Fanconi Anemia Research Fund (GRT 00016074), NCI R01 CA129609, and F30 DE020992. The project described was also supported by Award Number UL1RR025755 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. We thank Dr. Vernon Steele, National Cancer Institute, for providing us a gift sample of fenretinide. We also thank Merck, Evonik Degussa Corp., BASF., Lubrizol Corp., and Colorcon®, Inc., for the gift samples of fenretinide, Eudragit®, Soluplus®, Carbopol®, and HPMC polymers, respectively.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Michigan, 428 Church St., Ann Arbor, Michigan, USA

    Kashappa-Goud H. Desai & Steven P. Schwendeman

  2. Department of Oral Maxillofacial Surgery and Pathology, College of Dentistry and the Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA

    Susan R. Mallery & Andrew S. Holpuch

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  1. Kashappa-Goud H. Desai
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Corresponding author

Correspondence to Steven P. Schwendeman.

ELECTRONIC SUPPLEMENTARY MATERIAL

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Table SI

In vitro fenretinide release kinetics parameters obtained from Higuchi plot (linear regression of fraction of drug released vs. square root of time) for solubilizer-free and solubilizer-loaded Eudragit® RL PO mucoadhesive patches. (DOC 34 kb)

Table SII

In vitro fenretinide release kinetics parameters obtained from Korsmeyer-Peppas plot for solubilizer-free and solubilizer-loaded Eudragit® RL PO mucoadhesive patches. (DOC 34 kb)

Fig. S1

Kinetics of fenretinide release from solubilizer-free (a and b) and solubilizer-loaded (C-H) fenretinide/Eudragit® RL PO patches. Higuchi plot for Eudragit® RL PO patches containing 5 wt% fenretinide (a), 10 wt% fenretinide (b), 20 wt% sodium deoxycholate (c), 20 wt% Tween® 20 (d), 20 wt% Tween® 80 (e), 20 wt% Brij® 98 (f), 40 wt% sodium deoxycholate (g), and 40 wt% sodium deoxycholate + 20 wt% Tween® 80 (h). Fenretinide loading (theoretical) in c to h formulations was 5 wt%. Solubilizer-free patch formulation was prepared using triethyl citrate (20 wt%) as a plasticizer. Solubilizer-loaded patch was prepared without triethyl citrate. Release studies were conducted in simulated saliva (pH 6.8) containing 5%w/v sodium deoxycholate at 37°C. Lines represent least-squares linear regression lines of fraction released vs. sq. rt. time with parameters listed in Table SI. As the release was biphasic in solubilizer-free formulations (a and b), only the data after the lag phase was analyzed. (DOC 250 kb)

Fig. S2

Evaluation of stability of fenretinide. HPLC chromatograms of fenretinide samples before (a) and after incubation in PBS + 0.1% Tween® 20 for one day with exposure to light and oxygen (b), 8-h in vitro drug release and recovery from the polymer (c), and 8-h in vivo drug release and recovery from the polymer (d). Studies were done in PBS + 0.1% Tween® 20 (b) or simulated saliva +5% w/v sodium deoxycholate (c) at 37°C or rabbits (d). (DOC 53 kb)

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Desai, KG.H., Mallery, S.R., Holpuch, A.S. et al. Development and In Vitro-In Vivo Evaluation of Fenretinide-Loaded Oral Mucoadhesive Patches for Site-Specific Chemoprevention of Oral Cancer. Pharm Res 28, 2599–2609 (2011). https://doi.org/10.1007/s11095-011-0489-3

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