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Preparation, Optimization, and Evaluation of Hyaluronic Acid-Based Hydrogel Loaded with Miconazole Self-Nanoemulsion for the Treatment of Oral Thrush

Abstract

Miconazole nitrate (MZ) is a BCS class II antifungal poorly water-soluble drug with limited dissolution properties and gastrointestinal side effects. Self-nanoemulsifying delivery system-based gel of MZ can improve both solubility and oral mucosal absorption with enhanced antifungal activity. The study aims to formulate MZ self-nanoemulsion (MZ-NE) and combine it within hyaluronic acid-based gel. MZ solubility in various oils, surfactants, and cosurfactant used in NE formulations were evaluated. Mixture design was implemented to optimize the levels of NE components as a formulation variable to study their effects on the mean globule size and antifungal inhibition zones. Further, the optimized MZ-NE was loaded into a hyaluronic acid gel base. Rheological behavior of the prepared gel was assessed. Ex vivo permeability of optimized formulation across buccal mucous of sheep and inhibition against Candida albicans were examined. Mixture design was used to optimize the composition of MZ-NE formulation as 22, 67, and 10% for clove oil, Labrasol, and propylene glycol, respectively. The optimized formulation indicated globule size of 113 nm with 29 mm inhibition zone. Pseudoplastic flow with thixotropic behavior was observed, which is desirable for oral gels. The optimized formulation exhibited higher ex vivo skin permeability and enhanced antifungal activity by 1.85 and 2.179, respectively, compared to MZ-SNEDDS, and by 1.52 and 1.72 folds, respectively, compared to marketed gel. Optimized MZ-NE hyaluronic acid-based oral gel demonstrated better antifungal activity, indicating its potential in oral thrush pharmacotherapy.

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References

  1. Pfaller MA. Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am J Med. 2012 Jan 1;125(1):S3–13.

    CAS  Article  Google Scholar 

  2. Scully C, Epstein J, Sonis S. Oral mucositis: a challenging complication of radiotherapy, chemotherapy, and radiochemotherapy: part 1, pathogenesis and prophylaxis of mucositis. Head Neck. 2003;25(12):1057–70.

    Article  Google Scholar 

  3. Tsutsumi S, Iida M, Tada N, Kojima T, Ikeda Y, Moriwaki T, et al. Characterization and evaluation of miconazole salts and cocrystals for improved physicochemical properties. Int J Pharm. 2011;421(2):230–6.

    CAS  Article  Google Scholar 

  4. Stevens DA, Levine HB, Deresinski SC. Miconazole in coccidioidomycosis: II. Therapeutic and pharmacologic studies in man. Am J Med. 1976;60(2):191–202.

    CAS  Article  Google Scholar 

  5. Akpan A, Morgan R. Oral candidiasis. Postgrad Med J. 2002 Aug 1;78(922):455–9.

    CAS  Article  Google Scholar 

  6. Darouiche RO. Oropharyngeal and esophageal candidiasis in immunocompromised patients: treatment issues. Clin Infect Dis. 1998;26:259–72.

    CAS  Article  Google Scholar 

  7. Date AA, Desai N, Dixit R, Nagarsenker M. Self-nanoemulsifying drug delivery systems: formulation insights, applications and advances. Nanomedicine. 2010;5(10):1595–616.

    CAS  Article  Google Scholar 

  8. Mahmoud EA, Bendas ER, Mohamed MI. Effect of formulation parameters on the preparation of superporous hydrogel self-nanoemulsifying drug delivery system (SNEDDS) of carvedilol. AAPS PharmSciTech. 2010;11(1):221–5.

    CAS  Article  Google Scholar 

  9. Alexander A, Khichariya A, Gupta S, Patel RJ, Giri TK, Tripathi DK. Recent expansions in an emergent novel drug delivery technology: Emulgel. J Control Release. 2013;171(2):122–32.

    Article  Google Scholar 

  10. Goa KL, Benfield P. Hyaluronic acid. Drugs. 1994 Mar 1;47(3):536–66.

    CAS  Article  Google Scholar 

  11. Friedman PM, Mafong EA, Kauvar AN, Geronemus RG. Safety data of injectable nonanimal stabilized hyaluronic acid gel for soft tissue augmentation. Dermatol Surg. 2002;28(6):491–4.

    PubMed  Google Scholar 

  12. Patel VF, Liu F, Brown MB. Advances in oral transmucosal drug delivery. J Control Release. 2011;153(2):106–16.

    CAS  Article  Google Scholar 

  13. Gué E, Since M, Ropars S, Herbinet R, Le Pluart L, Malzert-Fréon A. Evaluation of the versatile character of a nanoemulsion formulation. Int J Pharm. 2016;498(1–2):49–65.

    Article  Google Scholar 

  14. Patil SS, Venugopal E, Bhat S, Mahadik KR, Paradkar AR. Microstructural elucidation of self-emulsifying system: effect of chemical structure. Pharm Res. 2012;29(8):2180–8.

    CAS  Article  Google Scholar 

  15. Chen S, Reyes KR, Gupta MK, McAlpine MC, Powell WB. Optimal learning in experimental design using the knowledge gradient policy with application to characterizing nanoemulsion stability. SIAM/ASA Journal on Uncertainty Quantification. 2015;3(1):320–45.

    Article  Google Scholar 

  16. Pouton CW. Formulation of self-emulsifying drug delivery systems. Adv Drug Deliv Rev. 1997;25(1):47–58.

    CAS  Article  Google Scholar 

  17. Venkatesh M, Mallesh K. Self-nano emulsifying drug delivery system (SNEDDS) for oral delivery of atorvastatin-formulation and bioavailability studies. Journal of Drug Delivery and Therapeutics. 2013;3(3):131–40.

    Article  Google Scholar 

  18. Hussain A, Samad A, Singh SK, Ahsan MN, Haque MW, Faruk A, et al. Nanoemulsion gel-based topical delivery of an antifungal drug: in vitro activity and in vivo evaluation. Drug Delivery. 2016;23(2):642–57.

    CAS  Article  Google Scholar 

  19. Lee Y, Chung HJ, Yeo S, Ahn CH, Lee H, Messersmith PB, et al. Thermo-sensitive, injectable, and tissue adhesive sol–gel transition hyaluronic acid/pluronic composite hydrogels prepared from bio-inspired catechol-thiol reaction. Soft Matter. 2010;6(5):977–83.

    CAS  Article  Google Scholar 

  20. Arora R, Aggarwal G, Harikumar SL, Kaur K. Nanoemulsion based hydrogel for enhanced transdermal delivery of ketoprofen. Adv Pharm. 2014;2014.

    Article  Google Scholar 

  21. Mayol L, Quaglia F, Borzacchiello A, Ambrosio L, La Rotonda MI. A novel poloxamers/hyaluronic acid in situ forming hydrogel for drug delivery: rheological, mucoadhesive and in vitro release properties. Eur J Pharm Biopharm 2008;70(1):199–206.

    CAS  Article  Google Scholar 

  22. Wooster TJ, Golding M, Sanguansri P. Impact of oil type on nanoemulsion formation and Ostwald ripening stability. Langmuir. 2008;24(22):12758–65.

    CAS  Article  Google Scholar 

  23. Abioye AO, Issah S, Kola-Mustapha AT. Ex vivo skin permeation and retention studies on chitosan–ibuprofen–gellan ternary nanogel prepared by in situ ionic gelation technique—a tool for controlled transdermal delivery of ibuprofen. Int J Pharm. 2015;490(1–2):112–30.

    CAS  Article  Google Scholar 

  24. Azeem A, Rizwan M, Ahmad FJ, Iqbal Z, Khar RK, Aqil M, et al. Nanoemulsion components screening and selection: a technical note. AAPS PharmSciTech. 2009;10(1):69–76.

    CAS  Article  Google Scholar 

  25. Patil Prashant P, Vaishali K, Santosh P. Potential investigation of peceol for formulation of ezetimibe self nano emulsifying drug delivery systems. Asian Journal of Biomedical and Pharmaceutical Sciences. 2016;6(54):20–47.

    Google Scholar 

  26. Azeem A, Rizwan M, Ahmad FJ, Khar RK, Iqbal Z, Talegaonkar S. Components screening and influence of surfactant and cosurfactant on nanoemulsion formation. Curr Nanosci. 2009;5(2):220–6.

    CAS  Article  Google Scholar 

  27. Bouchemal K, Briançon S, Perrier E, Fessi H. Nano-emulsion formulation using spontaneous emulsification: solvent, oil and surfactant optimisation. Int J Pharm. 2004 Aug 6;280(1–2):241–51.

    CAS  Article  Google Scholar 

  28. Chiappetta DA, Sosnik A. Poly (ethylene oxide)–poly (propylene oxide) block copolymer micelles as drug delivery agents: improved hydrosolubility, stability and bioavailability of drugs. Eur J Pharm Biopharm. 2007;66(3):303–17.

    CAS  Article  Google Scholar 

  29. Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother. 2004;58(3):173–82.

    Article  Google Scholar 

  30. Lee JH, Jung JY, Bang D. The efficacy of topical 0.2% hyaluronic acid gel on recurrent oral ulcers: comparison between recurrent aphthous ulcers and the oral ulcers of Behçet’s disease. J Eur Acad Dermatol Venereol. 2008;22(5):590–5.

    CAS  Article  Google Scholar 

  31. Baloglu E, Karavana SY, Senyigit ZA, Guneri T. Rheological and mechanical properties of poloxamer mixtures as a mucoadhesive gel base. Pharm Dev Technol. 2011;16(6):627–36.

    CAS  Article  Google Scholar 

  32. Kavanagh GM, Ross-Murphy SB. Rheological characterisation of polymer gels. Prog Polym Sci. 1998;23(3):533–62.

    CAS  Article  Google Scholar 

  33. Gorain B, Choudhury H, Kundu A, Sarkar L, Karmakar S, Jaisankar P, et al. Nanoemulsion strategy for olmesartan medoxomil improves oral absorption and extended antihypertensive activity in hypertensive rats. Colloids Surf B: Biointerfaces. 2014;115:286–94.

    CAS  Article  Google Scholar 

  34. Yin L, Ding J, He C, Cui L, Tang C, Yin C. Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery. Biomaterials. 2009;30(29):5691–700.

    CAS  Article  Google Scholar 

  35. Brøndsted H, Kopec̆ek J. Hydrogels for site-specific oral drug delivery: synthesis and characterization. Biomaterials. 1991 Aug 1;12(6):584–92.

    Article  Google Scholar 

  36. Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm Res. 1995;12(11):1561–72.

    CAS  Article  Google Scholar 

  37. Ahn TS, Lee JP, Kim J, Oh SY, Chun MK, Choi HK. Effect of pressure sensitive adhesive and vehicles on permeation of terbinafine across porcine hoof membrane. Arch Pharm Res. 2013;36(11):1403–9.

    CAS  Article  Google Scholar 

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Correspondence to Khaled M. Hosny.

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Hosny, K.M., Aldawsari, H.M., Bahmdan, R.H. et al. Preparation, Optimization, and Evaluation of Hyaluronic Acid-Based Hydrogel Loaded with Miconazole Self-Nanoemulsion for the Treatment of Oral Thrush. AAPS PharmSciTech 20, 297 (2019). https://doi.org/10.1208/s12249-019-1496-7

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  • DOI: https://doi.org/10.1208/s12249-019-1496-7

KEY WORDS

  • miconazole
  • self-nanoemulsion
  • hyaluronic acid
  • antifungal
  • oral thrush