AAPS PharmSciTech

, Volume 11, Issue 3, pp 1223–1231 | Cite as

Development and Characterization of Mucoadhesive In Situ Nasal Gel of Midazolam Prepared with Ficus carica Mucilage

  • Shyamoshree Basu
  • Amal Kumar BandyopadhyayEmail author
Research Article


The objective of the present study was to prepare mucoadhesive in situ nasal gels with mucilage isolated from fig fruits (Ficus carica, family: Moraceae) containing midazolam hydrochloride. Nasal gels of midazolam were prepared using three different concentrations (0.5%, 1.0% and 1.5% w/v) of F. carica mucilage (FCM) and synthetic polymers (hydroxypropylmethyl cellulose and Carbopol 934). Evaluation of FCM showed that it was as safe as the synthetic polymers for nasal administration. In situ gels were prepared with mixture Pluronic F127 and mucoadhesive agents. Evaluation of the prepared gels was carried out, including determination of viscosity, texture profile analysis and mucoadhesive strength. In vitro drug permeation study was conducted with the gels prepared with and without permeation enhancer (0.5% w/v sodium taurocholate) using excised goat nasal mucosa. In vitro permeation profiles were evaluated, and histological study of nasal mucosae before and after permeation study was also conducted to determine histological change, if any. In vivo experiments conducted in rabbits further confirmed that in situ nasal gels provided better bioavailability of midazolam than the gels prepared from synthetic mucoadhesive polymers. It was observed that the nasal gel containing 0.5% FCM and 0.5% sodium taurocholate exhibited appropriate rheological, mechanical and mucoadhesive properties and showed better drug release profiles. Moreover, this formulation produced no damage to the nasal mucosa that was used for the permeation study, and absolute bioavailability was also higher compared to gels prepared from synthetic polymers.


midazolam hydrochloride mucoadhesive nasal permeation enhancer 



The authors are grateful to AICTE National Doctoral Fellowship for providing financial assistance for carrying out the research work.


  1. 1.
    Wikipedia. The free encyclopedia. Accessed 20 July 2007.
  2. 2.
    DeLorenzo RJ, Pellock JM, Towne AR, Boggs JG. Epidemiology of status epilepticus. J Clin Neurophysiol. 1995;12:316–25.PubMedGoogle Scholar
  3. 3.
    Goldman RD. Intranasal drug delivery for children with acute illness. Curr Drug Ther. 2006;1:127–30.CrossRefGoogle Scholar
  4. 4.
    Pecking M, Montestruc F, Marquet P, Wodey E, Homery MC, Dostert P. Absolute bioavailability of midazolam after subcutaneous administration to healthy volunteers. Br J Clin Pharmacol. 2002;54:357–62.CrossRefPubMedGoogle Scholar
  5. 5.
    Geldner G, Hubmann M, Knoll R, Jacobi K. Comparison between three transmucosal routes of administration of midazolam in children. Paediatr Anaesth. 1997;7:103–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Scott RC, Besag FM, Neville BG. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet. 1999;353:623–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Schwagmeier R, Alincic S, Striebel HW. Midazolam pharmacokinetics following intravenous and buccal administration. Br J Clin Pharmacol. 1998;46:203–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Ugwoke MI, Verbeke N, Kinget R. The biopharmaceutical aspects of nasal mucoadhesive drug delivery. J Pharm Pharmcol. 2001;53:3–22.CrossRefGoogle Scholar
  9. 9.
    Illum L. Nasal drug delivery: new developments and strategies. Drug Discov Today. 2002;7:184–9.CrossRefGoogle Scholar
  10. 10.
    Türker S, Onur E, Özer Y. Nasal route and drug delivery systems. Pharm World Sci. 2004;26:137–42.CrossRefPubMedGoogle Scholar
  11. 11.
    Jeannet PY, et al. Home and hospital treatment of acute seizures in children with nasal midazolam. Eur J Paediatr Neurol. 1999;3:73–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Fisgin T, Gurer Y, Tezic T, Senbil N, Zorlu P, Okuyaz C, et al. Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study. J Child Neurol. 2002;17:123–6.CrossRefPubMedGoogle Scholar
  13. 13.
    Lahat E, Goldman M, Barr J, Bistritzer T, Berkovitch M. Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomized study. BMJ. 2000;21:83–6.CrossRefGoogle Scholar
  14. 14.
    Armijo JA, Herranz JL, Pena Pardo MA, Adin J. Intranasal and buccal midazolam in the treatment of acute seizures. Rev Neurol. 2004;38:458–68.PubMedGoogle Scholar
  15. 15.
    Mahmoudian T, Zadeh MM. Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children. Epilepsy Behav. 2004;5:253–5.CrossRefPubMedGoogle Scholar
  16. 16.
    Wilson MT, Macleod S, O'Regan ME. Nasal/buccal midazolam use in the community. Arch Dis Child. 2004;89:50–1.CrossRefPubMedGoogle Scholar
  17. 17.
    Bhattacharyya M, Kalra V, Gulati S. Intranasal midazolam vs rectal diazepam in acute childhood seizures. Pediatr Neurol. 2006;34:355–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Wolfe TR, Macfarlane TC. Intranasal midazolam therapy for pediatric status epilepticus. Am J Emerg Med. 2006;24:343–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Holsti M, Sill BL, Firth SD, Filloux FM, Joyce SM, Furnival RA. Prehospital intranasal midazolam for the treatment of pediatric seizures. Pediatr Emerg Care. 2007;23:148–53.CrossRefPubMedGoogle Scholar
  20. 20.
    Knoester PD, Jonker DM, van der Hoeven RTM, Vermeij TAC, Edelbroek PM, Brekelmans GJ, et al. Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers. Br J Clin Pharmacol. 2002;53:501–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Loftsson TH, Guðmundsdo´ ttir H, Sigurjo´nsdo´ ttir JF, Sigurðsson HH, Sigfu´sson SD, Ma´sson M, et al. Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray. Int J Pharm. 2001;212:29–40.CrossRefPubMedGoogle Scholar
  22. 22.
    Miyazaki S, Takeuchi S, Yokouchi C, Takada M. Pluronic F-127 gels as a vehicle for topical administration of anticancer agents. Chem Pharm Bull. 1984;10:4205–8.Google Scholar
  23. 23.
    Miyazaki S, Nakamura T, Yokouchi C, Takada M. Effect of Pluronic gels on the rectal absorption of indomethacin in rabbits. Chem Pharm Bull. 1987;35:1243–8.PubMedGoogle Scholar
  24. 24.
    Majithiya RJ, Ghosh, PK, Umrethia ML, Murthy RS. Thermoreversible-mucoadhesive gel for nasal delivery of sumatriptan. AAPS PharmSciTech. 2006;7(3):Article 67.Google Scholar
  25. 25.
    Zhang L, Parsons DL, Navarre C, Kompella UB. Development and in-vitro evaluation of sustained release Poloxamer 407 (P407) gel formulations of ceftiofur. J Control Release. 2002;85:73–81.CrossRefPubMedGoogle Scholar
  26. 26.
    Tease WB. Trease and Evans’ pharmacognosy. 15th ed. London: WB Saunders Company Ltd; 2002.Google Scholar
  27. 27.
    Park H, Robinson JR. Mechanisms of mucoadhesion of poly (acrylic acid) hydrogels. Pharm Res. 1987;4:457–64.CrossRefPubMedGoogle Scholar
  28. 28.
    Schmolka IR. Artificial skin. I. Preparation and properties of Pluronic F-127 gels for the treatment of burns. J Biomed Mater Res. 1972;6:571–82.CrossRefPubMedGoogle Scholar
  29. 29.
    Choi HK, Jung JH, Ryu JM, Yoon SJ, Oh YK, Kim CK. Development of in-situ gelling and mucoadhesive acetaminophen liquid suppository. Int J Pharm. 1998;165:33–44.CrossRefGoogle Scholar
  30. 30.
    Cevher E, Taha MAM, Orlu M, Araman A. Evaluation of mechanical and mucoadhesive properties of clomiphene citrate gel formulations containing carbomers and their thiolated derivatives. Drug Dev. 2008;15:57–67.CrossRefGoogle Scholar
  31. 31.
    Shih PE, Huang JD. Pharmacokinetics of midazolam and 1-hydroxymidazolam in Chinese with different cyp3a5 genotypes. Drug Metab Dispos. 2002;30:1491–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Marttin E, Shipper NGM, Verhoef JC, Merkus FWHM. Nasal mucociliary clearance as a factor in nasal drug delivery. Adv Drug Deliv Rev. 1998;29:13–38.CrossRefPubMedGoogle Scholar
  33. 33.
    Wei G, Xu H, Ding PT, Li SM, Zheng JM. Thermosetting gels with modulated gelation temperature for ophthalmic use: the rheological and gamma scintigraphic studies. J Control Release. 2002;83:65–74.CrossRefPubMedGoogle Scholar
  34. 34.
    Bansal K, Rawat MK, Jain A, Rajput A, Chaturvedi TP, Singh S. Development of satranidazole mucoadhesive gel for the treatment of periodontitis. AAPS PharmSciTech. 2009;10(3):716–23.CrossRefPubMedGoogle Scholar
  35. 35.
    Tan YTF, Peh KK, Al-Hanbali O. Effect of Carbopol and polyvinylpyrrolidone on the mechanical, rheological and release properties of bioadhesive polyethylene glycol gels. AAPS PharmSciTech. 2000;1:Article 24.Google Scholar
  36. 36.
    Lin H, Gebhardt M, Bian S, et al. Enhancing effect of surfactants on fexofenadine HCl transport across the human nasal epithelial cell monolayer. Int J Pharm. 2007;330:23–31.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2010

Authors and Affiliations

  1. 1.Department of Pharmaceutical TechnologyJadavpur UniversityKolkataIndia

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