AAPS PharmSciTech

, Volume 14, Issue 1, pp 412–424 | Cite as

Thermally Triggered Mucoadhesive In Situ Gel of Loratadine: β-Cyclodextrin Complex for Nasal Delivery

  • Reena M. P. Singh
  • Anil KumarEmail author
  • Kamla Pathak
Research Article


The aim of the present study was to increase the solubility of an anti-allergic drug loratadine by making its inclusion complex with β-cyclodextrin and to develop it’s thermally triggered mucoadhesive in situ nasal gel so as to overcome first-pass effect and consequently enhance its bioavailability. A total of eight formulations were prepared by cold method and optimized by 23 full factorial design. Independent variables (concentration of poloxamer 407, concentration of carbopol 934 P, and pure drug or its inclusion complex) were optimized in order to achieve desired gelling temperature with sufficient mucoadhesive strength and maximum permeation across experimental nasal membrane. The design was validated by extra design checkpoint formulation (F9) and Pareto charts were used to help eliminate terms that did not have a statistically significant effect. The response surface plots and possible interactions between independent variables were analyzed using Design Expert Software 8.0.2 (Stat Ease, Inc., USA). Faster drug permeation with zero-order kinetics and target flux was achieved with formulation containing drug: β-cyclodextrin complex rather than those made with free drug. The optimized formulation (F8) with a gelling temperature of 28.6 ± 0.47°C and highest mucoadhesive strength of 7,676.0 ± 0.97 dyn/cm2 displayed 97.74 ± 0.87% cumulative drug permeation at 6 h. It was stable for over 3 months and histological examination revealed no remarkable damage to the nasal tissue.


23 factorial design in situ nasal gel loratadine mucoadhesion temperature-induced gelation 



The authors are grateful to Dr. S.K. Garg (Dean and Professor) of Pt. Deen Dayal Upadhaya Pashu Chikitsa Vigyan Vishwavidyalya, Mathura for providing assistance in histopathological study and writing the report of nasal mucosal integrity. The author Reena MP Singh is thankful to AICTE, India, for providing financial assistance during the project.


  1. 1.
    Menardo J, Horak F, Danzig MR, Czarlewski W. A review of loratadine in the treatment of patients with allergic bronchial asthma. Clin Ther. 1997;19:1278–93.PubMedCrossRefGoogle Scholar
  2. 2.
    Moffat AC, Osselton MD, Widdop B (2004) Clarke’s analysis of drugs and poisons, 3rd ed. Pharmaceutical Press: London 2:1186–1187Google Scholar
  3. 3.
    Borgaonkar PA, Virsen TG, Hariprasanna RC, Najmuddin M. Formulation and in vitro evaluation of buccal tablets of loratadine for effective treatment of allergy. Int J Res Pharm Chem. 2011;1:551–9.Google Scholar
  4. 4.
    Shojaei H. Buccal mucosa as a route for systemic drug delivery: a review. J Pharm Pharmaceut Sci. 1998;1:15–30.Google Scholar
  5. 5.
    Merkus FWHM, Verhoef JC, Schipper NG, Martin E. Nasal mucociliary clearance as a factor in nasal drug delivery. Adv Drug Deliv Rev. 1998;29:13–38.PubMedCrossRefGoogle Scholar
  6. 6.
    Zhou M, Donovan MD. Intranasal mucociliary clearance of putative bioadhesive polymer gels. Int J Pharm. 1996;135:115–25.CrossRefGoogle Scholar
  7. 7.
    Martinac A, Grcic JF, Voinovich D, Perissutti B, Franceschinis E. Development and bioadhesive properties of chitosan-ethylcellulose microspheres for nasal delivery. Int J Pharm. 2005;291:69–77.PubMedCrossRefGoogle Scholar
  8. 8.
    Zaki NM, Awada GA, Mortadaa ND, Abd ElHady SS. Enhanced bioavailability of metoclopramide HCl by intranasal administration of a mucoadhesive in situ gel with modulated rheological and mucociliary transport properties. Eur J Pharm Sci. 2007;32:296–307.PubMedCrossRefGoogle Scholar
  9. 9.
    Higuchi T, Connors KA. Phase-solubility techniques. Adv Anal Chem Instrum. 1965;4:117–212.Google Scholar
  10. 10.
    Schmolka IR. Artificial skin. I. Preparation and properties of Pluronic F-127 gels for the treatment of burns. J Biomed Mater Res. 1972;6:71–582.CrossRefGoogle Scholar
  11. 11.
    Choi HG, Shim CK, Kim DD. Development of in situ gelling and mucoadhesive acetaminophen liquid suppository. Int J Pharm. 1998;165:33–44.CrossRefGoogle Scholar
  12. 12.
    Gupta A, Garg S, Khar RK. Measurement of bioadhesive strength of mucoadhesive buccal tablets: design of in vitro assembly. Indian Drugs. 1992;30:152–5.Google Scholar
  13. 13.
    Ramos LA, Cavalheiro ETG. Thermal behavior of loratadine. J Therm Anal Calorim. 2007;87:831–4.CrossRefGoogle Scholar
  14. 14.
    Sathigiri S, Chadha G, Lee YHP, Wright N, Parsons DL, Rangari VK, Fasina O, Babu RJ. Physicochemical characterization of Efavirenz-cyclodextrin inclusion complexes. AAPS PharmSciTech. 2009;10:81–7.CrossRefGoogle Scholar
  15. 15.
    Mahajan HS, Shah SK, Surana SJ. Nasal in situ gel containing hydroxy propyl β-cyclodextrin inclusion complex of arthemeter: development and in vitro evaluation. J Incl Phenom Macrocycl Chem. 2011;70:49–58.CrossRefGoogle Scholar
  16. 16.
    Nacsa A, Ambrus R, Berkesi O, Szabo-Revesz P, Aigner Z. Watersoluble loratadine inclusion complex: analytical control of the preparation by microwave irradiation. J Pharm Biomed Anal. 2008;48:1020–3.PubMedCrossRefGoogle Scholar
  17. 17.
    Pedersen NR, Kristensen JB, Bauw G, Ravoo BJ, Darcy R, Larsen KL. Thermolysin catalyses the synthesis of cyclodextrin esters in DMSO. Tetrahedron-Asymmetry. 2005;16:615–22.CrossRefGoogle Scholar
  18. 18.
    Majithiya RJ, Ghosh PK, Umrethia ML, Murthy RS. Thermoreversible-mucoadhesive gel for nasal delivery of sumatriptan. AAPS PharmSciTech. 2006;7:E1–7.CrossRefGoogle Scholar
  19. 19.
    Kabanov AV, Batrakova EV, Alakhov VU. Pluronic block copolymers as novel polymer therapeutics for drug and gene delivery. J Contr Release. 2002;82:189–212.CrossRefGoogle Scholar
  20. 20.
    Bromberg LE, Ron ES. Protein and peptide release from temperature-responsive gels and thermogelling polymer matrices. Adv Drug Deliv Rev. 1998;31:197–221.PubMedCrossRefGoogle Scholar
  21. 21.
    Kabanov AV, Lemieux P, Vinogradov S, Alakhov V. Pluronic block copolymers: novel functional molecules for gene therapy. Adv Drug Deliv Rev. 2002;54:223–33.PubMedCrossRefGoogle Scholar
  22. 22.
    Rassing J, Attwood D. Ultrasonic velocity and light scattering studies on polyoxyethylene-polyoxypropylene copolymer PF127 in aqueous solution. Int J Pharm. 1982;13:47–55.CrossRefGoogle Scholar
  23. 23.
    Charlton S, Jones NS, Davis SS, Illum L. Distribution and clearance of bioadhesive formulations from the olfactory region in man: effect of polymer type and nasal delivery device. Eur J Pharm Sci. 2007;30:295–302.PubMedCrossRefGoogle Scholar
  24. 24.
    Patel M, Thakkar H, Kasture PV. Preparation and evaluation of thermoreversible formulations of Flunarizine hydrochloride for nasal delivery. Int J Pharm Pharmaceut Sci. 2010;2:116–20.Google Scholar
  25. 25.
    Efentakis M, Koutlis A, Vlachou M. Development and evaluation of oral multiple-unit and single-unit hydrophilic controlled-release systems. AAPS PharmSciTech. 2000;1:E34.PubMedCrossRefGoogle Scholar
  26. 26.
    Kunisawa J, Okudaira A, Tsutusmi Y. Characterization of mucoadhesive microspheres for the induction of mucosal and systemic immune responses. Vaccine. 2000;19:589–94.PubMedCrossRefGoogle Scholar
  27. 27.
    Sangalli ME, Zema L, Maroni A, Foppoli A, Giordano F, Gazzaniga A. Influence of beta-cyclodextrin on the release of poorly soluble drugs from inert and hydrophilic heterogeneous polymeric matrices. Biomaterials. 2001;22:2647–51.PubMedCrossRefGoogle Scholar
  28. 28.
    Koester LS, Xavier CR, Mayorga P, Bassani VL. Influence of β-cyclodextrin complexation on carbamazepine release from hydroxypropyl methylcellulose matrix tablets. Eur J Pharm Biopharm. 2003;55:85–91.PubMedCrossRefGoogle Scholar
  29. 29.
    Masson M, Loftsson T, Masson G, Stefansson E. Cyclodextrins as permeation enhancers; some theoretical evaluations and in-vitro testing. J Contr Release. 1999;59:107–18.CrossRefGoogle Scholar
  30. 30.
    Marttin E, Verhoef JC, Spies F, Van der Meulen J, Nagelkerke JF, Koerten HK, Merkus F. The effect of methylated β-cyclodextrins on the tight junctions of the rat nasal respiratory epithelium: electron microscopic and confocal laser scanning microscophic visualization studies. J Contr Release. 1994;57:205–13.CrossRefGoogle Scholar
  31. 31.
    He C, Kim SW, Lee DS. In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery. J Contr Release. 2008;127:189–207.CrossRefGoogle Scholar
  32. 32.
    Mortensen K, Pedersen JS. Structural study on the micelle formation of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer in aqueous solution. Macromolecules. 1993;26:805–12.CrossRefGoogle Scholar
  33. 33.
    Riccia EJ, Lunardi LO, Nanclares DMA, Marchetti JM. Sustained release of lidocaine from Poloxamer 407 gels. Int J Pharm. 2005;288:235–44.CrossRefGoogle Scholar
  34. 34.
    Sun SS, Hsieh JF, Tsai SC, Ho YJ, Kao CH. Evaluation of nasal mucociliary clearance functions in allergic rhinitis patients with technetium-99 m labeled macroaggregated albumin rhinoscintigraphy. Ann Otol Rhinol Laryngol. 2002;111:73–90.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2013

Authors and Affiliations

  1. 1.Department of PharmaceuticsRajiv Academy for PharmacyMathuraIndia

Personalised recommendations