AAPS PharmSciTech

, Volume 19, Issue 4, pp 1730–1743 | Cite as

Formulation Development and Evaluation of Diphenhydramine Nasal Nano-Emulgel

  • Hina Javed
  • Syed Nisar Hussain Shah
  • Furqan Muhammad Iqbal
Research Article


The aim of present study is to formulate diphenhydramine nasal nano-emulgels, having lipophilic nano-sized interior droplets, with better penetration for targeted controlled delivery to mucous membrane. Different diphenhydramine (DPH) nasal nano-emulgels were developed having propylene glycol and olive oil (as permeation enhancers) by using RSM for optimization and then evaluated for physico-chemical characteristics and thermal stability. In-vitro drug release through cellophane membrane was conducted and results were analyzed statistically. Further, gelation, mucoadhesive stress, and ex-vivo and histopathological studies were performed on optimized formulation by using goat nasal membrane. Among all formulations, E2 showed maximum DPH release at higher concentration olive oil (4%) and lower concentration propylene glycol (PG) (25%) within 4 h. All formulations have followed first-order kinetics and drug release mechanism was Fickian diffusion. Analysis of variance (ANOVA) and multiple linear regression analysis (MLRA) were used to compare results among formulations and 3D surface plots were constructed also. Optimized formulation showed immediate prolong gelation in artificial nasal mucosa and excellent mucoadhesive property (72.5 ± 1.5 dynes/cm2). Approximately 97.1% optimized formulation was permeated through membrane within 4 h, having a high flux rate (33.19 ± 0.897 μg/cm2/min) with diffusion coefficient (0.000786 ± 4.56 × 10−5 cm2/min) while drug contents remained on mucosal membrane for 24 h. Histopathologically, change on intra-mucosal surface of excised membrane was observed due to passage of drug through it. In summary, combination of PG and olive oil in nasal DPH nano-emulgel can be utilized successfully for targeted controlled delivery. The optimized formulation has excellent permeability and prolonged residence time on mucosal surface, which prove its good anti-histaminic activity in case of allergic rhinitis.


nano-emulgel response surface methodology (RSM) gelatin mucoadhesive stress permeation histopathological examination 







Response surface methodology


Analysis of variance


Multiple linear regression analysis



All the authors hereby have acknowledged the laboratory facilities as provided by Chairman, Faculty of Pharmacy, Bahauddin Zakariya University, Multan.

Compliance with Ethical Standards

Approval by Ethical Committee

The approval for ex-vivo studies in animals and human were taken from the “Ethical Committee” of Faculty of Pharmacy, B.Z. University Multan under the reference number 104/PEC/2016.

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Kim D-D. In vitro cellular models for nasal drug absorption studies. In: Ehrhardt C, Kim KJ, editors. Drug absorption studies. Boston: Springer; 2008. p. 216–234.Google Scholar
  2. 2.
    Mathias NR, Hussain MA. Non-invasive systemic drug delivery: developability considerations for alternate routes of administration. J Pharm Sci. 2010;99(1):1–20.CrossRefPubMedGoogle Scholar
  3. 3.
    Costantino HR, et al. Intranasal delivery: physicochemical and therapeutic aspects. Int J Pharm. 2007;337(1):1–24.CrossRefPubMedGoogle Scholar
  4. 4.
    Donovan MD, Huang Y. Large molecule and particulate uptake in the nasal cavity: the effect of size on nasal absorption. Adv Drug Deliv Rev. 1998;29(1):147–55.CrossRefPubMedGoogle Scholar
  5. 5.
    Galgatte UC, Kumbhar AB, Chaudhari PD. Development of in situ gel for nasal delivery: design, optimization, in vitro and in vivo evaluation. Drug Deliv. 2014;21(1):62–73.CrossRefPubMedGoogle Scholar
  6. 6.
    Bitter C, Suter-Zimmermann K, Surber C. Nasal drug delivery in humans. In: Surber C, Elsner P, Farage MA, editors. Topical applications and the mucosa. Basel: Karger Publishers; 2011. p. 20–35.Google Scholar
  7. 7.
    Barry BW. Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci. 2001;14(2):101–14.CrossRefPubMedGoogle Scholar
  8. 8.
    Samant LR, Bhaskar A. Transdermal drug delivery system: review. J Pharm Res Vol. 2012;5(2):899–900.Google Scholar
  9. 9.
    Chien YW, Banga AK. Iontophoretic (transdermal) delivery of drugs: overview of historical development. J Pharm Sci. 1989;78(5):353–4.CrossRefPubMedGoogle Scholar
  10. 10.
    Brain KR, Walters KA, Watkinson AC. Methods for studying percutaneous absorption. Drugs and the Pharmaceutical Sciences. 2002;119:197–270.Google Scholar
  11. 11.
    Cho C-W, Choi J-S, Shin S-C. Development of the ambroxol gels for enhanced transdermal delivery. Drug Dev Ind Pharm. 2008;34(3):330–5.CrossRefPubMedGoogle Scholar
  12. 12.
    Steiger M. Topical emulsion-gel composition comprising diclofenac sodium. 2010. Google Patents.Google Scholar
  13. 13.
    Mohamed MI. Optimization of chlorphenesin emulgel formulation. AAPS J. 2004;6(3):81–7.CrossRefPubMedCentralGoogle Scholar
  14. 14.
    Peneva P, et al. In vitro survey of Ketoprofen release from emulgels. Medicine. 2014;4(1):118–21.Google Scholar
  15. 15.
    Khullar R, et al. Formulation and evaluation of mefenamic acid emulgel for topical delivery. Saudi Pharm J. 2012;20(1):63–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Mandal S, Mandal SS, Sawant KK. Design and development of microemulsion drug delivery system of atorvastatin and study its intestinal permeability in rats. Int J Drug Deliv. 2010;2(1):69–75.CrossRefGoogle Scholar
  17. 17.
    Stanos SP. Topical agents for the management of musculoskeletal pain. J Pain Symptom Manag. 2007;33(3):342–55.CrossRefGoogle Scholar
  18. 18.
    Banker GS. The theory and practice of industrial pharmacy. Vol. 1. Edited by Leon Lachman, Herbert A. Lieberman, and Joseph L. Kanig. Lea & Febiger, Philadelphia, PA 19106, 1970. xii + 811 pp. 15.5× 23 cm. Price $24.50. J Pharm Sci. 1970;59(10):1531–1.Google Scholar
  19. 19.
    Chapman CD, et al. Intranasal treatment of central nervous system dysfunction in humans. Pharm Res. 2013;30(10):2475–84.CrossRefPubMedGoogle Scholar
  20. 20.
    Merkus FW, van den Berg MP. Can nasal drug delivery bypass the blood-brain barrier? Drugs R D. 2007;8(3):133–44.CrossRefPubMedGoogle Scholar
  21. 21.
    Mygind N, Dahl R. Anatomy, physiology and function of the nasal cavities in health and disease. Adv Drug Deliv Rev. 1998;29(1):3–12.CrossRefPubMedGoogle Scholar
  22. 22.
    Levang AK, Zhao K, Singh J. Effect of ethanol/propylene glycol on the in vitro percutaneous absorption of aspirin, biophysical changes and macroscopic barrier properties of the skin. Int J Pharm. 1999;181(2):255–63.CrossRefPubMedGoogle Scholar
  23. 23.
    Americas I. The HLB system: a time-saving guide to emulsifier selection. Wilmington: ICI Americas, Incorporated; 1984.Google Scholar
  24. 24.
    Griffin WC. Classification of surface-active agents by “HLB”. J Soc Cosmet Chem. 1946;1:311–26.Google Scholar
  25. 25.
    Griffin WC. Calculation of HLB values of non-ionic surfactants. Am Perfume Essent Oil Rev. 1955;65:26–9.Google Scholar
  26. 26.
    Sowjanya G, Bandhavi P. Nanoemulsions an emerging trend: a review. IJPRD. 2012;4(6):137–52.Google Scholar
  27. 27.
    Ghica M, et al. Design and optimization of some collagen-minocycline based hydrogels potentially applicable for the treatment of cutaneous wound infections. Die Pharmazie-Int J Pharm Sci. 2011;66(11):853–61.Google Scholar
  28. 28.
    Chang J-S, et al. Formulation optimization of meloxicam sodium gel using response surface methodology. Int J Pharm. 2007;338(1):48–54.CrossRefPubMedGoogle Scholar
  29. 29.
    Samatı Y, Yüksel N, Tarimcı N. Preparation and characterization of poly (D, L-lactic-co-glycolic acid) microspheres containing flurbiprofen sodium. Drug Deliv. 2006;13(2):105–11.CrossRefPubMedGoogle Scholar
  30. 30.
    Wang S, Guo S, Cheng L. Disodium norcantharidate loaded poly (ɛ-caprolactone) microspheres: I. Preparation and evaluation. Int J Pharm. 2008;350(1):130–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Ruan G, Feng S-S. Preparation and characterization of poly (lactic acid)–poly (ethylene glycol)–poly (lactic acid)(PLA–PEG–PLA) microspheres for controlled release of paclitaxel. Biomaterials. 2003;24(27):5037–44.CrossRefPubMedGoogle Scholar
  32. 32.
    NM AMS, Abd El Gawad N. Preparation and characterization of benzophenone-3 loaded polymeric nanoparticles of lactide-co-ɛ-caprolactone as drug carriers. J Pharm Res Opin. 2012;2(2):28–41.Google Scholar
  33. 33.
    Baibhav J, et al. Development and characterization of clarithromycin emulgel for topical delivery. Int J Drug Dev Res. 2012;4(3):310–23.Google Scholar
  34. 34.
    Thakur NK, et al. Formulation and characterization of benzoyl peroxide gellified emulsions. Sci Pharm. 2012;80(4):1045–60.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Varshosaz J, Tavakoli N, Eram SA. Use of natural gums and cellulose derivatives in production of sustained release metoprolol tablets. Drug Deliv. 2006;13(2):113–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Badshah A, et al. Once daily controlled release matrix tablet of prochlorperazine maleate: Influence of Ethocel® and/or Methocel® on in vitro drug release and bioavailability. Drug Dev Ind Pharm. 2012;38(2):190–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Babar A, Bhandari R, Plakogiannis F. In-vitro release studies op chlorpheniramine maleate from topical bases using cellulose membrane and hairless mouse skin. Drug Dev Ind Pharm. 1991;17(8):1027–40.CrossRefGoogle Scholar
  38. 38.
    Zhang Y, et al. DDSolver: an add-in program for modeling and comparison of drug dissolution profiles. AAPS J. 2010;12(3):263–71.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Shah S, et al. Effect of permeation enhancers on the release behavior and permeation kinetics of novel tramadol lotions. Trop J Pharm Res. 2013;12(1):27–32.Google Scholar
  40. 40.
    Ayoub RK, et al. Formulation and permeation kinetic studies of flurbiprofen gel. Trop J Pharm Res. 2015;14(2):195–203.CrossRefGoogle Scholar
  41. 41.
    Akaike H. A new look at the statistical model identification. IEEE Trans Autom Control. 1974;19(6):716–23.CrossRefGoogle Scholar
  42. 42.
    Obata Y, et al. A statistical approach to the development of a transdermal delivery system for ondansetron. Int J Pharm. 2010;399(1):87–93.CrossRefPubMedGoogle Scholar
  43. 43.
    Shah SNH, et al. Formulation and evaluation of natural gum-based sustained release matrix tablets of flurbiprofen using response surface methodology. Drug Dev Ind Pharm. 2009;35(12):1470–8.CrossRefPubMedGoogle Scholar
  44. 44.
    Narayana RC, et al. Formulation and in vitro evaluation of in situ gels containing secnidazole for vaginitis. Yakugaku Zasshi. 2009;129(5):569–74.CrossRefPubMedGoogle Scholar
  45. 45.
    Shah SNH. Developing an efficacious diclofenac diethylamine transdermal formulation. J Food Drug Anal. 2012;20(2):464–70.Google Scholar
  46. 46.
    El-Houssieny BM, Hamouda HM. Formulation and evaluation of clotrimazole from pluronic F 127 gels. Drug Discov Ther. 2010:4(1).Google Scholar
  47. 47.
    Moran DT, et al. The fine structure of the olfactory mucosa in man. J Neurocytol. 1982;11(5):721–46.CrossRefPubMedGoogle Scholar
  48. 48.
    Pottorf RS. Peptide-based drug design: controlling transport and metabolism In: Taylor MD, Amidon GL, editors. Washington, DC: American Chemical Society; 1995. xviii + 567 pp. 18.5× 26 cm. $99.95. ACS Publications; 1996.Google Scholar
  49. 49.
    Hadgraft J, Lane ME. Advanced topical formulations (ATF). Int J Pharm. 2016;514(1):52–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Waheed S, et al. Comparative efficiency of propylene glycol and polyethylene glycol in enhancing percutaneous absorption and release of a drug through silicone membrane and rat skin. Pak J Zool. 2014;46(1):99–106.Google Scholar
  51. 51.
    Baroody FM, Naclerio RM. Nasal-ocular reflexes and their role in the management of allergic rhinoconjunctivitis with intranasal steroids. World Allergy Organ J. 2011;4(1):S1.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Broide DH. Allergic rhinitis: pathophysiology. In: Allergy and asthma proceedings, OceanSide Publications, Inc. 2010.Google Scholar
  53. 53.
    Morrison EE, Costanzo RM. Morphology of the human olfactory epithelium. J Comp Neurol. 1990;297(1):1–13.CrossRefPubMedGoogle Scholar
  54. 54.
    Baroody FM. Nasal and paranasal sinus anatomy and physiology. Clin Allergy Immunol. 2007;19:1.PubMedGoogle Scholar
  55. 55.
    Mathison S, Nagilla R, Kompella UB. Nasal route for direct delivery of solutes to the central nervous system: fact or fiction? J Drug Target. 1998;5(6):415–41.CrossRefPubMedGoogle Scholar
  56. 56.
    Gartner LP, Hiatt JL. Color textbook of histology e-book. Philadelphia: Elsevier Health Sciences; 2006.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Hina Javed
    • 1
  • Syed Nisar Hussain Shah
    • 1
  • Furqan Muhammad Iqbal
    • 1
  1. 1.Faculty of PharmacyBahauddin Zakariya UniversityMultanPakistan

Personalised recommendations