Skip to main content
Log in

Formulation, Development, and Comparative Study of Azelastine-Loaded Temperature Sensitive In Situ Gelling Micelles for Allergic Conjunctivitis

  • Original Article
  • Published:
Journal of Pharmaceutical Innovation Aims and scope Submit manuscript

Abstract

Purpose

The current investigative study was performed to analyze and compare the effect of gellan gum-mixed poloxamer 407 as compared to plain poloxamer 407 on the in situ gelling behavior as well as drug release of the best formulation.

Method

Azelastine hydrochloride-loaded poloxamer 407 micelles and poloxamer 407 gellan gum micelles were prepared with the help of thin film hydration followed by the characterization of the micelles by evaluating the particle size, entrapment efficiency, pH, and gelation as well as in vitro and in vivo drug release analysis.

Result

The azelastine hydrochloride poloxamer 407 with gellan gum micelles having a particle size below 100 nm were found to show low gelation temperature which further increases the retention time of the formulation at the site of administration and results in a controlled release formulation. The in vitro drug release showed significant release of 85% and 89% of drug in the 10th hour while the in vivo analysis showed similar effect as that of the marketed formulation of AzelastTM.

Conclusion

A controlled release in situ temperature sensitive gel was successfully formulated which showed significant effect to reduce allergic conjunctivitis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

Data Availability

Data cannot be shared openly but are available on request from the corresponding author.

References

  1. John JG, Devine DM, Kennedy KE, Geever LM, et al. The use of agar as a novel filler for monolithic matrices produced using hot melt extrusion. Eur J Pharm Biopharm. 2006;64(1):75–81. https://doi.org/10.1016/j.ejpb.2006.03.008.

    Article  CAS  Google Scholar 

  2. Odeku OA. Assessment of Albizia zygia gum as a binding agent in tablet formulations. Acts Pharma. 2005;55(3):263–76.

    CAS  Google Scholar 

  3. Pawar HD, Mello PD. Isolation of seed gum from Cassia Tora and preliminary study of its application as a binder for tablets. Indian Drugs. 2004;41:465-468. https://www.researchgate.net/deref/https%3A%2F%2Fwww.researchgate.net%2F%25E2%2580%25A6%2F50338741_Introduction_to_the_Bioc

  4. Odeku OA, Itiola OA. Evaluation of the effects of khaya gum on the mechanical and release properties of paracetamol tablets. Drug Dev Ind Pharm. 2003;29(3):311–20. https://doi.org/10.1081/ddc-120018205.

    Article  PubMed  CAS  Google Scholar 

  5. Kulkarni TG, Gowthamarajan K, Rao GB, Suresh B. Evaluation of binding properties of selected natural mucilages. Journal of Scientific and Industrial Research. 2022;61(7):529-532 Tripathi

  6. Das N, Tripathi N, Basu S, Bose C et al. Progress in the development of gelling agents for improved culturability of microorganisms. Front. Microbiol. 2015;6: https://doi.org/10.3389/fmicb.2015.00698

  7. Pathan IB, Chudiwal V, Farooqui I, Shingare P. Formulation design and evaluation of nasal in situ gel as a novel vehicle for Azelastine hydrochloride. International Journal of Drug Delivery. 2013;5(3):284–90.

    Google Scholar 

  8. Miyasaki S, Kawasaki N, Kubo W, Endo K, et al. Comparison of in situ gelling formulations for the oral delivery of cimetidine. Int J Pharm. 2001;220(1–2):161–8. https://doi.org/10.1016/s0378-5173(01)00669-x.

    Article  Google Scholar 

  9. Agnihotri SA, Jawalkar SS, Aminabhavi ™. Controlled release of cephalexin through gellan gum beads: effect of formulation parameters on entrapment efficiency, size, and drug release. Eur J Pharm Biopharm. 2006;63(3):249-61. https://doi.org/10.1016/j.ejpb.2005.12.008

  10. Dewan M, Sarkar G, Bhowmik M, Das B, et al. Effect of gellan gum on the thermogelation property and drug release profile of Poloxamer 407 based ophthalmic formulation. International Journal of Biological Macromolecules. 2017;102:258–65. https://doi.org/10.1016/j.ijbiomac.2017.03.194.

    Article  PubMed  CAS  Google Scholar 

  11. Milivojevic M, Pajic-Lijakovic I, Bugaraki B, Nayak AK et al. Chapter 6 - Gellan gum in drug delivery applications. Natural Polysaccharides in Drug Delivery and Biomedical Applications. 2019. Pp. 145-186. https://doi.org/10.1016/B978-0-12-817055-7.00006-6

  12. Gupta H, Jain S, Mathur R, Mishra P, et al. Sustained ocular drug delivery from a temperature and pH triggered novel in situ gel system. Drug Deliv. 2007;14(8):507–15. https://doi.org/10.1080/10717540701606426.

    Article  PubMed  CAS  Google Scholar 

  13. Cao Y, Zhang C, Shen W, Cheng Z, et al. Poly(N-isopropylacrylamide)-chitosan as thermosensitive in situ gel-forming system for ocular drug delivery. J Control Release. 2007;120(3):186–94. https://doi.org/10.1016/j.jconrel.2007.05.009.

    Article  PubMed  CAS  Google Scholar 

  14. Gupta S, Samanta MK, Raichur AM. Dual-drug delivery system based on in situ gel-forming nanosuspension of forskolin to enhance antiglaucoma efficacy. AAPS PharmSciTech. 2010;11(1):322–35. https://doi.org/10.1208/s12249-010-9388-x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Rokade M, Tambe B, Ruparel M. In situ gel-sustained nasal drug delivery. International Journal of Pharmaceutical Science and Research. 2015;4:4958–66.

    Google Scholar 

  16. Moghimipour E, Salimi A, Yousefvand T. Preparation and evaluation of celecoxib nanoemulsion for ocular drug delivery. Asian Journal of Pharmaceutics. 2017;11(3)(Suppl):S543

  17. Khare P, Chogale MM, Kakade P, Patravale VB. Gellan gum–based in situ gelling ophthalmic nanosuspension of Posaconazole. Drug Deliv and Transl Res. 2022;12:2920–35. https://doi.org/10.1007/s13346-022-01155-0.

    Article  CAS  Google Scholar 

  18. Gueudry J, Le Goff L, Lamoureux F, Pereira T, et al. Corneal pharmacokinetics of voriconazole and posaconazole following intrastromal injection and posaconazole eye drops instillation in rats. Current Eye Research. 2020;45(11):1369–72. https://doi.org/10.1080/02713683.2020.1749669.

    Article  PubMed  CAS  Google Scholar 

  19. Zhu L, Ao J, Li P. A novel in situ gel base of deacetylase gellan gum for sustained ophthalmic drug delivery of ketotifen: in vitro and in vivo evaluation. Drug Des Devel Ther. 2015;9:3943–3949. https://doi.org/10.2147/2FDDDT.S87368

  20. Kidd M, McKenzie SH, Steven I, Cooper C, et al. Efficacy and safety of ketotifen eye drops in the treatment of seasonal allergic conjunctivitis. Br J Ophthalmol. 2003;87(10):1206–11. https://doi.org/10.1136/bjo.87.10.1206.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Barnes J, Moshirfar M. Timolol. [Updated 2022 Dec 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

  22. Devi S, Saini V, Kumar M, Bhatt S, et al. A novel approach of drug localization through development of polymeric micellar system containing azelastine HCl for ocular delivery. Pharm Nanotechnology. 2019;20(4):231–45.

    Google Scholar 

  23. Williams PB, Crandall E, Sheppard JD. Azelastine hydrochloride, a dual-acting anti-inflammatory ophthalmic solution, for treatment of allergic conjunctivitis. Clin Ophthalmol. 2010;4:993–1001. https://doi.org/10.2147/opth.s13479.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Bodratti AM, Alexandridis P. Formulation of Poloxamers for Drug Delivery. J Funct Biomater. 2018;9(1):11. https://doi.org/10.3390/jfb9010011.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Patil S, Kadam A, Bandgar S, Patil S. Formulation and evaluation of an in situ gel for ocular drug delivery of anti conjunctival drug. Cellulose Chem Technol. 2015;49(1):35–40.

    CAS  Google Scholar 

  26. Dessi M, Borzacchiello A, Hashem T, Abdel-Fatah WI, et al. Novel biomimetic thermosensitive β-tricalcium phosphate/chitosan-based hydrogels for bone tissue engineering. Journal of Biomedical Materials Research Part A. 2013;101(10):

  27. Schwegmann H, Feitz AJ, Frimmel FH. Influence of the zeta potential on the sorption and toxicity of iron oxide nanoparticles on S. cerevisiae and E. coli. Journal of Colloid and Interface Science. 2010;347(1):43-48. https://doi.org/10.1016/j.jcis.2010.02.028

  28. Rasmussen MK, Pedersen JN, Marie R. Size and surface charge characterization of nanoparticles with a salt gradient. Nat Commun. 2020;11:2337. https://doi.org/10.1038/s41467-020-15889-3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Santosh SD, Manthan S, Nazeer N, Dharan SS. Formulation and assessment of ph triggered in situ ocular gel using selected fluoroquinolone antibiotic. J Pharm Sci & Res. 2020;12(10):1262–70.

    Google Scholar 

  30. Shinde UA, Shete JN, Nair HA, Singh KH. Design and characterization of chitosan-alginate microspheres for ocular delivery of azelastine. Pharm Dev Technol. 2014;19(7):813–23. https://doi.org/10.3109/10837450.2013.836217.

    Article  PubMed  CAS  Google Scholar 

  31. Singh RB, Liu L, Anchouche S, Yung A, et al. Ocular redness - I: Etiology, pathogenesis, and assessment of conjunctival hyperemia. Ocul Surf. 2021;21:134–44. https://doi.org/10.1016/j.jtos.2021.05.003.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Shoji J. Ocular allergy test and biomarkers on the ocular surface: clinical test for evaluating the ocular surface condition in allergic conjunctival diseases. Allergology International. 2020;69(4):496–504.

    Article  PubMed  CAS  Google Scholar 

  33. Elghobashy MR, Badran UM, Salem MY, Kelani KM. Stability indicating spectrophotometric and chromatographic methods for the determination of azelastine hydrochloride in presence of its alkaline degradant. Analytical Chemistry. 2014;14(4):135–42.

    CAS  Google Scholar 

  34. Cooper A. Heat capacity of hydrogen-bonded networks: an alternative view of protein folding thermodynamics. Biophys Chem. 2000;85(1):25–39. https://doi.org/10.1016/s0301-4622(00)00136-8.

    Article  PubMed  CAS  Google Scholar 

  35. Cooper A, Johnson CM, Lakey JH, Nöllmann M. Heat does not come in different colours: entropy-enthalpy compensation, free energy windows, quantum confinement, pressure perturbation calorimetry, solvation and the multiple causes of heat capacity effects in biomolecular interactions. Biophys Chem. 2001;93(2–3):215–30. https://doi.org/10.1016/s0301-4622(01)00222-8.

    Article  PubMed  CAS  Google Scholar 

  36. Cooper A. Biophysical Chemistry. London, UK: Royal Society of Chemistry. 2000;2004:103–7.

    Google Scholar 

  37. Gill P, Moghadam TT, Ranjbar B. Differential scanning calorimetry techniques: applications in biology and nanoscience. J Biomol Tech. 2010;21(4):167–93.

    PubMed  PubMed Central  Google Scholar 

  38. Patil S, Ujalambkar V, Rathore A, Rojatkar S, et al. Galangin loaded galactosylated pluronic F68 polymeric micelles for liver targeting. Biomedicine & Pharmacotherapy. 2019;112:108691. https://doi.org/10.1016/j.biopha.2019.108691

  39. Malekhosseini S, Rezaie A, Khaledian S, Abdoli M. Fabrication and characterization of hydrocortisone loaded Dextran-Poly Lactic-co-Glycolic acid micelle. Heliyon. 2020;6(5):e03975. http://dx.doi.org/https://doi.org/10.1016/j.heliyon.2020.e03975

  40. Nagarwal RC, Singh SKPN, Maiti P, Pandit JK. Polymeric nanoparticulate system: a potential approach for ocular drug delivery. J Control Release. 2009;136(1):2–13. https://doi.org/10.1016/j.jconrel.2008.12.018.

    Article  PubMed  CAS  Google Scholar 

  41. Zhou H-Y,Hao J-L, Wang Y, Zhang W-S. Nanoparticles in the ocular drug delivery. Int J Opthalmol. 2013;6(3):390-396. https://doi.org/10.3980/2Fj.issn.2222-3959.2013.03.25

  42. Wang K, Zhang T, Liu L, Wang X, et al. Novel micelle formulation of curcumin for enhancing antitumor activity and inhibiting colorectal cancer stem cells. International Journal of Nanomedicines. 2012;7:4487–97.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kavita Singh.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ranade, V., Dalal, Y., Palampalle, H.Y. et al. Formulation, Development, and Comparative Study of Azelastine-Loaded Temperature Sensitive In Situ Gelling Micelles for Allergic Conjunctivitis. J Pharm Innov 18, 1966–1980 (2023). https://doi.org/10.1007/s12247-023-09760-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12247-023-09760-3

Keywords

Navigation