Development and Characterization of Hyaluronic Acid-Incorporated Thermosensitive Nasal in situ Gel of Meclizine Hydrochloride

Kareem Khudhaier  Obayes; Lena Murad Thomas

doi:10.54133/ajms.v6i1.499

Authors

Kareem Khudhaier Obayes Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq; Ministry of Health and Environment, Babylon Health Directorate, Babylon, Iraq https://orcid.org/0009-0003-8285-3604
Lena Murad Thomas Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq https://orcid.org/0000-0002-3953-0741

DOI:

https://doi.org/10.54133/ajms.v6i1.499

Keywords:

Hyaluronic acid, In situ gels, Meclizine Hydrochloride, Poloxamer, Thermosensitive

Abstract

Background: Meclizine hydrochloride (MCZ) is an antihistamine that is used as an antiemetic to prevent and cure nausea and vomiting. Because of its limited water solubility and first-pass metabolism, it exhibits variable absorption. Objective: To formulate and evaluate MCZ as an intranasal in situ gel with increased residence time and permeability. Methods: We made an inclusion complex of MCZ using various cyclodextrins as a complexing agent to help the drug dissolve better. The complexes were studied, and the ones that were better at dissolving were chosen to be used in the creation of an in situ gel with poloxamer 407 (17–20% w/v) and hyaluronic acid (0.25–0.75% w/v). Prepared formulas were subjected to various evaluation tests, and the optimum formula was subjected to an ex vivo permeation study. Results: Hydroxypropyl-cyclodextrin (HP-CD) complexation increased the solubility of MCZ. A prepared complex (10 mg of MCZ) was used for nasal in situ gel preparation. Formula (F3) containing 17% poloxamer 407 and 0.75% hyaluronic acid exhibited favorable characteristics, including optimal gelation temperature (33.33°C), drug content (100.51%), gel strength (35.0 seconds), spreadability (4.2 cm), and 98.52% in vitro drug release over 5 hours in simulated nasal fluid (pH 6.8), and provided considerably high permeability. Conclusions: A mucoadhesive in situ gel formulation of MCZ (HP-β-CD) is a promising nasal formulation for the management of nausea and vomiting.

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References

Keller LA, Merkel O, Popp A. Intranasal drug delivery: opportunities and toxicologic challenges during drug development. Drug Deliv Transl Res. 2022;12(4):735–757. doi: 10.1007/s13346-020-00891-5.

Laffleur F, Bauer B. Progress in nasal drug delivery systems. Int J Pharm. 2021;607:120994. doi: 10.1016/j.ijpharm.2021.120994.

Wibble T, Engström J, Verrecchia L, Pansell T. The effects of meclizine on motion sickness revisited. Br J Clin Pharmacol. 2020;86(8):1510–1518. doi: 10.1111/bcp.14257.

Maltepe C, Koren G. The management of nausea and vomiting of pregnancy and hyperemesis gravidarum--a 2013 update. J Popul Ther Clin Pharmacol. 2013;20(2):e184-192. PMID: 23863612.

Sharma SK, Patel RP. Enhancing the solubility and dissolution rate of meclizine hydrochloride by inclusion complex. J Drug Deliv Ther. 2019;9(4):57–64. doi: 10.22270/jddt.v9i4.2981.

Anjali S, Abhijeet K, Ajay S. Nasal in situ gel: novel approach for nasal drug delivery. J Drug Deliv Ther. 2020;10:183–197. doi: 10.22270/jddt.v10i2-s.4029.

Rao M, Agrawal DK, Shirsath C. Thermoreversible mucoadhesive in situ nasal gel for treatment of Parkinson’s disease. Drug Dev Ind Pharm. 2017;43(1):142–150. doi: 10.1080/03639045.2016.1225754.

Zaki NM, Awad GA, Mortada ND, Abd El Hady 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(4–5):296–307. doi: 10.1016/j.ejps.2007.08.006.

Pereira GG, Dimer FA, Guterres SS, Kechinski CP, Granada JE, Cardozo NS. Formulation and characterization of poloxamer 407®: Thermoreversible gel containing polymeric microparticles and hyaluronic acid. Química Nova. 2013;36:1121-1125. doi: 10.1590/S0100-40422013000800008.

Cirri M, Maestrelli F, Nerli G, Mennini N, D’ambrosio M, Luceri C, et al. Development of a cyclodextrin-based mucoadhesive-thermo-sensitive in situ gel for clonazepam intranasal delivery. Pharmaceutics. 2021;13(7). doi: 10.3390/pharmaceutics13070969.

Mahajan HS, Shah SK, Surana SJ. Nasal in situ gel containing hydroxy propyl β-cyclodextrin inclusion complex of artemether: Development and in vitro evaluation. J Incl Phenom Macrocycl Chem. 2011;70(1–2):49–58. doi: 10.1007/s10847-010-9861-x.

Saokham P, Muankaew C, Jansook P, Loftsson T. Solubility of cyclodextrins and drug/cyclodextrin complexes. Molecules. 2018;23(5):1161. doi: 10.3390/molecules23051161.

George SJ, Vasudevan DT. Studies on the preparation, characterization, and solubility of 2-HP-β-cyclodextrin-meclizine HCl inclusion complexes. J Young Pharm. 2012;4(4):220–227. doi: 10.4103/0975-1483.104365.

Jadhav P, Pore Y. Physicochemical, thermodynamic and analytical studies on binary and ternary inclusion complexes of bosentan with hydroxypropyl-β-cyclodextrin. Bull Fac Pharmacy Cairo Univ. 2017;55(1):147-154. doi: 10.1016/j.bfopcu.2016.12.004.

Schmolka IR. Artificial skin I. Preparation and properties of pluronic F‐127 gels for treatment of burns. J Biomed Mater Res. 1972;6(6):571–582. doi: 10.1002/jbm.820060609.

Alabdly AA, Kassab HJ. Formulation variables effect on gelation temperature of nefopam hydrochloride intranasal in Situ Gel. Iraqi J Pharm Sci. 2022;31(5):32–44. doi: 10.31351/vol31issSuppl.pp32-44.

Maraie NK, Almajidi YQ. Application of nanoemulsion technology for preparation and evaluation of intranasal mucoadhesive nano- in-situ gel for ondansetron HCl. J Glob Pharma Technol. 2018;10(3):431–442. doi: 10.22159/ijap.2018v10i5.27396.

Vemula SK, Vangala M. Formulation development and characterization of meclizine hydrochloride sublimated fast dissolving tablets. Int Sch Res Notices. 2014;2014:281376. doi: 10.1155/2014/281376.

Thakkar H, Vaghela D, Patel BP. Brain targeted intranasal in-situ gelling spray of paroxetine: Formulation, characterization and in-vivo evaluation. J Drug Deliv Sci Technol. 2021;62:102317. doi: 10.1016/j.jddst.2020.102317.

Naresh WR, Dilip DV, Sunil KP. Xyloglucan based nasal in situ gel formulation of mirtazapine for treatment of depression. Indian J Pharm Educ Res. 2020;54:s210–219. doi: 10.5530/ijper.54.2s.77.

Sherafudeen SP, Vasantha PV. Development and evaluation of in situ nasal gel formulations of loratadine. Res Pharm Sci. 2015;10(6):466-476. PMID: 26779266.

Chaudhary B, Verma S. Preparation and evaluation of novel in situ gels containing acyclovir for the treatment of oral herpes simplex virus infections. Sci World J. 2014;2014. doi: 10.1155/2014/280928.

Corazza E, Di Cagno MP, Bauer-Brandl A, Abruzzo A, Cerchiara T, Bigucci F, et al. Drug delivery to the brain: In situ gelling formulation enhances carbamazepine diffusion through nasal mucosa models with mucin. Eur J Pharm Sci. 2022;179:106294. doi: 10.1016/j.ejps.2022.106294.

Thomas LM, Khasraghi AH, Saihood AH. Preparation and evaluation of lornoxicam in situ gelling liquid suppository. Drug Inven Today. 2018;10:1556–1563.

Alkufi HK, Kassab HJ. Formulation and evaluation of sustained release sumatriptan mucoadhesive intranasal in-situ gel. Iraqi J Pharm Sci. 2019;28(2):95–104. doi: 10.31351/vol28iss2pp95-104.

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. doi: 10.3109/10717544.2013.849778.

Loh GOK, Tan YTF, Peh KK. Enhancement of norfloxacin solubility via inclusion complexation with β-cyclodextrin and its derivative hydroxypropyl-β-cyclodextrin. Asian J Pharm Sci. 2016;11(4):536–546. doi: 10.1016/j.ajps.2016.02.009.

Xia Y, Li L, Huang X, Wang Z, Zhang H, Gao J, et al. Performance and toxicity of different absorption enhancers used in the preparation of Poloxamer thermosensitive in situ gels for ketamine nasal administration. Drug Dev Ind Pharm. 2020;46(5):697–705. doi: 10.1080/03639045.2020.1750625.

Wang Y, Jiang S, Wang H, Bie H. A mucoadhesive, thermoreversible in situ nasal gel of geniposide for neurodegenerative diseases. PLoS One. 2017;12(12):1–17. doi: 10.1371/journal.pone.0189478.

Mahajan HS, Tyagi V, Lohiya G, Nerkar P. Thermally reversible xyloglucan gels as vehicles for nasal drug delivery. Drug Deliv. 2012;19(5):270–276. doi: 10.3109/10717544.2012.704095.

Garg A, Aggarwal D, Garg S, Singla AK. Spreading of semisolid formulations: an update. Pharm Technol North Am. 2002;26(9):84.

Ahmed TA, Badr-Eldin SM, Ahmed OAA, Aldawsari H. Intranasal optimized solid lipid nanoparticles loaded in situ gel for enhancing trans-mucosal delivery of simvastatin. J Drug Deliv Sci Technol. 2018;48:499–508. doi: 10.1016/j.jddst.2018.10.027.

Pathan IB, More B. Formulation and characterization of intra nasal delivery of nortriptyline hydrochloride thermoreversible gelling system in treatment of depression. Acta Pharm Sci. 2017;55(2):35–44. doi: 10.23893/1307-2080.APS.05510.

Giuliano E, Paolino D, Fresta M, Cosco D. Mucosal applications of poloxamer 407-based hydrogels: An overview. Pharmaceutics. 2018;10(3):159. doi: 10.3390/pharmaceutics10030159.

Naresh WR, Dilip DV, Sunil KP. Xyloglucan based nasal in situ gel formulation of mirtazapine for treatment of depression. Indian J Pharm Educ Res. 2020;54:s210–219. doi: 10.5530/ijper.54.2s.77.

Tamer MA, Kassab HJ. the Development of a brain targeted mucoadhesive amisulpride loaded nanostructured lipid carrier. Farmacia. 2023;71(5):1032–1044. doi: 10.31925/farmacia.2023.5.18.

De PK, Ghatak S. Formulation optimization, permeation kinetic and release mechanism study of in-situ nasal gel containing ondansetron. Saudi J Med Pharm Sci. 2020;06(01):91–101. doi: 10.36348/sjmps.2020.v06i01.014.

Mali KK, Dhawale SC, Dias RJ, Havaldar VD, Ghorpade VS, Salunkhe NH. Nasal mucoadhesive in-situ gel of granisetron hydrochloride using natural polymers. J Appl Pharm Sci. 2015;5(7):84–93. doi: 10.7324/JAPS.2015.50714.

Vasvani S, Kulkarni P, Rawtani D. Hyaluronic acid: A review on its biology, aspects of drug delivery, route of administrations and a special emphasis on its approved marketed products and recent clinical studies. Int J Biol Macromol. 2020;151:1012-1029. doi: 10.1016/j.ijbiomac.2019.11.066.