Preparation of Idebenone as a Thermosetting Nasal Gel for Better Bioavailability and Histopathological Effect

Hussein J.  Kadhim; Khalid K. Al-Kinani

doi:10.32007/jfacmedbagdad.2082

Authors

Hussein J. Kadhim Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq. https://orcid.org/0000-0003-0686-5454
Khalid K. Al-Kinani Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq.

DOI:

https://doi.org/10.32007/jfacmedbagdad.2082

Keywords:

Bioavailability,, Idebenone, , Nanoemulsion,, Permeation

Abstract

Background Idebenone is an extensively metabolized drug with poor water solubility that is used to treat Leiber’s hereditary optical neuropathy.

Objective This study aims to prepare idebenone nanoemulsion as a poloxamer-based nasal gel to overcome the extensive rate of hepatic metabolism for better bioavalability and lower histopathological effects on the nasal mucosa.

Methods The formulation strategy was based on eliciting mutual concentration reduction between the nanoemulsion and the carrier gel by setting their gelation temperature between 30-32°C to overcome the mucociliary dose washout. The o/w nanoemulsions rely on cremophor EL and transcutol as an emulsifying system to stabilize idebenone-loaded lemongrass oil. The spontaneous emulsification method was used to prepare nanoemulsions that were characterized by zeta sizer while the thermosensitive hydrogels were prepared using the cold method. In-vitro dissolution test and ex-vivo permeation study through excised sheep nasal mucosa were performed to evaluate the enhanced permeation ratio, rate of permeation, and permeation coefficient. The histopathological effect of direct application on sheep nasal mucosa was studied using optical microscopy to evaluate cellular toxicity.

Results The formula prepared from NE1 with poloxamer 407: poloxamer188 in concentrations 10:3% w/w respectively, showed almost complete drug release in 120 minutes due to complete polymers blend erosion. Furthermore, thermosensitive nano-emulgel at a temperature of gelation 31.8°C was obtained at much lower concentrations of poloxamer 407 (10%) compared to previous studies. Nanoemulsions retained their globular size below 100nm due to further gel entrapment stabilization.

Conclusions Drug permeation through excised sheep nasal mucosa elicited an increase in enhanced permeation ratio to 20.3 times and other flux kinetics parameters compared to those of IDB oil dispersion. Direct cellular toxicity showed a minor inflammatory response characterized by serous infiltration of inflammatory cells and edema. In contrast, most of the epithelial cells retained their histological characteristics compared to control slides

Received: Mar. 2023

Revised: April 2023

Accepted: Aug 2023

Published: Oct.2023

Downloads

Download data is not yet available.

References

Patel RG. Nasal Anatomy and Function. Facial Plastic Surgery. 2017;33(1): 3–8. 2. Türker S, Onur E, Ózer Y. Nasal route and drug delivery systems., Pharmacy World and Sci. 2004;26:137–42.

https://doi.org/10.1023/b:phar.0000026823.82950.ff.

Bodratti AM, Alexandridis P. Amphiphilic block copolymers in drug delivery: advances in formulation structure and performance., Exp Opion D Del. Taylor and Francis Ltd; 2018;15:1085–104.

https://doi.org/10.1080/17425247.2018.1529756.

Huang Y, Ma M, Zhu X, Li M, Guo M, Liu P, et al. Effectiveness of idebenone nanorod formulations in the treatment of Alzheimer’s disease. J Con Rel. 2021 ;336:169–80. https://doi.org/10.1016/j.jconrel.2021.06.024.

Catarino CB, Klopstock T. Use of idebenone for the treatment of Leber’s hereditary optic neuropathy. J Inborn Errors Metab Screen. 2017; 5:1-8. https://doi.org/10.1177/2326409817731112.

Zhao X, Zhang Y, Lu L, Yang H. Therapeutic effects of idebenone on Leber hereditary optic neuropathy. Curr Eye Res. 2020; 45(10):1315–23. https://doi.org/10.1080/02713683.2020.1736307.

Varela-Fernández R, Lema-Gesto MI, González-Barcia M, Otero-Espinar FJ. Design, development, and characterization of an idebenone-loaded poly-ε-caprolactone intravitreal implant as a new therapeutic approach for LHON treatment. European Journal of Pharmaceutics and Biopharmaceutics. 2021; 168:195–207.

https://doi.org/10.1016/j.ejpb.2021.09.001.

Balakrishnan P, Park EK, Song CK, Ko HJ, Hahn TW, Song KW, et al. Carbopol-Incorporated thermoreversible gel for intranasal drug delivery. Molecules. 2015 ;20(3):4124–35. https://doi.org/10.3390/molecules20034124.

Bhattacharjee S. DLS and zeta potential - What they are and what they are not?, J of Cont Rel. 2016 ;235: 337–51

https://doi.org/10.1016/j.jconrel.2016.06.017

Sadoon NA, Ghareeb MM. Formulation and characterization of isradipine as oral nanoemulsion. Iraqi J of Pharm Sci. 2020; 29(1):143–53. https://doi.org/10.31351/vol29iss1pp143-153.

Hammodi ID, Abd Alhammid SN. Preparation and characterization of topical letrozole nanoemulsion for breast cancer. Iraqi J of Pharm Sci. 2020 ;29(1):195–206. https://doi.org/10.31351/vol29iss1pp195-206.

Maccelli A, Vitanza L, Imbriano A, Fraschetti C, Filippi A, Goldoni P, et al. Essential oils: chemical profiles/phytochemical screening, antimicrobial activity and o/w nanoemulsion formulations. Pharmaceutics. 2020 ;12(1):12010007. https://doi.org/10.3390/pharmaceutics12010007.

Blanchard J, Almeida H, Desai SD. In vitro evaluation of pluronic F127-based controlled-release ocular delivery systems for pilocarpine . 1998; 87(9):226-230 https://doi.org/10.1021/js970090e.

Abdulla NA, Balata GF, El-ghamry HA, Gomaa E. Intranasal delivery of clozapine using nanoemulsion-based in-situ gels: An approach for bioavailability enhancement. Saudi Pharmaceutical J. 2021 ;29(12):1466–85.

https://doi.org/10.1016/j.jsps.2021.11.006.

Jaiswal M, Kumar A, Sharma S. Nanoemulsions loaded Carbopol® 934 based gel for intranasal delivery of neuroprotective Centella asiatica extract: in–vitro and ex–vivo permeation study. J Pharm Investig. 2016 ;46(1):79–89. https://doi.org/10.1007/s40005-016-0228-1.

Abdulbaqi MR, Rajab NA. Apixaban ultrafine O/W nano emulsion transdermal drug delivery system: Formulation, in vitro and ex vivo characterization. Syst Rev in Pharmacy. 2020;11(2):82–94. http://dx.doi.org/10.5530/srp.2020.2.14

Nagda CD, Chotai NP, Nagda DC, et al. Development and characterization of mucoadhesive microspheres for nasal delivery of ketorolac. Pharmazie. 2011 ;66(4):249–57. https://doi.org/10.2174/156720112800234503.

Chen Y, Lee JH, Meng M, Cui N, Dai CY, Jia Q, et al. An overview on thermosensitive oral gel based on poloxamer 407. Materials.2021; 14: https://doi.org/10.3390/ma14164522.

Dumortier G, Grossiord JL, Agnely F, Chaumeil JC. A review of poloxamer 407 pharmaceutical and pharmacological characteristics., Pharmaceutical Res. 2006; 23(12): 2709–28. https://doi.org/10.1007/s11095-006-9104-4.

Giuliano E, Paolino D, Fresta M, et al. Mucosal applications of poloxamer 407-based hydrogels: An overview. Pharmaceutics. 2018; 10:10030159. https://doi.org/10.3390/pharmaceutics10030159.

le Garrec D, Leroux JC. Healthcare technology review micelles in anticancer drug delivery. Am J Drug Deliv. 2004;2(1):15-42. https://doi.org/10.2165/00137696-200402010-00002.

Letchford K, Burt H. A review of the formation and classification of amphiphilic block copolymer nanoparticulate structures: micelles, nanospheres, nanocapsules and polymersomes., Eur J Pharmaceutics and Biopharmaceutics. 2007; 65: 259–69. https://doi.org/10.1016/j.ejpb.2006.11.009.

Xu X, Shen Y, Wang W, Sun C, Li C, Xiong Y, et al. Preparation and in vitro characterization of thermosensitive and mucoadhesive hydrogels for nasal delivery of phenylephrine hydrochloride. European Journal of Pharmaceutics and Biopharmaceutics. 2014 ;88(3):998–1004. https://doi.org/10.1016/j.ejpb.2014.08.015.

Souza AG de, Ferreira RR, Aguilar ESF, Zanata L, Rosa D dos S. Cinnamon Essential Oil Nanocellulose-Based Pickering Emulsions: Processing Parameters Effect on Their Formation, Stabilization, and Antimicrobial Activity. Polysaccharides. 2021;2(3):608–25. https://doi.org/10.3390/polysaccharides2030037.

Espinoza LC, Silva-Abreu M, Clares B, Rodríguez-Lagunas MJ, Halbaut L, Cañas MA, et al. Formulation strategies to improve nose-to-brain delivery of donepezil. Pharmaceutics. 2019;11(2):11020064. https://doi.org/10.3390/pharmaceutics11020064.

Naqvi A, Ahmad M, Minhas MU, Khan KU, Batool F, Rizwan A. Preparation and evaluation of pharmaceutical co-crystals for solubility enhancement of atorvastatin calcium. Polymer Bulletin. 2020 ;77(12):6191–211. https://doi.org/10.1007/s00289-019-02997