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Preparation, characterization, and optimization of asenapine maleate mucoadhesive nanoemulsion using Box-Behnken design: In vitro and in vivo studies for brain targeting.
Int J Pharm. 2020 Jun 04; 586:119499.IJ

Abstract

The tight junctions between capillary endothelial cells of the blood-brain barrier (BBB) restricts the entry of therapeutics into the brain. Potential of the intranasal delivery tool has been explored in administering the therapeutics directly to the brain, thus bypassing BBB. The objective of this study was to develop and optimize an intranasal mucoadhesive nanoemulsion (MNE) of asenapine maleate (ASP) in order to enhance the nasomucosal adhesion and direct brain targetability for improved efficacy and safety. Box-Behnken statistical design was used to recognize the crucial formulation variables influencing droplet size, size distribution and surface charge of ASP-NE. ASP-MNE was obtained by incorporating GRAS mucoadhesive polymer, Carbopol 971 in the optimized NE. Optimized ASP-MNE displayed spherical morphology with a droplet size of 21.2 ± 0.15 nm and 0.355 polydispersity index. Improved ex-vivo permeation was observed in ASP-NE and ASP-MNE, compared to the ASP-solution. Finally, the optimized formulation was found to be safe in ex-vivo ciliotoxicity study on sheep nasal mucosa. The single-dose pharmacokinetic study in male Wistar rats revealed a significant increase in concentration of ASP in the brain upon intranasal administration of ASP-MNE, with a maximum of 284.33 ± 5.5 ng/mL. The time required to reach maximum brain concentration (1 h) was reduced compared to intravenous administration of ASP-NE (3 h). Furthermore, it has been established during the course of present study, that the brain targeting capability of ASP via intranasal administration had enhanced drug-targeting efficiency and drug-targeting potential. In the animal behavioral studies, no extrapyramidal symptoms were observed after intranasal administration of ASP-MNE, while good locomotor activity and hind-limb retraction test established its antipsychotic activity in treated animals. Thus, it can be concluded that the developed intranasal ASP-MNE could be used as an effective and safe tool for brain targeting of ASP in the treatment of psychotic disorders.

Authors+Show Affiliations

School of Pharmaceutical Sciences, Jaipur National University, Jaipur 302017, Rajasthan, India; Department of Pharmaceutics, STES's Sinhgad Institute of Pharmacy (Affiliated to Savitribai Phule Pune University), Narhe, Pune 411041, Maharashtra, India.Department of Pharmaceutics, STES's Sinhgad Institute of Pharmacy (Affiliated to Savitribai Phule Pune University), Narhe, Pune 411041, Maharashtra, India.School of Pharmaceutical Sciences, Jaipur National University, Jaipur 302017, Rajasthan, India. Electronic address: director_pharmacy@jnujaipur.ac.in.School of Pharmacy, Faculty of Health and Medical Science, Taylor's University, 47500 Subang Jaya, Selangor, Malaysia.Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, 57000 Kuala Lumpur, Malaysia. Electronic address: HiraChoudhury@imu.edu.my.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32505580

Citation

Kumbhar, Santosh Ashok, et al. "Preparation, Characterization, and Optimization of Asenapine Maleate Mucoadhesive Nanoemulsion Using Box-Behnken Design: in Vitro and in Vivo Studies for Brain Targeting." International Journal of Pharmaceutics, vol. 586, 2020, p. 119499.
Kumbhar SA, Kokare CR, Shrivastava B, et al. Preparation, characterization, and optimization of asenapine maleate mucoadhesive nanoemulsion using Box-Behnken design: In vitro and in vivo studies for brain targeting. Int J Pharm. 2020;586:119499.
Kumbhar, S. A., Kokare, C. R., Shrivastava, B., Gorain, B., & Choudhury, H. (2020). Preparation, characterization, and optimization of asenapine maleate mucoadhesive nanoemulsion using Box-Behnken design: In vitro and in vivo studies for brain targeting. International Journal of Pharmaceutics, 586, 119499. https://doi.org/10.1016/j.ijpharm.2020.119499
Kumbhar SA, et al. Preparation, Characterization, and Optimization of Asenapine Maleate Mucoadhesive Nanoemulsion Using Box-Behnken Design: in Vitro and in Vivo Studies for Brain Targeting. Int J Pharm. 2020 Jun 4;586:119499. PubMed PMID: 32505580.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Preparation, characterization, and optimization of asenapine maleate mucoadhesive nanoemulsion using Box-Behnken design: In vitro and in vivo studies for brain targeting. AU - Kumbhar,Santosh Ashok, AU - Kokare,Chandrakant R, AU - Shrivastava,Birendra, AU - Gorain,Bapi, AU - Choudhury,Hira, Y1 - 2020/06/04/ PY - 2020/03/18/received PY - 2020/05/04/revised PY - 2020/05/31/accepted PY - 2020/6/9/pubmed PY - 2020/6/9/medline PY - 2020/6/8/entrez KW - Antipsychotic activity KW - Asenapine maleate KW - Box-Behnken design KW - Brain targeting potential KW - Intranasal delivery KW - Mucoadhesive nanoemulgel SP - 119499 EP - 119499 JF - International journal of pharmaceutics JO - Int J Pharm VL - 586 N2 - The tight junctions between capillary endothelial cells of the blood-brain barrier (BBB) restricts the entry of therapeutics into the brain. Potential of the intranasal delivery tool has been explored in administering the therapeutics directly to the brain, thus bypassing BBB. The objective of this study was to develop and optimize an intranasal mucoadhesive nanoemulsion (MNE) of asenapine maleate (ASP) in order to enhance the nasomucosal adhesion and direct brain targetability for improved efficacy and safety. Box-Behnken statistical design was used to recognize the crucial formulation variables influencing droplet size, size distribution and surface charge of ASP-NE. ASP-MNE was obtained by incorporating GRAS mucoadhesive polymer, Carbopol 971 in the optimized NE. Optimized ASP-MNE displayed spherical morphology with a droplet size of 21.2 ± 0.15 nm and 0.355 polydispersity index. Improved ex-vivo permeation was observed in ASP-NE and ASP-MNE, compared to the ASP-solution. Finally, the optimized formulation was found to be safe in ex-vivo ciliotoxicity study on sheep nasal mucosa. The single-dose pharmacokinetic study in male Wistar rats revealed a significant increase in concentration of ASP in the brain upon intranasal administration of ASP-MNE, with a maximum of 284.33 ± 5.5 ng/mL. The time required to reach maximum brain concentration (1 h) was reduced compared to intravenous administration of ASP-NE (3 h). Furthermore, it has been established during the course of present study, that the brain targeting capability of ASP via intranasal administration had enhanced drug-targeting efficiency and drug-targeting potential. In the animal behavioral studies, no extrapyramidal symptoms were observed after intranasal administration of ASP-MNE, while good locomotor activity and hind-limb retraction test established its antipsychotic activity in treated animals. Thus, it can be concluded that the developed intranasal ASP-MNE could be used as an effective and safe tool for brain targeting of ASP in the treatment of psychotic disorders. SN - 1873-3476 UR - https://www.unboundmedicine.com/medline/citation/32505580/Preparation,_characterization,_and_optimization_of_asenapine_maleate_mucoadhesive_nanoemulsion_using_Box-Behnken_design:_In_vitro_and_in_vivo_studies_for_brain_targeting L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-5173(20)30483-X DB - PRIME DP - Unbound Medicine ER -
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