Optimization and Appraisal of Chitosan-Grafted PLGA Nanoparticles for Boosting Pharmacokinetic and Pharmacodynamic Effect of Duloxetine HCl Using Box-Benkhen Design

Duloxetine HCl (DXH) is a psychiatric medicine employed for treating major depressive disorder. Nonetheless, its low water solubility, high first-pass metabolism, and acid instability diminish the absolute oral bioavailability to 40%, thus necessitating frequent administration. Therefore, the aim of...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2023-02, Vol.112 (2), p.544-561
Main Authors: Salem, Heba F., Ali, Adel A., Rabea, Yasmine K., Abo El-Ela, Fatma I., Khallaf, Rasha A.
Format: Article
Language:English
Subjects:
Animals
Chitosan - metabolism
Depression
Depressive Disorder, Major
Drug Carriers - metabolism
Duloxetine HCl
Duloxetine Hydrochloride - pharmacology
Male
Nanoparticles
Nose-to-brain delivery
Particle Size
Pharmacodynamics
Pharmacokinetics
Polylactic Acid-Polyglycolic Acid Copolymer
Rats
Rats, Wistar
Surface-modified nanoparticles
Tissue Distribution
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Summary:Duloxetine HCl (DXH) is a psychiatric medicine employed for treating major depressive disorder. Nonetheless, its low water solubility, high first-pass metabolism, and acid instability diminish the absolute oral bioavailability to 40%, thus necessitating frequent administration. Therefore, the aim of the current study was to formulate DXH as nasal chitosan-grafted polymeric nanoparticles to improve its pharmacokinetic and pharmacodynamic properties. Applying the Box-Behnken design, DXH loaded PLGA-Chitosan nanoparticles (DXH-PLGA-CS-NPs) were fabricated and optimized using polylactide-co-glycolic acid (PLGA), chitosan (CS), and polyvinyl alcohol (PVA) as the independent factors. Particle size, entrapment efficiency, release percent, and cumulative amount permeated after 24 h of DXH-PLGA-CS-NPs (dependent variables) were evaluated. The in-vivo biodistribution and pharmacodynamic studies were done in male Wistar rats. The optimized DXH-PLGA-CS-NPs had a vesicle size of 122.11 nm and EE% of 66.95 with 77.65% release and Q24 of 555.34 (µg/cm2). Ex-vivo permeation study revealed 4-folds increase in DXH permeation from DXH-PLGA-CS-NPs after 24 h compared to DXH solution. Intranasal administration of optimized DXH-PLGA-CS-NPs resulted in significantly higher (p < 0.05) Cmax, AUCtotal, t1/2, and MRT in rat brain and plasma than oral DXH solution. Pharmacodynamics investigation revealed that intranasally exploited optimal DXH-PLGA-CS-NPs could be deemed a fruitful horizon for DXH as a treatment for depression. [Display omitted]
ISSN:0022-3549
1520-6017
DOI:10.1016/j.xphs.2022.08.034