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 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.

Glycerosomal thermosensitive in situ gel of duloxetine HCl as a novel nanoplatform for rectal delivery: in vitro optimization and in vivo appraisal.

Duloxetine HCl (DXH) is a reuptake inhibitor of serotonin and norepinephrine used to treat the major depressive disorder. Following its extensive hepatic metabolism, acid-labile nature, and limited aqueous solubility, DXH has poor oral bioavailability (40%). The rectal route has been suggested as another route of administration to surmount such challenges. The present study aimed to prepare DXH-loaded glycerosomal (DXH-GLYS) in situ gel for rectal administration to increase DXH permeability and improve its bioavailability. Box-Behnken design (BBD) was adopted to prepare and optimize nanoglycerosomes. The impact of Phospholipon 90G (PL90G), Tween 80 concentrations, and glycerol percentage on encapsulation efficiency, nanoglycerosomal size, % cumulative DXH released, and the cumulative DXH permeated per unit area after 24 h were studied by the design. The pharmacokinetic and pharmacodynamic behavior of optimized formulation was investigated in rats. The formulated DXH-GLYS had a vesicle size ranging between 135.9 and 430.6 nm and an entrapment efficiency between 69.11 and 98.12%. The permeation experiment revealed that the optimized DXH-GLYS in situ gel increased DXH permeation by 2.62-fold compared to DXH solution. Pharmacokinetics studies disclosed that the DXH-GLYS in situ rectal gel exhibited 2.24-times increment in DXH bioavailability relative to oral DXH solution. The pharmacodynamic study revealed that the DXH-GLYS rectal treatment significantly improved the behavioral analysis parameters and was more efficacious as an antidepressant than the oral DXH solution. Collectively, these findings demonstrate that GLYS can be considered a potentially valuable rectal nanocarrier that could boost the DXH efficacy.

A novel transdermal nanoethosomal gel of lercanidipine HCl for treatment of hypertension: optimization using Box-Benkhen design, in vitro and in vivo characterization.

Poor bioavailability of drugs via oral route is the greatest challenge facing drug formulation. To overcome this obstacle, transdermal route was commonly used as an alternative route to improve bioavailability. Lercanidipine HCl (LER) is a vasoselective calcium-channel blocker that has a poor oral bioavailability of 10% due to its hepatic metabolism and low solubility. The main objective of this study was to develop nanoethosomal LER gel for transdermal delivery to increase its skin permeation and promote bioavailability. Nanoethosomes were prepared and optimized using a Box-Behnken design employing ethanol injection method. The design studied the influence of Phospholipon 90G (PL90G), LER, and ethanol concentrations on entrapment efficiency (EE%); vesicle size; % cumulative LER release (CLERR); and cumulative LER permeated per unit area at 24 h Q24 (µg/cm2). The pharmacokinetic parameters of the optimized formulation were determined in rats. Nanoethosomes showed a mean vesicle size between 210.87 and 400.57 nm and EE% ranging from 49.26 to 97.22%. The developed nanoethosomes enhanced % CLERR and Q24 values compared to drug suspension. The experimental parameters of optimized formulation were very close to those calculated by software. The pharmacokinetics study showed three times statistically significant (p < 0.05) enhancement in LER bioavailability following nanoethosomal LER gel transdermal application compared to that of oral LER suspension. Nanoethosomes can be considered as a promising carrier for LER transdermal delivery, thus will be fruitful therapy in hypertension management. Graphical abstract.

Correction to: A novel transdermal nanoethosomal gel of lercanidipine HCl for treatment of hypertension: optimization using Box-Benkhen design, in vitro and in vivo characterization.

In the original article, there are errors in Tables 2 and 6. Following are the corrected tables.