Abstract
Paroxetine (PX) is the most potent serotonin reuptake inhibitor utilized in depression and anxiety treatment. It has drawbacks, such as having a very bitter taste, low water solubility, and undergoing extensive first pass metabolism, leading to poor oral bioavailability (<50%). This work aimed to develop and optimize palatable oral fast-dissolving films (OFDFs) loaded with a paroxetine nanosuspension. A PX nanosuspension was prepared to increase the PX solubility and permeability via the buccal mucosa. The OFDFs could increase PX bioavailability due to their rapid dissolution in saliva, without needing water, and the rapid absorption of the loaded drug through the buccal mucosa, thus decreasing the PX metabolism in the liver. OFDFs also offer better convenience to patients with mental illness, as well as pediatric, elderly, and developmentally disabled patients. The PX nanosuspension was characterized by particle size, poly dispersity index, and zeta potential. Twelve OFDFs were formulated using a solvent casting technique. A 22 × 31 full factorial design was applied to choose the optimized OFDF, utilizing Design-Expert® software (Stat-Ease Inc., Minneapolis, MN, USA). The optimized OFDF (F1) had a 3.89 ± 0.19 Mpa tensile strength, 53.08 ± 1.28% elongation%, 8.12 ± 0.13 MPa Young’s modulus, 17.09 ± 1.30 s disintegration time, and 96.02 ± 3.46% PX dissolved after 10 min. This optimized OFDF was subjected to in vitro dissolution, ex vivo permeation, stability, and palatability studies. The permeation study, using chicken buccal pouch, revealed increased drug permeation from the optimized OFDF; with a more than three-fold increase in permeation over the pure drug. The relative bioavailability of the optimized OFDF in comparison with the market tablet was estimated clinically in healthy human volunteers and was found to be 178.43%. These findings confirmed the success of the OFDFs loaded with PX nanosuspension for increasing PX bioavailability.
Highlights
Paroxetine (PX) is a phenylpiperidine compound and is the most selective and potent serotonin reuptake inhibitor
The low value of the poly dispersity index (PDI) indicates the small distribution of the particle sizes, and, the homogeneity of the diameter of particles
zeta potential (ZP) is an essential parameter for indicating the physical stability of prepared nanosuspensions
Summary
Paroxetine (PX) is a phenylpiperidine compound and is the most selective and potent serotonin reuptake inhibitor. This work aimed to develop and optimize novel palatable oral fast dissolving films (OFDFs) loaded with a paroxetine nanosuspension, to improve PX oral bioavailability by decreasing its broad metabolism in the liver and increasing PX solubility and permeability through the buccal mucosa. Tween 80 was incorporated as a wetting agent to accelerate the disintegration of the prepared OFDFs within seconds, releasing the loaded drug rapidly [15,16] It was used as a permeation enhancer to increase the PX penetration through the buccal mucosa, because of its non-ionic nature, high HLB value, and low critical micelle concentration [17]. The bioavailability of the optimized PX OFDF was clinically investigated in healthy human volunteers and compared with the market tablet
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