Development of Atomoxetine-Loaded NLC In Situ Gel for Nose-to-Brain Delivery: Optimization, In Vitro, and Preclinical Evaluation

Abstract

The present study investigates the brain-targeted efficiency of atomoxetine (AXT)-loaded nanostructured lipid carrier (NLC)-laden thermosensitive in situ gel after intranasal administration. AXT-NLC was prepared by the melt emulsification ultrasonication method and optimized using the Box–Behnken design (BBD). The optimized formulation (AXT-NLC) exhibited particle size PDI, zeta potential, and entrapment efficiency (EE) of 108 nm, 0.271, −42.3 mV, and 84.12%, respectively. The morphology of AXT-NLC was found to be spherical, as confirmed by SEM analysis. DSC results displayed that the AXT was encapsulated within the NLC matrix. Further, optimized NLC (AXT-NLC13) was incorporated into a thermosensitive in situ gel using poloxamer 407 and carbopol gelling agent and evaluated for different parameters. The optimized in situ gel (AXT-NLC13G4) formulation showed excellent viscosity (2532 ± 18 Cps) at 37 °C and formed the gel at 28–34 °C. AXT-NLC13-G4 showed a sustained release of AXT (92.89 ± 3.98% in 12 h) compared to pure AXT (95.47 ± 2.76% in 4 h). The permeation flux through goat nasal mucosa of AXT from pure AXT and AXT-NLC13-G4 was 504.37 µg/cm2·h and 232.41 µg/cm2·h, respectively. AXT-NLC13-G4 intranasally displayed significantly higher absolute bioavailability of AXT (1.59-fold higher) than intravenous administration. AXT-NLC13-G4 intranasally showed 51.91% higher BTP than pure AXT (28.64%) when administered via the same route (intranasally). AXT-NLC13-G4 showed significantly higher BTE (207.92%) than pure AXT (140.14%) when administered intranasally, confirming that a high amount of the AXT reached the brain. With the disrupted performance induced by L-methionine, the AXT-NLC13-G4 showed significantly (p < 0.05) better activity than pure AXT as well as donepezil (standard). The finding concluded that NLC in situ gel is a novel carrier of AXT for improvement of brain delivery by the intranasal route and requires further investigation for more justification.

Natural-Origin Betaine Surfactants as Promising Components for the Stabilization of Lipid Carriers

“…Among the ways of application of colloidal systems based on solid lipids extensively documented in the literature are cosmetic [5,8,9], food [4,6,10], and, above all, in the pharmaceutical industry (i.e., drug delivery) [7,11,12]. In recent years, lipid formulations have enabled the effective encapsulation of active substances successfully delivered intravenously [13][14][15], orally [16][17][18], transdermally [19][20][21], and also directly into the eye [22][23][24] or nose [25][26][27].…”

Xanthan-Gum/Pluronic-F-127-Based-Drug-Loaded Polymeric Hydrogels Synthesized by Free Radical Polymerization Technique for Management of Attention-Deficit/Hyperactivity Disorder

“…Teaima and coworkers prepared solid lipid nanoparticles for the brain targeting of ATMH and sustained the release of ATMH for 8 h [6]. Mohanty et al (2023) prepared ATMH-loaded nanostructured lipid carriers and demonstrated the sustained release of ATMH for 12 h [7]. Similarly, Stanojevic and coworkers prepared tablets for the sustained release of ATMH of up to 8 h [8].…”