Lipid nanocarriers overlaid with chitosan for brain delivery of berberine via the nasal route

This research aimed to design, optimize, and evaluate berberine-laden nanostructured lipid carriers overlaid with chitosan (BER-CTS-NLCs) for efficient brain delivery via the intranasal route. The nanostructured lipid carriers containing berberine (BER-NLCs) were formulated via hot homogenization and ultrasonication strategy and optimized for the influence of a variety of causal variables, including the amount of glycerol monostearate (solid lipid), poloxamer 407 (surfactant) concentration, and oleic acid (liquid lipid) amount, on size of the particles, entrapment, and the total drug release after 24 h. The optimal BER-NLCs formulation was then coated with chitosan. Their diameter, in vitro release, surface charge, morphology, ex vivo permeability, pH, histological, and in vivo (pharmacokinetics and brain uptake) parameters were estimated. BER-CTS-NLCs had a size of 180.9 ± 4.3 nm, sustained-release properties, positive surface charge of 36.8 mV, and augmented ex-vivo permeation via nasal mucosa. The histopathological assessment revealed that the BER-CTS-NLCs system is safe for nasal delivery. Pharmacokinetic and brain accumulation experiments showed that animals treated intranasally with BER-CTS-NLCs had substantially greater drug levels in the brain. The ratios of BER brain/blood levels at 30 min, AUCbrain/AUCblood, drug transport percentage, and drug targeting efficiency for BER-CTS-NLCs (IN) were higher compared to BER solution (IN), suggesting enhanced brain targeting. The optimized nanoparticulate system is speculated to be a successful approach for boosting the effect of BER in treating CNS diseases, such as Alzheimer’s disease, through intranasal therapy

Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers

Pyrimidines play an important role in modern medical fields. They have a wide spectrum of biological activities such as antimicrobial, anticancer, anti-allergic, anti-leishmanial, antioxidant agents and others. Moreover, in recent years, 3,4-dihydropyrimidin-2(1H)ones have attracted researchers to synthesize them via Biginelli reaction and evaluate their antihypertensive activities as bioisosters of Nifedipine, which is a famous calcium channel blocker. Our new target compounds were prepared through one-pot reaction of thiourea 1, ethyl acetoacetate 2 and/or 1H-indole-2-carbaldehyde, 2-chloroquinoline-3-carbaldehyde, 1,3-diphenyl-1H-pyrazole-4-carbaldehyde, 3a–c in acid medium (HCl) yielding pyrimidines 4a–c, which in turn were hydrolyzed to carboxylic acid derivatives 5a–c which were chlorinated by SOCl2 to give acyl chlorides 6a–c. Finally, the latter were reacted with some selected aromatic amines, namely, aniline, p-toluidine and p-nitroaniline, producing amides 7a–c, 8a–c, and 9a–c. The purity of the prepared compounds was examined via TLC monitoring, and structures were confirmed by different spectroscopic techniques such as IR, 1HNMR, 13CNMR, and mass spectroscopy. The in vivo evaluation of the antihypertensive activity revealed that compounds 4c, 7a, 7c, 8c, 9b and 9c had comparable antihypertensive properties with Nifedipine. On the other hand, the in vitro calcium channel blocking activity was evaluated by IC50 measurement and results revealed that compounds 4c, 7a, 7b, 7c, 8c, 9a, 9b, and 9c had comparable calcium channel blocking activity with the reference Nifedipine. Based on the aforementioned biological results, we selected compounds 8c and 9c to be docked onto Ryanodine and dihydropyridine receptors. Furthermore, we developed a structure–activity relationship. The designed compounds in this study show promising activity profiles in reducing blood pressure and as calcium channel blockers, and could be considered as new potential antihypertensive and/or antianginal agents

Intranasal Nanotransferosomal Gel for Quercetin Brain Targeting: II. Antidepressant Effect in an Experimental Animal Model

Depression is a serious mental disorder and the most prevalent cause of disability and suicide worldwide. Quercetin (QER) demonstrated antidepressant effects in rats exhibiting anxiety and depressive-like behaviors. In an attempt to improve QER’s antidepressant activity, a QER-loaded transferosome (QER-TFS) thermosensitive gel for intranasal administration was formulated and optimized. The therapeutic effectiveness of the optimized formulation was assessed in a depressed rat model by conducting a behavioral analysis. Behavioral study criteria such as immobility, swimming, climbing, sucrose intake, number of crossed lines, rearing, active interaction, and latency to feed were all considerably enhanced by intranasal treatment with the QER-TFS in situ gel in contrast to other formulations. A nasal histopathological study indicated that the QER-TFS thermosensitive gel was safe for the nasal mucosa. An immunohistochemical analysis showed that the animals treated with the QER-TFS thermosensitive gel had the lowest levels of c-fos protein expression, and brain histopathological changes in the depressed rats were alleviated. According to pharmacodynamic, immunohistochemical, and histopathological experiments, the intranasal administration of the QER-TFS thermosensitive gel substantially alleviated depressive symptoms in rats. However, extensive preclinical investigations in higher animal models are needed to anticipate its effectiveness in humans

Intranasal nanotransferosomal gel for quercetin brain targeting: I. optimization, characterization, brain localization, and cytotoxic studies

<p>Numerous neurological disorders have a pathophysiology that involves an increase in free radical production in the brain. Quercetin (QER) is a nutraceutical compound that shields the brain against oxidative stress-induced neurodegeneration. Nonetheless, its low oral bioavailability diminishes brain delivery. Therefore, the current study aimed to formulate QER-loaded transferosomal nanovesicles (QER-TFS) in situ gel for QER brain delivery via the intranasal route. This study explored the impacts of lipid amount, edge activator (EA) amount, and EA type on vesicle diameter, entrapment, and cumulative amount permeated through nasal mucosa (24 h). The optimum formulation was then integrated into a thermosensitive gel after its physical and morphological characteristics were assessed. Assessments of the optimized QER-TFS showed nanometric vesicles (171.4 ± 3.4 nm) with spherical shapes and adequate entrapment efficiency (78.2 ± 2.8%). The results of short-term stability and high zeta potential value (−32.6 ± 1.4 mV) of QER-TFS confirmed their high stability. Compared with the QER solution, the optimized QER-TFS in situ gel formulation exhibited sustained release behavior and augmented nasal mucosa permeability. CT scanning of rat brains demonstrated the buildup of gold nanoparticles (GNPs) in the brains of all treatment groups, with a greater level of GNPs noted in the rats given the transferosomal gel. Additionally, in vitro studies on PCS-200-014 cells revealed minimal cytotoxicity of QER-TFS in situ gel. Based on these results, the developed transferosomal nanovesicles may be a suitable nanocarrier for QER brain targeting through the intranasal route.</p&gt

Antibiotic-Loaded Psyllium Husk Hemicellulose and Gelatin-Based Polymeric Films for Wound Dressing Application

Wound infections are one of the major reasons for the delay in the healing of chronic wounds and can be overcome by developing effective wound dressings capable of absorbing exudate, providing local antibiotic release, and improving patient comfort. Arabinoxylan (AX) is a major hemicellulose present in psyllium seed husk (PSH) and exhibits promising characteristics for developing film dressings. Herein, AX-gelatin (GL) films were prepared by blending AX, gelatin (GL), glycerol, and gentamicin (antibiotic). Initially, the optimal quantities of AX, GL, and glycerol for preparing transparent, bubble-free, smooth, and foldable AX-GL films were found. Physiochemical, thermal, morphological, drug release, and antibacterial characteristics of the AX-GL films were evaluated to investigate their suitability as wound dressings. The findings suggested that the mechanical, water vapor transmission, morphological, and expansion characteristics of the optimized AX-GL films were within the required range for wound dressing. The results of Fourier-transform infrared (FTIR) analyses suggested chemical compatibility among the ingredients of the films. In in vitro drug release and antibacterial activity experiments, gentamicin (GM)-loaded AX-GL films released approximately 89% of the GM in 24 h and exhibited better antibacterial activity than standard GM solution. These results suggest that AX-GL films could serve as a promising dressing to protect against wound infections

Antibiotic-Loaded Psyllium Husk Hemicellulose and Gelatin-Based Polymeric Films for Wound Dressing Application

Wound infections are one of the major reasons for the delay in the healing of chronic wounds and can be overcome by developing effective wound dressings capable of absorbing exudate, providing local antibiotic release, and improving patient comfort. Arabinoxylan (AX) is a major hemicellulose present in psyllium seed husk (PSH) and exhibits promising characteristics for developing film dressings. Herein, AX-gelatin (GL) films were prepared by blending AX, gelatin (GL), glycerol, and gentamicin (antibiotic). Initially, the optimal quantities of AX, GL, and glycerol for preparing transparent, bubble-free, smooth, and foldable AX-GL films were found. Physiochemical, thermal, morphological, drug release, and antibacterial characteristics of the AX-GL films were evaluated to investigate their suitability as wound dressings. The findings suggested that the mechanical, water vapor transmission, morphological, and expansion characteristics of the optimized AX-GL films were within the required range for wound dressing. The results of Fourier-transform infrared (FTIR) analyses suggested chemical compatibility among the ingredients of the films. In in vitro drug release and antibacterial activity experiments, gentamicin (GM)-loaded AX-GL films released approximately 89% of the GM in 24 h and exhibited better antibacterial activity than standard GM solution. These results suggest that AX-GL films could serve as a promising dressing to protect against wound infections