Search Results (40)

Background/Objectives: Non-invasive central nervous system (CNS) therapies are limited by complex mechanisms and the blood–brain barrier, but nasal delivery offers a promising alternative. The study planned to develop a non-invasive in situ intranasal mucoadhesive thermosensitive gel to deliver CNS-active risperidone via nose-to-brain targeting. Risperidone, a second-generation antipsychotic, has shown efficacy in managing both psychotic and mood-related symptoms. The mucoadhesive gel formulations help to prolong the residence time at the nasal absorption site, thereby facilitating the uptake of the drug. Methods: The poloxamer 407 (18.0% w/v), HPMC K100M and K15M (0.3–0.5% w/v), and benzalkonium chloride (0.1% v/v) were used as thermosensitive polymers, a mucoadhesive agent, and a preservative, respectively, for the development of in situ thermosensitive gel. The developed formulations were evaluated for various parameters. Results: The pH, gelation temperature, gelation time, and drug content were found to be 6.20 ± 0.026–6.37 ± 0.015, 34.25 ± 1.10–37.50 ± 1.05 °C, 1.65 ± 0.30–2.50 ± 0.55 min, and 95.58 ± 2.37–98.03 ± 1.68%, respectively. Furthermore, the optimized F3 formulation showed satisfactory gelling capacity (9.52 ± 0.513 h) and an acceptable mucoadhesive strength (1110.65 ± 6.87 dyne/cm²). Diffusion of the drug through the egg membrane depended on the formulation’s viscosity, and the F3 formulation explained the first-order release kinetics, indicating concentration-dependent drug diffusion with n < 0.45 (0.398) value, indicating the Fickian-diffusion (diffusional case I). The pharmacokinetic study was performed with male Wistar albino rats, and the F3 in situ thermosensitive risperidone gel confirmed significantly (p < 0.05) ~5.4 times higher brain AUC_0–∞ when administered intranasally compared to the oral solution. Conclusions: Based on physicochemical, in vitro, and in vivo parameters, it can be concluded that in situ thermosensitive gel is suitable for administration of risperidone through the nasal route and can enhance patient compliance through ease of application and with less repeated administration. Full article

Background: The neuroprotective efficacy of glibenclamide (GLIB) has been demonstrated in multiple rodent models of ischemia, hemorrhagic stroke, traumatic brain damage, spinal cord injury, and metastatic brain tumors. Due to its poor solubility, GLIB has low oral bioavailability, limiting its transportation to the brain via the oral route. Objectives: Here, we attempted to develop and optimize an intranasal mucoadhesive in situ gel of GLIB-loaded bilosomes using a 3² Box–Behnken design for brain drug delivery. Methods: To facilitate a longer residence time of the administered dose within the nasal cavity, the prepared bilosomes were loaded into a mucoadhesive in situ gel providing resistance to rapid mucociliary clearance. The amounts of sodium deoxycholate, the cholesterol/Span 40 mixture, and the molar ratio between the mixture’s components were chosen as independent variables, while the entrapment efficiency and in vitro drug release were selected as dependent variables. Results and conclusions: The optimal formulation was analyzed for particle size and entrapment efficiency, which were found to be 270.6 nm and 68.39%, respectively. In vitro drug release from optimal formulation after 12 h was 87.29 ± 1.98% as compared to 52.01 ± 2.04% of plain in situ gel of drug. An in vivo brain drug delivery study performed on Swiss albino mice showed that the brain concentration of drug through intranasal administration from mucoadhesive in situ gel of GLIB-bilosomes after 12 h was 2.12 ± 0.16 µg/mL as compared to 0.68 ± 0.04 µg/mL from plain in situ gel of drug. Conclusively, the developed bilosomal formulation offers a favorable intranasal substitute with enhanced therapeutic drug delivery to the brain. Full article

Itraconazole (ITZ) is a potent antifungal agent. Its oral administration is associated with systemic toxicity, and its efficacy in ocular formulations is limited. This study aims to enhance ITZ’s ocular permeation and antifungal efficacy by loading it into deformable liposomes (DLs) based on Tween 80 (T) or Poloxamer 188 (P). Moreover, ITZ was loaded into biopolymer-coated DLs to augment its ocular availability. ITZ-loaded DLs were coated with hyaluronic acid (HA-DLs), chitosan (CS-DLs), or a layer-by-layer coating (CS/HA-DLs). These formulations were further laden into pH-sensitive in situ gels to provide a hybrid system to intensify their ocular adhesion properties. The prepared DLs were successfully prepared with vesicle sizes in nonorange (<200 nm). The zeta potential values of DLS were negative before coating and shifted to high negativity with HA coating and positivity with CS and CS/HA bilayer coating. These variations of zeta potential indicate successful CS and HA coatings. The optimized A high EE% was achieved with DLs-T: 89% (CS/HA-DLs-T), 86% (CS-DLs-T), 85% (HA-DLs-T), and 79% (HA-DLs-T). Therefore, DLs-T were incorporated into in situ gels, displaying optimal gelling capacity and viscosity. The release rate of ITZ from the coated DLs-laden in situ gels was slower than that observed with the uncoated DLs-gel. CS/HA-DLs-T laden-in situ gels showed the highest ex vivo transcorneal permeability and antifungal efficacy. These data suggest that the layer-by-layer-CS/HA-DLs-T presents a hopeful strategy for the ocular delivery of ITZ, offering a promising approach for managing ocular fungal infections. Full article

Imipramine hydrochloride (IMP), a tricyclic antidepressant used for major depression, enuresis, and neuropathic pain, is limited by gastrointestinal complications, low oral bioavailability (44%), and complex dosing requirements. This study aimed to explore a novel non-invasive nasal delivery system using chitosan nanoparticles (Cs NPs) embedded in an in situ gel to address the limitations of oral IMP administration. Cs NPs loaded with IMP were synthesized via ionic gelation and assessed for precision in drug concentration using a validated HPLC method. The particles were integrated into a thermoresponsive polymer, Pluronic F127, to form an in situ gel suitable for nasal administration. The formulation was characterized for gelation temperature, duration, viscosity, mucoadhesive strength, and overall gel robustness. Drug release kinetics and the controlled release mechanism were studied using ex vivo permeation tests with Franz diffusion cells and nasal sheep mucosa. The optimized nanoparticle formulation (F4-50) exhibited a consistent PS of 141.7 ± 2.2 nm, a zeta potential (ZP) of 16.79 ± 2.1 mV, and a high encapsulation efficiency of 67.71 ± 1.9%. The selected in situ gel formulation, F4-50-P1, demonstrated a gelation temperature of 33.6 ± 0.94 °C and a rapid gelation time of 48.1 ± 0.7 s. Transform-attenuated total reflectance infrared spectroscopy (ATR-IR) confirmed the compatibility and effective encapsulation of IMP within the formulation. The release profile of F4-50 included an initial burst release followed by a sustained release phase, with F4-50-P1 showing improved control over the burst release. The flux rates were 0.50 ± 0.01 mg/cm²/h for F4-50 and 0.33 ± 0.06 mg/cm²/h for F4-50-P1, indicating effective permeation. The developed chitosan nanoparticle-based in situ gel formulation provides a promising approach for the controlled release of IMP, enhancing therapeutic efficacy and patient compliance while mitigating the disadvantages associated with oral delivery. Full article

Background/Objectives: Patients with schizophrenia have significant challenges in adhering to and complying with oral medicines, resulting in adverse consequences such as symptom worsening and psychotic relapse. Methods: This study aimed to develop clove oil-based bilosomes using definitive screening design (DSD) to maximize the anti-schizophrenic action of clozapine and promote its nose-to-brain delivery. The target was to optimize the physicochemical properties of bilosomes and incorporate them into mucoadhesive intranasal in situ gels, searching for augmented ex vivo and in vivo clozapine delivery. Results: The bilosomes’ particle size was decreased by increasing the span, SDC, and clove oil amounts. In addition to using a high lipid amount, the aforementioned components also helped increase the entrapment efficiency values. Increased zeta potential was only observed by increasing surfactant amount and reducing clozapine concentration. After incorporation of optimized liquid clove oil-based bilosomes, which had a spherical nano-sized vesicular shape, into P 407-dependent gels, an HPMC (2% w/w)/P 407 (20% w/w)-containing formulation (G6) was selected as an optimized gel owing to its acceptable gelation time (13.28 s), gel strength (27.72 s), viscosity (12,766.67 cP), and mucoadhesive strength (4273.93 dyne/cm²). The optimized G6 exhibited higher J_ss (50.86 μg/cm²·h⁻¹) through the nasal mucosa compared to the control gel (23.03 μg/cm²·h⁻¹). Compared to the control gel, G6 displayed higher relative bioavailability (491.37%) than a commercial tablet (264.46%). Following ELISA analysis, dopamine and serotonin were significantly reduced, while BDNF was remarkably increased after administration of optimized G6 into schizophrenic rats. Conclusion: Our study indicates the potential of intranasal bilosomal gels in upgrading the anti-schizophrenic and neuroprotective activity of clozapine. Full article

Sulpiride (Sul) is a medication that blocks dopamine D₂ receptors. It is used to treat gastrointestinal disturbances and has antipsychotic effects depending on the dose given. Sulpiride is subject to P-glycoprotein efflux, resulting in limited bioavailability and erratic absorption. Hence, the aim of this study was to generate a glycerosomal in situ gel of sulpiride for intranasal administration, specifically targeting children with schizophrenia who may have difficulty swallowing traditional solid medications, for enhancing its bioavailability. This study aimed to demonstrate the efficacy of intranasal administration of glycerin-encapsulated lipid-nanovesicles (glycerosomes) mixed with in situ gels for prolonged release of anti-psychotic medication. A Box–Behnken design was utilized to create sulpiride-loaded glycerosomes (Sul-GMs), with the lipid amount (A), glycerin concentration (B), and sonication time (C) acting as independent variables. Their impact on the entrapment efficiency, EE% (Y₁), and in vitro drug release (Y₂) were evaluated. The sulpiride EE% showed an increase when the glycerin concentration was raised to 25% v/v. Nevertheless, when the glycerin concentration was raised to 40% v/v, there was a notable decrease in the EE%. The optimized glycerosome was added to pH triggered carbopol 974P in situ gel formulations including HPMC K15M with different concentrations. The in situ gel formulation (G3) comprising 0.6% carbopol 974P and 0.6% hydroxypropyl methyl cellulose-K15M (HPMC K15M) demonstrated suitable pH, viscosity, desired gel strength, spreadability, and mucoadhesive strength. Consequently, it was selected for in vitro study, ex vivo permeation investigation, and in vivo evaluations. The glycerosomal in situ gel exhibited favorable ex vivo permeability of SU when applied to the nasal mucosa. The pharmacokinetic investigation revealed that the optimized Sul-loaded glycerosomal in situ gel exhibited a significant fourfold and twofold enhancement in systemic bioavailability compared to both the control gel and the commercially available formulation. Finally, the intranasal administration of Sul-loaded glycerosomal in situ gel is a promising alternative to oral treatment for pediatric patients with psychosis. Full article

The present research emphasizes fabrication alongside the assessment of an innovative nano-vesicular membranous system known as invasomes (NVMs) laden with Mirtazapine for rectal administration. This system could circumvent the confines of orally administered counterparts regarding dose schedules and bioavailability. Mirtazapine invasomes were tailored by amalgamating phospholipid, cineole, and ethanol through a thin-film hydration approach rooted in the Box–Behnken layout. Optimization of composition parameters used to fabricate desired NVMs’ physicochemical attributes was undertaken using the Design-Expert^® program. The optimal MRZ-NVMs were subsequently transformed to a pH-triggered in situ rectal gel followed by animal pharmacodynamic and pharmacokinetic investigations relative to rectal plain gel and oral suspension. The optimized NVMs revealed a diameter size of 201.3 nm, a z potential of −28.8 mV, an entrapment efficiency of 81.45%, a cumulative release within 12 h of 67.29%, and a cumulative daily permeated quantity of 468.68 µg/cm². Compared to the oral suspension, pharmacokinetic studies revealed a 2.85- and 4.45-fold increase in calculated rectal bioavailability in circulation and brain, respectively. Pharmacodynamic and immunohistopathology evaluations exposed superior MRZ-NVMs attributed to the orally administered drug. Consequently, rectal MRZ-NVMs can potentially be regarded as a prospective nanoplatform with valuable pharmacokinetics and tolerability assets. Full article

Nitroimidazoles comprise a class of broad-spectrum anti-microbial drugs with efficacy against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. Among these drugs, metronidazole (MTZ) is commonly used with other antibiotics to prevent infection in open fractures. However, the effect of MTZ on bone remains understudied. In this paper, we evaluated six nitroimidazole drugs for their impact on osteoblast differentiation and identified MTZ as having the highest osteogenic effect. MTZ enhanced bone regeneration at the femur osteotomy site in osteopenic ovariectomized (OVX) rats at the human equivalent dose. Moreover, in OVX rats, MTZ significantly improved bone mass and strength and improved microarchitecture compared to the vehicle-treated rats, which was likely achieved by an osteogenic mechanism attributed to the stimulation of the Wnt pathway in osteoblasts. To mitigate the reported neurological and genotoxic effects of MTZ, we designed an injectable sustained-release in situ gel formulation of the drug that improved fracture healing efficacy by 3.5-fold compared to oral administration. This enhanced potency was achieved through a significant increase in the circulating half-life and bioavailability of MTZ. We conclude that MTZ exhibits osteogenic effects, further accentuated by our sustained-release delivery system, which holds promise for enhancing bone regeneration in open fractures. Full article

Management of rheumatoid arthritis (RA) requires long-term administration of different medications since there has been no cure until now. Etodolac (ETD) is a nonsteroidal anti-inflammatory drug commonly used for RA management. However, its long-term administration resulted in severe side effects. This study aimed to develop a transdermal in situ gel incorporating ETD-loaded polymeric nanoparticles (NPs) to target the affected joints for long-term management of RA. Several PLGA NPs incorporating 1% ETD were prepared by nanoprecipitation and optimized according to the central composite design. The optimum NPs (F1) exhibited 96.19 ± 2.31% EE, 282.3 ± 0.62 nm PS, 0.383 ± 0.04 PDI, and −6.44 ± 1.69 ZP. A hyaluronate coating was applied to F1 (H-F1) to target activated macrophages at inflammation sites. H-F1 exhibited 287.4 ± 4.2 nm PS, 0.267 ± 0.02 PDI, and −23.7 ± 3.77 ZP. Pluronic F-127 in situ gel (H-F1G) showed complete gelation at 29 °C within 5 min. ETD permeation from H-F1G was sustained over 48 h when applied to microporated skin and exhibited significant enhancement of all permeation parameters. Topical application of H-F1G (equivalent to 8 mg ETD) to Wistarrat microporated skin every 48 h resulted in antirheumatic therapeutic efficacy comparable to commercial oral tablets (10 mg/kg/day). Full article

Curcumin and resveratrol are polyphenolic compounds that have been shown to exhibit synergistic therapeutic properties including anti-inflammatory, anticancer, and antiulcer activities, which may be exploited for the treatment of gastric diseases. However, both compounds have poor aqueous solubility and rapid metabolism, resulting in a low oral bioavailability. In situ gelling, liquid formulations were developed to produce a gastroretentive, raft-forming delivery vehicle to improve bioavailability. Solid dispersions containing a mixture of curcumin and resveratrol with Eudragit^® EPO (Cur/Res-SD) were first prepared using solvent evaporation, to improve the solubility and dissolution of the compounds. Solid dispersions of a weight ratio of 1:10 curcumin/resveratrol to Eudragit^® EPO were subsequently incorporated into in situ gelling, liquid formulations based on the gelling polymers, sodium alginate (low viscosity and medium viscosity), pectin, and gellan gum, respectively. Calcium carbonate and sodium bicarbonate were included to produce carbon dioxide bubbles in the gel matrix, on exposure to gastric fluid, and to achieve flotation. Moreover, the calcium ions acted as a crosslinking agent for the hydrogels. Optimized formulations floated rapidly (<60 s) in simulated gastric fluid (pH = 1.2) and remained buoyant, resulting in the gradual release of more than 80% of the curcumin and resveratrol content within 8 h. The optimized formulation based on medium-viscosity sodium alginate exhibited enhanced cytotoxic activity toward human gastric adenocarcinoma cell lines (AGS), compared with unformulated curcumin and resveratrol compounds, and increased anti-inflammatory activity against RAW 264.7 macrophage cells compared with the NSAID, indomethacin. These findings demonstrate that in situ gelling, liquid formulations, loaded with a combination of curcumin and resveratrol in the form of solid dispersions, show potential as gastroretentive delivery systems for local and systemic effects. Full article

Schizophrenic patients often face challenges with adherence to oral regimens. The study aimed to highlight the potentiality of intranasal ethanol/glycerin-containing lipid-nanovesicles (glycethosomes) incorporated into in situ gels for sustaining anti-psychotic risperidone (RS) release. The Box–Behnken Design (BBD) was followed for in vitro characterization. Glycethosomal-based in situ gels were examined by physical, ex vivo, and in vivo investigations. The ethanol impact on minimizing the vesicle size (VS) and enhancing the zeta potential (ZP) and entrapment efficiency (EE%) of nanovesicles was observed. Glycerin displayed positive action on increasing VS and ZP of nanovesicles, but reduced their EE%. After incorporation into various mucoadhesive agent-enriched poloxamer 407 (P407) in situ gels, the optimized gel containing 20% P407 and 1% hydroxypropyl methyl cellulose-K4M (HPMC-K4M) at a 4:1 gel/glycethosomes ratio showed low viscosity and high spreadability with acceptable pH, gel strength, and mucoadhesive strength ranges. The ethanol/glycerin mixture demonstrated a desirable ex vivo skin permeability of RS through the nasal mucosa. By pharmacokinetic analysis, the optimized gel showed eight-fold and three-fold greater increases in RS bioavailability than the control gel and marketed tablet, respectively. Following biochemical assessments of schizophrenia-induced rats, the optimized gel boosted the neuroprotective, anti-oxidant, and anti-inflammatory action of RS in comparison to other tested preparations. Collectively, the intranasal RS-loaded glycethosomal gel offered a potential substitute to oral therapy for schizophrenic patients. Full article

Novel in situ gelling liquid formulations incorporating garcinia extract were developed to achieve prolonged delivery of hydroxycitric acid (HCA), an active compound displaying anti-obesity function, following oral administration. The optimized formulation was composed of sodium alginate (1.5% w/v), hydroxypropyl methylcellulose (HPMC K100) (0.25% w/v), calcium carbonate (1% w/v) and garcinia extract (2% w/v). The formulation displayed rapid gelation in less than a minute on exposure to 0.1 N hydrochloric acid (pH 1.2) and remained afloat for more than 24 h. The formulations were capable of gradually releasing more than 80% of HCA load over 8 h, depending on the composition. The resulting gels exhibited high values of gel strength by texture analysis, suggesting they would offer resistance to breakdown under the action of stomach content movement. The optimized formulation loaded garcinia extract significantly reduced lipid accumulation in 3T3-L1 adipocyte cells and displayed moderate anti-inflammatory activity by inhibiting the production of nitric oxide (NO) in LPS-stimulated RAW 264.7 macrophage cells. These findings demonstrate that oral in situ gelling liquid formulations based on sodium alginate and HPMC K100 offer much potential for sustained delivery of HCA and other anti-obesity compounds. Full article

Curcumin, a potent active compound found in turmeric and Curcuma xanthorrhiza oil, possesses a wide range of therapeutic properties, including antibacterial, anti-inflammatory, antioxidant, and wound healing activities. However, its clinical effectiveness is hindered by its low bioavailability and rapid elimination from the body. To overcome these limitations, researchers have explored innovative delivery systems for curcumin. Some promising approaches include solid lipid nanoparticles, nanomicelle gels, and transdermal formulations for topical drug delivery. In the field of dentistry, curcumin gels have shown effectiveness against oral disorders and periodontal diseases. Moreover, Pickering emulsions and floating in situ gelling systems have been developed to target gastrointestinal health. Furthermore, curcumin-based systems have demonstrated potential in wound healing and ocular medicine. In addition to its therapeutic applications, curcumin also finds use as a food dye, contraception aid, corrosion-resistant coating, and environmentally friendly stain. This paper primarily focuses on the development of gel compositions of curcumin to address the challenges associated with its clinical use. Full article

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. Full article

Oral candidiasis encompasses fungal infections of the tongue and other oral mucosal sites with fungal overgrowth and its invasion of superficial oral tissues. Borneol was assessed in this research as the matrix-forming agent of clotrimazole-loaded in situ forming gel (ISG) comprising clove oil as the co-active agent and N-methyl pyrrolidone (NMP) as a solvent. Their physicochemical properties, including pH, density, viscosity, surface tension, contact angle, water tolerance, gel formation, and drug release/permeation, were determined. Their antimicrobial activities were tested using agar cup diffusion. The pH values of clotrimazole-loaded borneol-based ISGs were in the range of 5.59–6.61, which are close to the pH of 6.8 of saliva. Increasing the borneol content in the formulation slightly decreased the density, surface tension, water tolerance, and spray angle but increased the viscosity and gel formation. The borneol matrix formation from NMP removal promoted a significantly (p < 0.05) higher contact angle of the borneol-loaded ISGs on agarose gel and porcine buccal mucosa than those of all borneol-free solutions. Clotrimazole-loaded ISG containing 40% borneol demonstrated appropriate physicochemical properties and rapid gel formation at microscopic and macroscopic levels. In addition, it prolonged drug release with a maximum flux of 370 µg·cm⁻² at 2 days. The borneol matrix generated from this ISG obsentively controlled the drug penetration through the porcine buccal membrane. Most clotrimazole amounts still remained in formulation at the donor part and then the buccal membrane and receiving medium, repectively. Therefore, the borneol matrix extended the drug release and penetration through the buccal membrane efficiently. Some accumulated clotrimazole in tissue should exhibit its potential antifugal activity against microbes invading the host tissue. The other predominant drug release into the saliva of the oral cavity should influence the pathogen of oropharyngeal candidiasis. Clotrimazole-loaded ISG demonstrated efficacious inhibition of growth against S. aureus, E. coli, C. albicans, C. krusei, C. Lusitaniae, and C. tropicalis. Consequently, the clotrimazole-loaded ISG exhibited great potential as a drug delivery system for oropharyngeal candidiasis treatment by localized spraying. Full article