Novel nasal niosomes loaded with lacosamide and coated with chitosan: A possible pathway to target the brain to control partial-onset seizures.

This work aimed to develop and produce lacosamide-loaded niosomes coated with chitosan (LCA-CTS-NSM) using a thin-film hydration method and the Box-Behnken design. The effect of three independent factors (Span 60 amount, chitosan concentration, and cholesterol amount) on vesicle size, entrapment efficiency, zeta potential, and cumulative release (8 h) was studied. The optimal formulation of LCA-CTS-NSM was chosen from the design space and assessed for morphology, in vitro release, nasal diffusion, stability, tolerability, and in vivo biodistribution for brain targeting after intranasal delivery. The vesicle size, entrapment, surface charge, and in vitro release of the optimal formula were found to be 194.3 nm, 58.3%, +35.6 mV, and 81.3%, respectively. Besides, it exhibits sustained release behavior, enhanced nasal diffusion, and improved physical stability. Histopathological testing revealed no evidence of toxicity or structural damage to the nasal mucosa. It demonstrated significantly more brain distribution than the drug solution. Overall, the data is encouraging since it points to the potential for non-invasive intranasal administration of LCA as an alternative to oral or parenteral routes.

Multifunctional 99mTc-5-azacitidine Gold Nanoparticles: Formulation, In Vitro Cytotoxicity, Radiosynthesis, and In Vivo Pharmacokinetic Study.

BACKGROUND: 5-azacitidine is a very potent chemotherapeutic agent that suffers from certain disadvantages. OBJECTIVE: This study aims to prepare gold nanoparticles as a new nano-formula of 5-azacitidine that can improve its bioavailability and decrease its side effects. METHODS: 5-azacytidine-loaded GA-AuNPs were prepared and characterized by UV-Vis spectroscopy, infrared (IR), and electronic transmission microscope (TEM). This new platform was characterized in vitro by measuring its zeta potential, particle size, and drug loading efficacy, and the anti-proliferative effect on the MCF-7 cell line was evaluated. In vivo biodistribution studies of 99mTc-5-aza solution and 99mTc-5-aza-gold nano formula were conducted in tumor-bearing mice by different routes of administration (intravenous and intra-tumor). RESULTS: 5-Aza-GA-AuNPs formula was successfully prepared with an optimum particle size of ≈34.66 nm, the zeta potential of -14.4 mV, and high entrapment efficiency. 99mTc-5-Aza-GA-AuNPs were successfully radiosynthesized with a labeling yield of 95.4%. Biodistribution studies showed high selective accumulation in tumor and low uptake in non-target organs in the case of the 5-Aza-GA-AuNPs formula than the 99mTc-5-azacitidine solution. CONCLUSION: 99mTc-5-Aza-GA-AuNPs improved the selectivity and uptake of 5-azacitidine in cancer. Moreover, 99mTc-5-Aza-GA-AuNPs could be used as hopeful theranostic radiopharmaceutical preparation for cancer.

Intranasal Delivery of Granisetron to the Brain via Nanostructured Cubosomes-Based In Situ Gel for Improved Management of Chemotherapy-Induced Emesis.

This research aimed to boost granisetron (GS) delivery to the brain via the intranasal route to better manage chemotherapy-induced emesis. Glycerol monooleate (GMO), Poloxamer 407 (P 407) and Tween 80 (T 80) were used to formulate GS-loaded cubosomes (GS-CBS) utilizing a melt dispersion-emulsification technique. GS-CBS were characterized by testing particle diameter, surface charge and entrapment efficiency. The formulations were optimized using a Box-Behnken statistical design, and the optimum formula (including GMO with a concentration of 4.9%, P 407 with a concentration of 10%, and T 80 with a concentration of 1%) was investigated for morphology, release behavior, ex vivo permeation through the nasal mucosa, and physical stability. Moreover, the optimal formula was incorporated into a thermosensitive gel and subjected to histopathological and in vivo biodistribution experiments. It demonstrated sustained release characteristics, increased ex vivo permeability and improved physical stability. Moreover, the cubosomal in situ gel was safe and biocompatible when applied to the nasal mucosa. Furthermore, compared to a drug solution, the nose-to-brain pathway enhanced bioavailability and brain distribution. Finally, the cubosomal in situ gel may be a potential nanocarrier for GS delivery to the brain through nose-to-brain pathway.

Potential Use of Tailored Citicoline Chitosan-Coated Liposomes for Effective Wound Healing in Diabetic Rat Model.

PURPOSE: This study aimed to formulate citicoline-loaded chitosan-coated liposomes (CT-CS-LPs) for topical administration and evaluated for wound healing in a diabetic animal model. METHODS: CT-LPs were formulated via a thin-film hydration approach and coated with chitosan (CS). Box-Behnken statistical design investigated the effects of lipid amount, chitosan concentration, and cholesterol amount on vesicle diameter, surface charge, and entrapment efficiency. The potential of the optimized CT-CS-LPs gel for wound healing was further evaluated in streptozocin-induced diabetic rats. The different healing stages were evaluated by several techniques, including general and special staining techniques, in addition to antibody immunohistochemistry. RESULTS: The optimized CT-CS-LPs obtained had a mean size of 211.6 nm, a 50.7% entrapment efficiency, and a positive surface charge of 32.1 mV. In addition, the optimized CT-CS-LPs exhibited in vitro sustained release behavior. The in vivo experiments revealed that treatment with the optimized CT-CS-LPs boosts the healing process of the skin wound in diabetic rats by reducing inflammation, accelerating re-epithelization, angiogenesis, fibroblast proliferation, and connective tissue remodeling, leading to rapid wound closure. CONCLUSION: Chitosan-coated liposomes containing citicoline have emerged as a potential approach for promoting the healing process in diabetic rats. However, the therapeutic effectiveness of the suggested approach in diabetic patients needs to be investigated.

Development of omega-3 loxoprofen-loaded nanoemulsion to limit the side effect associated with NSAIDs in treatment of tooth pain.

The majority of newly developed drugs need to be incorporated with delivery systems to maximize their effect and minimize side effects. Nanoemulsions (NEs) are one type of delivery system that helps to improve the solubility and dissolution of drugs, attempting to enhance their bioavailability and onset of action. The objective of this investigation was to develop an omega-3 oil-based NE loaded with loxoprofen (LXP) to enhance its dissolution, in vitro release, and mucosal penetration and decrease its mucosal ulcerative effects when applied in an oral treatment. LXP-loaded NEs were formulated with varying levels of omega-3 oil (10-30%), surfactant polyoxyethylene-C21-ethers (laureth-21) (40-60%), and co-surfactant polyethylene glycol-40 hydrogenated castor oil (HCO-40) (30-50%) using an extreme vertices mixture design. The developed NEs were characterized for globule size and drug loading capacity. The optimal formulation was tested for in vitro drug release, ex vivo permeation, and ulcer index value. The developed NE acquired a globule size ranging 71-195 nm and drug loading capacity of 43-87%. Considering the results of the in vitro release study, the optimized NE formulation achieved 2.45-fold and 2-fold increases in drug permeation across tested mucosa compared to a marketed tablet and drug aqueous dispersion, respectively. Moreover, the optimum NE exhibited the best ulcer index in comparison to drug aqueous suspension and different formulations when tested in rats. Overall, this research highlights the capacity of NEs to deliver LXP with enhanced solubility, drug release, and permeation while effectively protecting the application site from side effects of the model drug.

Response Surface Optimization of Ultra-Elastic Nanovesicles Loaded with Deflazacort Tailored for Transdermal Delivery: Accentuated Bioavailability and Anti-Inflammatory Efficacy.

PURPOSE: The aim of the present study was to develop deflazacort (DFZ) ultra-elastic nanovesicles (UENVs) loaded gel for topical administration to evade gastrointestinal adverse impacts accompanying DFZ oral therapy. METHODS: UENVs were elaborated according to D-optimal mixture design employing different edge activators as Span-60, Tween-85 and sodium cholate which were incorporated into the nanovesicles to improve the deformability of vesicles bilayer. DFZ-UENVs were formulated by thin-film hydration technique followed by characterization for different parameters including entrapment efficiency (%EE), particle size, in vitro release and ex vivo permeation studies. The composition of the optimized DFZ-UENV formulation was found to be DFZ (10 mg), Span-60 (30 mg), Tween-85 (30 mg), sodium cholate (3.93 mg), L-α phosphatidylcholine (60 mg) and cholesterol (30 mg). The optimum formulation was incorporated into hydrogel base then characterized in terms of physical parameters, in vitro drug release, ex vivo permeation study and pharmacodynamics evaluation. Finally, pharmacokinetic study in rabbits was performed via transdermal application of UENVs gel in comparison to oral drug. RESULTS: The optimum UENVs formulation exhibited %EE of 74.77±1.33, vesicle diameter of 219.64±2.52 nm, 68.88±1.64% of DFZ released after 12 h and zeta potential of -55.57±1.04 mV. The current work divulged successful augmentation of the bioavailability of DFZ optimum formulation by about 1.37-fold and drug release retardation compared to oral drug tablets besides significant depression of edema, cellular inflammation and capillary congestion in carrageenan-induced rat paw edema model. CONCLUSION: The transdermal DFZ-UENVs can achieve boosted bioavailability and may be suggested as an auspicious non-invasive alternative platform for oral route.

Development of Provesicular Nanodelivery System of Curcumin as a Safe and Effective Antiviral Agent: Statistical Optimization, In Vitro Characterization, and Antiviral Effectiveness.

Curcumin is a natural compound that has many medical applications. However, its low solubility and poor stability could impede its clinical applications. The present study aimed to formulate dry proniosomes to overcome these pitfalls and improve the therapeutic efficacy of Curcumin. Curcumin-loaded proniosomes were fabricated by the slurry method according to 32 factorial design using Design-Expert software to demonstrate the impact of different independent variables on entrapment efficiency (EE%) and % drug released after 12 h (Q12h). The optimized formula (F5) was selected according to the desirability criteria. F5 exhibited good flowability and appeared, after reconstitution, as spherical nanovesicles with EE% of 89.94 ± 2.31% and Q12h of 70.89 ± 1.62%. F5 demonstrated higher stability and a significant enhancement of Q12h than the corresponding niosomes. The docking study investigated the ability of Curcumin to bind effectively with the active site of DNA polymerase of Herpes simplex virus (HSV). The antiviral activity and the safety of F5 were significantly higher than Curcumin. F5 improved the safety of Acyclovir (ACV) and reduced its effective dose that produced a 100% reduction of viral plaques. Proniosomes could be promising stable carriers of Curcumin to be used as a safe and efficient antiviral agent.

Asthmatic children and MDI verbal inhalation technique counseling.

OBJECTIVES: The present work aimed to study the role of metered-dose inhalers (MDI) verbal counseling on asthmatic children patients inhalation technique and their pulmonary functions. METHODS: In this study many children younger than 18 years old with asthma were collected from University hospital outpatient clinics throughout two years period Their MDI inhalation technique was checked and the number of MDI inhalation technique mistakes were detected and corrected at the first visit and every month for two more visits (three visits). Their peak expiratory flow (PEF) and forced expiratory volume in 1 s (FEV1) as a percentage of the forced vital capacity (FVC) were checked at every visit. RESULTS: 81 asthmatic subjects (54 female) younger than 18 years old were collected with a mean (SD) age 14.4 (1.8) years old. Most of the patients' owned MDI contained salbutamol, however, some patients were using Beclometasone MDI or Beclometasone and salbutamol combination MDI. The mean number of correct steps performed was significantly increased (p < 0.05) as the number of visits increased. "Place the MDI mouthpiece between the teeth and seal with lips" and "To maintain slow inhalation rate until lungs are full" were the least steps correctly performed by the asthmatics children studied. There was a significant increase (p < 0.05) in the pulmonary function test scores at the third visit. CONCLUSIONS: MDI's verbal counseling should be repeated and checked at every opportunity, especially with children, to improve and maintain the recommended MDI inhalation technique. That could be a tool to possibly improve patients' pulmonary functions.

Novel in situ gelling vaginal sponges of sildenafil citrate-based cubosomes for uterine targeting.

Sildenafil citrate (SIL), a type 5-specific phosphodiesterase inhibitor, demonstrates valuable results in the management of infertility in women; however, the absence of vaginal dosage form in addition to the associated oral adverse effects minimize its clinical performance. The present study is concerned with SIL uterine targeting following intravaginal administration via optimization of cubosomal in situ gelling sponges (CIS). An emulsification method was employed for preparation of cubosomal dispersions incorporating glyceryl monooleate as a lipid phase and poloxamer 407 as a surfactant with or without polyvinyl alcohol as a stabilizer. Cubosomes were estimated regarding entrapment efficiency (EE%), particle size, and in vitro drug release. Chitosan (2% w/w) was incorporated into the optimum formulation and then lyophilized into small sponges. For the CIS, in vivo histopathological and pharmacokinetic studies were conducted on female Wistar rats and compared with intravaginal free SIL sponges (FIS) and oral SIL solution. SIL-loaded cubosomes showed EE% ranging between 32.15 and 72.01%, particle size in the range of 150.81-446.02 nm and sustained drug release over 8 h. Histopathological study revealed a significant enlargement in endometrial thickness with congestion and dilatation of endometrial blood vessels in intravaginal CIS compared to intravaginal FIS and oral-treated groups. The pharmacokinetic study demonstrated higher AUC0-∞ and Cmax with oral administration compared to intravaginal CIS or intravaginal FIS indicating potential involvement of first uterine pass effect after intravaginal administration. Finally, intravaginal CIS could be considered as a promising platform for SIL uterine targeting with minimized systemic exposure and side effects.

Transdermal delivery of atorvastatin calcium from novel nanovesicular systems using polyethylene glycol fatty acid esters: Ameliorated effect without liver toxicity in poloxamer 407-induced hyperlipidemic rats.

CONTEXT: Atorvastatin calcium (ATV), a cholesterol-lowering agent, suffers from poor systemic availability (14%) after oral administration in addition to other side effects on the gastrointestinal tract, liver and muscle. OBJECTIVE: The goal of the present investigation was to improve ATV bioavailability and overcome complications attendant with peroral administration by developing a new nanovesicular system encapsulating ATV for its delivery via the transdermal route. METHODS: The vesicular systems were prepared by incorporating different polyethylene glycol fatty acid esters such as Labrasol, Cremophor EL, Gelucire 44/14 and Tween 80 as edge activators (EAs) in the lipid bilayer. The effect of the phosphatidylcholine (PC):EA molar ratio on the physicochemical properties of the vesicles was investigated. The pharmacokinetic studies of the optimized formulation were evaluated in rats. The optimized formulation was tested in poloxamer 407-induced hyperlipidemic rats. The plasma lipid profile, activity of liver enzymes, and oxidative stress parameters were measured using commercially available kits. RESULTS: The results revealed high ATV entrapment efficiency (EE%) ranging from 55.62 to 83.91%. The formulations that contained Labrasol showed the highest EE%. The mean diameter of the vesicles was in the range of 186-583nm. T8 containing Gelucire 44/14 as an EA in the molar ratio of 15:1 (PC:EA) gave the smallest size and exhibited the best permeation parameters across the skin. The pharmacokinetic studies revealed that about three times statistically significant (p<0.05) improvement in bioavailability, after transdermal administration of nanotransfersomal ATV gel compared to oral ATV suspension. The transdermal vesicular system exhibited a significant decrease in plasma total cholesterol, triglycerides and LDL cholesterol comparable to oral ATV. Additionally, it lowered the malondialdehyde levels in plasma and abolished the increase in liver enzyme activity. CONCLUSION: The results obtained suggest that the proposed transdermal vesicular system can serve as a promising alternative means for delivery of ATV.

Transbuccal delivery of betahistine dihydrochloride from mucoadhesive tablets with a unidirectional drug flow: in vitro, ex vivo and in vivo evaluation.

OBJECTIVE: Betahistine dihydrochloride (BH.2HCl), an anti-vertigo histamine analog used in the treatment of Ménière's disease, undergoes extensive first-pass metabolism and suffers from short biological half-life. The aim of the present work was to develop and estimate controlled release mucoadhesive buccal tablets of BH.2HCl with a unidirectional drug flow to overcome this encumbrance. METHODS: A direct compression method was adopted for preparation of the tablets using mucoadhesive polymers like guar gum, hydroxypropyl methyl cellulose K4M, sodium carboxymethyl cellulose and their combinations. The tablets were coated from all surfaces except one surface with a solution of 5% (w/v) cellulose acetate and 1% (w/v) dibutyl phthalate. Different permeation enhancers like 2% sodium deoxycholate, 2% sodium cholate hydrate (SCH) and 5% menthol were tested. Swelling index, ex vivo residence time, mucoadhesion strength, in vivo testing of mucoadhesion time, in vitro dissolution and ex vivo permeation were carried out. Furthermore, compatibility and accelerated stability studies were performed for the drug excipients. Finally, drug bioavailability of the BH.2HCl-optimized buccal mucoadhesive formulation was compared with that of the orally administered Betaserc® 24 mg tablet in six healthy male volunteers. RESULTS: Formulation F10, which contained a combination of 35% guar gum and 5% sodium carboxymethyl cellulose, exhibited long adhesion time, high adhesion strength and diminished irritation to volunteers and showed zero-order release kinetics. SCH produced a significant enhancement in permeation of BH.2HCl across buccal mucosa. BH.2HCl-optimized buccal mucoadhesive formulation showed percentage relative bioavailability of 177%. CONCLUSION: The developed mucoadhesive tablets represent a promising alternative for the buccal delivery of BH.2HCl.