Febuxostat ternary inclusion complex using SBE7-ßCD in presence of a water-soluble polymer: physicochemical characterization, in vitro dissolution, and in vivo evaluation.

Febuxostat (FBX), a potent xanthine oxidase inhibitor, is widely used as a blood uric acid-reducing agent and has recently shown a promising repurposing outcome as an anti-cancer. FBX is known for its poor water solubility, which is the main cause of its weak oral bioavailability. In a previous study, we developed a binary system complex between FBX and sulfobutylether-ß-cyclodextrin (SBE7-ßCD) with improved dissolution behavior. The aim of the current study was to investigate the effect of incorporating a water-soluble polymer with a binary system forming a ternary one, on further enhancement of FBX solubility and dissolution rate. In vivo oral bioavailability was also studied using LC-MS/MS chromatography. The polymer screening study revealed a marked increment in the solubility of FBX with SBE7-ßCD in the presence of 5% w/v polyethylene glycol (PEG 6000). In vitro release profile showed a significant increase in the dissolution rate of FBX from FBX ternary complex (FTC). Oral in vivo bioavailability of prepared FTC showed more than threefold enhancement in Cmax value (17.05 ± 2.6 µg/mL) compared to pure FBX Cmax value (5.013 ± 0.417 µg/mL) with 257% rise in bioavailability. In conclusion, the association of water-soluble polymers with FBX and SBE7-ßCD system could significantly improve therapeutic applications of the drug.

Curcumin/Fusidic Acid Bitherapy Loaded Mixed Micellar Nanogel for Acne Vulgaris Treatment: In Vitro and In Vivo Studies.

The combination of herbal drugs with a topical antibacterial for managing a chronic disease like acne vulgaris has emerged lately to settle side effects and bacterial multidrug resistance. Mixed micelles (MMs) incorporated into nanogel were explored for hybrid delivery of curcumin (Cur) and fusidic acid (FA) combination presenting a multi-strategic treatment. Curcumin-fusidic acid-loaded mixed micelles (Cur-FA-MMs) were assessed for size, surface charge, compatibility, in vitro release, and encapsulation. The selected formula was further loaded into nanogel and investigated for viscosity, ex vivo permeation, and in vivo potential. Cur-FA-MMs exhibited uniform nanosized spherical morphology, and negative surface charge affording high encapsulation for both drugs with a biphasic in vitro release over a period of 48h and good colloidal stability. The attained Cur-FA-MM-loaded nanogel had optimum viscosity with remarkable permeation coefficient values nearly 2-fold that related to plain nanogel. The pharmacodynamic effect of Cur on FA was pronounced by the significant improvement of the skin's degree of inflammation, epidermal hypertrophy, and congestion in animals treated with Cur-FA-MM-loaded nanogel. In conclusion, micellar nanogel could enable the progressive effect of Cur (an antioxidant with reported antibiotic activity) on FA (antibiotic) and decrease the risk of emerging antibiotic resistance by enhancing the solubility and permeation of Cur.

Preparation of Lambda-Cyhalothrin-Loaded Chitosan Nanoparticles and Their Bioactivity against Drosophila suzukii.

The encapsulation of pesticides within nanoparticles is a promising approach of advanced technology in sustainable agriculture. Lambda-cyhalothrin (LC) was encapsulated by the ionotropic gelation technique into chitosan (CS)/tripolyphosphate (TPP) and CS/alginate (ALG) matrixes. CS-LC nanoparticles were characterized, and their efficacy was then evaluated against the key pest of soft fruits in Europe and the United States, Drosophila suzukii. The encapsulation efficiency (74%), nanoparticle yield (80%), polydispersity index (0.341), zeta potential (-23.1 mV) and particle size (278 nm) were determined at the optimum conditions. FTIR confirmed the cross-linkage between CS and TPP/ALG in the nanoparticles. The optimum formula recommended by the fractional factorial design was associated with the formulation variables of CS of high or low molecular weight, cross-linking agent (TPP), LC concentration (1.5% w/v) and stirring rate (1500 rpm), showing the highest desirability value (0.5511). CS-LC nanoparticles of the lowest particle size (278 nm) exhibited the highest percent mortality of D. suzukii males (86%) and females (84%), exceeding that caused by the commercial product (Karate-zeon® 10% CS) at 2 HAT. This is the first work to use the ionic gelation technique to make LC nanoparticles, to the best of our knowledge. The encapsulation of chemical pesticides within biodegradable polymeric nanoparticles could be helpful for establishing a sustainable IPM strategy with benefits for human and environmental health and the lifetime of pesticides.

Ethosomal gel for rectal transmucosal delivery of domperidone: design of experiment, in vitro, and in vivo evaluation.

Despite high efficiency of domperidone (DOM) in prophylaxis of emesis accompanied with radiotherapy and chemotherapy, it still can bother cancer patients by its powerful side effects and difficulty of its oral administration. The study was designed to develop and optimize DOM loaded ethosomal gel for rectal transmucosal delivery. Ethosomal formulations were prepared using a 21, 51 full-factorial design where the impact of lecithin concentration and additives were investigated. The optimum ethosomal vesicles were subsequently incorporated in Carbopol gel base where rheological behavior, spreadability, mucoadhesion, and in vivo pharmacokinetic parameters were studied. Based on Design Expert® software (Stat Ease, Inc., Minneapolis, MN), the optimum formulation illustrated entrapment efficiency of 70.02%±5.52%, and vesicular size of 112 ± 3.3 nm, polydispersity index of 0.32 ± 0.01, zeta potential of -59 ± 0.28 mV, and % drug released after 6 h of 76.30%±2.45%. Moreover, ex vivo permeation through rabbit intestinal mucosa increased four times compared to free DOM suspension. The gel loaded with ethosomes showed excellent mucoadhesion to rectal mucosa. DOM ethosomal gel showed a raise in Cmax and AUC0-48 of DOM by twofolds compared to free DOM gel. The study suggested that ethosomes incorporated in gels could be an efficient candidate for rectal transmucosal delivery of DOM.

Polymeric versus lipid nanocapsules for miconazole nitrate enhanced topical delivery: in vitro and ex vivo evaluation.

Nanocapsules can be equated to other nanovesicular systems in which a drug is entrapped in a void containing liquid core surrounded by a coat. The objective of the present study was to investigate the potential of polymeric and lipid nanocapsules (LNCs) as innovative carrier systems for miconazole nitrate (MN) topical delivery. Polymeric nanocapsules and LNCs were prepared using emulsification/nanoprecipitation technique where the effect of poly(ε-caprolactone (PCL) and lipid matrix concentrations with respect to MN were assessed. The resulted nanocapsules were examined for their average particle size, zeta potential, %EE, and in vitro drug release. Optimum formulation in both polymeric and lipidic nanocapsules was further subjected to anti-fungal activity and ex vivo permeation tests. Based on the previous results, nanoencapsulation strategy into polymeric and LNCs created formulations of MN with slow biphasic release, high %EE, and improved stability, representing a good approach for the delivery of MN. PNCs were best fitted to Higuchi's diffusion while LNCs followed Baker and Lonsdale model in release kinetics. The encapsulated MN either in PNCs or LNCs showed higher cell viability in WISH amniotic cells in comparison with free MN. PNCs showed less ex vivo permeation. PNCs were accompanied by high stability and more amount drug deposition (32.2 ± 3.52 µg/cm2) than LNCs (12.7 ± 1.52 µg/cm2). The antifungal activity of the PNCs was high 19.07 mm compared to 11.4 mm for LNCs. In conclusion, PNCs may have an advantage over LNCs by offering dual action for both superficial and deep fungal infections.

Formulation and Evaluation of Topical Biodegradable Films Loaded with Levofloxacin Lipid Nanocarriers.

Skin ulcers have increased sharply due to rise in the incidence of obesity and diabetes. This study investigated lipid nanocarriers as a strategy to improve the efficacy of levofloxacin (LV) in penetrating skin. Two surfactant types and different lipid mixtures were used in preparation of lipid nanocarriers. Mean particle size, percentage entrapment efficiency (%EE), in vitro release, and antimicrobial activity were examined. The selected formula was incorporated into a chitosan (CS) film that was subjected to physic-chemical characterization and ex vivo permeation study. The selected formula showed particle size, PDI, and ZP: 80.3 nm, -0.21, and -26 mV, respectively, synchronized with 82.12 %EE. In vitro release study showed slow biphasic release of LV from lipid nanocarriers. The antimicrobial effect illustrated statistically significant effect of lipid nanocarriers on decreasing the minimum effective concentration (MIC) of LV, particularly against E. coli. The optimized nanocarriers' formula loaded into CS film was clear, colorless, translucent, and smooth in texture. Based on the release profiles, it could be speculated that the CS film loaded with LV nanocarriers can maintain the antibacterial activity for 4 consecutive days. Thus, the local delivery of the drug in a sustained release manner could be predicted to enhance the therapeutic effect. Further clinical studies are strongly recommended. Graphical Abstract.

Design, optimization, and in-vivo hypoglycaemic effect of nanosized glibenclamide for inhalation delivery.

The aim of this research was the development and optimization of nanoniosomes for delivery of glibenclamide (Gbn) as hypoglycaemic agent to the lung in an inhaler dosage form. Fifteen formulae of niosomal dispersions were prepared according to Box-Behnken design. The effect of drug amount, Cholesterol molar ratio, and Hydrophilic lipophilic balance (HLB) values of the surfactant on the mean vesicle size, Zeta potential (ZP), polydispersity index (PDI), entrapment efficiency, and in-vitro released of Gbn were investigated. A quality control check was performed on an inhaler filled with the optimum nanoniosomal formula. The in-vivo hypoglycaemic effect of nanoniosomal inhalation was also evaluated. The vesicle size observed of the optimized formula was 172 ± 4.6 nm, PDI was 0.304 ± 0.06 and ZP was -49.9 ± 1.5 mv with 69 ± 9.3% in-vitro drug release after 2 h. The Cholesterol molar ratio and the HLB value showed a statistically significant effect on dependent variables. In-vivo results proved that nanoniosomes were efficiently delivered from the inhalation canister showing a mass median aerodynamic diameter of 1.4 micron. The inhaled nanoniosomal dispersion loaded with Gbn showed a decrease in blood glucose level of hyperglycaemic rats by 51.42 ± 5.2%± after 180 min which was nearly two folds compared to oral Gbn. Gibenclamide nanoniosomes inhaler could be suggested as a novel effective dosage form for the treatment of Diabetes mellitus.

Formulation and evaluation of cubosomes containing colchicine for transdermal delivery.

Gout is a common inflammatory disease that is characterized by the deposition of serum urate crystals in the synovial fluids and joints. In spite of high efficiency of colchicine (COL) in treatment of gout, it has potential side effects associated with its oral administration. This study was aimed to enhance COL bioavailability and minimize associated side effects through transdermal delivery of COL-loaded cubosomes. Eight cubosomal dispersions were prepared according to Box-Behnken factorial design and the effect of COL, glyceryl monooleate (GMO), and surfactant (P407) concentrations on particle size distribution, zeta potential, and entrapment efficiency were assessed. The results revealed that the optimum formula exhibited a mean particle size of 73.07 ± 2.18 nm and entrapped 32.40 ± 2.33% of COL. The influence of transdermal application of COL cubosomal gel on the in vivo absorption of the drug was studied in rats compared with oral COL solution. The results of in vivo study showed that transdermal application of COL cubosomal gel significantly improves the drug absorption compared with oral COL solution, with evidence of a relative bioavailability of 4.6 times greater than that of oral COL solution. In conclusion, transdermal application of COL cubosomal gel may be a promising delivery system for enhancing the bioavailability of COL. Graphical abstract.

Glibenclamide nanosuspension inhaler: development, in vitro and in vivo assessment.

Objective: The development of nanosuspension for targeted delivery of glibenclamide as hypoglycemic agent to the lung in an inhaler dosage form.Method: Glibenclamide nanosuspension formulations were prepared using Box-Behnken design to investigate the effect of independent factors on the dependent variables, Fourier-transform Infrared spectroscopy, Differential Scanning Calorimetry, evaluation of glibenclamide nanosuspension inhaler and in vivo hypoglycemic efficacy were performed to determine glibenclamide nanosuspension inhaler effect.Results: The results revealed that the mean particle sizes of the prepared nanosuspension ranged from 0.216 to 0.856 µm, zeta potential from +9 to +16 mV, the solubility ranged from 43% to 75%, the mass median aerodynamic diameter was 2.34 µm and the glucose level in rat was significantly reduced by about 60%.Conclusion: These results confirmed that glibenclamide nanosuspension inhaler enhance hypoglycemic effectiveness and reduce adverse effect of glibenclamide, opening up new dosage form in Diabetes mellitus treatment.

Fabrication Of Gold Nanoparticles In Absence Of Surfactant As In Vitro Carrier Of Plasmid DNA.

PURPOSE: This work aimed to synthesize surfactant-free AuNPs for targeted delivery of plasmid DNA encoded p53 gene and to avoid conventional production method of Gold nanoparticles (AuNPs) which may adversely affect the final shape, diversity, and size due to accumulation of the formulated surfactant - gold complex to the surface. METHODS: The AuNPs were fabricated using seeded-growth method with L-Cystine methyl ester hydrochloride as capping agent, then loaded with plasmid DNA encoded p53 gene. The resultant AuNPs and AuNPs-p53 complex were evaluated for physical characteristics and morphology. Confirmation of complex formation was performed using gel electrophoresis. Furthermore, the efficient delivery and cytotoxicity behavior of the encoded gene were examined on both healthy lung cells (WI38) and cancerous lung cells (A549). RESULTS: L-cysteine methyl ester hydrochloride AuNPs showed acceptable physical characteristics (30 nm, +36.9 mv, and spherical morphology). P53 attachment to AuNPs was confirmed by gel electrophoresis. The RT-PCR proved the overexpression of p53 by the fabricated AuNPs-p53 complex. The high percentage of cell viability in normal lung cell line (WI 38) proved the safety of L-cysteine methyl ester functionalized AuNPs. Additionally, the apoptotic effect due to expression of p53 gene loaded on AuNPs was only prominent in lung cancer cell line (A549), revealing selectivity and targeting efficiency of anticancer AuNPs-p53 complex. CONCLUSION: AuNPs can be considered as a potential delivery system for effective transfection of plasmid DNA which can be used for successful treatment of cancer.

Nanogel loaded with surfactant based nanovesicles for enhanced ocular delivery of acetazolamide.

Objective: Intraocular pressure has always been a great challenge for topical ophthalmic drugs. The study aimed to develop ocular surfactant based nanovesicles (NVs) carried in mucoadhesive nanogel providing efficient topical delivery of acetazolamide (ACZ). Methods: For the sake of optimizing formulation parameters, the effect of the type of edge activator and its ratio to sorbitan monostearate (Span 60) on the mean particle size, entrapment efficiency (%EE), and zeta potential (ZP) of produced NVs was investigated. Results: The selected formulation composed of Span 60:sodium deoxycholate with ratio 80:20 showed an average diameter of 202.90 nm, %EE of 90.2%, and ZP of -38.1 mV with a spherical and smooth surface. The ACZ loaded nanovesicles (ACZ-NVs) were embedded in different concentrations of Chitosan-sodium tripolyphosphate (CS-TPP) nanogels. The nanogel prepared using 1.5% CS showed the most promising viscosity, adhesion time, and rheological behavior (118,246 cP, 290 min, and thixotropic behavior, respectively). The in vitro release of ACZ showed a controlled release profile after incorporation in nanogels. The in vivo irritation test showed minimal irritation for the nanogel formulation compared to ACZ topical suspension. The effect of intraocular pressure lowering was significantly prolonged using ACZ-NV nanogels compared to ACZ oral tablets. Histopathological examination emphasized the healing power of CS on retinal atrophy. Conclusion: The research work indicated a promising potential for successful topical delivery of ACZ.

Evaluation of mucoadhesive hydrogels loaded with diclofenac sodium-chitosan microspheres for rectal administration.

Considering the advantageous for the rectal administration of non-steroidal anti-inflammatory drugs, the objective of this study was to formulate and evaluate rectal mucoadhesive hydrogels loaded with diclofenac-sodium chitosan (DFS-CS) microspheres. Hydroxypropyl methylcellulose (HPMC; 5%, 6%, and 7% w/w) and Carbopol 934 (1% w/w) hydrogels containing DFS-CS microspheres equivalent to 1% w/w active drug were prepared. The physicochemical characterization revealed that all hydrogels had a suitable pH for rectal application (6.5-7.4). The consistency of HPMC hydrogels showed direct proportionality to the concentration of the gelling agent, while carbopol 934 gel showed its difficulty for rectal administration. Farrow's constant for all hydrogels were greater than one indicating pseudoplastic flow. In vitro drug release from the mucoadhesive hydrogel formulations showed a controlled drug release pattern, reaching 34.6-39.7% after 6 h. The kinetic analysis of the release data revealed that zero-order was the prominent release mechanism. The mucoadhesion time of 7% w/w HPMC hydrogel was 330 min, allowing the loaded microspheres to be attached to the surface of rectal mucosa. Histopathological examination demonstrated the lowest irritant response to the hydrogel loaded with DFS-CS microspheres in response to other forms of the drug.