Ameliorative effect of rubiadin-loaded nanocarriers in STZ-NA-induced diabetic nephropathy in rats: formulation optimization, molecular docking, and in vivo biological evaluation.

Diabetic nephropathy (DN) is a significant source of end-stage renal illness all over the world in both developed and developing countries. The aim of the study was to optimize rubiadin-loaded niosomes (RLN) using Box-Behnken design for the management of streptozotocin-nicotinamide (STZ-NA)-induced DN in Wistar rats. The RLN were formulated by a "thin-layer hydration technique." The optimization of RLN was done by Box-Behnken design; the independent variables were cholesterol (CHOL), Span 80, and methanol, while the dependent factors were the vesicle size, zeta potential, and entrapment efficiency. The optimized formulation was characterized for various biochemical parameters including anti-diabetic activity in Wistar rats. The optimized RLN presented vesicle size of 238 nm, zeta potential -68 mV, and entrapment efficiency 85%. A noteworthy decreased in blood glucose level was detected in STZ-NA-induced DN rats when orally treated with RLN (100 mg/kg/week and 200 mg/kg/week). Oral administration of RLN formulation considerably decreased the levels of urea, uric acid, and creatinine in DN rats. In addition, treatment of DN rats with RLN formulation considerably improves the level of TBARS, GSH, SOD, and CAT. The lipid profile of DN rats was also improved on treatment with RLN formulation. This study revealed that the prepared RLN formulation was successfully optimized by Box-Behnken design and found to be useful for the management of STZ-NA-induced DN in Wistar rats.

Preparation and optimization of fisetin loaded glycerol based soft nanovesicles by Box-Behnken design.

The present study focused on the development and optimization of glycerosomes for dermal delivery of fisetin. The fisetin loaded glycerosomes formulation was optimized by Box-Behnken design. The independent variables were the lipoid S 100, glycerol, and sonication time, whereas the dependent variables were the vesicles size, entrapment efficiency, and flux. The mechanism of skin penetration of fisetin loaded glycerosomes formulation was determined by the DSC and FTIR studies. Confocal scanning microscopy was used to detect the penetration ability of glycerosomes. The optimized fisetin loaded glycerosomes formulation was converted into a Carbopol® gel matrix, and the latter was analyzed for various parameters. The optimized formulation of glycerosomes presented vesicles size, entrapment efficiency and flux of 138.8 ± 4.09 nm, 86.41 ± 2.95% and 5.04 ± 0.17 µg/cm2/h, respectively. The transmission electron microscopy of optimized fisetin loaded formulation revealed the spherical and sealed structure of glycerosomes vesicles. The confocal study confirmed that the Rhodamine B incorporated glycerosomes penetrated up to deeper layers of skin. The DSC and FTIR studies revealed that the hydration of skin layers and skin lipid fluidization could be the penetration mechanism of fisetin glycerosomes formulation. The optimized fisetin loaded glycerosomes gel formulation presented a flux of 4.24 ± 0.14 µg/cm2/h, and exhibited zero-order release kinetics. The texture analysis of fisetin glycerosomes gel displayed a sufficient hardness, consistency, cohesiveness, and index of viscosity. It was concluded that the prepared fisetin loaded glycerosomes gel was suitable for the dermal application.

Optimization of Nanostructured Lipid Carriers of Lurasidone Hydrochloride Using Box-Behnken Design for Brain Targeting: In Vitro and In Vivo Studies.

Intranasal nanostructured lipid carrier (NLC) of lurasidone hydrochloride (LRD) for brain delivery was prepared by the solvent evaporation method. The effects of independent variables, X1-lipid concentration, X-2 surfactant, and X-3 sonication times on dependent variables, Y1-particle size, Y-2 polydispersity index, and Y-3% entrapment efficiency were determined using Box-Behnken design. Optimized LRD-NLC was selected from the Box-Behnken design and evaluated for their morphological, physiological, nasal diffusion, and in vivo distribution in the brain after intranasal administration. Particle size, polydispersity index, and entrapment efficiency of optimized LRD-NLC were found to be 207.4 ± 1.5 nm, 0.392 ± 0.15, and 92.12 ± 1.0%, respectively. Transmission electron microscopy and scanning electron microscopy was used to determine the particle size and surface morphology of LRD-NLC. The prepared LRD-NLC follows biphasic in vitro drug release. Prepared NLC showed a 2-fold increase in LRD concentration in the brain when compared with the drug solution following intranasal administration. Results showed that intranasal route can be a good and efficient approach for delivering the drug directly to the brain and enhancing the drug efficacy in the brain for the management of schizophrenia and a good alternative to oral drug delivery.

Fisetin loaded binary ethosomes for management of skin cancer by dermal application on UV exposed mice.

Fisetin loaded binary ethosomes were prepared and optimized using Box-Behnken design for dermal application to alleviate skin cancer. The prepared formulations were evaluated for vesicle size, entrapment efficiency and flux of fisetin. Additionally, the optimized formulation was further evaluated by transmission electron microscopy, confocal laser microscopy, vesicles-skin interaction, dermatokinetic study and DPPH (2, 2-diphenyl-1-picryl-hydrazyl) assay. The in vivo study was carried out for the evaluation of tumor incidence, pro-inflammatory cytokines such as TNF-α and IL-1α, lipid peroxidation values, glutathione content and catalase activity in mice. The optimized binary ethosomes formulation presented sealed unilamellar shaped vesicles, with vesicles size, entrapment efficiency and flux of 99.89 ±â€¯3.24 nm, 89.23 ±â€¯2.13% and 1.01 ±â€¯0.03 µg/cm2/h respectively. The confocal images of rat skin clearly illustrated the deeper penetration of rhodamine B loaded binary ethosomes formulation. Further, the binary ethosomes gel treated rat skin showed substantial increase in CSkin max and AUC0-8 in comparison to rat skin treated with conventional gel. In vivo study revealed that the mice pre-treated with fisetin binary ethosomes gel caused marked decrease in the levels of TNF-α and IL-1α as compared to the mice exposed to UV only. Further the binary ethosomes gel treated mice group had demonstrated less percentage of tumour incidences (49%) as compared to mice treated with UV only (96% tumour incidence). The novelty of the work lies in successful optimization of formulation using Box-Behnken design and characterization of binary ethosomes carrier of fisetin and demonstration of improved dermal delivery of the same. The overall data suggest that the fisetin loaded binary ethosomes formulation is a potential dermal delivery system for the management of skin cancer.

Lamotrigine encapsulated intra-nasal nanoliposome formulation for epilepsy treatment: Formulation design, characterization and nasal toxicity study.

The purpose of this study was to develop lamotrigine nanoliposomes (LTG-NLs) for the treatment in seizures. The formulation was prepared using thin film hydration and rehydration method using the phospholipon 90 G, cholesterol and tween 80 as main ingredients. The nanoliposomes were optimized by plucket burman design (PBD) and response surface methodology (RSM) optimization techniques. The optimized LTGNLopt was further characterized for surface morphology, in-vitro release, stability study, confocal laser scanning microscopic (CLSM) study and naso toxicity study. The results showed that LTGNLopt shown nano size with high entrapment and drug release. The ex-vivo permeation study and confocal laser microscopy study confirmed the enhancement in permeation across the goat nasal mucosa. From the study, it was concluded that the independent variables used to optimize the NLs shown significant effect on the dependent variables and consider effective lipid carrier system for intranasal delivery.

Ursolic acid loaded intra nasal nano lipid vesicles for brain tumour: Formulation, optimization, in-vivo brain/plasma distribution study and histopathological assessment.

The aim was to formulate an optimized ursolic acid (UA) loaded lipid vesicle using formulation by design approach (FbD) for improving the drug targeting by nasal route for brain tumor. Three factors were evaluated at three different levels using anethole (terpene) (A), ethanol (B) and phospholipid90 G (C) as independent variables and their individual and combined effects were observed for PDI (Y1), vesicle size (Y2) and encapsulation efficiency (Y3) to select an optimal system (UALVopt). The optimized formulation was further converted into gel and evaluated for drug release, nasal permeation study, brain/plasma uptake and histopathology study. The UALVopt formulation containing anethole as terpene (1% as A), ethanol (2.6% as B) and phospholipid90 G (8.8 mg as C) showed low PDI (0.212), vesicle size (115.56 nm) and high entrapment efficiency (76.42%). The in-vitro drug release and ex-vivo permeation study results revealed prolonged drug release and permeation. The brain/blood ratio for UALVGopt remained significantly higher at all the time points with respect to UALVopt indicating higher and prolonged retention of drug at site of action. The histopathological study of the nasal mucosa and brain confirmed non-toxic nature of developed formulation. The formulation UALVGopt could serve as a better alternative for the brain targeting via the intranasal route which in turn could subsequently improve its efficacy.

Development of transethosomes formulation for dermal fisetin delivery: Box-Behnken design, optimization, in vitro skin penetration, vesicles-skin interaction and dermatokinetic studies.

The present study was conducted for the optimization of transethosomes formulation for dermal fisetin delivery. The optimization of the formulation was carried out using "Box-Behnken design". The independent variables were Lipoid S 100, ethanol and sodium cholate. The prepared formulations were characterized for vesicle size, entrapment efficiency and in vitro skin penetration study. The vesicles-skin interaction, confocal laser scanning microscopy and dermatokinetic studies were performed with optimized formulation. Results of the present study demonstrated that the optimized formulation presented vesicle size of 74.21 ± 2.65 nm, zeta potential of -11.0 mV, entrapment efficiency of 68.31 ± 1.48% and flux of 4.13 ± 0.17 µg/cm2/h. The TEM image of optimized formulation exhibited sealed and spherical shape vesicles. Results of thermoanalytical techniques demonstrated that the prepared transethosomes vesicles formulation had fluidized the rigid membrane of rat's skin for smoother penetration of fisetin transethosomes. The confocal study results presented well distribution and penetration of Rhodamine B loaded transethosomes vesicles formulation up to deeper layers of the rat's skin as compared to the Rhodamine B-hydro alcoholic solution. Present study data revealed that the developed transethosomes vesicles formulation was found to be a potentially useful drug carrier for fisetin dermal delivery.