P-gp inhibition and enhanced oral bioavailability of amikacin Sulfate: A novel approach using Thiolated Chito-PEGylated Lipidic Hybrids.

This study aimed to develop oral lipidic hybrids of amikacin sulfate (AMK), incorporating thiolated chitosan as a P-glycoprotein (P-gp) inhibitor to enhance intestinal absorptivity and bioavailability. Three formulations were designed: PEGylated Liposomes, Chitosan-functionalized PEGylated (Chito-PEGylated) Lipidic Hybrids, and Thiolated Chito-PEGylated Lipidic Hybrids. The physical characteristics of nanovesicles were assessed. Ex-vivo permeation and confocal laser scanning microscopy (CLSM) studies were conducted to evaluate the formulations' potential to enhance AMK intestinal permeability. In-vivo pharmacokinetic studies in rats and histological/biochemical investigations assessed the safety profile and oral bioavailability. The AMK-loaded Thiolated Chito-PEGylated Lipidic Hybrids exhibited favorable physical characteristics, higher ex-vivo permeation parameters, and verified P-gp inhibition via CLSM. They demonstrated heightened oral bioavailability (68.62% absolute bioavailability) and a sufficient safety profile. Relative bioavailability was significantly higher (1556.3% and 448.79%) compared to PEGylated Liposomes and Chito-PEGylated Lipidic Hybrids, respectively, indicating remarkable oral AMK delivery with fewer doses, reduced side effects, and enhanced patient compliance.

Can Essential Oils/Botanical Agents Smart-Nanoformulations Be the Winning Cards against Psoriasis?

Although psoriasis remains one of the most devastating inflammatory disorders due to its huge negative impact on patients' quality of life, new "green" treatment approaches still need to be fully explored. The purpose of this review article is to focus on the utilization of different essential oils and active constituents of herbal botanical origin for the treatment of psoriasis that proved efficacious via both in vitro and in vivo models. The applications of nanotechnology-based formulations which displayed great potential in augmenting the permeation and delivery of these agents is also addressed. Numerous studies have been found which assessed the potential activity of natural botanical agents to overcome psoriasis. Nano-architecture delivery is applied in order to maximize the benefits of their activity, improve properties, and increase patient compliance. This field of natural innovative formulations can be a promising tool to optimize remediation of psoriasis while minimizing adverse effects.

PEGylated Tween 80-functionalized chitosan-lipidic nano-vesicular hybrids for heightening nose-to-brain delivery and bioavailability of metoclopramide.

A PEGylated Tween 80-functionalized chitosan-lipidic (PEG-T-Chito-Lip) nano-vesicular hybrid was developed for intranasal administration as an alternative delivery route to help improve the poor oral bioavailability of BCS class-III model/antiemetic (metoclopramide hydrochloride; MTC). The influence of varying levels of chitosan, cholesterol, PEG 600, and Tween 80 on the stability/release parameters of the formulated nanovesicles was optimized using Draper-Lin Design. Two optimized formulations (Opti-Max and Opti-Min) with both maximized and minimized MTC-release goals, were predicted, characterized, and proved their vesicular outline via light/electron microscopy, along with the mutual prompt/extended in-vitro release patterns. The dual-optimized MTC-loaded PEG-T-Chito-Lip nanovesicles were loaded in intranasal in-situ gel (ISG) and further underwent in-vivo pharmacokinetics/nose-to-brain delivery valuation on Sprague-Dawley rats. The absorption profiles in plasma (plasma-AUC0-∞) of the intranasal dual-optimized MTC-loaded nano-vesicular ISG formulation in pretreated rats were 2.95-fold and 1.64-fold more than rats pretreated with orally administered MTC and intranasally administered raw MTC-loaded ISG formulation, respectively. Interestingly, the brain-AUC0-∞ of the intranasal dual-optimized MTC-loaded ISG was 10 and 3 times more than brain-AUC0-∞ of the MTC-oral tablet and the intranasal raw MTC-loaded ISG, respectively. It was also revealed that the intranasal dual-optimized ISG significantly had the lowest liver-AUC0-∞ (862.19 ng.g-1.h-1) versus the MTC-oral tablet (5732.17 ng.g-1.h-1) and the intranasal raw MTC-loaded ISG (1799.69 ng.g-1.h-1). The brain/blood ratio profile for the intranasal dual-optimized ISG was significantly enhanced over all other MTC formulations (P < 0.05). Moreover, the 198.55% drug targeting efficiency, 75.26% nose-to-brain direct transport percentage, and 4.06 drug targeting index of the dual-optimized formulation were significantly higher than those of the raw MTC-loaded ISG formulation. The performance of the dual-optimized PEG-T-Chito-Lip nano-vesicular hybrids for intranasal administration evidenced MTC-improved bioavailability, circumvented hepatic metabolism, and enhanced brain targetability, with increased potentiality in heightening the convenience and compliance for patients.

Incorporating sodium deoxycholate endorsed the buccal administration of avanafil to heighten the bioavailability and duration of action.

The highly effective phosphodiesterase type 5 inhibitor (avanafil; AVA) is routinely prescribed to treat erectile dysfunction. The drug has poor oral bioavailability and undergoes a significant first-pass metabolism. Therefore, altering AVA's solubility and choosing a different delivery method may boost its effectiveness. Nine different solid dispersion formulations utilizing polyvinylpyrrolidone (PVP) at three different ratios were prepared and characterized. The Box-Behnken design was employed to optimize AVA-buccal tablets. The pre-compression and post-compression characteristics of the tablets were assessed. The mucoadhesion strength of the optimized tablet was investigated using cow buccal mucosal tissue. In vivo performance of the optimized tablets was examined on human volunteers compared to the commercial tablets. PVP K90 at 2:1 drug to polymer ratio showed the highest solubilization capacity. The mucoadhesive polymer type and percentage and the mucopenetration enhancer percentage were significantly affect the mucoadhesion strength, tablet hardness, and the initial and cumulative AVA released from the prepared tablets. The optimized AVA-buccal tablet showed 4.96 folds increase in the mean residence time, higher plasma exposure, and an improvement in the relative bioavailability of AVA by 1076.27% compared with the commercial tablet. Therefore, a successful approach to deal with AVA first-pass metabolism and low bioavailability could be to employ buccal tablets containing a solubility-enhanced form of AVA.

Effect of nanovesicular surface-functionalization via chitosan and/or PEGylation on cytotoxicity of tamoxifen in induced-breast cancer model.

AIMS: The effect of surface-modification of Tamoxifen (Tam)-loaded-niosomes on drug cytotoxicity and bio-distribution, via functionalization with chitosan and/or PEGylation, was investigated. MATERIALS AND METHODS: Tam-loaded hybrid-nanocarriers (Tam-loaded niosomes, chitosomes, PEGylated niosomes, and PEGylated chitosomes) were formulated and characterized. KEY FINDINGS: Chitosanization with/without PEGylation proved to selectively enhance Tam-release at the cancerous-acidic micromilieu. Cytotoxic activity study showed that Tam-loaded PEGylated niosomes had a lower IC50 value on MCF-7 cell line (0.39, 0.35, and 0.27 times) than Tam-loaded PEGylated chitosomes, Tam-loaded niosomes, and Tam-loaded chitosomes, respectively. Cell cycle analysis showed that PEGylation and/or Chitosanization significantly impact Tam efficiency in inducing apoptosis, with a preferential influence of PEGylation over chitosanization. The assay of Annexin-V/PI double staining revealed that chitosanized-nanocarriers had a significant role in increasing the incidence of apoptosis over necrosis. Besides, PEGylated-nanocarriers increased apoptosis, as well as total death and necrosis percentages more than what was shown from free Tam. Moreover, the average changes in both Bax/Bcl-2 ratio and Caspase 9 were best improved in cells treated by Tam-loaded PEGylated niosomes over all other formulations. The in-vivo study involving DMBA-induced-breast cancer rats revealed that PEGylation made the highest tumor-growth inhibition (84.9 %) and breast tumor selectivity, while chitosanization had a lower accumulation tendency in the blood (62.3 ng/ml) and liver tissues (103.67 ng/ml). The histopathological specimens from the group treated with Tam-loaded PEGylated niosomes showed the best improvement over other formulations. SIGNIFICANCE: All these results concluded the crucial effect of both PEGylation and chitosan-functionalization of Tam-loaded niosomes in enhancing effectiveness, targetability, and safety.

Oleic acid-reinforced PEGylated polymethacrylate transdermal film with enhanced antidyslipidemic activity and bioavailability of atorvastatin: A mechanistic ex-vivo/in-vivo analysis.

To enhance the poor bioavailability and extensive liver metabolism of atorvastatin calcium (ATC), we have developed an oleic acid-reinforced PEGylated polymethacrylate (OLA-PEG-E-RLPO) transdermal film as a convenient and alternative delivery system. The effect of varying levels of Eudragit RLPO, PEG 400, and oleic acid on the target product profile was optimized through Quality by Design (QbD) approach. The ATC-loaded OLA-PEG-E-RLPO transdermal films were evaluated in ex-vivo experiments using full thickness skin, utilizing Franz cell studies, and undergone in-vivo pharmacokinetics/pharmacodynamics (PK/PD) assessment, using poloxamer-induced dyslipidemic Sprague-Dawley rats. At 2 and 12 h, the optimized ATC films with a thickness of 0.79 mm showed permeation of 37.34% and 97.23% into the receptor compartment, respectively. Steady-state flux was 0.172 mg/cm2h, with 7.01 × 10-4 cm/h permeability coefficient, and 0.713 × 10-3 cm2/h diffusion coefficient. In-vivo PK results indicated that the absorption profiles (AUC0-∞) of the optimized film in pre-treated group of animals were 8.6-fold and 2.8-fold greater than controls pre-treated with non-PEGylated non-oleic acid film and orally administered ATC, respectively. PD assessment of the lipid panel indicated that the lipid profile of the optimized film pre-treated group reached normal levels after 12 h, along with the significant enhancement over the non-PEGylated non-oleic acid film and the oral marketed tablet groups. The histopathological findings revealed near-normal hepatocyte structure for the optimized film pre-treated animal group. Our results further indicate that transdermal delivery films based on an optimized ATC-loaded OLA-PEG-E-RLPO were successfully developed and their assessment in both ex-vivo and in-vivo suggests enhanced permeability and improvement in bioavailability and antidyslipidemic activity of ATC. This approach can provide several advantages, especially during chronic administration of ATC, including improvement in patient compliance, therapeutic benefits, bioavailability, and feasibility for commercialization and as a platform for other drug classes.

Fluticasone propionate-loaded solid lipid nanoparticles with augmented anti-inflammatory activity: optimisation, characterisation and pharmacodynamic evaluation on rats.

This work aimed to elaborate an optimised fluticasone propionate (FP)-loaded solid lipid nanoparticles (SLNs) to enhance FP effectiveness for topical inflammatory remediation. The influences of drug amount, lipid, and surfactant ratios, on drug release pattern and stability were investigated utilising Box-Behnken design. Elaboration, characterisation, and pharmacodynamic evaluation in comparison with the marketed formulation (Cutivate® cream, 0.05%w/w FP), were conducted for the optimised SLNs. The optimised SLNs with a size of 248.3 ± 1.89 nm (PDI = 0.275) and -32.4 ± 2.85 mV zeta potential were evidenced good stability physiognomies. The optimised SLNs pre-treated rats exhibited non-significant difference in paw volume from that of the control group and showed a significant reduction in both PGE2 and TNF-α levels by 51.5 and 61%, respectively, in comparison with the Carrageenan group. The optimised FP-loaded SLNs maximised the efficacy of FP towards inflammation alleviation that increase its potential as efficient implement in inflammatory skin diseases remediation.

Stimuli-Responsive Nano-Architecture Drug-Delivery Systems to Solid Tumor Micromilieu: Past, Present, and Future Perspectives.

The microenvironment characteristics of solid tumors, renowned as barriers that harshly impeded many drug-delivery approaches, were precisely studied, investigated, categorized, divided, and subdivided into a complex diverse of barriers. These categories were further studied with a particular perspective, which makes all barriers found in solid-tumor micromilieu turn into different types of stimuli, and were considered triggers that can increase and hasten drug-release targeting efficacy. This review gathers data concerning the nature of solid-tumor micromilieu. Past research focused on the treatment of such tumors, the recent efforts employed for engineering smart nanoarchitectures with the utilization of the specified stimuli categories, the possibility of combining more than one stimuli for much-greater targeting enhancement, examples of the approved nanoarchitectures that already translated clinically as well as the obstacles faced by the use of these nanostructures, and, finally, an overview of the possible future implementations of smart-chemical engineering for the design of more-efficient drug delivery and theranostic systems and for making nanosystems with a much-higher level of specificity and penetrability features.

Date seed oil loaded niosomes: development, optimization and anti-inflammatory effect evaluation on rats.

OBJECTIVE: An optimized date seed oil (DSO) loaded niosomes was formulated. SIGNIFICANCE: Maximize the extract anti-inflammatory efficacy and govern its release characteristics from nanoparticles for osteoarthritis prevention and treatment purposes. METHODS: By using Box-Behnken Design, the effect of three formulation factors on the entrapment efficiency percentage (Y1), initial DSO release percentage after 2 h (Y2), and cumulative DSO release percentage of DSO after 12 h (Y3), were optimized and studied. The optimized DSO formulation was specified, elaborated, particle size and zeta potential assessed, examined morphologically under electron and light microscope, and in vivo evaluated via carrageenan-induced rat paw edema study. RESULTS: 65.89%, 18.39%, and 58.27% were the measured responses of the optimized niosomes for Y1, Y2, and Y3, respectively. The vesicular structure of the optimized DSO loaded nano-vesicles with nano-size range and good stability features were confirmed. Furthermore, a distinguished anti-inflammatory activity in both prompt and sustained effectiveness were exhibited via the optimized DSO niosomes. Interestingly, the delayed efficacy outcomes of the extract loaded nanoparticles showed a similarity profile as well as the negative control group outcomes. CONCLUSIONS: To emphasize, DSO loading in niosomes revealed a significant enhancement toward inflammation alleviation, which offers a promising implement in osteoarthritis remediation and prohibition.

Polymeric nanoparticles: Promising platform for drug delivery.

Nano medicine had viewed countless breakthroughs in drug delivery implementations. The main objective of nanotechnology application in delivering and carrying many promising therapeutics is to assure drugs carriage to their action sites, to maximize the pharmacological desired influence of remedies and to overcome their limitations and drawbacks that would hinder the required effectiveness. One of these applications was the particulates type of nano-range in size and tremendous impact in achievement. About this specific diversity of particulates, the different elaboration methodologies, mandatory and elementary components for design, and examples of splendid success stories for these particulates were emphasized in this humble review. Challenges such as oral delivery probability for peptide moieties and enhancement the harshly passage process of drugs across the blood brain barriers were accepted and defeated by the almost insurmountable latterly mentioned particulates. Behold, the polymeric nanoparticles.

Maximizing the Therapeutic Efficacy of Imatinib Mesylate-Loaded Niosomes on Human Colon Adenocarcinoma Using Box-Behnken Design.

This research purposed to formulate an optimized imatinib mesylate (IM)-loaded niosomes to improve its chemotherapeutic efficacy. The influence of 3 formulation factors on niosomal vesicular size (Y1), zeta potential (Y2), entrapment capacity percentage (Y3), the percentage of initial drug release after 2 h (Y4), and the percentage of cumulative drug release after 24 h (Y5) were studied and optimized using Box-Behnken design. Optimum desirability was specified and the optimized formula was prepared, stability tested, morphologically examined, checked for vesicular bilayer formation and evaluated for its in vitro cytotoxicity on 3 different cancer cell lines namely MCF-7, HCT-116, and HepG-2 in addition to 1 normal cell line to ensure its selectivity against cancer cells. The actual responses of the optimized IM formulation were 425.36 nm, -62.4 mV, 82.96%, 18.93%, and 89.45% for Y1, Y2, Y3, Y4, and Y5, respectively. The optimized IM-loaded niosomes confirmed the spherical vesicular shape imaged by both light and electron microscopes and further proven by differential scanning calorimetry. Moreover, the optimized formula exhibited improved stability on storage at 4 ± 2°C and superior efficacy on MCF7, HCT-116, and HepG2 as IC50 values were 6.7, 16.4, and 7.3 folds less than those of free drug, respectively. Interestingly, IC50 of the optimized formula against normal cell line was ranged from 3 to 11 folds higher than in different cancer cells indicating a higher selectivity of the optimized formula to cancer cells. In conclusion, the incorporation of IM in niosomes enhanced its efficacy and selectivity toward cancer cells, presenting a promising tool to fight cancer using this approach.