Star-shaped poly(oligoethylene glycol) copolymer-based gels: thermo-responsive behaviour and bioapplicability for risedronate intranasal delivery

The aim of this work was to obtain an intranasal delivery system with improved mechanical and mucoadhesive properties that could provide prolonged retention time for the delivery of risedronate (RS). For this, novel in situ forming gels comprising thermo-responsive star-shaped polymers, utilizing either polyethylene glycol methyl ether (PEGMA-ME 188, Mn 188) or polyethylene glycol ethyl ether (PEGMA-EE 246, Mn 246), with polyethylene glycol methyl ether (PEGMA-ME 475, Mn 475), were synthesized and characterized. RS was trapped in the selected gel-forming solutions at a concentration of 0.2% w/v. The pH, rheological properties, in vitro drug release, ex vivo permeation as well as mucoadhesion were also examined. MTT assays were conducted to verify nasal tolerability of the developed formulations. Initial in vivo studies were carried out to evaluate anti-osteoporotic activity in a glucocorticoid induced osteoporosis model in rats. The results showed successful development of thermo-sensitive formulations with favorable mechanical properties at 37 °C, which formed non-irritant, mucoadhesive porous networks, facilitating nasal RS delivery. Moreover, sustained release of RS, augmented permeability and marked anti-osteoporotic efficacy as compared to intranasal (IN) and intravenous (IV) RS solutions were realized. The combined results show that the in situ gels should have promising application as nasal drug delivery systems

Bilosomes as a promising nanoplatform for oral delivery of an alkaloid nutraceutical:improved pharmacokinetic profile and snowballed hypoglycemic effect in diabetic rats

Diabetes mellitus is a life-threatening metabolic disease. At the moment, there is no effective treatment available to combat it. In this study, we aimed to develop berberine-loaded bilosomes (BER-BLS) to boost the oral bioavailability and therapeutic efficacy of berberine, a natural antidiabetic medication. The BER-BLS was fabricated using a thin-film hydration strategy and optimized using a central composite design (face-centered). The average vesicle size, entrapment efficiency, and surface charge of the optimized BER-BLS preparation were 196.5 nm, 89.7%, (−) 36.4 mV, respectively. In addition, it exhibited higher stability and better-sustained release of berberine than the berberine solution (BER-SOL). BER-BLS and BER-SOL were administered to streptozocin-induced diabetic rats. The optimized BER-BLS formulation had a significant hypoglycemic impact, with a maximum blood glucose decrease of 41%, whereas BER-SOL only reduced blood glucose by 19%. Furthermore, the pharmacological effect of oral BER-BLS and BER-SOL corresponded to 99.3% and 31.7%, respectively, when compared to subcutaneous insulin (1 IU). A pharmacokinetic analysis found a 6.4-fold rise in the relative bioavailability of berberine in BER-BLS when compared to BER-SOL at a dosage of 100 mg/kg body weight. Histopathological investigation revealed that BER-BLS is suitable for oral administration. Our data demonstrate that BLS is a potential nanocarrier for berberine administration, enhancing its oral bioavailability and antidiabetic activity

Exploring optimized methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) crystalline cored micelles in anti-glaucoma pharmacotherapy

Methoxy-poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-PCL) polymeric micelles (PMs) open a promising avenue through which ocular drug delivery with superior efficacy and tolerability can be potentially obtained. Methazolamide (MTZ) is an anti-glaucoma drug exhibiting poor corneal penetration, making it an ideal candidate for new polymeric micellar systems. MTZ-PMs were prepared using the thin film hydration procedure and optimized using a Design of Experiment (DoE) approach. In vitro drug release, thermal analyses and FT-IR characterization were also evaluated. MTT assay and histopathological assessment were carried out to verify ocular tolerability as well as Draize irritancy test. In vivo studies were conducted on rabbits to evaluate anti-glaucoma activity in a glucocorticoid-induced glaucoma model. The results showed successful entrapment of MTZ inside PMs matrix as reflected by the complete vanishing of drug melting peak in DSC thermogram and the possible formation of hydrogen bonding between MTZ and mPEG-PCL copolymer in FT-IR spectrum. The selected formula exhibited a particle size of 60 nm, entrapment efficiency of 93% and discrete spherical particles. Moreover, sustained release of MTZ, cellular and tissue biocompatibility and marked anti-glaucoma efficacy, as compared to MTZ solution, were realized. The combined results show that PMs could potentiate the therapeutic outcome of nanotechnology ocular drug delivery

Gamma oryzanol loaded into micelle-core/chitosan-shell: from translational nephroprotective potential to emphasis on sirtuin-1 associated machineries

Gamma oryzanol (ORZ) is a nutraceutical that is poorly water soluble with poor intestinal absorption. In the current work, ORZ was nanoformulated into uncoated and chitosan coated micelles based on methoxy-poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-PCL) and poly(ε-caprolactone)-b-methoxy-poly(ethylene glycol)-b-poly(ε-caprolactone) (PCL-PEG-PCL) copolymers for augmenting ORZ oral delivery. The physicochemical properties, morphological study, in-vitro release and safety of the nanoplaforms were determined. Importantly, the nephroprotective competence of the nanoplaforms was analyzed against acute kidney injury (AKI) rat model and the sirtuin-1 associated machineries were assessed. The results revealed that the micelles exerted particle size (PS) from 97.9 to 117.8 nm that was markedly increased after chitosan coating. The reversal of zeta potential from negative to highly positive further confirmed efficient coating. In vitro release profiles demonstrated prolonged release pattern. The nanoforms conferred higher cell viability values than free ORZ on Vero cell line. The designed micelles displayed augmented nephroprotection compared to free ORZ with the supremacy of CS coated micelles over uncoated ones in restoring kidney parameters to normal levels. The attenuated AKI was fulfilled via the modulation of sirtuin-1 signaling pathways translated by restoring the histological features, increasing renal antioxidant states, renal autophagy and decreasing renal inflammation and renal apoptosis. These outcomes confirmed that surface modification with chitosan had a considerable leverage on micelles safety, release behavior and in vivo performance

Polymeric nanoparticles based topical gel of poorly soluble drug: Formulation, ex-vivo and in vivo evaluation

The study was conducted to evaluate the potential application of nanocapsules and nanospheres as topical drug delivery systems for indomethacin (as model drug). Both were prepared by nanoprecipitation using poly (ɛ-caprolactone) and hydroxypropyl β-cyclodextrin polymers and evaluated for morphology, particle size, zeta potential, EE% and in vitro drug release then incorporated in methylcellulose and Carbopol 940 gel bases and evaluated for in vitro release. The selected formulations and market product were evaluated for ex vivo human skin permeation and anti-inflammatory and analgesic activities by paw edema and hot plate methods respectively. Results showed that nanocapsules had slight higher EE% and larger particle sizes than nanospheres. In vitro release and zeta potential were nearly similar. Methylcellulose exhibited higher in vitro release than Carbopol 940 after 3 h (except NS2). Ex vivo skin permeation studies showed significant higher cumulative amount of IND (and flux) from NC1/MC and NS1/MC (1573.06 ± 14.23 µg/cm2 and 1452.24 ± 23.18 µg/cm2 respectively) than market product. They also showed enhancement ratio and permeability coefficient rate of ∼1.5 and ∼2 respectively. NC1/MC proved to be significantly higher pharmacodynamic effects than market product. All results showed that NC1/MC could provide a promising formula as a topical delivery of indomethacin

Quercetin Loaded Monolaurate Sugar Esters-Based Niosomes: Sustained Release and Mutual Antioxidant-Hepatoprotective Interplay

Flavonoids possess different interesting biological properties, including antibacterial, antiviral, anti-inflammatory and antioxidant activities. However, unfortunately, these molecules present different bottlenecks, such as low aqueous solubility, photo and oxidative degradability, high first-pass effect, poor intestinal absorption and, hence, low systemic bioavailability. A variety of delivery systems have been developed to circumvent these drawbacks, and among them, in this work niosomes have been selected to encapsulate the hepatoprotective natural flavonoid quercetin. The aim of this study was to prepare nanosized quercetin-loaded niosomes, formulated with different monolaurate sugar esters (i.e., sorbitan C12; glucose C12; trehalose C12; sucrose C12) that act as non-ionic surfactants and with cholesterol as stabilizer (1:1 and 2:1 ratio). Niosomes were characterized under the physicochemical, thermal and morphological points of view. Moreover, after the analyses of the in vitro biocompatibility and the drug-release profile, the hepatoprotective activity of the selected niosomes was evaluated in vivo, using the carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. Furthermore, the levels of glutathione and glutathione peroxidase (GSH and GPX) were measured. Based on results, the best formulation selected was glucose laurate/cholesterol at molar ratio of 1:1, presenting spherical shape and a particle size (PS) of 161 ± 4.6 nm, with a drug encapsulation efficiency (EE%) as high as 83.6 ± 3.7% and sustained quercetin release. These niosomes showed higher hepatoprotective effect compared to free quercetin in vivo, measuring serum biomarker enzymes (i.e., alanine and aspartate transaminases (ALT and AST)) and serum biochemical parameters (i.e., alkaline phosphatase (ALP) and total proteins), while following the histopathological investigation. This study confirms the ability of quercetin loaded niosomes to reverse CCl4 intoxication and to carry out an antioxidant effect