Nanostructured lipid carriers loaded with simvastatin: effect of PEG/glycerides on characterization,stability, cellular uptake efficiency and in vitro cytotoxicity

Objective: The aim of this study is to evaluate the use of PEG/glycerides of different HLB; oleoyl macrogol-6-glycerides (Labrafil^® M 1944 CS) and caprylocaproylmacrogol-8-glycerides (Labrasol^®), compared to Labrafac lipophile^® as PEG-free glyceride in the preparation of nanostructured lipid carriers (NLCs). PEG/glycerides are suggested to perform a dual function; as the oily component, and as the PEG-containing substrate required for producing the PEGylated carriers without physical or chemical synthesis.

Methods: Lipid nanocarriers were loaded with simvastatin (SV) as a promising anticancer drug. An optimization study of NLC fabrication variables was first conducted. The effect of lyophilization was investigated using cryoprotectants of various types and concentrations. The prepared NLCs were characterized in terms of particle size (PS), size distribution (PDI), zeta potential (ZP), drug entrapment, in vitro drug release, morphology and drug–excipient interactions. The influence of glycerides?±?PEG on the cytotoxicity of SV was evaluated on MCF-7 breast cancer cells, in addition to the cellular uptake of fluorescent blank NLCs.

Results: The alteration between different oil types had a significant impact on PS, ZP and drug release. Both sucrose and trehalose showed the lowest increase in PS and PDI of the reconstituted lyophilized NLCs. The in vitro cytotoxicity and cellular uptake studies indicated that SV showed the highest antitumor effect on MCF-7 cancer cells when loaded into Labrasol^® NLCs demonstrating a high cellular uptake as well.

Conclusion: The study confirms the applicability of PEG/glycerides in the development of NLCs. Encapsulating SV in Labrasol^®-containing NLC could enhance the antitumor effect of the drug.     

Mydriatics release from solid and semi-solid ophthalmic formulations using different in vitro methods

The aim of the present paper was the development of semi-solid (hydrogels) and solid (film) ophthalmic formulations for the controlled release of two mydriatics: phenylephrine and tropicamide. The formulations – based on polyvinylalcohol and hyaluronic acid – were characterized, and release studies were performed with three different in vitro set-ups, i.e. Franz-type diffusion cell, vial method and inclined plane; for comparison, a solution and a commercial insert, both clinically used to induce mydriasis, were evaluated. Both gels and film allowed for a controlled release of drugs, appearing a useful alternative for mydriatics administration. However, the release kinetic was significantly influenced by the method used, highlighting the need for optimization and standardization of in vitro models for the evaluation of drug release from ophthalmic dosage forms.     

Facile development,characterization, and optimization of new metformin-loaded nanocarrier system for efficient colon cancer adjunct therapy

Purpose: Metformin hydrochloride (MF) repurposing as adjuvant anticancer therapy for colorectal cancer (CRC) proved effective. Several studies attempted to develop MF-loaded nanoparticles (NPs), however the entrapment efficiency (EE%) was poor. Thus, the present study aimed at the facile development of a new series of chitosan (CS)-based semi-interpenetrating network (semi-IPN) NPs incorporating Pluronic^® nanomicelles as nanocarriers for enhanced entrapment and sustained release of MF for efficient treatment of CRC.

Methods: The NPs were prepared by ionic gelation and subsequently characterized using FTIR, DSC, TEM, and DLS. A full factorial design was also adopted to study the effect of various formulation variables on EE%, particle size, and zeta-potential of NPs.

Results: NPs had a spherical shape and a mean particle size ranging between 135 and 220?nm. FTIR and DSC studies results were indicative of successful ionic gelation with the drug being dispersed in its amorphous form within CS-Pluronic^® matrix. Maximum EE% reaching 57.00?±?12.90% was achieved using Pluronic^®-123 based NPs. NPs exhibited a sustained release profile over 48?h. The MF-loaded NPs sensitized RKO CRC cells relative to drug alone.

Conclusion: The reported results highlighted the novel utility of the developed NPs in the arena of colon cancer treatment.     

Preparation,characterization, and pharmacokinetics study of a novel genistein-loaded mixed micelles system

Genistein (GEN), is a natural dietary isoflavone, has been reported to show anticancer activities. However, its poor aqueous solubility and oral bioavailability limit its clinical application. We designed a novel genistein-loaded mixed micelles (GEN-M) system composed of Soluplus^® and Vitamin E d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were prepared by organic solvent evaporation aimed to overcome the challenges of GEN’s poor solubility and then further improve its oral bioavailability. The optimized, spherical-shaped GEN-M was obtained at a ratio of 10:1 (Soluplus^®:TPGS). The mean particle size of GEN-M was 184.7?±?2.8?nm, with a narrow polydispersity index (PDI) of 0.162?±?0.002. The zeta potential value of GEN-M was ?2.92?±?0.01?mV. The micelles solutions was transparent with blue opalescence has high the entrapment efficiency (EE) and drug loading (DL) of 97.12?±?2.11 and 3.87?±?1.26%, respectively. GEN-M was demonstrated a sustained release behavior when formed micelles shown in drug release in vitro. The solubility of GEN in water increased to 1.53?±?0.04?mg/mL after encapsulation. The permeability of GEN across a Caco-2 cell monolayer was enhanced, and the pharmacokinetics study of GEN-M showed a 2.42-fold increase in relative oral bioavailability compared with free GEN. Based on these findings, we conclude that this novel nanomicelles drug delivery system could be leveraged to deliver GEN and other hydrophobic drugs.     

Formulation and evaluation of diclofenac potassium fast-disintegrating tablets and their clinical application in migraine patients

The aim of this study was to prepare fast-disintegrating tablets (FDTs) of diclofenac potassium with sufficient integrity as well as a pleasant taste, using two different fillers and binders: Tablettose 70® and Di-Pac^®. Tablets were made with direct compression method. Tablet properties such as porosity, hardness, and disintegration time were determined. Diclofenac potassium determinations were carried out using a validated spectrophotometric method for the analysis of drug. Furthermore, in vivo experiments were carried out to compare the analgesic effect and the time to relieve migraine headache between the commercial tablets and FDTs of diclofenac potassium against placebo. Results showed that FDTs of diclofenac potassium with durable structure and desirable taste can be prepared using both fillers and binders but tablets prepared with Di-Pac had a better taste so the tablet formulation containing Di-Pac was chosen for in vivo experiments. Placebo controlled in vivo trial demonstrated that 50 mg diclofenac potassium, administered as a single dose of FDTs or commercial tablets, was effective in relieving the pain and both of them were superior to placebo.     

Design and development of a self-microemulsifying drug delivery system of olmesartan medoxomil for enhanced bioavailability

Olmesartan medoxomil (OM) is a hydrophobic antihypertensive drug with low bioavailability (26%) and is known to have adverse effects such as celiac disease and enteropathy. The purpose of this study was to develop SMEDDS to increase bioavailability and decrease potential side effects of OM. Hydrophilic lipophilic balance was calculated by testing solubility of OM in different oils, surfactants, and cosurfactants to obtain the most suitable combination of SMEDDS. Pseudoternary phase diagram was used to select the better oil/water formulation of SMEDDS. After a test for 3-month stability, dissolution tests and parallel artificial membrane permeability assay (PAMPA) were conducted to investigate drug solubility and permeability. Biodistribution of fluorescent marked SMEDDS was observed by using in vivo imaging system. The pharmacodynamics of the drug were determined by measuring blood pressure from tails of rats. At the end of the experiment, intestines were examined for adverse effects of OM. Compared with tablet formulation according to the dissolution study, SMEDDS formulation showed 1.67 times improvement in solubility of OM. PAMPA studies suggested a much faster permeability rate for OM SMEDDS compared to the suspension form. Labeled SMEDDS gave 3.96 times stronger fluorescent emission than control dye administered mice in in vivo imaging system (IVIS^®) studies, indicating an increased bioavailability. Treating effect of SMEDDS was 3.1 times more efficient compared to suspension in hypertensive rats. It caused neither celiac-like enteropathy nor diarrhea, during 21-day noninvasive blood pressure system (NIBP) assay. Our results suggest that SMEEDS formulation improves dissolution and oral bioavailability of OM while reducing its adverse effects.     

Application of hot melt extrusion for improving bioavailability of artemisinin a thermolabile drug

Hot melt extrusion has been used to produce a solid dispersion of the thermolabile drug artemisinin. Formulation and process conditions were optimized prior to evaluation of dissolution and biopharmaceutical performance. Soluplus^®, a low T_g amphiphilic polymer especially designed for solid dispersions enabled melt extrusion at 110?°C although some drug-polymer incompatibility was observed. Addition of 5% citric acid as a pH modifier was found to suppress the degradation. The area under plasma concentration time curve (AUC_0–24h) and peak plasma concentration (C_max) were four times higher for the modified solid dispersion compared to that of pure artemisinin.     

Influences of copolymers (Copovidone,Eudragit RL PO and Kollicoat MAE 30 DP) on stability and bioactivity of spray-dried and freeze-dried lysozyme

Protein stability is the most crucial factor in protein pharmaceutical preparations. Various techniques were applied for producing stable protein formulations such as spray-drying and freeze-drying. However, heating and freezing stresses are disadvantages for proteins using these methods, respectively. Accordingly, excipients have been used to preserve therapeutic effects of proteins during processing and for long period of time. Therefore, influences of Copovidone, Eudragit^® RL-PO and Kollicoat^® MAE-30 DP (as excipients) on stability and integrity of lysozyme (as a model protein) in spray-dried and freeze-dried forms were investigated. Protein formulations in both dried forms were prepared without and with the addition of mentioned excipients at different concentrations. Protein formulations were characterized for yield determination, morphology using scanning electron microscopic (SEM), thermal analysis by Differential Scanning Calorimetry (DSC), secondary structure stability using Fourier transform infrared (FT-IR) spectroscopy and biological activity. All protein formulations were subjected to a stability study as solid protein formulations for 3 weeks at 24?°C/76% relative humidity and aqueous protein samples were stored at 50?°C for 30?min in a water bath. Results showed that Copovidone successfully preserved integrity and biological activity of lysozyme before and after storage in both spray-dried and freeze-dried forms with more advantage for using higher concentration of the same excipient. Smooth spheres of spray-dried lysozyme formulations with Copovidone were smaller than spray-dried lysozyme without and with Kollicoat^® MAE-30 DP, which affected %yield produced. Copovidone has demonstrated valuable protection ability for lysozyme.     

Granulated colloidal silicon dioxide-based self-microemulsifying tablets,as a versatile approach in enhancement of solubility and therapeutic potential of anti-diabetic agent: formulation design and in vitro/in vivo evaluation

The current research work was executed with an aim to explore and promote the potential of self-microemusifying drug delivery systems (SMEDDS) in the form of tablets, in order to enhance solubility and oral bioavailability of poorly aqueous soluble drug Repaglinide (RPG). RPG-loaded liquid SMEDDS were developed consisting Labrafil M 1944CS, Kolliphor EL and Propylene glycol, which were then characterized on various parameters. After characterization and optimization, liquid SMEDDS were converted into solid form by adsorbing on Aeroperl® 300 pharma and polyplasdone^TM XL. Further, selection of suitable excipients was done and mixed with prepared solidified SMEDDS powder followed by the preparation of self-microemulsifying tablets (SMET’s) wet granulation–compression method. SMET’s were subjected to differential scanning calorimetry (DSC) and particle X-ray diffraction (RXRD) studies, results of which indicated transformation of crystalline structure of RPG because of dispersion of RPG at molecular level in liquid SMEDDS. This was further assured by micrographs obtained from scanning electron microscope. SMET’s shown more than 85% (30?min) of in vitro drug release in contrast to conventional marketed tablets (13.2%) and pure RPG drug (3.2%). Results of in vivo studies furnished that SMET’s had shown marked decrease in the blood glucose level and prolonged duration of action (up to 8?h) in comparison with conventional marketed tablets and pure RPG drug. In conclusion, SMET’s serves as a promising tool for successful oral delivery of poorly aqueous soluble drug(s) such as RPG.     

Luminescence of nano- and macrosized LaPO4:Ce,Tb excited by synchrotron radiation

Comparing the luminescence properties of nanosized and macroscopic LaPO₄:Ce,Tb powders are performed in wide spectral range using synchrotron radiation. In the present study, LaPO₄:Ce,Tb nanopowder was produced by means of a microwave-induced synthesis in ionic liquids, whereas the bulk sample represents a commercial lamp phosphor. Emission and excitation of both, Ce³⁺ and Tb³⁺ luminescence, is observed to be different when comparing bulk and nanosized LaPO₄:Ce,Tb. In particular, it was shown that the fine structure of the Ce³⁺ as well as the Tb³⁺ related emission is poorly resolved for the nanomaterial. It is suggested that the nanoparticles surface plays a key role regarding the perturbation of rare-earth ions and changes their luminescence properties. Furthermore, it is demonstrated that allowed f-d transitions on Tb³⁺ at high energy are significantly suppressed for nanosized LaPO₄:Ce,Tb. Energy transfer is required to initiate Tb³⁺ emission even in the vacuum ultraviolet spectral range.     

Optimization of hot melt extrusion parameters for sphericity and hardness of polymeric face-cut pellets

The aim of this study was to formulate face-cut, melt-extruded pellets, and to optimize hot melt process parameters to obtain maximized sphericity and hardness by utilizing Soluplus^® as a polymeric carrier and carbamazepine (CBZ) as a model drug. Thermal gravimetric analysis (TGA) was used to detect thermal stability of CBZ. The Box–Behnken design for response surface methodology was developed using three factors, processing temperature (?°C), feeding rate (%), and screw speed (rpm), which resulted in 17 experimental runs. The influence of these factors on pellet sphericity and mechanical characteristics was assessed and evaluated for each experimental run. Pellets with optimal sphericity and mechanical properties were chosen for further characterization. This included differential scanning calorimetry, drug release, hardness friability index (HFI), flowability, bulk density, tapped density, Carr’s index, and fourier transform infrared radiation (FTIR) spectroscopy. TGA data showed no drug degradation upon heating to 190?°C. Hot melt extrusion processing conditions were found to have a significant effect on the pellet shape and hardness profile. Pellets with maximum sphericity and hardness exhibited no crystalline peak after extrusion. The rate of drug release was affected mainly by pellet size, where smaller pellets released the drug faster. All optimized formulations were found to be of superior hardness and not friable. The flow properties of optimized pellets were excellent with high bulk and tapped density.     

Spectroscopic characterization and optical waveguide fabrication in Ce, Tb and Ce/Tb doped zinc–sodium–aluminosilicate glasses

A spectroscopy investigation of Ce³⁺ and Tb³⁺ ions in sodium–zinc–aluminosilicate glasses is performed using the photoluminescence technique. Blue–white light, with x = 0.24 and y = 0.24 CIE chromaticity coordinates, is obtained for the Tb³⁺ singly-doped glass excited at 351 nm. When the sodium–zinc–aluminosilicate glass is co-doped with Ce³⁺ and Tb³⁺ a non-radiative energy transfer from Ce³⁺ to Tb³⁺ ions is observed upon 320 nm excitation. From an analysis of the cerium emission decay curve, the Ce³⁺ → Tb³⁺ energy transfer microscopic parameter and efficiency are obtained. Different concentrations of Ce³⁺ and Tb³⁺ ions in the glass host gives rise to blue and blue–green emissions, with different CIE coordinates. Optical waveguides were produced in the samples by Ag⁺–Na⁺ ion-exchange, and their characterization is presented.     

Nifedipine molecular dispersion in microparticles of ammonio methacrylate copolymer and ethylcellulose binary blends for controlled drug delivery: effect of matrix composition

The objective of this study is to explore matrix-type microparticles, comprising a solid dispersion of drug with an ammonio methacrylate copolymer and ethylcellulose binary blend, for use in the controlled release of a poorly water-soluble drug, nifedipine. Microparticles consisting of an ethylcellulose N7 (N7) and Eudragit RL® (RL) binary blend at different ratios were prepared using phase-separation methodology. The effects of matrix composition on microparticle properties were evaluated by polarized light microscopy, differential scanning calorimetry (DSC), FT-infrared and UV-visible spectroscopy, stability, and drug release studies. Study results indicate that the particle size distribution, particle morphology, and drug release rate from the microparticles were influenced by the ratio of RL to N7. Discrete spherical microparticles with a narrow size distribution and a controlled release profile were obtained when the ratio of RL to N7 was in the range from 1:1 to 2:1 w/w. Solid-state characterization and release kinetic studies on these microparticles confirmed that the nifedipine release from the microparticles followed the Baker and Lonsdale's matrix diffusion model (1974) for microspheres containing dissolved drug, and the nifedipine diffusion in the microparticle matrix was the rate-limiting step. As the ratio of RL to N7 was changed from 0:1 to 4:1 w/w, the effective drug diffusion coefficient in the micro-matrix increased from 5.8 × 10^-10 to 8.6 × 10^-9 (cm²/h). In addition, probably due to formation of a stable molecular dispersion promoted by hydrogen bonding between nifedipine and the polymers, no significant changes in the nifedipine physical form or release kinetics were observed after 1-year storage at ambient room temperature followed by 3-month accelerated stability at 40°C/75% RH in a closed container.     

Effects of coating layer and release medium on release profile from coated capsules with Eudragit FS 30D: an in vitro and in vivo study

The aim of the present research was to evaluate the impact of coating layers on release profile from enteric coated dosage forms. Capsules were coated with Eudragit FS 30D using dipping method. The drug profile was evaluated in both phosphate buffer and Hank’s solutions. Utilization X-ray imaging, gastrointestinal transmission of enteric coated capsules was traced in rats. According to the results, no release of the drug was found at pH 1.2, and the extent of release drug in pH 6.8 medium was decreased by adding the coating layers. The results indicated single-layer coated capsules in phosphate buffer were significantly higher than that in Hank’s solution. However, no significant difference was observed from capsules with three coating layers in two different dissolution media. X-ray imaging showed that enteric coated capsules were intact in the stomach and in the small intestine, while disintegrated in the colon.     

Hydrogel containing dexamethasone-loaded nanocapsules for cutaneous administration: preparation,characterization, and in vitro drug release study

Context: Our group previously reported the development of dexamethasone-loaded polymeric nanocapsules as an alternative for topical dermatological treatments. Objective: Our study aimed to prepare and characterize a hydrogel containing this system to improve the effectiveness of the glucocorticoid for cutaneous disorders. Methods: For the antiproliferative activity assay, a dexamethasone solution and D-NC were tested on Allium cepa root meristem model. D-NC were prepared by the interfacial deposition of preformed polymer. Hydrogels were prepared using Carbopol Ultrez® 10 NF, as polymer, and characterized according to the following characteristics: pH, drug content, spreadability, viscosity, and in vitro drug release. Results and Discussion: Nanocapsules showed mean particle size and zeta potential of 201 ± 6 and ?5.73 ± 0.42 nm, respectively. They demonstrated a lower mitotic index (4.62%) compared to free dexamethasone (8.60%). Semisolid formulations presented acidic pH values and adequate drug content (between 5.4% and 6.1% and 100% and 105%, respectively). The presence of nanocapsules in hydrogels led to a decrease in their spreadability factor. Intact nanoparticles were demonstrated by TEM as well as by dynamic light scattering (mean particle size < 300 nm). In vitro studies showed a controlled dexamethasone release from hydrogels containing the drug associated to the nanocapsules following the Higuchi's squared root model (k = 20.21 ± 2.96 mg/cm²/h^1/2) compared to the hydrogels containing the free drug (k = 26.65 ± 2.09 mg/cm²/h^1/2). Conclusion: Taking all these results together, the hydrogel containing D-NC represent a promising approach to treat antiproliferative-related dermatological disorders.     

Nanorods of white light emitting Sr2SiO4:Eu2+: microemulsion-based synthesis,EPR, photoluminescence,and thermoluminescence studies

White light emitting Sr₂SiO₄:Eu²⁺ nanoparticles were prepared using reverse micellar route using Tergitol as a surfactant. The systems were characterised by X-ray diffraction, scanning electron microscopy (SEM), photoluminescence, thermoluminescence (TL), and electron paramagnetic resonance (EPR) spectroscopy. SEM shows the formation of silicate nanorods. Two emission bands of bluish-green at 490 nm (S(I)) and of orange-red at 605 nm (S(II)) were observed. The two emission bands are assigned to the 4f–5d transition of Eu²⁺ ions in two different cation sites in α′-Sr₂SiO₄ orthorhombic lattices. Gamma-irradiated Sr₂SiO₄:Eu showed the presence of three TL glow peaks at 437, 487 K and weak peak at 540 K; however, no glow was observed in the undoped sample. Reduction of Eu³⁺ to Eu²⁺ is confirmed by EPR spectroscopy.     

Enhanced G4 emission in NaLaF4: Pr, Yb and charge transfer in NaLaF4: Ce, Yb studied by fourier transform luminescence spectroscopy

A high resolution luminescence study of NaLaF₄: 1%Pr³⁺, 5%Yb³⁺ and NaLaF₄: 1%Ce³⁺, 5%Yb³⁺ in the UV to NIR spectral range using a InGaAs detector and a fourier transform interferometer is reported. Although the Pr³⁺(³P₀ → ¹G₄), Yb³⁺(²F_7/2 → ²F_5/2) energy transfer step takes place, significant Pr³⁺¹G₄ emission around 993, 1330 and 1850 nm is observed. No experimental proof for the second energy transfer step in the down-conversion process between Pr³⁺ and Yb³⁺ can be given. In the case of NaLaF₄: Ce³⁺, Yb³⁺ it is concluded that the observed Yb³⁺ emission upon Ce³⁺ 5d excitation is the result of a charge transfer process instead of down-conversion.     

Mesoporous Au/TiO2 composites preparation,characterization, and photocatalytic properties

In this work, mesoporous Au/TiO₂ composites have been synthesized and tested on photodegradation of methylene blue dye solution. Mesoporous TiO₂ prepared at 450 °C using triblock polymer F127 as structure-directing agent was applied as substrate, while various HAuCl₄ concentrations were used for Au loading through deposition-precipitation method using urea as precipitator and hydrogen reducing process. The influences of Au loading on the microstructures of mesoporous TiO₂ including degree of dispersion, particle size, surface area, light absorption, and band gap were studied with transmission electron microscopy (TEM), X-ray diffraction (XRD), diffuse reflection infrared Fourier transformed spectroscopy (DRIFT), N₂ adsorption–desorption isotherm analysis (BET), and UV–Vis diffuse reflectance spectra. With Au loading, the size of TiO₂ nanoparticles in Au/TiO₂ composites is similar as that of TiO₂ substrate. However, the degree of dispersion was greatly improved. Furthermore, an obvious surface plasmon resonance centered at 570 nm was found in UV–Vis diffuse reflectance spectra for Au/TiO₂ composites. Au loading also induced an obvious red shift of light absorption from UV region to visible region and strengthened both UV and visible light absorption in contrast to substrate. Photodegradation results verified that photocatalytic activity of mesoporous TiO₂ was improved by Au loading. 0.25%Au/TiO₂ composite showed the highest activity, which may be ascribed to its high surface hydroxyl content and the formed Schottky junction after Au loading. These results suggested that noble metal modification is a promising way to synthesize photocatalysts with both high activity and visible light sensitivity.     

The blue-light emission enhancement mechanism of Eu in Eu, Dy: SiO2 matrix

A Eu, Dy co-doped SiO₂ matrix xerogel with blue emission was prepared by the sol–gel method. Strong blue emission located between 425 nm and 525 nm with a peak at 486 nm is observed under UV laser excitation at room temperature, which is related to a 4f → 5d energy transition of Eu²⁺. Such techniques as FT-IR and TGA–DSC were used to measure the microstructure of the luminescent materials. The influence of Dy³⁺ ions on the luminescent property of Eu²⁺ was investigated. The emission intensity of Eu, Dy-codoped samples is stronger than that of Eu doped samples. The emission enhancement mechanism relating to Eu²⁺ is attributed to an energy transfer involving Dy³⁺ → Eu²⁺. Using energy transition theory, we speculate that the mechanism may be one of the resonance transfers via multi-polar interactions, and present a possible energy transfer model. The Eu²⁺ blue emission intensity reaches the maximum when the Dy³⁺ concentration is 0.1 mol%. When the concentration of Dy³⁺ is 0.3 mol%, a fluorescence quenching appears which might be related to the overlap part of Eu²⁺ excitation and emission levels, and also suggests the existence of Eu²⁺ → Eu²⁺ energy transfer.