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1.  A Comparative Evaluation of Mono-, Di- and Triglyceride of Medium Chain Fatty Acids by Lipid/Surfactant/Water Phase Diagram, Solubility Determination and Dispersion Testing for Application in Pharmaceutical Dosage Form Development 
Pharmaceutical Research  2011;29(1):285-305.
ABSTRACT
Purpose
To compare physiochemical properties of mono-, di- and triglycerides of medium chain fatty acids for development of oral pharmaceutical dosage forms of poorly water-soluble drugs using phase diagrams, drug solubility, and drug dispersion experiments.
Methods
Phase diagrams were prepared using a monoglyceride (glycerol monocaprylocaprate: Capmul MCM® EP), a diglyceride (glycerol dicaprylate) and two triglycerides (glycerol tricaprylate: Captex 8000®; caprylic/capric triglycerides: Captex 355 EP/NF®) in combination with a common surfactant (PEG-35 castor oil: Cremophor EL®) and water. Psuedoternary phase diagrams using mixtures of monoglyceride with either diglyceride or triglyceride were constructed to determine any potential advantage of using lipid mixtures.
Result
The monoglyceride gave microemulsion (clear or translucent liquid) and emulsion phases, whereas di- and triglycerides exhibited an additional gel phase. Among individual mono-, di- and triglycerides, the oil-in-water microemulsion region was the largest for the diglyceride. Gel phase region within diglyceride and triglyceride phase diagrams could be practically eliminated and microemulsion regions expanded by mixing monoglyceride with di- or tri-glycerides (1:1). Addition of a model drug, danazol, had no effect on particle sizes of microemulsions formed. Dispersion of drug in aqueous media from mixtures of mono- and diglyceride or mono- and triglyceride was superior to individual lipids.
Conclusion
Systematic study on comparison of mono-, di- and triglyceride of medium chain fatty acids will help formulators select components for optimal lipid-based formulation.
doi:10.1007/s11095-011-0541-3
PMCID: PMC3246583  PMID: 21861203
danazol; diglyceride; drug dispersion; drug solubility; lipid-based drug delivery; medium chain lipid; monoglyceride; phase diagram; triglyceride
2.  Stability of Lyophilized siRNA Nanosome Formulations 
The goal of this study is to evaluate the stability of lyophilized siRNA formulations. The gene silencing efficiency of a stored lyophilized siRNA formulation (i.e. siRNA nanosomes) was evaluated in interferon-α (IFN-α) resistant hepatitis C virus (HCV) at different time points up to three months in an in vitro cell culture model and compared with freshly prepared siRNA formulations. Novel siRNA sequences were encapsulated within nanosize liposomes following condensation with protamine sulfate. The siRNA encapsulated nanosomes were lyophilized and stored at 4°C for 3 months, along with liquid liposomes (L) and lyophilized liposome powder (P) which were subsequently used to prepare siRNA nanosomes (L) and siRNA nanosomes (P), respectively at different time points. Physiochemical and biological properties of all three formulations were compared at different time points up to 3 months. The particle size of the stored siRNA nanosomes (642±25 nm) was considerably larger initially in comparison with the liquid liposomes (134±5 nm) and lyophilized liposomes (118±3). However, the particle size gradually became smaller over time (413±128 nm by the third month). The zeta potential of all three formulations was initially very high (> +40 mV), followed by a gradual decrease over time. The amount of siRNA in the stored siRNA nanosomes decreased ~ 18% during the 3 month storage period (1.16±0.03 nmol initially on day 1 vs. 0.95±0.04 nmol after 3 months). With respect to biological potency, all three formulations were significantly effective to knock-down HCV throughout the storage time. The cell viability was well-maintained throughout this period. Thus, this study indicates that the stored lyophilized siRNA formulation is as effective as the fresh preparation and that long-term storage could be a viable option to treat deadly diseases such as cancer and viral infection.
doi:10.1016/j.ijpharm.2011.11.040
PMCID: PMC3298087  PMID: 22172291
siRNA delivery; Hepatitis C virus; Nanosome; Lyophilization; Stability
3.  Novel vehicle based on cubosomes for ophthalmic delivery of flurbiprofen with low irritancy and high bioavailability 
Acta Pharmacologica Sinica  2010;31(8):990-998.
Aim:
To develop a novel vehicle based on cubosomes as an ophthalmic drug delivery system for flurbiprofen (FB) to reduce ocular irritancy and improve bioavailability.
Methods:
FB-loaded cubosomes were prepared using hot and high-pressure homogenization. Cubosomes were then characterized by particle size, zeta potential, encapsulation efficiency, particle morphology, inner cubic structure and in vitro release. Corneal permeation was evaluated using modified Franz-type cells. Ocular irritation was then evaluated using both the Draize method and histological examination. The ocular pharmacokinetics of FB was determined using microdialysis.
Results:
The particle size of each cubosome formulation was about 150 nm. A bicontinuous cubic phase of cubic P-type was determined using cryo-transmission electron microscopy (cryo-TEM) observation and small angle X-ray scattering (SAXS) analysis. In vitro corneal permeation study revealed that FB formulated in cubosomes exhibited 2.5-fold (F1) and 2.0-fold (F2) increase in Papp compared with FB PBS. In the ocular irritation test, irritation scores for each group were less than 2, indicating that all formulations exhibited excellent ocular tolerance. Histological examination revealed that neither the structure nor the integrity of the cornea was visibly affected after incubation with FB cubosomes. The AUC of FB administered as FB cubosome F2 was 486.36±38.93 ng·mL−1·min·μg−1, which was significantly higher than that of FB Na eye drops (P<0.01). Compared with FB Na eye drops, the Tmax of FB cubosome F2 was about 1.6-fold higher and the MRT was also significantly longer (P<0.001).
Conclusion:
This novel low-irritant vehicle based on cubosomes might be a promising system for effective ocular drug delivery.
doi:10.1038/aps.2010.98
PMCID: PMC4007820  PMID: 20686524
flurbiprofen; cubosomes; ocular drug delivery systems; corneal permeability; ocular irritation
4.  Green biosynthesis of silver nanoparticles using Curcuma longa tuber powder 
Green synthesis of noble metal nanoparticles is a vastly developing area of research. Metallic nanoparticles have received great attention from chemists, physicists, biologists, and engineers who wish to use them for the development of a new-generation of nanodevices. In this study, silver nanoparticles were biosynthesized from aqueous silver nitrate through a simple and eco-friendly route using Curcuma longa tuber-powder extracts, which acted as a reductant and stabilizer simultaneously. Characterizations of nanoparticles were done using different methods, which included ultraviolet-visible spectroscopy, powder X-ray diffraction, transmission electron microscopy, scanning electron microscopy, energy-dispersive X-ray fluorescence spectrometry, and Fourier-transform infrared spectroscopy. The ultraviolet-visible spectrum of the aqueous medium containing silver nanoparticles showed an absorption peak at around 415 nm. Transmission electron microscopy showed that mean diameter and standard deviation for the formation of silver nanoparticles was 6.30 ± 2.64 nm. Powder X-ray diffraction showed that the particles are crystalline in nature, with a face-centered cubic structure. The most needed outcome of this work will be the development of value-added products from C. longa for biomedical and nanotechnology-based industries.
doi:10.2147/IJN.S36786
PMCID: PMC3546626  PMID: 23341739
silver nanoparticles; Curcuma longa; biosynthesis; green synthesis; transmission electron microscopy
5.  Absorption of Cholesterol from a Micellar Solution: Intestinal Perfusion Studies in Man* 
Journal of Clinical Investigation  1967;46(5):874-890.
The absorption of cholesterol has been studied in man by perfusing the upper jejunum with a micellar solution of bile salt, 1-monoglyceride, and cholesterol-14C, with a triple lumen tube with collection sites 50 cm apart. The absorption of micellar components between the collection sites was calculated from their concentration changes relative to those of the watersoluble marker, polyethylene glycol. Control experiments were performed with cholesterol-free perfusions of saline or bile salt-monoglyceride solutions. Steady state conditions were obtained.
Each of the components of the micelle was absorbed to a different extent during passage through the test segment of jejunum. Bile salt was not absorbed (mean, -3%), but micellar monoglyceride was rapidly hydrolyzed and absorbed almost completely (mean, 98%). Cholesterol radioactivity was absorbed to an intermediate extent (mean, 73%), and the absorption of chemically determined cholesterol (mean, 46%) indicated that much of the disappearance of radioactivity represented true absorption and not simple exchange.
The specific activity of the perfused cholesterol fell during passage through the loop. This fall was interpreted as signifying the continuous addition of nonradioactive endogenous cholesterol by the test segment. However, the decrease in specific activity may also be considered to signify exchange, in that nonradioactive molecules entered the lumen as radioactive molecules were absorbed. Plant sterols appeared in the intestinal contents during the perfusion and must have been contributed by the perfused segment.
The perfusate and samples taken from the upper and lower collection sites were examined by ultracentrifugation to define the physical state of cholesterol. It was found that cholesterol in the perfusate or upper collection site samples did not sediment, but that 23% of the cholesterol in the lower collection site samples was sedimentable (mean of three experiments); bile salt, as control, was not sedimentable. Solubility experiments in model systems showed that cholesterol possessed low solubility in bile salt solution; its solubility increased markedly and in linear proportion to the amount of fatty acid or monoglyceride or both that was added to the bile salt solution. These findings suggest that polar lipid such as fatty acid or monoglyceride as well as bile salt is essential for normal micellar solubilization of cholesterol in intestinal content. They suggest the necessity of considering an insoluble sedimentable phase of particulate sterol in intestinal content as well as an oil and micellar phase for a complete description of sterol absorption.
The marked difference in the rates of absorption of individual micellar components suggests that micellar lipid is not absorbed as an intact aggregate and is consistent with the view that polar lipid such as fatty acid is absorbed in molecular form by diffusion from a micellar solution. The experiments confirm previous findings demonstrating that fat absorption without bile salt absorption occurs in the upper small intestine in man.
Images
PMCID: PMC297089  PMID: 6025488
6.  Impact of agglomeration state of nano- and submicron sized gold particles on pulmonary inflammation 
Background
Nanoparticle (NP) toxicity testing comes with many challenges. Characterization of the test substance is of crucial importance and in the case of NPs, agglomeration/aggregation state in physiological media needs to be considered. In this study, we have addressed the effect of agglomerated versus single particle suspensions of nano- and submicron sized gold on the inflammatory response in the lung. Rats were exposed to a single dose of 1.6 mg/kg body weight (bw) of spherical gold particles with geometric diameters of 50 nm or 250 nm diluted either by ultrapure water or by adding phosphate buffered saline (PBS). A single dose of 1.6 mg/kg bw DQ12 quartz was used as a positive control for pulmonary inflammation. Extensive characterization of the particle suspensions has been performed by determining the zetapotential, pH, gold concentration and particle size distribution. Primary particle size and particle purity has been verified using transmission electron microscopy (TEM) techniques. Pulmonary inflammation (total cell number, differential cell count and pro-inflammatory cytokines), cell damage (total protein and albumin) and cytotoxicity (alkaline phosphatase and lactate dehydrogenase) were determined in bronchoalveolar lavage fluid (BALF) and acute systemic effects in blood (total cell number, differential cell counts, fibrinogen and C-reactive protein) 3 and 24 hours post exposure. Uptake of gold particles in alveolar macrophages has been determined by TEM.
Results
Particles diluted in ultrapure water are well dispersed, while agglomerates are formed when diluting in PBS. The particle size of the 50 nm particles was confirmed, while the 250 nm particles appear to be 200 nm using tracking analysis and 210 nm using TEM. No major differences in pulmonary and systemic toxicity markers were observed after instillation of agglomerated versus single gold particles of different sizes. Both agglomerated as well as single nanoparticles were taken up by macrophages.
Conclusion
Primary particle size, gold concentration and particle purity are important features to check, since these characteristics may deviate from the manufacturer's description. Suspensions of well dispersed 50 nm and 250 nm particles as well as their agglomerates produced very mild pulmonary inflammation at the same mass based dose. We conclude that single 50 nm gold particles do not pose a greater acute hazard than their agglomerates or slightly larger gold particles when using pulmonary inflammation as a marker for toxicity.
doi:10.1186/1743-8977-7-37
PMCID: PMC3014867  PMID: 21126342
7.  Differences in estimates of size distribution of beryllium powder materials using phase contrast microscopy, scanning electron microscopy, and liquid suspension counter techniques 
Accurate characterization of the physicochemical properties of aerosols generated for inhalation toxicology studies is essential for obtaining meaningful results. Great emphasis must also be placed on characterizing particle properties of materials as administered in inhalation studies. Thus, research is needed to identify a suite of techniques capable of characterizing the multiple particle properties (i.e., size, mass, surface area, number) of a material that may influence toxicity. The purpose of this study was to characterize the morphology and investigate the size distribution of a model toxicant, beryllium. Beryllium metal, oxides, and alloy particles were aerodynamically size-separated using an aerosol cyclone, imaged dry using scanning electron microscopy (SEM), then characterized using phase contrast microscopy (PCM), a liquid suspension particle counter (LPC), and computer-controlled SEM (CCSEM). Beryllium metal powder was compact with smaller sub-micrometer size particles attached to the surface of larger particles, whereas the beryllium oxides and alloy particles were clusters of primary particles. As expected, the geometric mean (GM) diameter of metal powder determined using PCM decreased with aerodynamic size, but when suspended in liquid for LPC or CCSEM analysis, the GM diameter decreased by a factor of two (p < 0.001). This observation suggested that the smaller submicrometer size particles attached to the surface of larger particles and/or particle agglomerates detach in liquid, thereby shifting the particle size distribution downward. The GM diameters of the oxide materials were similar regardless of sizing technique, but observed differences were generally significant (p < 0.001). For oxides, aerodynamic cluster size will dictate deposition in the lung, but primary particle size may influence biological activity. The GM diameter of alloy particles determined using PCM became smaller with decreasing aerodynamic size fraction; however, when suspended in liquid for CCSEM and LPC analyses, GM particle size decreased by a factor of two (p < 0.001) suggesting that alloy particles detach in liquid. Detachment of particles in liquid could have significance for the expected versus actual size (and number) distribution of aerosol delivered to an exposure subject. Thus, a suite of complimentary analytical techniques may be necessary for estimating size distribution. Consideration should be given to thoroughly understanding the influence of any liquid vehicle which may alter the expected aerosol size distribution.
doi:10.1186/1743-8977-4-3
PMCID: PMC1810321  PMID: 17328812
8.  The role of curvature in silica mesoporous crystals 
Interface Focus  2012;2(5):634-644.
Silica mesoporous crystals (SMCs) offer a unique opportunity to study micellar mesophases. Replication of non-equilibrium mesophases into porous silica structures allows the characterization of surfactant phases under a variety of chemical and physical perturbations, through methods not typically accessible to liquid crystal chemists. A poignant example is the use of electron microscopy and crystallography, as discussed herein, for the purpose of determining the fundamental role of amphiphile curvature, namely mean curvature and Gaussian curvature, which have been extensively studied in various fields such as polymer, liquid crystal, biological membrane, etc. The present work aims to highlight some current studies devoted to the interface curvature on SMCs, in which electron microscopy and electron crystallography (EC) are used to understand the geometry of silica wall surface in bicontinuous and cage-type mesostructures through the investigation of electrostatic potential maps. Additionally, we show that by altering the synthesis conditions during the preparation of SMCs, it is possible to isolate particles during micellar mesophase transformations in the cubic bicontinuous system, allowing us to view and study epitaxial relations under the specific synthesis conditions. By studying the relationship between mesoporous structure, interface curvature and micellar mesophases using electron microscopy and EC, we hope to bring new insights into the formation mechanism of these unique materials but also contribute a new way of understanding periodic liquid crystal systems.
doi:10.1098/rsfs.2011.0098
PMCID: PMC3438573  PMID: 24098848
silica mesoporous crystals; mean curvature; Gaussian curvature; surfactant packing parameter; electron crystallography
9.  CRYSTALLIZATION OF SYNTHETIC HAEMOZOIN (β-HAEMATIN) NUCLEATED AT THE SURFACE OF LIPID PARTICLES 
Summary
The mechanism of formation of haemozoin, a detoxification by-product of several blood-feeding organisms including malaria parasites, has been a subject of debate; however, recent studies suggest that neutral lipids may serve as a catalyst. In this study, a model system consisting of an emulsion of neutral lipid particles was employed to investigate the formation of β-haematin, the synthetic counterpart of haemozoin, at the lipid-water interface. A solution of monoglyceride, either monostearoylglycerol (MSG) or monopalmitoylglycerol (MPG), dissolved in acetone and methanol was introduced to an aqueous surface. Fluorescence, confocal and transmission electron microscopic (TEM) imaging and dynamic light scattering analysis of samples obtained from beneath the surface confirmed the presence of homogeneous lipid particles existing in two major populations: one in the low micrometer size range and the other in the hundred nanometre range. The introduction of haem (Fe(III)PPIX) to this lipid particle system under biomimetic conditions (37 °C, pH 4.8) produced β-haematin with apparent first order kinetics and an average half life of 0.5 min. TEM of monoglycerides (MSG or MPG) extruded through a 200 nm filter with haem produced β-haematin crystals aligned and parallel to the lipid/water interface. These TEM data, together with a model system replacing the lipid with an aqueous organic solvent interface using either methyl laurate or docosane demonstrated that the OH and C=O groups are apparently necessary for efficient nucleation. This suggests that β-haematin crystallizes via epitaxial nucleation at the lipid-water interface through interaction of Fe(III)PPIX with the polar head group. Once nucleated, the crystal grows parallel to the interface until growth is terminated by the curvature of the lipid particle. The hydrophobic nature of the mature crystal favours an interior transport resulting in crystals aligned parallel to the lipid-water interface and each other, strikingly similar to that seen in malaria parasites.
doi:10.1039/b914359a
PMCID: PMC2889375  PMID: 20104349
10.  Synthesis of silver/montmorillonite nanocomposites using γ-irradiation 
Silver nanoparticles (Ag-NPs) were synthesized into the interlamellar space of montmorillonite (MMT) by using the γ-irradiation technique in the absence of any reducing agent or heat treatment. Silver nitrate and γ-irradiation were used as the silver precursor and physical reducing agent in MMT as a solid support. The MMT was suspended in the aqueous AgNO3 solution, and after the absorption of silver ions, Ag+ was reduced using the γ-irradiation technique. The properties of Ag/MMT nanocomposites and the diameters of Ag-NPs were studied as a function of γ-irradiation doses. The interlamellar space limited particle growth (d-spacing [ds] = 1.24–1.42 nm); powder X-ray diffraction and transmission electron microscopy (TEM) measurements showed the production of face-centered cubic Ag-NPs with a mean diameter of about 21.57–30.63 nm. Scanning electron microscopy images indicated that there were structure changes between the initial MMT and Ag/MMT nanocomposites under the increased doses of γ-irradiation. Furthermore, energy dispersive X-ray fluorescence spectra for the MMT and Ag/ MMT nanocomposites confirmed the presence of elemental compounds in MMT and Ag-NPs. The results from ultraviolet-visible spectroscopy and TEM demonstrated that increasing the γ-irradiation dose enhanced the concentration of Ag-NPs. In addition, the particle size of the Ag-NPs gradually increased from 1 to 20 kGy. When the γ-irradiation dose increased from 20 to 40 kGy, the particle diameters decreased suddenly as a result of the induced fragmentation of Ag-NPs. Thus, Fourier transform infrared spectroscopy suggested that the interactions between Ag-NPs with the surface of MMT were weak due to the presence of van der Waals interactions. The synthesized Ag/MMT suspension was found to be stable over a long period of time (ie, more than 3 months) without any sign of precipitation.
doi:10.2147/IJN.S15033
PMCID: PMC3000206  PMID: 21170354
nanocomposites; silver nanoparticles; montmorillonite; γ-irradiation; powder X-ray diffraction
11.  Pharmacokinetics and enhanced oral bioavailability in beagle dogs of cyclosporine A encapsulated in glyceryl monooleate/poloxamer 407 cubic nanoparticles 
Efforts to improve the oral bioavailability of cyclosporine A (CyA) remains a challenge in the field of drug delivery. In this study, glyceryl monooleate (GMO)/poloxamer 407 cubic nanoparticles were evaluated as potential vehicles to improve the oral bioavailability of CyA. Cubic nanoparticles were prepared via the fragmentation of a bulk GMO/poloxamer 407 cubic phase gel by sonication and homogenization. The cubic inner structure formed was verified using Cryo-TEM. The mean diameters of the nanoparticles were about 180 nm, and the entrapment efficiency of these particles for CyA was over 85%. The in vitro release of CyA from these nanoparticles was less than 5% at 12 h. The results of a pharmacokinetic study in beagle dogs showed improved absorption of CyA from cubic nanoparticles as compared to microemulsion-based Neoral®; higher Cmax (1371.18 ± 37.34 vs 969.68 ± 176.3 ng mL−1), higher AUC0–t (7757.21 ± 1093.64 vs 4739.52 ± 806.30 ng h mL−1) and AUC0–∞ (9004.77 ± 1090.38 vs 5462.31 ± 930.76 ng h mL−1). The relative oral bioavailability of CyA cubic nanoparticles calculated on the basis of AUC0–∞ was about 178% as compared to Neoral®. The enhanced bioavailability of CyA is likely due to facilitated absorption by cubic nanoparticles rather than improved release.
PMCID: PMC2819904  PMID: 20161984
nanoparticles; cubosomes; cyclosporine A; glyceryl monooleate; oral drug delivery; bioavailability; beagle dogs
12.  Powder properties and their influence on dry powder inhaler delivery of an antitubercular drug 
AAPS PharmSciTech  2002;3(4):7-16.
The purpose of this study was to determine if aerosol delivery of drug loaded microparticles to lungs infected withMycobacterium tuberculosis may be achieved by predicting dispersion of dry powders through knowledge of particle surface properties. Particle sizes of rifampicin-loaded poly(lactide-co-glycolide) microparticles (R-PLGA), rifampicin alone, and lactose and maltodextrin carrier particles (bulk and 75-125-μm sieved fractions) were determined by electron microscopy for the projected area diameter (Dp) and laser diffraction for the volume diameter (Dv). Surface energies (Y) of R-PLGA, rifampicin alone, lactose, and maltodextrin were obtained by inverse phase gas chromatography, surface areas (Sa) by N2 adsorption, and cohesive energy densities by calculation. Particle dispersion was evaluated (Andersen nonviable impactor) for 10% blends of R-PLGA and rifampicin alone with bulk and sieved fractions of the carriers. Dp for R-PLGA and rifampicin alone was 3.02 and 2.83 μm, respectively. Dv was 13±1 and 2±1 μm for R-PLGA and rifampicin alone, respectively, indicating that R-PLGA was more aggregated. This was evident in Y of 35±1 and 19±6 mJ/m2 for R-PLGA and rifampicin alone. Dp for lactose and maltodextrin (sieved and bulk) was approximately 40 mm. Bulk maltodextrin (Dv=119±6 mm) was more aggregated than bulk lactose (Dv=54±2 mm). This was a result of the higher Sa for maltodextrin (0.54 m2/g) than for lactose (0.21 m2/g). The Y of bulk lactose and maltodextrin was 40±4 and 60±6 mJ/m2 and of sieved lactose and maltodextrin was 39±1 and 50±1 mJ/m2. Impaction studies yielded higher fine particle fractions of R-PLGA from sieved lactose, 13%±3%, than from sieved maltodextrin, 7%±1%, at 90 L/min. An expression, based on these data, is proposed as a predictor of drug dispersion from carrier particles.
Delivery of dry powder formulations can be achieved by characterizing particle surfaces and predicting impact on dispersion.
doi:10.1208/pt030428
PMCID: PMC2751343  PMID: 12916922
surface energy; surface area; cohesive energy density; dry powder inhalers; aerosol dispersion
13.  Glyceryl Monooleate/Poloxamer 407 Cubic Nanoparticles as Oral Drug Delivery Systems: I. In Vitro Evaluation and Enhanced Oral Bioavailability of the Poorly Water-Soluble Drug Simvastatin 
AAPS PharmSciTech  2009;10(3):960-966.
Glyceryl monooleate (GMO)/poloxamer 407 cubic nanoparticles were investigated as potential oral drug delivery systems to enhance the bioavailability of the water-insoluble model drug simvastatin. The simvastatin-loaded cubic nanoparticles were prepared through fragmentation of the GMO/poloxamer 407 bulk cubic-phase gel using high-pressure homogenization. The internal structure of the cubic nanoparticles was identified by cryo-transmission electron microscopy. The mean diameter of the cubic nanoparticles varied within the range of 100–150 nm, and both GMO/poloxamer 407 ratio and theoretical drug loading had no significant effect on particle size and distribution. Almost complete entrapment with efficiency over 98% was achieved due to the high affinity of simvastatin to the hydrophobic regions of the cubic phase. Release of simvastatin from the cubic nanoparticles was limited both in 0.1 M hydrochloride solution containing 0.2% sodium lauryl sulfate and fasted-state simulated intestinal fluid with a total release of <3.0% at 10 h. Pharmacokinetic profiles in beagle dogs showed sustained plasma levels of simvastatin for cubic nanoparticles over 12 h. The relative oral bioavailability of simvastatin cubic nanoparticles calculated on the basis of area under the curve was 241% compared to simvastatin crystal powder. The enhancement of simvastatin bioavailability was possibly attributable to facilitated absorption by lipids in the formulation rather than improved release.
doi:10.1208/s12249-009-9292-4
PMCID: PMC2802151  PMID: 19636709
cubic nanoparticles; glyceryl monooleate; oral bioavailability; poloxamer 407; simvastatin
14.  Synthesis of Silver Nanoparticles Using Hydroxyl Functionalized Ionic Liquids and Their Antimicrobial Activity 
We report a new one phase method for the synthesis of uniform monodisperse crystalline Ag nanoparticles in aqueous systems that has been developed by using newly synthesized mono and dihydroxylated ionic liquids and cationic surfactants based on 1,3-disubstituted imidazolium cations and halogens anions. The hydroxyl functionalized ionic liquids (HFILs) and hydroxyl functionalized cationic surfactants (HFCSs) also simultaneously acts both as the reductant and protective agent. By changing the carbon chain length, alcohol structure and anion of the 1,3-imidazolium based HFILs and HFCSs the particle size, uniform and dispersibility of nanoparticles in aqueous solvents could be controlled. Transmission electron microscopy (TEM), electron diffraction, UV-Vis and NMR, were used for characterization of HFILs, HFCSs and silver nanoparticles. TEM studies on the solution showed representative spherical silver nanoparticles with average sizes 2–8 nm, particularly 2.2 nm and 4.5 nm in size range and reasonable narrow particle size distributions (SD-standard distribution) 0.2 nm and 0.5 nm respectively. The all metal nanoparticles are single crystals with face centered cubic (fcc) structure. The silver nanoparticles surface of plasmon resonance band (λmax) around 420 nm broadened and little moved to the long wavelength region that indicating the formation of silver nanoparticles dispersion with broad absorption around infrared (IR) region. Silver complexes of these HFILs as well as different silver nanoparticles dispersions have been tested in vitro against several gram positive and gram negative bacteria and fungus. The silver nanoparticles providing environmentally friendly and high antimicrobial activity agents.
doi:10.3390/ijms9050807
PMCID: PMC2635708  PMID: 19325785
Silver nanoparticles; hydroxyl functionalized ionic liquids; hydroxyl functionalized cationic surfactants; antimicrobial activity
15.  Optimized dispersion of nanoparticles for biological in vitro and in vivo studies 
Background
The aim of this study was to establish and validate a practical method to disperse nanoparticles in physiological solutions for biological in vitro and in vivo studies.
Results
TiO2 (rutile) dispersions were prepared in distilled water, PBS, or RPMI 1640 cell culture medium. Different ultrasound energies, various dispersion stabilizers (human, bovine, and mouse serum albumin, Tween 80, and mouse serum), various concentrations of stabilizers, and different sequences of preparation steps were applied. The size distribution of dispersed nanoparticles was analyzed by dynamic light scattering and zeta potential was measured using phase analysis light scattering. Nanoparticle size was also verified by transmission electron microscopy. A specific ultrasound energy of 4.2 × 105 kJ/m3 was sufficient to disaggregate TiO2 (rutile) nanoparticles, whereas higher energy input did not further improve size reduction. The optimal sequence was first to sonicate the nanoparticles in water, then to add dispersion stabilizers, and finally to add buffered salt solution to the dispersion. The formation of coarse TiO2 (rutile) agglomerates in PBS or RPMI was prevented by addition of 1.5 mg/ml of human, bovine or mouse serum albumin, or mouse serum. The required concentration of albumin to stabilize the nanoparticle dispersion depended on the concentration of the nanoparticles in the dispersion. TiO2 (rutile) particle dispersions at a concentration lower than 0.2 mg/ml could be stabilized by the addition of 1.5 mg/ml albumin. TiO2 (rutile) particle dispersions prepared by this method were stable for up to at least 1 week. This method was suitable for preparing dispersions without coarse agglomerates (average diameter < 290 nm) from nanosized TiO2 (rutile), ZnO, Ag, SiOx, SWNT, MWNT, and diesel SRM2975 particulate matter.
Conclusion
The optimized dispersion method presented here appears to be effective and practicable for preparing dispersions of nanoparticles in physiological solutions without creating coarse agglomerates.
doi:10.1186/1743-8977-5-14
PMCID: PMC2584664  PMID: 18990217
16.  Characterization of Wear Particles Generated from CoCrMo Alloy under Sliding Wear Conditions 
Biological effects of wear products (particles and metal ions) generated by metal-on-metal (MoM) hip replacements made of CoCrMo alloy remain a major cause of concern. Periprosthetic osteolysis, potential hypersensitivity response and pseudotumour formation are possible reactions that can lead to early revisions. To accurately analyse the biological response to wear particles from MoM implants, the exact nature of these particles needs to be characterized. Most previous studies used energy-dispersive X-ray spectroscopy (EDS) analysis for characterization. The present study used energy filtered transmission electron microscopy (TEM) and electron diffraction pattern analysis to allow for a more precise determination of the chemical composition and to gain knowledge of the crystalline structure of the wear particles.
Particles were retrieved from two different test rigs: a reciprocating sliding wear tribometer (CoCrMo cylinder vs. bar) and a hip simulator according to ISO 14242-1 (CoCrMo head vs. CoCrMo cup). All tests were conducted in bovine serum. Particles were retrieved from the test medium using a previously published enzymatic digestion protocol.
Particles isolated from tribometer samples had a size of 100 – 500 nm. Diffraction pattern analysis clearly revealed the lattice structure of strain induced hcp ε-martensite. Hip simulator samples revealed numerous particles of 15 – 30 nm and 30 – 80 nm size. Most of the larger particles appeared to be only partially oxidized and exhibited cobalt locally. The smallest particles were Cr2O3 with no trace of cobalt. It optically appeared that these Cr2O3 particles were flaking off the surface of larger particles that depicted a very high intensity of oxygen, as well as chromium, and only background noise of cobalt. The particle size difference between the two test rigs is likely related to the conditions of the two tribosystems, in particular the difference in the sample geometry and in the type of sliding (reciprocating vs. multidirectional).
Results suggest that there may be a critical particle size at which chromium oxidation and cobalt ionization is accelerated. Since earlier studies have shown that wear particles are covered by organic residue which may act as a passive layer inhibiting further oxidation, it would suggest that this organic layer may be removed during the particle isolation process, resulting in a change of the particle chemical composition due to their pyrophoric properties. However, prior to being isolated from the serum lubricant, particles remain within the contact area of head and cup as a third-body. It is therefore possible that during that time, particles may undergo significant transformation and changes in chemical composition in the contact area of the head and cup within the tribological interface due to mechanical interaction with surface asperities.
doi:10.1016/j.wear.2010.12.045
PMCID: PMC3144580  PMID: 21804652
Wear particles; hip joint; CoCrMo; Wear; TEM
17.  Synthesis and Characterization of Bicontinuous Cubic Poly(3,4-ethylene dioxythiophene) Gyroid (PEDOT GYR) Gels 
We describe the synthesis and characterization of bicontinuous cubic poly(3,4-ethylenedioxythiophene) (PEDOT) conducting polymer gels prepared within lyotropic cubic poly(oxyethylene)10 nonylphenol ether (NP-10) templates with Ia3̄d (gyroid, GYR) symmetry. The chemical polymerization of EDOT monomer in the hydrophobic channels of the NP-10 GYR phase was initiated by AgNO3, a mild oxidant that is activated when exposed to ultraviolet (UV) radiation. The morphology and physical properties of the resulting PEDOT gels were examined as a function of temperature and frequency using optical and electron microscopy, small angle X-ray scattering (SAXS), dynamic mechanical spectroscopy, and electrochemical impedance spectroscopy (EIS). Microscopy and SAXS results showed that the PEDOT gels remained ordered and stable after the UV-initiated chemical polymerization, confirming the successful templated-synthesis of PEDOT in bicontinuous GYR nanostructures. In comparison to unpolymerized 3,4-ethylenedioxythiophene (EDOT) gel phases, the PEDOT structures had a higher storage modulus, presumably due to the formation of semi-rigid PEDOT-rich nanochannels. Additionally, the G′ for PEDOT gels decreased only modestly with increasing temperature, from ~1.2 × 103 Pa (10 °C) to ~7 × 104 Pa (40 °C), whereas G′ for the NP-10 and EDOT gels decreased dramatically, from ~5.0 × 104 Pa (10 °C) to ~1.5 × 102 Pa (40 °C). EIS revealed that the impedance of the PEDOT gels was smaller than the impedance of EDOT gels at both high frequencies (PEDOT ~102 Ω and EDOT 2 – 3 × 103 Ω at 105 Hz) and low frequencies (PEDOT 103–105 Ω and EDOT ~5 × 105 Ω at 10−1 Hz). These results indicated that PEDOT gels were highly ordered, mechanically stable and electrically conductive, and thus should be of interest for applications for which such properties are important, including low impedance and compliant coatings for biomedical electrodes.
doi:10.1039/c4cp04426f
PMCID: PMC4319663  PMID: 25600651
PEDOT; bicontinuous cubic structures; conductive gels
18.  Insights from theory and experiments on slip flow in chromatography 
Journal of separation science  2013;36(12):1871-1876.
Slip flow has become a topic of interest in reversed-phase liquid chromatography because it gives a flow enhancement that facilitates the use of submicrometer particles, providing a large improvement in separation efficiency. Moreover, slip flow provides an additional improvement in efficiency by reducing the velocity distribution in the mobile phase. The phenomenon of slip flow in open tubes is described in chromatographically relative terms. A recent paper in this journal is discussed, as it provides the first theoretical study of slip flow in packed beds, in this case for face-centered cubic geometry. The theory paper reveals that the presence of the packed bed introduces a heterogeneity in fluid velocities that is absent in open tubes, reducing the additional improvement in efficiency from slip flow. The recent paper also suggests that there is yet another factor improving efficiency, which is size-exclusion of proteins from regions of stagnant flow. The latter is supported by recently published data on restricted protein diffusion in face-centered cubic silica colloidal crystals. Extremely low plate heights are enabled by use of submicrometer particles, and further improvement appears to be possible when the analyte size is on the order of 1% of the particle diameter or larger.
doi:10.1002/jssc.201300462
PMCID: PMC4107457  PMID: 23686940
Efficiency; face-centered cubic crystal (fcc); Protein; Slip
19.  Comparative analysis of inhaled particles contained in human bronchoalveolar lavage fluids, lung parenchyma and lymph nodes. 
Environmental Health Perspectives  1994;102(Suppl 5):257-259.
Translocation of inhaled particles from the alveolar spaces to lung parenchyma and lymph nodes is one of the mechanisms that determine the biopersistence of particles. This study compares the nonfibrous particulate burden in bronchoalveolar lavage (BAL) fluids, lung parenchyma, and thoracic lymph nodes and attempts to detect the degree of differentiation, if any, based on particle size or type. This comparison can only be done on BAL, lung parenchyma, and lymph node samples collected from the same subject over a short time. Patients undergoing surgical lung resection are suitable for this purpose. Particles recovered by digestion-filtration were counted, sized, and analyzed by analytical transmission electron microscopy. Total particle load ranges grossly between 10(5) to 10(7) p/ml in BAL, 10(9) to 10(10) p/g dry tissue in parenchyma and 10(10) to 10(11) p/g dry tissue in lymph nodes. Diameters are log-normally distributed and mean diameters range between 0.5 to 0.9 micron. Nonlamellar silicate particles have a significantly larger diameter in lymph nodes. Differences in particle type between the three sampling sites are small and nonsystematic.
PMCID: PMC1567249  PMID: 7882946
20.  Catharanthus roseus: a natural source for the synthesis of silver nanoparticles 
Objective
To develop a simple rapid procedure for bioreduction of silver nanoparticles (AgNPs) using aqueous leaves extracts of Catharanthus roseus (C. roseus).
Methods
Characterization were determined by using UV-Vis spectrophotometry, scanning electron microscopy (SEM), energy dispersive X-ray and X-ray diffraction.
Results
SEM showed the formation of silver nanoparticles with an average size of 67 nm to 48 nm. X-ray diffraction analysis showed that the particles were crystalline in nature with face centered cubic geometry.
Conclusions
C. roseus demonstrates strong potential for synthesis of silver nanoparticles by rapid reduction of silver ions (Ag+ to Ag0). This study provides evidence for developing large scale commercial production of value-added products for biomedical/nanotechnology-based industries.
doi:10.1016/S2221-1691(11)60041-5
PMCID: PMC3614229  PMID: 23569773
Nanoparticles; Nanotechnology; Silver; Catharanthus roseus
21.  Biocompatible Dispersion Methods for Carbon Black 
Toxicological Research  2012;28(4):209-216.
The biological activity of particles is largely dependent on their size in biological systems. Dispersion in the aqueous phase has been both a critical impediment to and a prerequisite for particle studies. Carbon black has been used as a surrogate to investigate the biological effects of carbonaceous particles. Here, biocompatible methods were established to disperse carbon black into ultrafine and fine particles which are generally distinguished by the small size of 100 nm. Carbon black with a distinct particle size, N330 and N990 were suspended in blood plasma, cell culture media, Krebs-Ringer’s solution (KR), or physiological salt solution (PSS). Large clumps were observed in all dispersion preparations; however, sonication improved dispersion - averaged particle sizes for N330 and N990 were 85.0 ± 42.9 and 112.4 ± 67.9 nm, respectively, in plasma; the corresponding sizes in culture media were 84.8 ± 38.4 and 164.1 ± 77.8 nm. However, sonication was not enough to disperse N330 less than 100 nm in either KR or PSS. Application of Tween 80 along with sonication reduced the size of N330 to less than 100 nm, and dispersed N990 larger than 100 nm (73.6 ± 28.8 and 80.1 ± 30.0 nm for N330 and 349.5 ± 161.8 and 399.8 ± 181.1 nm for N990 in KR and PSS, respectively). In contrast, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) exhibited little effect. Electron microscopy confirmed the typical aciniform structure of the carbon arrays; however, zeta potential measurement failed to explain the dispersibility of carbon black. The methods established in this study could disperse carbon black into ultrafine and fine particles, and may serve as a useful model for the study of particle toxicity, particularly size-related effects.
doi:10.5487/TR.2012.28.4.209
PMCID: PMC3834425  PMID: 24278612
Carbon black; Carbonaceous core; Particle dispersion; Biocompatible media; Ultrafine particles; Fine particles
22.  Assessing the accuracy of routine photon correlation spectroscopy analysis of heterogeneous size distributions 
AAPS PharmSciTech  2003;4(3):62-70.
The aim of the current study was to investigate the ability of a fixed-angle routine photon correlation spectrometer (PCS) to resolve bimodal size distributions. The focus was on dispersions consisting of a majority of smaller and a minority of bigger particles. Monodisperse latex beads of sizes from 21 to 269 nm were measured first as single-size dispersions and then with various binary blends. For single-size dispersions, the mean diameters obtained were as indicated by the manufacturer, except for 21- and 34-nm particles, which were somewhat smaller. PCS analysis of blends of 21+102-nm and 34+102-nm particles resulted in bimodal distributions with particle diameters of the 2 peaks in the expected magnitude down to critical blending ratios of 0.002% and 0.08% of bigger particles, respectively. At these ratios, PCS results became inconsistent, and an increased number of monomodal results and/or high residuals were seen. For 21+102-nm blends, at even smaller ratios (0.001%), more consistent results were obtained again with predominantly monomodal distributions in the size range of the smaller particles (ie, the bigger particles were neglected). PCS analysis of blends of 21+269-nm particles yielded bimodal distributions with diameters within the expected magnitude as long as the content of bigger particles did not exceed 0.005%. Above this ratio, predominantly monomodal results with mean diameters in the magnitude of the bigger particles were obtained (ie, the smaller particles were neglected). In conclusion, a routine PCS instrument can resolve bimodal size distributions of colloidal dispersions only at certain ratios of the 2 subpopulations. Both low and high ratios lead to 1 of the 2 subpopulations being neglected.
doi:10.1208/pt040336
PMCID: PMC2750629  PMID: 14621968
dynamic laser light scattering; quasielastic light scattering; latex colloids; particle size; size analysis
23.  Synthesis of silver nanoparticles using leaves of Catharanthus roseus Linn. G. Don and their antiplasmodial activities 
Objective
To develop a novel approach for the green synthesis of silver nanoparticles using aqueous leaves extracts of Catharanthus roseus (C. roseus) Linn. G. Don which has been proven active against malaria parasite Plasmodium falciparum (P. falciparum).
Methods
Characterizations were determined by using ultraviolet-visible (UV-Vis) spectrophotometry, scanning electron microscopy (SEM), energy dispersive X-ray and X-ray diffraction.
Results
SEM showed the formation of silver nanoparticles with an average size of 35–55 nm. X-ray diffraction analysis showed that the particles were crystalline in nature with face centred cubic structure of the bulk silver with the broad peaks at 32.4, 46.4 and 28.0.
Conclusions
It can be concluded that the leaves of C. roseus can be good source for synthesis of silver nanoparticle which shows antiplasmodial activity against P. falciparum. The important outcome of the study will be the development of value added products from medicinal plants C. roseus for biomedical and nanotechnology based industries.
doi:10.1016/S2221-1691(12)60100-2
PMCID: PMC3609350  PMID: 23569974
Silver nanoparticles; Catharanthus roseus; Plasmodium falciparum; Antiplasmodial activity
24.  Factors influencing the spatial extent of mobile source air pollution impacts: a meta-analysis 
BMC Public Health  2007;7:89.
Background
There has been growing interest among exposure assessors, epidemiologists, and policymakers in the concept of "hot spots", or more broadly, the "spatial extent" of impacts from traffic-related air pollutants. This review attempts to quantitatively synthesize findings about the spatial extent under various circumstances.
Methods
We include both the peer-reviewed literature and government reports, and focus on four significant air pollutants: carbon monoxide, benzene, nitrogen oxides, and particulate matter (including both ultrafine particle counts and fine particle mass). From the identified studies, we extracted information about significant factors that would be hypothesized to influence the spatial extent within the study, such as the study type (e.g., monitoring, air dispersion modeling, GIS-based epidemiological studies), focus on concentrations or health risks, pollutant under study, background concentration, emission rate, and meteorological factors, as well as the study's implicit or explicit definition of spatial extent. We supplement this meta-analysis with results from some illustrative atmospheric dispersion modeling.
Results
We found that pollutant characteristics and background concentrations best explained variability in previously published spatial extent estimates, with a modifying influence of local meteorology, once some extreme values based on health risk estimates were removed from the analysis. As hypothesized, inert pollutants with high background concentrations had the largest spatial extent (often demonstrating no significant gradient), and pollutants formed in near-source chemical reactions (e.g., nitrogen dioxide) had a larger spatial extent than pollutants depleted in near-source chemical reactions or removed through coagulation processes (e.g., nitrogen oxide and ultrafine particles). Our illustrative dispersion model illustrated the complex interplay of spatial extent definitions, emission rates, background concentrations, and meteorological conditions on spatial extent estimates even for non-reactive pollutants. Our findings indicate that, provided that a health risk threshold is not imposed, the spatial extent of impact for mobile sources reviewed in this study is on the order of 100–400 m for elemental carbon or particulate matter mass concentration (excluding background concentration), 200–500 m for nitrogen dioxide and 100–300 m for ultrafine particle counts.
Conclusion
First, to allow for meaningful comparisons across studies, it is important to state the definition of spatial extent explicitly, including the comparison method, threshold values, and whether background concentration is included. Second, the observation that the spatial extent is generally within a few hundred meters for highway or city roads demonstrates the need for high resolution modeling near the source. Finally, our findings emphasize that policymakers should be able to develop reasonable estimates of the "zone of influence" of mobile sources, provided that they can clarify the pollutant of concern, the general site characteristics, and the underlying definition of spatial extent that they wish to utilize.
doi:10.1186/1471-2458-7-89
PMCID: PMC1890281  PMID: 17519039
25.  Preparation and Characterization of Dexamethasone Microemulsion Based on Pseudoternary Phase Diagram 
Background
The increased incidence of inflammatory diseases has necessitated the need to search for new topical dosage form of dexamethasone.
Objectives
The purpose of the present study was the preparation and evaluation of novel microemulsion as a topical delivery system for dexamethasone by mixing appropriate amount of surfactant including Tween 80 and Labrasol, cosurfactant such as capryol 90 and oil phase including labrafac lipophile wl-transcutol P (10:1 ratio).
Materials and Methods
The prepared microemulsions were evaluated regarding their particle size, zeta potential, X-Ray scattering, conductivity, stability, viscosity, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), refractory index (RI), pH, and x-ray diffraction (XRD).
Results
The results showed that the maximum oil was incorporated in microemulsion system that contained surfactant to cosurfactant ratio of 4:1. The mean droplet size range of microemulsion formulation was in the range of 5.09 to 159 nm, and its refractory index (RI) and pH were 1.44 and 7, respectively. Viscosity range was 57-226 cps. Drug release profile showed that 48.18% of the drug released in the 24 hours of experiment. Also, Hexagonal, cubic and lamellar structures were seen in the SEM photograph and XRD peak of microemulsions.
Conclusions
This study demonstrated that physicochemical properties and in vitro release were dependent upon the contents of S/C, water, and oil percentage in formulations. SAXS technique and SEM obtained important information about microstructure of microemulsions. W/O and bicontinuous microemulsion with different microstructures were found in formulations.
PMCID: PMC3941903  PMID: 24624198
Dexamethasone; Emulsion; Calorimetry, Differential Scanning

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