Biomedical subjects

Nissim Garti

Publications and source records attributed to Nissim Garti.

13 recordsLinked to original sources

PubMed2006

Microemulsions as transdermal drug delivery vehicles.

Microemulsions are clear, stable, isotropic mixtures of oil, water, and surfactant, frequently in combination with a cosurfactant. Microemulsions have been intensively studied during the last decades by many scientists and technologists because of their great potential in many food and pharmaceutical applications. The use of microemulsions is advantageous not only due to the facile and low cost preparation, but also because of the improved bioavailability. The increased absorption of drugs in topical applications is attributed to enhancement of penetration through the skin by the carrier. Saturated and unsaturated fatty acids serving as an oil phase are frequently used as penetration enhancers. The most popular enhancer is oleic acid. Other permeation enhancers commonly used in transdermal formulations are isopropyl myristate, isopropyl palmitate, triacetin, isostearylic isostearate, R(+)-limonene and medium chain triglycerides. The most popular among the enhancing permeability surfactants are phospholipids that have been shown to enhance drug permeation in a different mode. l-alpha-phosphatidylcholine from egg yolk, l-alpha-phosphatidylcholine 60%, from soybean and dioleylphosphatidyl ethanolamine which are in a fluid state may diffuse into the stratum corneum and enhance dermal and transdermal drug penetration, while distearoylphosphatidyl choline which is in a gel-state has no such capability. Other very commonly used surfactants are Tween 20, Tween 80, Span 20, Azone, Plurol Isostearique and Plurol Oleique. As cosurfactants commonly serve short-chain alkanols such as ethanol and propylene glycol. Long-chain alcohols, especially 1-butanol, are known for their enhancing activity as well. Decanol was found to be an optimum enhancer among other saturated fatty alcohols that were examined (from octanol to myristyl alcohol). Many enhancers are concentration-dependent; therefore, optimal concentration for effective promotion should be determined. The delivery rate is dependent on the type of the drug, the structure and ingredients of the carrier, and on the character of the membrane in use. Each formulation should be examined very carefully, because every membrane alters the mechanism of penetration and can turn an enhancer to a retarder. Various potential mechanisms to enhance drug penetration through the skin include directly affecting the skin and modifying the formulation so the partition, diffusion, or solubility is altered. The combination of several enhancement techniques such as the use of iontophoresis with fatty acids leads to synergetic drug penetration and to decrease in skin toxicity. Selected studies of various microemulsions containing certain drugs including retinoic acid, 5-fluorouracil, triptolide, ascorbic acid, diclofenac, lidocaine, and prilocaine hydrochloride in transdermal formulations are presented in this review. In conclusion, microemulsions were found as an effective vehicle of the solubilization of certain drugs and as protecting medium for the entrapped of drugs from degradation, hydrolysis, and oxidation. It can also provide prolonged release of the drug and prevent irritation despite the toxicity of the drug. Yet, in spite of all the advantages the present formulations lack several key important characteristics such as cosmetic-permitted surfactants, free dilution in water capabilities, stability in the digestive tracts and sufficient solubilization capacity.

Administration, Cutaneous↗

PubMed2006

Fully dilutable microemulsions embedded with phospholipids and stabilized by short-chain organic acids and polyols.

Evidence on the role of phosphatidylcholine (PC) as a membrane permeability enhancer was the driving force in forming new liquid nanosized (modified microemulsions) oral delivery system containing PC molecules. In this study we have demonstrated the feasibility of constructing phase diagrams with a large isotropic regions capable of being fully diluted with water. The microemulsions were stabilized with mixtures composed of PC and nonionic surfactant (polyoxyethylene-40 hydrogenated castor oil, HECO40) and short-chain organic acid as cosurfactant/cosolvent. When propionic acid served as the cosurfactant/cosolvent, the isotropic region was at its maximum (ca. 72% of the total phase diagram area). The presence of a blend of PC and HECO40 seems to have synergistic effects, forming an isotropic region comprising 72% of the area of the phase diagram, in comparison to 20 and 50% in systems stabilized by PC and HECO40, alone, respectively. The role of the PC molecules in the formation of those microemulsions is demonstrated by comparing three soy lecithins. Lecithin with a high PC content forms larger isotropic regions with more "free dilution" lines. Several nonionic surfactants have been investigated, yet only HECO40 seems to have a packing parameter suitable for the formation of large isotropic U-type systems.

Administration, Oral↗

PubMed2006

Improved solubilization of Celecoxib in U-type nonionic microemulsions and their structural transitions with progressive aqueous dilution.

Celecoxib (clxb) is an important drug for treatment of rheumatoid arthritis and osteoarthritis by specifically inhibiting the enzyme cyclooxygenase-2 (COX-2). Clxb is a type 2 drug characterized by low water solubility (<5 mug/ml) and fast transmembrane transport. The present formulations require high dosage since the transmembrane transport fluctuates and is very difficult to control. Dissolving the drug within an oil phase was not practical since its dissolution was very small and its dispersion in water was impossible. In our recent studies, we learned to construct U-type phase diagrams and to formulate reverse microemulsions (oil-based concentrates) that are progressively and fully dilutable with aqueous phase. In the present study, we solubilized clxb in nanostructures of reverse micelles of U-type nonionic microemulsions that consisted of R(+)-limonene, alcohol, propylene glycol (PG), and hydrophilic surfactant (Tween 60). The solubilization capacity of the drug in these systems is many times higher than in either the oil or the aqueous phase. The clxb solubilized microemulsions are fully diluted with aqueous phase without phase separation. The solubilization capacity decreases as the water content increases. Electrical conductivity, viscosity, and self-diffusion (SD) coefficients of the microemulsion components were measured along a suitable water dilution line. The three major microemulsion regions were detected and the transitions between the W/O to bicontinuous phase and from this phase to the O/W droplets were identified (at 30 and 70 wt% aqueous phase, respectively). From the SD coefficients, it was found that the drug is initially solubilized at the interface of the W/O droplets and there are no significant structural changes. The transition to a bicontinuous phase occurs at the same water content as in the empty (i.e., without drug) system. From the viscosity profiles, we concluded that the drug affects the structure of the bicontinuous phase as reflected in the water content at which the oil-continuous network is destroyed and full inversion occurs (50 vs 55 wt% in the drug-loaded system). Upon further dilution the drug remains solubilized at the interface and is oriented with its hydrophilic part facing the water, and is strongly affects the inversion to O/W droplets. From Small Angle X-ray Scattering (SAXS) measurements we learned that the drug effects the structure of microemulsion droplets and forms "ill-defined structures," probably less spherical. Yet, the overall droplet sizes at the high dilutions did not change very much.

Journal Article↗

PubMed2005

Effects of spontaneous deamidation on the cytotoxic activity of the Bacillus anthracis protective antigen.

Protective antigen (PA) is a central virulence factor of Bacillus anthracis and a key component in anthrax vaccines. PA binds to target cell receptors, is cleaved by the furin protease, self-aggregates to heptamers, and finally internalizes as a complex with either lethal or edema factors. Under mild room temperature storage conditions, PA cytotoxicity decreased (t(1/2) approximately 7 days) concomitant with the generation of new acidic isoforms, probably through deamidation of Asn residues. Ranking all 68 Asn residues in PA based on their predicted deamidation rates revealed five residues with half-lives of <60 days, and these residues were further analyzed: Asn10 in the 20-kDa region, Asn162 at P6 vicinal to the furin cleavage site, Asn306 in the pro-pore translocation loop, and both Asn713 and Asn719 in the receptor-binding domain. We found that PA underwent spontaneous deamidation at Asn162 upon storage concomitant with decreased susceptibility to furin. A panel of model synthetic furin substrates was used to demonstrate that Asn162 deamidation led to a 20-fold decrease in the bimolecular rate constant (k(cat)/Km) of proteolysis due to the new negatively charged residue at P6 in the furin recognition sequence. Furthermore, reduced PA cytotoxicity correlated with a decrease in PA cell binding and also with deamidation of Asn713 and Asn719. On the other hand, neither deamidation of Asn10 or Asn306 nor impairment of heptamerization could be observed upon prolonged PA storage. We suggest that PA inactivation during storage is associated with susceptible deamidation sites, which are intimately involved in both mechanisms of PA cleavage by furin and PA-receptor binding.

Amino Acid Sequence↗

PubMed2005

Transitions induced by solubilized fat into reverse hexagonal mesophases.

Lyotropic liquid crystals of glycerol monooleate (GMO) and water binary mixtures have been extensively studied and their resemblance to human membranes has intrigued many scientists. Biological systems as well as food mixtures are composed of lipids and fat components including triacylglycerols (TAGs, triglycerides) that can affect the nature of the assembly of the mesophase. The present study examines the effect of TAGs of different chain lengths (C(2)-C(18)) at various water/GMO compositions, on phase transitions from lamellar or cubic to reverse hexagonal (L(alpha)-H(II) and Q-H(II)). The ability of the triglycerides to promote the formation of an H(II) mesophase is chain length-dependent. It was found that TAG molecules with very short acyl chains (triacetin) can hydrate the head groups of the lipid and do not affect the critical packing parameter (CPP) of the amphiphile; therefore, they do not affect the self-assembly of the GMO in water, and the mesophase remains lamellar or cubic. However, TAGs with medium chain fatty acids will solvate the tails of the lipid, and will affect the CPP of the GMO, and transform the lamellar or cubic phases into hexagonal mesophase. TAGs with long chain fatty acids are very bulky, not very miscible with the GMO, and therefore, kinetically are very slow to solvate the lipid tails of the amphiphile and are difficult to accommodate into the lipophilic parts of the GMO. Their effect on the transitions from a lamellar or cubic phase to hexagonal is detected only after months of equilibration. In order to enhance the effect of the TAG on the phase transitions in the GMO/triglyceride/water systems, temperature and electrolytes effects were examined. In the presence of short and medium chain triglycerides, increasing temperature caused a transition from lamellar or hexagonal to L(2) phase (highest CPP value). However, in the presence of long chain TAGs, increasing temperature to ca. 40 degrees C caused a formation of H(II) mesophase. In addition, it was found that in tricaprylin/GMO/water systems, the increase in temperature caused a decrease in the lattice parameter. The effect of NaCl on the H(II) mesophase revealed interesting results. At low concentration of tricaprylin (5 wt%), the addition of only 0.1 wt% of NaCl was sufficient to cause the formation of well-defined H(II) mesophase, while further addition of electrolyte increased the hexagonal lattice parameters. At higher TAGs concentrations (10 wt%), addition of electrolyte resulted in the formation of H(II) with modifications of the lattice parameter. All the examined effects were more pronounced with increasing water content.

Caprylates↗

PubMed2004

Five-component food-grade microemulsions: structural characterization by SANS.

In this paper we present the structural characterization of a five-component food-grade microemulsion containing Tween 80, R(+)-limonene, ethanol, glycerol, and water. Our main approach to investigating the microstructure of dense microemulsions, and how it can be influenced by the various components, was to employ small-angle neutron scattering and the new evaluation technique for dense, interacting systems, the Generalized Indirect Fourier Transformation. We started our investigation with the impact of glycerol and ethanol on Tween 80 micelles in water. We found that glycerol increases the aggregation number and withdraws the hydrating agents from the headgroup region of the surfactant, resulting in a higher packing density of molecules in a micelle at slightly increasing size. The same trend holds when the micelles are oil swollen and/or ethanol is present. Ethanol, on the other hand, redistributes mainly between water and the interface-headgroup region of the surfactant. Part of it replaces surfactant molecules in the micelles, which increases the available interface and results in a higher number of micelles with shrinking size. The same trend holds when the micelles are oil swollen and/or glycerol is present in the aqueous phase. We also investigated samples along the dilution of a mixture of surfactant and oil phase (R(+)-limonene and ethanol), which can be diluted with aqueous phase (mixture of water and glycerol) without the occurrence of phase separation. In some samples of this dilution most probably bicontinuous structures are present. To elucidate this point, we also employed dynamic light scattering, viscosity, and conductivity measurements.

Journal Article↗

PubMed2003

Phenolic constituents of shea (Vitellaria paradoxa) kernels.

Analysis of the phenolic constituents of shea (Vitellaria paradoxa) kernels by LC-MS revealed eight catechin compounds-gallic acid, catechin, epicatechin, epicatechin gallate, gallocatechin, epigallocatechin, gallocatechin gallate, and epigallocatechin gallate-as well as quercetin and trans-cinnamic acid. The mean kernel content of the eight catechin compounds was 4000 ppm (0.4% of kernel dry weight), with a 2100-9500 ppm range. Comparison of the profiles of the six major catechins from 40 Vitellaria provenances from 10 African countries showed that the relative proportions of these compounds varied from region to region. Gallic acid was the major phenolic compound, comprising an average of 27% of the measured total phenols and exceeding 70% in some populations. Colorimetric analysis (101 samples) of total polyphenols extracted from shea butter into hexane gave an average of 97 ppm, with the values for different provenances varying between 62 and 135 ppm of total polyphenols.

Africa↗

PubMed2003

Solubilization patterns of lutein and lutein esters in food grade nonionic microemulsions.

Lutein, a naturally occurring carotenoid, is widely distributed in fruits and vegetables and is particularly concentrated in the Tagetes erecta flower. Epidemiological studies suggest that a high lutein intake (6 mg/day) increases serum levels that are associated with a lower risk of cataract and age-related macular degeneration. Lutein can either be free or esterified (myristate, palmitate, or stearate). Both are practically insoluble in aqueous systems, and their solubility in food grade solvents (oils) is very limited, resulting is low bioavailability. To improve its solubility and bioavailability, lutein was solubilized in U-type food grade microemulsions based on ethoxylated sorbitan fatty acid esters, glycerol, R-(+)-limonene, and ethanol. Some of the main findings are as follows: (1) reverse micellar and W/O compositions solubilized both luteins better than an O/W microemulsion, and maximum solubilization is obtained within the bicontinuous phase; (2) free lutein is solubilized better than the esterified one, in the W/O microemulsions, whereas the esterified lutein is better accommodated within the O/W microemulsion; (3) vegetable oils decrease the solubilization of free lutein; (4) glycerol and alcohol enhance the solubilization of both luteins; (5) solubilization is surfactant-dependent in all mesophase structures, but its strongest effect is in the bicontinuous phase.

Biological Availability↗

PubMed2003

Self-diffusion nuclear magnetic resonance, microstructure transitions, and solubilization capacity of phytosterols and cholesterol in Winsor IV food-grade microemulsions.

Microemulsions are of growing interest to the food industry as vehicles for delivering and enhancing solubilization of natural food supplements with nutritional and health benefits. The incorporation of molecular phytosterols, cholesterol-lowering agents, in food products is of great interest to the food industry. In this work is demonstrated the use of water dilutable food-grade microemulsions consisting of ethoxylated sorbitan ester (Tween 60), water, R-(+)-limonene, ethanol, and propylene glycol as vehicles for enhancing the phytosterols solubilization. Phytosterols were solubilized up to 12 times more than the dissolution capacity of the oil [R-(+)-limonene] for the same compounds. The solubilization capacity of phytosterols and cholesterol along a dilution line in a pseudo-ternary phase diagram [on this dilution line the weight ratio of R-(+)-limonene/ethanol/Tween 60 is constant at 1:1:3] was correlated to the microstructure transitions along the dilution line. Structural aspects were studied by self-diffusion NMR spectroscopy. The ability of phytosterols to compete with cholesterol for penetration into bile salt micelles in the gut may be limited to rich aqueous systems (O/W microemulsion).

Cholesterol↗

PubMed2002

Food-grade microemulsions based on nonionic emulsifiers: media to enhance lycopene solubilization.

Water-dilutable food-grade microemulsions consisting of ethoxylated sorbitan esters, and in some cases blended with other emulsifiers, water, (R)-(+)-limonene, ethanol, and propylene glycol, have been prepared. These microemulsions are of growing interest to the food industry as vehicles for delivering and enhancing solubilization of natural food supplements with nutritional and health benefits. Lycopene, an active natural lipophilic antioxidant from tomato, has solubilized in water-in-oil, bicontinuous, and oil-in-water types of microemulsions up to 10 times the oil [(R)-(+)-limonene] dissolution capacity. The effects of aqueous-phase dilution, nature of surfactant (hydrophilic-lypophilic balance), and mixed surfactant on solubilization capacity and solubilization efficiency were studied. Structural aspects studied by self-diffusion NMR were correlated to the solubilization capacity, and transformational structural changes were identified.

Carotenoids↗

PubMed2002

Furfural-cysteine model reaction in food grade nonionic oil/water microemulsions for selective flavor formation.

The thermal reaction between cysteine and furfural was investigated at 65 degrees C in five-component food grade oil/water (O/W) microemulsions of R-(+)-limonene/ethanol, EtOH/water/propylene glycol, PG/Tween 60 as apart of a systematic study on the generation of aroma compounds by utilizing structured W/O and O/W fluids. The furfural-cysteine reaction led to the formation of unique aroma compounds such as 2-furfurylthiol (FFT), 2-(2-furanyl)thiazolidine (main reaction product), 2-(2-furanyl)thiazoline, and N-(2-mercaptovinyl)-2-(2-furanyl)thiazolidine. These products were determined and characterized by GC-MS. Enhancement in flavor formation is termed "microemulsion catalysis". The chemical reaction occurs preferably at the interfacial film, and therefore a pseudophase model was assumed to explain the enhanced flavor formation. The product internal composition is dictated by process conditions such as temperature, time, pH, and mainly the nature of the interface. Increasing water/PG ratio leads to a dramatic increase in the initial reaction rate (V(0)). V(0) increased linearly as a function of the aqueous phase content, which could be due to the increase in the interfacial concentration of furfural. Microemulsions offer a new reaction medium to produce selective aroma compounds and to optimize their formation.

Cyclohexenes↗

PubMed2002

Preparation of amorphous aluminum oxide-hydroxide nanoparticles in amphiphilic silicone-based copolymer microemulsions.

Organo-inorgano nanocomposites with colloidal dimensions have interesting optical, catalytic, and mechanical properties, particularly when such hybrids are reinforced with transition metal oxide nanoparticles. Nanoparticles with a mean size of 1.0-2.4 nm are obtained through hydrolysis of aluminum isopropoxide in the L(2) phase of amphiphilic (PDMS-POE) polydimethylsiloxane-polyoxyethylene Silwet L-7607-octanol/acetylacetone-water mixtures. The particle sizes are related weakly to the microemulsion composition: 0.8-1.2 nm for 20 wt% Silwet L-7607 and 2.0-2.4 nm for 50 wt% Silwet L-7607. Protection of the particles against aggregation is ensured through their confinement in the intraaggregate colloidal domains. Factors affecting the hydrolysis-condensation process of acetylacetone-complexed aluminum isopropoxide in copolymer-poor and copolymer-rich regions of PDMS-POE W/O microemulsions are studied by Fourier transform infrared spectroscopy, small angle X-ray scattering, and transmission electron microscopy. Prepared nanoparticulate dispersions possess long-term stability and form clear mixtures in different organic polar and nonpolar solvents.

Journal Article↗

PubMed2001

Sugar-Ester Nonionic Microemulsion: Structural Characterization.

Surfactants containing sugar components and fatty acids satisfy the quality standards for food application. The food grade sugar ester in this study is a commercial sucrose monoester of stearic acid (abbreviated SES), the oil phase consists of a 1:1 mixture of n-tetradecane and l-butanol. The originally planned food grade oil, a medium chain triglyceride, is substituted by tetradecane because tetradecane is available as a fully deuterated product, which is necessary for some structural investigations. The investigated system is solid at room temperature, but liquefies and structures into a homogeneous microemulsion when heated to above 37 degrees C. The structural characterization of such microemulsions is the aim of this work. The established methods for this purpose are scattering methods, such as small-angle scattering of X-rays and neutrons and dynamic light scattering. These scattering techniques can be used to obtain valuable information on the size, shape, and internal structure of colloids and complex fluids. We started our investigation with the pseudobinary system SES, tetradecane and l-butanol, varying the SES content. The scattering results show that the sugar ester form inverse globular micelles in the oil phase. The size of these micelles is about 6 nm. While the size is nearly constant in a wide SES concentration regime (5 up to 40% surfactant), the volume or aggregation number increases significantly with SES. This is explained by an increasing replacement of l-butanol molecules by sugar-ester molecules in the micelles formed. Moreover, it can be shown that these micelles strongly overlap. Their center-to-center distance is about 3.8 nm at 40% SES at a micellar diameter of 6 nm. The micellar overlap leads to a highly reduced diffusion of the micelles as was found with dynamic light scattering. When incorporating water in the micellar core, the micelles swell up to about 10 nm and the shape of the aggregates becomes more and more elongated with higher water content. Copyright 2001 Academic Press.

Journal Article↗