Effect of the concentration of amino-decorated polyamidoamine dendrimers with ethylenediamine core at the (trans)dermal delivery of 5-Fluorouracil Pavlína Chladová Dendrimers are synthetic, symmetrically tree-like branched molecules. They are composed of repeating units (monomers). They have high density of surface functional groups and spherical shape in solution. Since their molecular weight is highly controllable, they are characterized by monodispersity and this is their main difference from classical polymers. Dendrimers have a wide spectrum of applications in biomedicine. Due to the empty space between the branches of the molecule, they can encapsulate drugs, and by conjugation and complexation to the surface groups, they are able to carry even larger drug molecules. Thus, dendrimers can be used as drug delivery systems. In addition, they have been used for skin application of several active molecules, either as topical or transdermal delivery. Suitable properties for (trans)dermal application have been demonstrated for dendrimers which consist of monomers with amine groups and are connected with amide bonds. The goal of this thesis was the preparation of dendrimers with these characteristics and the evaluation of their concentration influence to the permeability of 5-Fluorouracil (5-FU) to human...

Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Technology Supervisor: Dr. Georgios Paraskevopoulos, Ph.D. Consultant: Mgr. Anna Nová ková Author: Denisa Houšková Title of thesis: Effect of the generation of amino-decorated polyamidoamine dendrimers with ethylenediamine core at the (trans)dermal delivery of 5-fluorouracil. Dendrimers can be defined like highly branched, star-shaped macromolecules with nanometer-scale dimensions and unlimited applications in both biological and materials sciences. Polyamidoamine (PAMAM) dendrimers have been used to effectively enhance the (trans)dermal drug delivery of several active substances. Inspired by the structure of PAMAM dendrimers, a new class of dendrimers was designed having amino-functionalized periphery and ethylenediamine core. A repeating motif of bis(2-aminoethyl)glycine was used for generation growth up to the third generation. The new dendritic molecules of zero, first, second and third generation were tested for their ability to enhance the deposition of 5-fluorouracil in the different layers of human skin ex vivo by using Franz diffusion cells. The results suggest that the new dendrimers, at a concentration of 20 mg/mL in 60 % propylene glycol in water as vehicle, are able to deliver 5-fluorouracil at the...

Passive permeation through biological membranes is an important mechanism for transporting molecules and regulating the cellular content. Studying and understanding passive permeation is also extremely relevant to many industrial applications, including drug design and nanotechnology. In vivo membranes typically consist of mixtures of lamellar and nonlamellar lipids. Lamellar lipids are characterised by their tendency to form lamellar bilayer phases, which are predominant in biology. Nonlamellar lipids, when isolated, instead form non-bilayer structures such as inverse hexagonal phases. While mixed lamellar/nonlamellar lipid membranes tend to adopt the ubiquitous bilayer structure, the presence of nonlamellar lipids is known to have profound effects on key membrane properties, such as internal distributions of stress and elastic properties. This dissertation examines permeation through lamellar and nonlamellar lipid membranes by utilising atomistic molecular dynamics simulations in conjunction with two di erent methods, the z-constraint and the z-restraint, in order to obtain transfer free energy profiles, diffusion profiles and permeation coefficients. An assessment of these methods is performed in search for the optimal, with the goal to create an automated, accurate and robust permeation study framework. Part of the dissertation involves the creation of the corresponding software. Furthermore, this work examines the effect of changing the lamellar vs. nonlamellar lipid composition on the passive permeation mechanism of a series of 13 small molecules and drugs. These nonlamellar lipids are known to affect the lateral pressure distribution inside the membranes. This work investigates the hypothesis that the differences in lateral pressure should increase the resistance to permeation. The results indicate that, upon addition of nonlamellar lipids, permeation is hindered for small molecules but is facilitated for the largest. All results are in agreement with previous experimental and computational studies. This work represents an advancement towards the development of more realistic in silico permeability assays, which may have a substantial future impact in the area of rational drug design.

The seed coat is the barrier controlling exchange of solutes between the plant embryo and its environment. This exchange is of importance for example in the uptake of germination inhibitors or in the uptake of agrochemicals applied as seed treatment. A thorough understanding of the basic mechanisms underlying solute permeation across the seed coat would help to improve the effectiveness of seed treatment formulations. In seed treatment formulations, additives can be used to enhance or decrease mobility or uptake of the active ingredient (AI). In the present study the seed coat barrier properties and the seed coat permeation process was examined with the model species Pisum sativum and with a set of model solutes. The lipophilic fraction of the seed coat was analysed by gas chromatography and mass spectrometry and it was found that the total lipophilic compartment of the seed coat represents 0.61 % of the weight of a swollen seed coat. The seed is covered by a lipophilic cuticle. The seed coat coverage with cuticular waxes is ten to 18-fold lower than wax coverage of pea leaves, though. In order to examine sorption of solutes in the small lipophilic compartment of the seed coat, seed coat/water partition coefficients were determined. These cover a much smaller range than the corresponding n-octanol/water partition coefficients. The lipophilic sorption compartment as calculated from the seed coat/water partition coefficient data is smaller than the analysed total lipophilic compartment of the seed coat since not all of the lipid components can act as sorption compartment. During seed swelling, the pea seed nearly doubles its weight. The uptake of water is driven by the very low water potential of the dry seed and controlled by the seed coat hydraulic conductivity both of which increase during seed swelling. Depending on the available form of water, water uptake can take place by diffusion from air humidity or by mass flow from liquid water. Water uptake by a seed in moist sand takes place by a combination of both uptake mechanisms. The basic transport mechanism underlying solute permeation of seed coats was analysed by steady-state experiments with a newly devised experimental setup. The permeance P for permeation of the set of model compounds across isolated seed coat halves ranged from 3.34 x 10-8 m s-1 for abamectin to 18.9 x 10-8 m s-1 for caffeine. It was found that solute permeation across the seed coat takes aqueous pathways. This was concluded from the facts that molar volume instead of lipophilicity of the solutes determine permeation and that the temperature effect on permeation is very small. This is in contrast to typical leaf and fruit cuticular uptake where lipophilic pathways dominate. Solute uptake across the seed coat can take place by two different mechanisms both of which take aqueous pathways. Uptake can be by diffusion and in the presence of a bulk flow of water driven by a water potential difference also by solvent drag. The presence of the solvent drag uptake mechanism shows that the aqueous pathways form an aqueous continuum across the seed coat. These findings indicate that the seed coat covering cuticle does not form a continuous barrier enclosing the seed. In order to examine solute uptake across the seed coat under conditions close to a situation taking place in the field, the process of uptake of a seed treatment AI in the field was simulated. In the situation of a treated seed in the field, the seed treatment residue dissolves and then the AI can move either into the surrounding soil or across the seed coat into the seed. Uptake across the seed coat can take place either by diffusion or during seed swelling by the solvent drag mechanism. Since the seed treatment residue depletes over time, non-steady-state uptake takes place. To simulate these processes, laboratory scale seed treatment methods were established to produce treated seeds and isolated treated seed coat halves. Experimental setups for non-steady-state uptake experiments were established with whole treated seeds and with isolated treated seed coat halves as simplified screening tool. By modelling of the AI uptake as a first-order process the rate constant k and the final relative uptake amount Mt→∞ M0-1 were obtained. With k and Mt→∞ M0-1 a quantification and comparison of the uptake curves was possible. Both in the experiments with whole treated seeds and with isolated treated seed coats, uptake of metalaxyl-M was much faster than uptake of sedaxane. In the uptake of a seed treatment AI, not only the solute's molar volume but also its water solubility determine uptake. The solute's water solubility is important for dissolution of the AI from the seed treatment residue and thus determines availability of the AI for uptake. Water solubility also controls the possible concentration in solution and thus the driving force for diffusive uptake. Furthermore, the AI amount taken up by solvent drag is determined by concentration in the inflowing water and thus by water solubility. In the experiments with whole treated seeds the additive effects on uptake were smaller than in the experiments with isolated treated seed coats or not significant. Adigor functions as an emulsifier and can lead to a slight increase of AI mobilisation from the seed treatment residue. NeoCryl A-2099 can cause a slowed down release of the AI from the seed treatment residue. The effects of both additives were smaller than the effect caused by different AI physico-chemical properties. Therefore, the most important factor determining uptake of a seed treatment AI are the AI's physico-chemical properties, especially its water solubility. / Die Samenschale fungiert als Barriere, welche den Stoffaustausch zwischen dem pflanzlichen Embryo und seiner Umgebung kontrolliert. Dieser Stoffaustausch ist beispielsweise bei der Aufnahme von keimungshemmenden Substanzen oder aufgebeizten Pestiziden von Bedeutung. Ein besseres Verständnis des zugrundeliegenden Mechanismus bei der Permeation über die Samenschale wäre hilfreich für die Optimierung von Beizmittelformulierungen. Bei der Formulierung von Beizprodukten kann die Mobilität oder Aufnahme der Wirkstoffe je nach Bedarf durch Zugabe von Additiven beschleunigt oder verlangsamt werden. In der vorliegenden Arbeit wurden daher die Barriereeigenschaften der Samenschale und der Permeationsprozess über die Samenschale anhand der Modellpflanze Pisum sativum und mit einem Set von Modellsubstanzen untersucht. Die lipophile Fraktion der Samenschale wurde mittels Gaschromatographie und Massenspektrometrie analysiert. Hierdurch konnte ermittelt werden, dass das komplette lipophile Kompartiment der Samenschale 0.61 % des Gewichtes ausmacht. Die Samenschale wird, wie es auch bei Blättern der Fall ist, von einer lipophilen Kutikula bedeckt. Die Bedeckung mit kutikulären Wachsen ist bei Erbsensamen allerdings zehn- bis 18-fach geringer als bei Blättern von Erbsenpflanzen. Um die Sorption von Substanzen in dem kleinen lipophilen Kompartiment der Samenschale zu untersuchen, wurden Samenschale/Wasser Verteilungskoeffizienten bestimmt. Diese erfassen einen sehr viel kleineren Größenbereich als die entsprechenden n-Oktanol/Wasser Verteilungskoeffizienten. Das lipophile Sorptionskompartiment, welches mittels der Samenschale/Wasser Verteilungskoeffizienten berechnet wurde, ist kleiner als das analysierte lipophile Kompartiment, da nicht alle analysierten lipophilen Samenschalenbestandteile als Sorptionskompartiment fungieren können. Bei der Quellung von Erbsensamen kommt es nahezu zu einer Verdoppelung des Gewichtes. Die Wasseraufnahme wird durch das sehr niedrige Wasserpotential des trockenen Samens angetrieben und über die hydraulische Leitfähigkeit der Samenschale kontrolliert, wobei beide während der Quellung ansteigen. Je nachdem in welcher Form das verfügbare Wasser vorliegt kann die Wasseraufnahme durch Diffusion aus Luftfeuchte oder über einen Massenfluss aus flüssigem Wasser erfolgen. Ein Same in feuchtem Sand nimmt Wasser mittels einer Kombination beider Mechanismen auf. Der zugrunde liegende Transportmechanismus in der Substanzpermeation über Samenschalen wurde mit einem neu entwickelten Versuchsaufbau in Steady-State Versuchen analysiert. Der Leitwert P für die Permeation der Modellsubstanzen lag hierbei zwischen 3.34 x 10-8 m s-1 für Abamectin und 18.9 x 10-8 m s-1 für Koffein. Die Substanzpermeation über die Samenschale verläuft über wässrige Permeationswege. Dies wurde daraus geschlossen, dass das molare Volumen anstelle der Substanzlipophilie den Leitwert bestimmt und dass der Temperatureffekt auf die Permeation klein ist. Dies ist im Gegensatz zur typischen Permeation über die Kutikeln von Blättern und Früchten, welche meist über lipophile Wege verläuft. Substanzaufnahme kann durch zwei verschiedene Mechanismen über die wässrigen Wege durch die Samenschale stattfinden. Aufnahme kann sowohl durch Diffusion stattfinden oder, in Gegenwart eines Volumenflusses von Wasser welcher durch eine Wasserpotentialdifferenz angetrieben wird, auch durch den solvent drag Mechanismus. Das Vorhandensein des solvent drag Aufnahmemechanismus beweist, dass die wässrigen Wege in der Samenschale ein wässriges Kontinuum durch die Samenschale bilden. Diese Ergebnisse zeigen, dass die Kutikula, welche der Samenschale aufliegt, keine kontinuierliche Barriere um den Samen bildet. Um den Aufnahmeprozess von Substanzen unter anwendungsnahen Bedingungen zu untersuchen, wurde die Aufnahme eines aufgebeizten Pflanzenschutzmittelwirkstoffes im Feld in Versuchen simuliert. In der Situation eines gebeizten Samens im Feld löst sich der Beizrückstand an und der Wirkstoff kann sich entweder in Richtung umgebender Erde oder über die Samenschale in das Sameninnere bewegen. Die Aufnahme über die Samenschale kann mittels Diffusion oder durch den solvent drag Mechanismus erfolgen. Da der Beizmittelrückstand auf der Samenoberfläche mit der Zeit verarmt, liegt eine non-steady-state Aufnahmesituation vor. Um diese Prozesse zu simulieren, wurden Versuchsaufbaue für non-steady-state Versuche mit ganzen gebeizten Samen sowie als vereinfachtes Modell mit isolierten gebeizten Samenschalen etabliert. Indem die gemessene Wirkstoffaufnahme als Prozess erster Ordnung modelliert wurde, konnten die Geschwindigkeitskonstante k sowie die finale relative Aufnahmemenge Mt→∞ M0-1 berechnet werden. Mit k und Mt→∞ M0-1 konnten dann die Aufnahmekurven quantifiziert und verglichen werden. Sowohl in den Versuchen mit ganzen gebeizten Samen als auch in den Versuchen mit isolierten gebeizten Samenschalen war die Aufnahme von Metalaxyl-M um ein Vielfaches schneller als die Aufnahme von Sedaxane. Bei der Aufnahme von einem Beizmittelwirkstoff über die Samenschale spielt nicht nur das molare Volumen des Wirkstoffes eine Rolle, sondern auch seine Wasserlöslichkeit. In den Versuchen mit ganzen gebeizten Erbsen war der Effekt der Additive kleiner als in den Versuchen mit isolierten gebeizten Schalen oder nicht signifikant. In beiden Fällen war der Additiv-Effekt kleiner als der Effekt, der durch die Unterschiede in den Substanzeigenschaften hervorgerufen wurde. Daher sind die physikalisch-chemischen Eigenschaften des Wirkstoffes, insbesondere seine Wasserlöslichkeit, die wichtigsten Faktoren welche die Aufnahme in den gebeizten Samen bestimmen.

No description available.

Industrial utilization of polymeric gas separation membranes is predicted to increase significantly over the next 20 years. This growth will be driven by application of membrane based separations to increasingly aggressive feed streams. In this work, the performance of defect-free Matrimid asymmetric hollow fiber membranes in the presence of high pressure carbon dioxide and trace levels of toluene and n-heptane in the feed stream are studied. Specifically, this work shows a significant decrease in the carbon dioxide plasticization pressure and the carbon dioxide permeance prior to plasticization as a result of accelerated physical aging at ambient temperature. Interestingly, sub-Tg thermal annealing at 220 oC reverses the effects of physical aging by increasing the plasticization pressure and the carbon dioxide permeance prior to plasticization for a typical polyimide commonly used in membranes. The performance of Matrimid asymmetric hollow fiber membranes in feed streams contaminated with up to 1200 ppm toluene and 2000 ppm n-heptane is investigated. In the presence of both feed stream contaminants, the productivity and efficiency of the membrane are observed to significantly decrease in this work. These decreases in performance are shown to be the result of antiplasticization, and a free volume based model is developed to correlate the effect of feed stream contamination on membrane performance

No description available.

Univ., Diss.--Halle-Wittenberg, 1997.

This thesis aims to the assessment of methods used in in vitro analysis of dermal permeation and absorption of caffeine. Guarantee of standard processes during an experiment is essential for the rightness of results evaluation and interpretation. First part is focused on alternatives and different transport ways of substances through the skin barrier. As transdermal drug delivery offers an increasing number of advantages, the number of studies performing transdermal experiments with drug delivery grows up. On the other hand we are also able to observe or predict the risk of intoxication of individuals after exposure to different kinds of chemicals. The standard methods assessment is of great importance to obtain reproducible results. In this thesis, caffeine was chosen as a model hydrophilic compound. Skin barrier was simulated by dermatomed pig skin of two different thicknesses from ear and abdomen. Eight experimets were carried out with different types of skin using Franz cells in two types of dosing - finite and infinite. Experimental part of the thesis aims on actual determination of caffeine permeation . Measurements were taken in receptor fluid, in particular layers of the skin and on its surface. Spectrophotometry and HPLC analysis were used for the assessment. The ability of caffeine...

Water Stuff & Sun are developing a hydrogen battery based on a technology called SFEER’s. The SFEER’s are spherical high-pressure gas storage containers that are the size of a tennis ball. They consist of a carbon fiber-shell that is lined on the inside with a polymer called PA6. The aim of this literature review is to present suitable materials that can be utilized as a coating on the PA6 liner in the SFEER’s to minimize the hydrogen permeability. The metallic coatings that were investigated are compounds based on chromium, boron, alu- minum and titanium. The non-metallic coatings that were investigated are lamellar inorganic components (LIC) in combination with PA6 and modified graphene oxide (GO). The coating methods that were investigated are some different PVD and CVD methods (sputter deposition, plasma enhanced CVD, ALD), electrodeposition and cold spray. The lowest permeability out of all the coatings was observed for alumina, Al2O3. Titanium nitride, TiN, was also found to have very low permeability. Since these two coatings had the lowest permeabilities they were further compared considering other factors. This resulted in alumina being chosen as the final recommendation for coating the SFEER’s. A comparison was also made to find the most suitable coating method for alumina. Cold spray was found to be very promising but if it can not be used the PVD and CVD methods are other potential candidates.