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Study of lipid membranes with lysolipids as models of atopic dermatitis
Pospíšilová, Markéta ; Vávrová, Kateřina (advisor) ; Zbytovská, Jarmila (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of inorganic and organic chemistry Candidate: Pospíšilová, Markéta Supervisor: Assoc. Prof. PharmDr. Kateřina Vávrová, Ph.D. Title of Diploma Thesis: Study of lipid membranes with lysolipids as models of atopic dermatitis We are protected against the harmful influence of the external environment by a skin barrier, which is located in the stratum corneum. The skin barrier also prevents excessive water loss through the skin. Ceramides have the most important role in the barrier function of the skin. The healthy skin's ceramides are synthesized of glucosylceramide and sphingomyelin via enzymes sphingomyelinase and glucocerebrosidase. If there is a lack of ceramide in the stratum corneum, which means, if these mechanisms work insufficiently, it gives rise to atopic dermatitis. In the stratum corneum of a patient who suffers from atopic dermatitis are glucosylceramide and sphingomyelin hydrolyzed by glucosylceramide/sphingomyeline deacylase which leads to free fatty acids and lysolipids (glucosylsphingosine and sphingosinephosphorylcholine) generation. In this work, we prepared model membranes which simulate a composition of lipids of the stratum corneum of a patient with atopic dermatitis, in which ceramides are replaced by...
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Evaluation of the in vitro skin permeation of selected compounds using static Franz diffusion cells
Dvořáková, Tereza ; Vávrová, Kateřina (advisor) ; Zbytovská, Jarmila (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic & Organic Chemistry Student: Tereza Dvořáková Title of diploma thesis: EVALUATION OF THE IN VITRO SKIN PERMEATION OF SELECTED COMPOUNDS USING STATIC FRANZ DIFFUSION CELLS The work focuses testing the transdermal permeation of selected substances - tacrine and 7-methoxytacrine (7-Meota). Tacrine is an acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease. For its hepatotoxicity and side- effects is no longer used today. Transdermal administration could be a good alternative to reduce those side effects. 7-Meota is tacrine derivative, which in previous in vitro testing demonstrated lower toxicity in comparison with tacrine. The aim of this thesis was to clarify if and to what extent has tacrine and 7-Meota ability for transdermal permeation. Experiments were performed in vitro by using Franz diffusions cells. As receptor fluid was used for tacrine a phosphate buffer solution and for 7-Meota was a phosphate buffer solution for one part of the trial and for a second part was water. Substances were applied in an infinite dose in aqueous solution onto the surface of pig skin, which was cut to a thickness of 500 µm and 1000 µm. For the comparison was part of the experiments conducted in a...
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Study of transdermal and dermal absorption of 2,6-diaminopurine acyclic nucleoside phosphonates
Diblíková, Denisa ; Vávrová, Kateřina (advisor) ; Zbytovská, Jarmila (referee)
Acyclic nucleoside phosphonates (ANP) are broad-spectrum antivirals highly effective against herpes-, retro- and hepadnaviruses. They also exhibit cytostatic, antiparasitic, immunomodulatory activities. Their transdermal delivery offers an attractive and advantageous route of administration, but is limited due to the polar character of their phosphonate moiety. The aim of this work was to study the possibility of both transdermal and dermal application of a series of 2,6-diaminopurine derivatives including (R)-PMPDAP and (S)-PMPDAP, (S)-HPMPDAP, (S)-8-azaHPMPDAP, cyclic (S)-HPMPDAP and lysolipid prodrugs, i.e., hexadecyloxypropyl (HDP) esters of (R)-HDP-PMPDAP and (S)-HDP- HPMPDAP. Ability of ANP to penetrate trough the skin by themselves is generally very low. For this reason the influence of permeation enhancer dodecylester of 6- (dimethylamino)hexanoic acid (DDAK) through and into human skin was investigated. The evaluation was performed in vitro by using Franz diffusion cells and human skin. The results of this work confirm that ANP (60 mM in 60 % propylene glycol) delivery through the skin is very low (flux 0.53-1.40 nmol/cm2 /h), except for the lysolipid prodrugs (R)-HDP-PMPDAP and (S)-HDP-HPMPDAP), which were not detected in the acceptor phase at all. 1 % DDAK enhanced transdermal flux of...
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Study of transdermal and dermal absorption of 2,6-diaminopurine acyclic nucleoside phosphonates
Diblíková, Denisa ; Vávrová, Kateřina (advisor) ; Zbytovská, Jarmila (referee)
Acyclic nucleoside phosphonates (ANP) are broad-spectrum antivirals highly effective against herpes-, retro- and hepadnaviruses. They also exhibit cytostatic, antiparasitic, immunomodulatory activities. Their transdermal delivery offers an attractive and advantageous route of administration, but is limited due to the polar character of their phosphonate moiety. The aim of this work was to study the possibility of both transdermal and dermal application of a series of 2,6-diaminopurine derivatives including (R)-PMPDAP and (S)-PMPDAP, (S)-HPMPDAP, (S)-8-azaHPMPDAP, cyclic (S)-HPMPDAP and lysolipid prodrugs, i.e., hexadecyloxypropyl (HDP) esters of (R)-HDP-PMPDAP and (S)-HDP- HPMPDAP. Ability of ANP to penetrate trough the skin by themselves is generally very low. For this reason the influence of permeation enhancer dodecylester of 6- (dimethylamino)hexanoic acid (DDAK) through and into human skin was investigated. The evaluation was performed in vitro by using Franz diffusion cells and human skin. The results of this work confirm that ANP (60 mM in 60 % propylene glycol) delivery through the skin is very low (flux 0.53-1.40 nmol/cm2 /h), except for the lysolipid prodrugs (R)-HDP-PMPDAP and (S)-HDP-HPMPDAP), which were not detected in the acceptor phase at all. 1 % DDAK enhanced transdermal flux of...
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Study of the Termotropic Behaviour of Short-chain Ceramid Analogues
Vavrysová, Helena ; Zbytovská, Jarmila (advisor) ; Doležal, Pavel (referee)
Ceramides of stratum corneum (SC) play a crucial role in maintaining the barrier function of the skin. This work deals with series short-chain analogues of ceramides with structure identical to naturally occuring ceramide NS, acyl chain length from 2 to 12. Acyl chain length is very important for barrier properties. Ceramides with chain length 4-8C lose barrier function, conversely were able to increase skin peremability. Ceramides with 2 and 12C showed no increase in permeability. Calorimetric and infrared spectroscopic measuring data were used for studying thermotropic phase behaviour analogues of ceramides and compared to the physiological cermide NS. At physiological temperatures, all crystalline phases of ceramides exhibit lamellar structures with highly ordered hydrocarbon chains. Structure-activity relationships and potential permeable aktivity of these ceramides were observed. Short-chain ceramides do not act as natural ceramides and their biological activity has been widely investigated.
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The study of thermotropic phase behaviour of ceramide 2 and its mixtures with cholesterol.
Voršilková, Klára ; Zbytovská, Jarmila (advisor) ; Berka, Pavel (referee)
Diploma Thesis 2007, Petra Nerudová Abstract Thermotropic behaviour of mixtures of Ceramide (NS) with cholesterol were studied by DSC method and evaluated using IR spectrum of ceramide itself. Depending on the concentration of individual components there were shifts in melting temperature of the next phase transitions. From the measurements we found the value eutectic mixtures in which the ratio of Ceramide NS / cholesterol was 5:5 after the first heating and 3:7 after second heating. It was found that hydration also affects the behaviour of thermotropic mixture.The results of IR spectra correlated with the DSC. The temperature at which the IR measurements shown changes of Ceramide (NS) structure was in a good relation with melting temperatures determined by DSC.
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The study of thermotropic phase behaviourof pseudoceramide 14S24 and its mixtures with cholesterol.
Toningerová, Lenka ; Zbytovská, Jarmila (advisor) ; Doležal, Pavel (referee)
A study of the thermotropic phase behaviour of the pseudoceramide 14S24 and its mixture with cholesterol Abstract The thermotropic phase behaviour of mixture of ceramide analogue 14S24 with cholesterol was scoped in this diploma thesis. The samples were measured under non-hydrated and hydrated conditions for the various ratios of 14S24. Two methods were used for the measurement and determination, namely DSC and Infrared spectroscopy. The phase transitions and the changes in a structure of the ceramide analogue 14S24 were studied. The influence of concentration on temperature was monitored by DSC. Interestingly, the eutectic mixture occurred with 30% content of ceramide analogue 14S24. Furthermore, a hydration of the mixture influenced its melting point by means of decrease. The crystalline lattice was determined by IR showing triclinic or optional hexagonal structure.
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The physico-chemical characterization of prospective transdermal absorption enhancers.
Vavrysová, Helena ; Zbytovská, Jarmila (advisor) ; Vávrová, Kateřina (referee)
THE PHYSIOCHEMICAL CHARACTERISATION OF POSSIBLE ENHANCERS FOR ABSORPTION The work is deal with studies of lipid and characterisation of the thermotopic behaviour of selected possible enhancers for transdermal absorption. The thermotropic behaviour was observed by combination DSC and IR spectroscopy of five synthetic compounds with similar structure as skin ceramides. We can deduce that all studied enhancers are highly ordered structures with high numer of trans conformers and triclinical lipid chain packing. With increased temperatur growth number of gauche conformers and increase fluidity of lipid chain. At the same time dissapear hydrogen bounds which form on the polar heads between lipid chains. Temperature differencies of phase transitions of measuring compounds is considerable. It can be caused insuficient heating of ATR crystal but exists linear dependence of correlation. With increased temperature growth measurement error. This dependence can be used for other measurements.
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Srovnávací in vitro studie permeace vybraných léčiv z lipofilních roztoků přes lidskou kůži
Koláčková, Lenka ; Doležal, Pavel (advisor) ; Zbytovská, Jarmila (referee)
A COMPARISON IN VITRO STUDY OF PERMEATION OF SELECTED DRUGS FROM LIPOPHILIC SOLUTIONS TROUGH HUMAN SKIN ABSTRACT The aim of the study was to compare the permeation of testosterone (TST), caffeine (CAF), flufenamic acid (FA) and benzoic acid (BA) from highly liquid paraffin through human heat-separated epidermis (HSE). For evaluation of saturation concentration of the drugs in the vehicle(csat), an excess of BA, CAF, FA or TST was suspended in 5 ml of highly liquid paraffin in a screw top scintillation vial (500 rpm, 32 řC; 24 h). After sedimentation of non- dissolved substance, samples were drawn from the supernatant, diluted 1:10 with dichloromethane and analyzed via UV/VIS-spectroscopy: (Lambda 35; Perkin Elmer, BA 228 nm; CAF 277 nm; FA 287 nm; TST 238 nm). Permeation experiments over human HSE of two donors (6 pieces of each) were performed in Franz diffusion cells at 32 řC. The donor was composed of TST, FA, BA (0.4 mg/ml), CAF (0.1 mg/ml) dissolved in paraffin. Samples of 0.4 ml were collected over the time, replaced by fresh acceptor solution (Soerensen phosphate buffer pH 7.4) and quantified by validated HPLC methods. The steady state flux (J) was evaluated from the linear part of cumulative amount versus time plots and dividing it by donor concentration (cdon), the apparent permeability coefficient...
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Transdermal in vitro permeation of cyclosporine. III.
Krejčová, Hana ; Doležal, Pavel (advisor) ; Zbytovská, Jarmila (referee)
Diploma Thesis, Hana Krejčová 2006 Abstract The theoretical part of thesis provides a brief overview of the transdermal administration of drugs, including the use of transdermal enhancer. Part concerning the CyA includes information about its structure, pharmacological effects, including adverse effects, its use in therapy and application possibilities. Experimental section presents the results of in vitro permeation experiments on pig skin. Acceptor phase consisted of propylene glycol and Tris-buffer pH 7.1 at a 1:1 ratio. The permeant determination was performed by HPLC with UV detection at 220 nm. It was confirmed that the choice of the acceptor and the mobile phase was appropriate. As a donor samples were used supersaturated CyA systems without enhancer, and also with the addition of 5% or Azone, methyl pyrrolidone or dodecyl pyrrolidone, or 1% of transkarbam 12. All the enhancers in the concentrations increase depot formation in skin, transkarbam 12 although used in the lowest concentration did it most.
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