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M.A. PELLETT1, A.C. WATKINSON2, K.R. BRAIN2 AND J. HADGRAFT11Welsh School of Pharmacy, UWC, Cardiff and 2An-eX, Redwood Building, Cardiff, CF1 3XF, UK sample of the supernatant, saturatedconcentrations of flurbiprofen in each of the The transport of drugs across the stratum cosolvent mixtures were determined using HPLC.
corneum (SC) often requires enhancement, and anumber of methods to achieve this are available.
Preparation of Isolated Human Stratum Corneum Many of the mechanisms of action areindependent of each other, which offers the potential to exploit synergism between different methods of enhancement. This study investigated dissection, and the epidermis removed by heat a possible synergistic effect on the enhancement separation. This involved immersion of full- of flurbiprofen permeation across human skin thickness skin in water at 60°C for one minute, using supersaturated solutions and oleic acid followed by careful teasing of the epidermis from (OA). Supersaturated states of a drug increase the dermis. The viable tissue was removed by the thermodynamic activity beyond that of a soaking in a phosphate buffered saline solution saturated solution, such that the leaving tendency pH 7.4 containing 0.0001% trypsin overnight at of a drug from a vehicle exceeds that from a 37°C. The tissue was then washed thoroughly in saturated solution1,2. OA is thought to exhibit an water and quickly dipped into hexane to aid in the enhancing effect by increasing the diffusivity of a manipulation of the tissue. The SC was then drug in the SC3. In terms of Fick’s first law of spread onto the surface of some tepid water and floated onto a filter paper support. Thepreparations were allowed to air dry before storage in the freezer until required. This procedure has been shown not to compromise the (where J is the flux, D is the diffusion coefficient, K is the integrity of the barrier properties of SC4.
apparent partition coefficient, A is the area available for diffusion, h is the diffusional pathlength, and C is the concentration of permeant in the donor phase) OA is thought to increase D, whereas super- Regular static skin diffusion cells presenting a saturated systems increase C . Thus, increasing diffusional surface area of ~1cm2, and a receptor both these parameters would be expected to volume of ~2.5ml were used. Isolated human SC result in a multiplicative effect on J. Such a result was mounted between the cell compartments.
would also infer independent mechanisms of action for these two methods of enhancement.
phosphate buffered saline pH 7.4, which had beendegassed by vacuum filtration through a Whatman 0.45µm membrane filter. Constant mixing of thereceptor phase was achieved by inclusion of magnetic bars in the receptor compartments. Thecells were placed on a magnetic stirring bed Flurbiprofen was from Boots Plc (Nottingham, submerged in a water bath at 37°C, and allowed UK), propylene glycol (PG) and chloroform from to equilibrate overnight (~16hrs). Under these Fisons (Loughborough, UK), HPLC grade aceto- conditions, the surface of the SC was maintained nitrile and methanol from Rathburn (Walkerburn, at 32°C (in vivo condition). Donor compartments UK), hydroxypropylmethyl cellulose (HPMC) from were completely filled (~1.5ml) with the test Shin-Etsu Chemical Co. Ltd (Tokyo, Japan) and solutions, and occluded for the duration of the bovine trypsin from Aldrich (UK). All other experiment. At pre-determined time points, 400µl chemicals (Aldrich) were of at least reagent grade samples were removed from the receptor phase and used as supplied, unless indicated. Human and replaced with an equal volume of pre- skin was obtained after cosmetic surgery from a equilibrated receptor phase. The samples were local hospital and stored frozen until required.
Water was double distilled and then purified by aMilli-Q Plus water polishing system (Millipore) The preparation of supersaturated solutions has which yielded a product of resistivity 18.2MΩ cm.
been described in detail elsewhere1. In thisinstance, supersaturated solutions of flurbiprofen were prepared by diluting solutions of flurbiprofenin PG with phosphate citrate buffer pH 3.0. The Saturated solubilities of flurbiprofen in PG/buffer resultant cosolvent mixtures consisted of 25% PG pH 3.0 mixtures were determined by stirring and 75% buffer pH 3.0, and 1% HPMC added as excess solid for 48hrs at either 25°C or 32°C.
antinucleant. Supersaturated solutions up to 10 After centrifugation and appropriate dilution of a degrees of saturation (equivalent to a ten fold increase in the concentration of a saturated into the SC was calculated for each degree of solution) were prepared, and their penetration saturation. Due to evaporation of water from the across isolated human SC was monitored.
solvent mixtures at high temperatures, it wasnecessary to perform this part of the study at The effect of different concentrations of the ambient temperature. Therefore, supersaturated penetration enhancer, OA, on the permeation of solutions were prepared in relation to the flurbiprofen across SC from saturated solutions of saturated solubility of flurbiprofen at 25°C.
25%/75% PG/buffer mixtures was investigated.
The SC in the diffusion cells was pre-treated for 1hr with 70µl of ethanol (control), or ethanolicsolutions of 1.4% (50mM), 2.8% (100mM) or 5.6% An LDC Constametric IIIG pump (1ml/min) and Spectromonitor III UV detector (247nm) wereused with an LDC CI4100 computing integrator, Synergy between these two types of penetration 25cm x 4.6mm Apex ODS 5µm column (Jones, enhancement was investigated by pre-treating SC UK) and mobile phase of 50% acetonitrile/50% with a 2.8% ethanolic solution of OA, and then water adjusted to pH 3.0 with acetic acid.
applying a supersaturated solution with six Samples were injected via a 20µl loop using a Spark Holland Marathon autosampler. Retentiontime for flurbiprofen was ~9mins, and calibration Diffusion profiles were plotted using cumulative curves were constructed using peak areas.
amounts of flurbiprofen diffused against time, andthe P P equation (Eq. 2) used to calculate flux Saturated solubilities for flurbiprofen in PG/buffer mixtures are given in Table 1. Values increasedmarkedly with increasing percentage of PG. The where u represents the mass per unit area entering the degrees of saturation that can be achieved with receptor phase at time, t. P and P represent Kh and D/h2 respectively, and C is the concentration of permeant in the saturated solubility of flurbiprofen in 25%/75%PG/buffer at 25°C was 0.088mg/ml.
A best fit to the diffusion profiles was obtained Table 1 Solubility of flurbiprofen in PG/buffer pH
using Ultrafit software and with n=10. The 3.0 mixtures at 32°C (mean values, n=4).
product P P equates to DK/h (the permeability Values in brackets indicate maximum
coefficient) which, when multiplied by the degrees of saturation that could be
concentration in the vehicle, gives a value for the achieved with each mixture
Sections of isolated SC were fully hydrated by floating them onto the surface of some water and then onto a teflon mesh (which was used to aid in the removal of any residual water droplets). TheSC was weighed, and then soaked at ambient temperature (~25°C) overnight in saturated andsupersaturated (up to 10 degrees of saturation) Diffusion of a range of supersaturated solutions of solutions of flurbiprofen in 25%/75% PG/buffer flurbiprofen from 25%/75% PG/buffer vehicles vehicles. The SC was washed in water to remove across isolated human SC was monitored and flux any vehicle droplets off the surface, and blotted values determined using Equation 2 (Fig. 1). Flux dry with tissue. The flurbiprofen was extracted increased linearly up to six degrees of saturation, from the SC with three separate 2ml volumes of a after which the flux plateaued. There are two 50%/50% chloroform/methanol mixture. The SC possible explanations for this behaviour.
was allowed to soak in the first two volumes for Supersaturated solutions are inherently unstable 2hrs, before 1.5ml was removed. For the third and the drug may have crystallised out of solution volume, the SC was allowed to soak for 14hrs.
in the donor compartment. This would reduce the The first two 1.5ml volumes were combined, and driving force for diffusion, and hence a lower flux the samples were evaporated to dryness. The residue was redissolved in 0.5ml mobile phase crystallisation process occurs, it would normally (see below) and analysed for flurbiprofen by continue until a more stable state was obtained which would usually be a saturated solution.
chloroform/methanol was also analysed by HPLC Therefore, the flux would be expected to fall so to demonstrate that all of the drug had been that it was the same as that for a saturated extracted. The amount of drug that partitioned solution, but this did not actually occur.
Flux of flurbiprofen from supersaturated
Effect of concentrations of OA on the
solutions in 25%/75% PG/buffer across
diffusion of flurbiprofen from saturated
human SC. Mean±SE, n 4
solutions. Mean±SE, n=6
Control (ethanol)1.4% OA in ethanol2.8% OA in ethanol An alternative possibility is that the drug may have crystallised within the SC. Previous work has shown that for penetration enhancement fromsupersaturated solutions to be successful, the Multiplicative, synergistic enhancement of flurbiprofen across human SC was investigated by supersaturated state6. Thus, if the degree of pre-treating the membrane with OA for 1hr and supersaturation that the SC would support was then introducing a supersaturated solution to the limited then the drug may have crystallised within donor compartment (Fig. 4). Flux values were this membrane. Fig. 2 shows the uptake of determined using Equation 2, and enhancement Uptake of flurbiprofen into SC from
Synergistic effects on enhancement
supersaturated solutions. Mean±SE, n=3
of flurbiprofen across human SC using
supersaturated solutions and OA

( pre-treatments and degrees of
saturation shown in the legend).
Mean ±SE, n 5

2.8% in EtOH / 6-fold supersaturated soln.
There was a linear correlation betweenconcentration of flurbiprofen in SC and the degree of saturation. However, as with the flux values(Fig. 1), this relationship only held up to 6 degrees of saturation. Beyond this point, the amount of flurbiprofen in the membrane fell to almost halfthat at 8 degrees of saturation, before rising slightly to 10 degrees of saturation. These results suggested that both of the above phenomena may have been involved in the flux limitation beyond 6degrees of saturation. The enhancing effect of OA on penetration of flurbiprofen across human SC supersaturated solution after pre-treatment with was investigated by pre-treating the membrane ethanol was 4.5, and the enhancement ratio with different concentrations of OA in ethanol (Fig.
observed after pre-treatment with OA was 2.1.
3). The lack of significant differences between the Therefore, a multiplicative effect would be expected to result in a 9.5-fold increase (4.5 x 2.1) concentrations of OA implied that the mechanism in penetration. In fact, a 9.9-fold increase was Table 2 Flux values and enhancement ratios (ER)
for penetration of flurbiprofen across
human SC.

The authors would like to thank the EPSRC andAn-eX, for providing financial support for thisproject, and Adrian Davis for some helpful References
1. Davis AF and Hadgraft J, Effect of super- saturation on membrane transport: 1. Hydro- cortisone acetate, Int J.Pharm., 76, 1-8 (1991) 2. Pellett MA, Castellano S, Hadgraft J and Davis AF, Penetration of supersaturated solutions of piroxicam across silicone membranes andhuman skin in vitro, J.Cont.Rel., 46, 205-214 3. Mak VHW, Potts RO and Guy RH, Oleic acid concentration and effect in human stratumcorneum: non-invasive determination by The fact that multiplicative effects on flux were attenuated total reflectance infrared spectro- observed suggested that the mechanisms of scopy in vivo, J.Cont.Rel.,12, 67-75 (1990) enhancement for supersaturation and OA wereindependent of each other. In other situations, 4. Pellett MA, Watkinson AC, Green DM, Brain with other methods of enhancement, it is possible KR and Hadgraft J, Measurement of diffusional that the mechanisms of action are not as mutually pathlengths using diffusion cells and ATR-FTIR spectrsocopy. Part 2 - Stratum corneum, Proc.
24th Int. Symp. on Contr. Rel. of Bioact. Mat., Furthermore, with reference to Fick’s first law of diffusion (Equation 2), it is possible to alter otherparameters using other methods of enhancement 5. Watkinson AC, Brain KR and Walters KA, The so that similar multiplicative effects are observed, penetration of ibuprofen through human skin in vitro: vehicle, enhancer and pH effects,Prediction of Percutaneous Penetration , Vol 3b, 1993, (eds KR Brain, VJ James and KAWalters) STS Publishing, Cardiff, pp335-341 These experiments demonstrated that synergisticmultiplicative enhancement of the permeation of 6. Pellett MA, Roberts MS and Hadgraft J, flurbiprofen across isolated human SC can be Supersaturated solutions evaluated with an in achieved using different methods of enhancement vitro stratum corneum tape stripping technique,


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