Nanoparticles are thought to present a unique hazard to human health. Furthermore, the increasing use of nanomaterials in consumer products has not been accompanied by relevant risk assessments. It is conceivable that skin flexion may assist the translocation of nanoparticles across the stratum corneum. However, current in vitro methodology to study dermal absorption involves the exclusive use of immobile skin within diffusion cells. Therefore, a novel skin-flexing diffusion cell system (“CutaFlex™”) was developed to incorporate reproducible skin flexing (2 flexes min-1; 6 mm maximum amplitude). The initial aims of this Thesis were to characterise the CutaFlex™ system to eliminate the possibility of flexion-induced (experimental) skin damage, demonstrate equivalence with historical permeability data to model compounds and assess the effect of skin flexing on barrier disruption. Subsequent work aimed to investigate the hypothesis that nanoparticles require dermal flexion to penetrate intact skin. In supporting these aims, this Thesis also performed work to assess the correlation between direct measurements of skin barrier function (using tritiated water) and transepidermal water loss (TEWL), the effect of flexing on the performance of topical skin protectants (barrier creams) and to further validate in vitro diffusion cell measurements against in vivo data acquired under identical conditions. The results demonstrated that skin flexing did not alter skin barrier function and that the CutaFlex™ system was in general agreement with historical measurements of skin permeability. Furthermore, controlled chemical or physical damage to the stratum corneum was not exacerbated by skin flexing. Skin flexion did not facilitate the dermal absorption of a range of nanoparticles (quantum dots). However, differences in the partitioning of nanoparticles into the stratum corneum were observed (independent of the degree of flexing), with greater amounts of negatively charged nanoparticles found in the superficial layers of the stratum corneum in comparison with positive or neutral nanoparticles. Flexing had a modest effect on the performance of a skin barrier cream which was limited to low dose applications; an effect tentatively ascribed to flexion-induced movement of cream to previously untreated areas. A poor correlation was found between 3H2O water permeability and TEWL flux. Most importantly, there was excellent agreement between in vitro skin permeability studies and in vivo studies (which used a surrogate measure of skin permeability). To summarise, the data in this Thesis has led to the development and characterisation of a novel diffusion cell (CutaFlex™), capable of simultaneously flexing skin whilst performing dermal absorption measurements comparable with the OECD-compliant models.

<p> A diffusion cell of the "shearing type" was used to diminish the effect of convection which is always present when two liquid phases are brought into contact with each other in a diffusion cell. Also a special optical arrangement was used to photograph the refractive index distribution of the system. For those systems with refractive index changing linearly with concentration, the concentration profiles were obtained and diffusion coefficients were calculated at different concentrations. </p> <p> This optical method gave only fair reproducibility- the deviation among diffusivities found for systems investigated varying from 3 to 10%- however, it permitted rapid analysis and on this basis is recommended for situations where speed is essential and high accuracy is not required. </p> / Thesis / Master of Engineering (ME)

A rotating diffusion cell (RDC) has been used to study the kinetics of extraction of the transition metals cobalt (II), nickel (II), copper (II) and zinc (II) from sulphate solutions into either of two extractants held in n-heptane; di-(2-ethylhexyl) phosphoric acid (D2EHPA) or di-(2- ethylhexyl) dithiophosphoric acid (D2EHDTPA). The metal concentration was 10 mM and the aqueous pH was held at 4.5. The extractant concentration was varied between 0.015 to 0.4 M. In the case of cobalt extraction by D2EHPA, the metal concentration and the pH were varied Different diluents and modifiers were also studied.The rate of extraction by D2EHDTPA was found to be faster than D2EHPA. A comprehensive mathematical model, based upon established two film theory, was developed and used to describe the above experimental results. The model was also used to predict values of the important parameters. ... These values compared well with those found by other authors but using quite different experimental techniques. OS4 In the case of cobalt extraction by D2EHPA, the more polar diluents lowered the initial rate. The overall model predicts such behaviour where the rate is also dependent on the partition coefficients of the extractant. Finally, the theory of the RDC allows the prediction of the diffusion layer thicknesses, this information together with the reaction zone thickness is used to explore the influences of diffusion and chemical reaction on the overall transfer process. The diffusion processes are calculated to be the most important of the two. This is especially so for the D2EHDTPA systems.

Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

5-Fluorouracil (5FU) is a pyrimidine analogue, indicated for the therapy of proliferative skin diseases such as actinic keratosis (AK), superficial basal cell carcinoma and psoriasis. It has also been used for the treatment of solid tumours like colorectal, breast and liver carcinomas for nearly 40 years. Although 5FU has always been administered parenterally and orally, metabolism is rapid and absorption is erratic. Several severe side-effects are also commonly associated with 5FU therapy, including myelosuppression, hand-foot syndrome and gastrointestinal effects. Seeing that 5FU is an important part of the treatment of several malignant and pre-malignant disorders, it would be advantageous to find a delivery route and delivery system that negate absorption and metabolic variation and decrease side-effects. The transdermal route provides a promising alternative to the above-mentioned conventional delivery routes, solving most of the problems associated with parenteral and oral administration. That being said, the formidable barrier situated in the skin is not easily breached. The stratum corneum, the outermost skin layer, is mostly lipophilic in nature, preventing hydrophilic molecules such as 5FU from entering. 5FU-containing creams and lotions are currently commercially available, but absorption is still very limited. The transdermal absorption from these formulations has been compared to that obtained with the use of new transdermal delivery vehicles, with the newer formulations proving to be promising. It was decided to entrap 5FU in a novel therapeutic system, in the form of the Pheroid™ system, to increase its transdermal penetration. Pheroid™ vesicles are stable spherical structures in a unique, emulsion-like formulation, and fall in the submicron range. The main components of the Pheroid™ system are the ethyl esters of the essential fatty acids linoleic acid and linolenic acid, as well as the cys-form of oleic acid, and water. The formulation is saturated with nitrous oxide (N20). Although Pheroid™ vesicles may resemble other lipid-based vehicles, such as liposomes and micro-emulsions, they are unique in the sense that they have inherent therapeutic qualities as well. The Pheroid™ formulation can be specifically manipulated to yield different types of vesicles, ensuring a fast transport rate, high entrapment efficiency, rapid delivery and stability of the delivery system for a specific drug. In this study, 5FU was entrapped in the Pheroid™ formulation. Transdermal permeation studies were then performed to evaluate the influence of this delivery system on the transdermal flux of 5FU. Vertical Franz diffusion cells were utilised to determine the transdermal penetration of 5FU. Only Caucasian female abdominal skin was used to minimise physiological variables. Diffusion studies were done over 12 hour periods, with the entire receptor phase being withdrawn at predetermined intervals. Samples were analysed using high performance liquid chromatography (HPLC), after which the cumulative concentration of active was plotted against time. The linear portion of this graph represents the flux of 5FU through the skin. It was found that there were differences in the results between formulations containing 5FU in a phosphate buffer solution (PBS)-based Pheroid™ and water-based Pheroid™, though the difference was not statistically significant. The 0.5 % 5FU in water-based Pheroid™ resulted in a significantly bigger yield than the control (1 % 5FU in water) as well as a significant difference to the 1 % 5FU in PBS-based Pheroid™ formulation. In general the water-based Pheroid™ formulations had greater average cumulative concentrations, yields and fluxes than the other formulations. The fluxes obtained with the water-based Pheroid™ formulations also correlated well with a previous study done by Kilian (2004). Thus it can be concluded that the Pheroid™ therapeutic delivery system enhances the transdermal penetration of 5FU. Water-based Pheroid™ formulations proved to be more effective than PBS-based Pheroid™ formulations. It can also be concluded that a 0.5 % 5FU in water-based Pheroid™ formulation can be used instead of a 1 % formulation, because there were no statistically significant differences between the two formulations. This would be advantageous - patient compliance can be enhanced because of a more tolerable formulation with fewer side effects, while manufacturing cost is lowered by using a lower concentration of active. It is recommended that some aspects of the study be investigated further to optimise the transdermal delivery of 5FU using the Pheroid™ therapeutic system. These aspects include optimising the composition of the Pheroid formulation, investigating the entrapment process of 5FU within Pheroid™ spheres, the influence of PBS and water as basis of the Pheroid™ formulation and the amount of 5FU remaining in the epidermis after the 12 hour period of the diffusion study. Keywords: 5-Fluorouracil, Franz diffusion cell, Heat separated epidermis, Skin penetration, Transdermal, Drug delivery system, Pheroid™ / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

5-Fluorouracil (5FU) is a pyrimidine analogue, indicated for the therapy of proliferative skin diseases such as actinic keratosis (AK), superficial basal cell carcinoma and psoriasis. It has also been used for the treatment of solid tumours like colorectal, breast and liver carcinomas for nearly 40 years. Although 5FU has always been administered parenterally and orally, metabolism is rapid and absorption is erratic. Several severe side-effects are also commonly associated with 5FU therapy, including myelosuppression, hand-foot syndrome and gastrointestinal effects. Seeing that 5FU is an important part of the treatment of several malignant and pre-malignant disorders, it would be advantageous to find a delivery route and delivery system that negate absorption and metabolic variation and decrease side-effects. The transdermal route provides a promising alternative to the above-mentioned conventional delivery routes, solving most of the problems associated with parenteral and oral administration. That being said, the formidable barrier situated in the skin is not easily breached. The stratum corneum, the outermost skin layer, is mostly lipophilic in nature, preventing hydrophilic molecules such as 5FU from entering. 5FU-containing creams and lotions are currently commercially available, but absorption is still very limited. The transdermal absorption from these formulations has been compared to that obtained with the use of new transdermal delivery vehicles, with the newer formulations proving to be promising. It was decided to entrap 5FU in a novel therapeutic system, in the form of the Pheroid™ system, to increase its transdermal penetration. Pheroid™ vesicles are stable spherical structures in a unique, emulsion-like formulation, and fall in the submicron range. The main components of the Pheroid™ system are the ethyl esters of the essential fatty acids linoleic acid and linolenic acid, as well as the cys-form of oleic acid, and water. The formulation is saturated with nitrous oxide (N20). Although Pheroid™ vesicles may resemble other lipid-based vehicles, such as liposomes and micro-emulsions, they are unique in the sense that they have inherent therapeutic qualities as well. The Pheroid™ formulation can be specifically manipulated to yield different types of vesicles, ensuring a fast transport rate, high entrapment efficiency, rapid delivery and stability of the delivery system for a specific drug. In this study, 5FU was entrapped in the Pheroid™ formulation. Transdermal permeation studies were then performed to evaluate the influence of this delivery system on the transdermal flux of 5FU. Vertical Franz diffusion cells were utilised to determine the transdermal penetration of 5FU. Only Caucasian female abdominal skin was used to minimise physiological variables. Diffusion studies were done over 12 hour periods, with the entire receptor phase being withdrawn at predetermined intervals. Samples were analysed using high performance liquid chromatography (HPLC), after which the cumulative concentration of active was plotted against time. The linear portion of this graph represents the flux of 5FU through the skin. It was found that there were differences in the results between formulations containing 5FU in a phosphate buffer solution (PBS)-based Pheroid™ and water-based Pheroid™, though the difference was not statistically significant. The 0.5 % 5FU in water-based Pheroid™ resulted in a significantly bigger yield than the control (1 % 5FU in water) as well as a significant difference to the 1 % 5FU in PBS-based Pheroid™ formulation. In general the water-based Pheroid™ formulations had greater average cumulative concentrations, yields and fluxes than the other formulations. The fluxes obtained with the water-based Pheroid™ formulations also correlated well with a previous study done by Kilian (2004). Thus it can be concluded that the Pheroid™ therapeutic delivery system enhances the transdermal penetration of 5FU. Water-based Pheroid™ formulations proved to be more effective than PBS-based Pheroid™ formulations. It can also be concluded that a 0.5 % 5FU in water-based Pheroid™ formulation can be used instead of a 1 % formulation, because there were no statistically significant differences between the two formulations. This would be advantageous - patient compliance can be enhanced because of a more tolerable formulation with fewer side effects, while manufacturing cost is lowered by using a lower concentration of active. It is recommended that some aspects of the study be investigated further to optimise the transdermal delivery of 5FU using the Pheroid™ therapeutic system. These aspects include optimising the composition of the Pheroid formulation, investigating the entrapment process of 5FU within Pheroid™ spheres, the influence of PBS and water as basis of the Pheroid™ formulation and the amount of 5FU remaining in the epidermis after the 12 hour period of the diffusion study. Keywords: 5-Fluorouracil, Franz diffusion cell, Heat separated epidermis, Skin penetration, Transdermal, Drug delivery system, Pheroid™ / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

Transdermal drug delivery (TDD) is limited by high resistance of the outer layer of the skin, namely stratum corneum which blocks any molecule that is larger than 500 Da. Research on TDD has become very active in recent years and various technologies have been developed to overcome the resistance of the stratum corneum. In particular, researchers have started to consider the possibility of combining the TDD technologies in order to achieve further increment for drug permeability. Microneedles (MNs) and sonophoresis are both promising technologies that can perform notable enhancement in drug permeation via different mechanisms and therefore give a good potential for combining with each other. We discuss the possible ways to achieve this combination as well as how this combination would increase the permeability. Some of the undeveloped (weaker) research areas of MNs and sonophoresis are also discussed in order to understand the true potential of combining the two technologies when they are developed further in the future. We propose several hypothetical combinations based on the possible mechanisms of MNs and sonophoresis.

The diploma thesis focuses on utilization of diffusion cells in reactivity mapping study on humic acids. In the experimental part, samples 6 humic acids of different origin or chemical modification were studied. All the samples were characterized by basic analytical and physico-chemical methods (elemental analysis, thermogravimetry, determination of acidity, spectrometry). Methylene blue was utilized as a model reactive probe and agarose gel as an inert support medium. An effect of interactions between humic acids and methylene blue on diffusivity of the dye in the hydrogel was determined and discussed.

A rotating diffusion cell (RDC) has been used to study the kinetics of extraction of the transition metals cobalt (II), nickel (II), copper (II) and zinc (II) from sulphate solutions into either of two extractants held in n-heptane; di-(2-ethylhexyl) phosphoric acid (D2EHPA) or di-(2- ethylhexyl) dithiophosphoric acid (D2EHDTPA). The metal concentration was 10 mM and the aqueous pH was held at 4.5. The extractant concentration was varied between 0.015 to 0.4 M. In the case of cobalt extraction by D2EHPA, the metal concentration and the pH were varied Different diluents and modifiers were also studied.The rate of extraction by D2EHDTPA was found to be faster than D2EHPA. A comprehensive mathematical model, based upon established two film theory, was developed and used to describe the above experimental results. The model was also used to predict values of the important parameters. ... These values compared well with those found by other authors but using quite different experimental techniques. OS4 In the case of cobalt extraction by D2EHPA, the more polar diluents lowered the initial rate. The overall model predicts such behaviour where the rate is also dependent on the partition coefficients of the extractant. Finally, the theory of the RDC allows the prediction of the diffusion layer thicknesses, this information together with the reaction zone thickness is used to explore the influences of diffusion and chemical reaction on the overall transfer process. The diffusion processes are calculated to be the most important of the two. This is especially so for the D2EHDTPA systems. / University of Bradford Scholarship Award

No description available.