Extra pulmonary tuberculosis makes up 10% of all tuberculosis cases and cutaneous tuberculosis (CTB) only a fraction of this 10%. CTB is caused by mainly Mycobacterium tuberculosis and can lead to scarring and deformities. The disease presents in different forms, from superficial granulomas to deeper ulceration and necrosis. Tissue cultures, polymerase chain reactions or purified protein derivative staining is used for the diagnosis of CTB (Barbagallo etal., 2002:320). Since the current treatment for CTB is oral anti-tubercular regimens and no topical treatment is available yet (Barbagallo et a!., 2002:320), this study aims to provide a topical preparation of isoniazide and rifampicin which will prevent the deformities and scarring caused by CTB and deliver quicker healing. This topical preparation is to be used in addition to oral treatment. Isoniazide and rifampicin are powerful first-line anti-tubercular drugs, active against both intra- and extracellular bacteria (SAMF, 2005:293). Human skin is a resistant and protective barrier against the external environment and the stratum corneum is the main barrier against diffusion of compounds through the skin (Williams, 2003:9). The physicochemical characteristics (lipophilicity and molecular size) of neither isoniazide nor rifampicin are optimal for penetration of the stratum corneum and the skin-friendly Pheroid™ delivery system was incorporated in two of the formulations to investigate the possibility of improving drug delivery. In this study the transdermal delivery of isoniazide and rifampicin was studied after formulation into four different topical preparations. The stability of these formulations were determined over a six month period under three different conditions of temperature and humidity (25°C/60% RH (relative humidity), 30°C/60% RH and 40°C/75% RH). Isoniazide and rifampicin were formulated into two Pheroid™ and two non-Pheroid™ spray formulations: lotion, Pheroid™ lotion, emulgel and Pheroid™ emulgel. Micrographs were taken with a confocal laser scanning microscope and it was seen that the formulations were homogenous and oil droplets were smaller than 10 urn, allowing permeation through skin. Vertical Franz diffusion cells were used for in vitro permeation studies, with cellulose acetate membranes, for 12 h periods at pH 7.4, to determine drug release. The donor phase was the formulation, with 5 mg/ml of isoniazide and 10 mg/ml of rifampicin. The actives were released from the formulations and small concentrations penetrated the membranes. Release for isoniazide was best from the Pheroid™ emulgel and for rifampicin from the Pheroid™ lotion. Thus it can be concluded that the Pheroid™ improved drug release. The diffusion study was repeated, substituting the membranes with female abdominal skin in order to investigate transdermal delivery. Isoniazide and rifampicin failed to permeate the skin from any of the formulations and no isoniazide or rifampicin could be found in the skin by means of tape stripping after 12 h. Stability tests performed at 4, 8, 12 and 24 weeks was the determination of drug concentrations, pH, weight loss, viscosity, particle size, physical appearance and colour change tests. In these emulsion-type formulations, rifampicin proved to be more stable than isoniazide and after 24 weeks minimal concentrations of isoniazide (20.2 ug/ml) was left. The Pheroid™ formulations were proven to be more stable than the non-Pheroid™ formulations. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Acne vulgaris is the single, most common disease that presents a significant challenge to dermatologists, due to its complexity, prevalence and range of clinical expressions. This condition can be found in 85% of teenage boys and 80% of girls (Gollnick, 2003:1580). Acne can cause serious psychological consequences (low self–esteem, social inhibition, depression, etc.), if left untreated, and should therefore be recognised as a serious disorder (Webster, 2001:15). The pathogenesis of acne is varied, with factors that include plugging of the follicle, accumulation of sebum, growth of Propionibacterium acnes (P. acnes), and inflammatory tissue responses (Wyatt et al., 2001:1809). Acne treatment focuses on the reduction of inflammatory and non–inflammatory acne lesions, and thus halts the scarring process (Railan & Alster, 2008:285). Non–inflammatory acne lesions can be expressed as open and closed comedones, whereas inflammatory lesions comprise of papules, pustules, nodules and cysts (Gollnick, 2003:1581). Acne treatment may be topical, or oral. Topical treatment is the most suitable first–line therapy for non–inflammatory comedones, or mildly inflammatory disease states, with the advantage of avoiding the possible systemic effects of oral medications (Federman & Kirsner, 2000:80). Topical retinoids were very successfully used for the treatment of acne in the 1980s. Their effectiveness in long–term therapies was limited though, due to local skin irritations that occurred in some individuals (Julie & Harper, 2004:S36). Vitamin A acetate presented a new approach in the treatment of acne, showing less side effects (Cheng & Depetris, 1998:7). In this study, vitamin A acetate and zinc acetate were formulated into semisolid, combination formulations for the possible treatment of acne. Whilst vitamin A controls the development of microcomedones, reduces existing comedones, diminishes sebum production and moderately reduces inflammation (Verschoore et al., 1993:107), zinc normalises hormone imbalances (Nutritional–supplements–health–guide.com, 2005:2) and normalises the secretion of sebum (Hostýnek & Maibach, 2002:35). Although the skin presents many advantages to the delivery of drugs, it unfortunately has some limitations. The biggest challenge in the transdermal delivery of drugs is to overcome the natural skin barrier. Its physicochemical properties are a good indication(s) of the transdermal behaviour of a drug. The ideal drug to be used in transdermal delivery would have sufficient lipophilic properties to partition into the stratum corneum, but it would also have sufficient hydrophilic properties to partition into the underlying layers of the skin (Kalia & Guy, 2001:159). Pheroid technology was also implemented during this study, in order to establish whether it would enhance penetration of the active ingredients across the skin. The Pheroid consists of vesicular structures that contain no phospholipids, nor cholesterol, but consists of the same essential fatty acids that are present in humans (Grobler et al., 2008:283). The aim of this study hence was to investigate the transdermal delivery of vitamin A acetate and zinc acetate, jointly formulated into four topical formulations for acne treatment. Vitamin A acetate (0.5%) and zinc acetate (1.2%) were formulated into a cream, Pheroid cream, emulgel and Pheroid emulgel. An existing commercial product, containing vitamin A acetate, was used to compare the results of the formulated products with. The transdermal, epidermal and dermal diffusion of the formulations were determined during a 6 h diffusion study, using Franz diffusion cells and tape stripping techniques. Experimental determination of the diffusion studies proved that vitamin A acetate did not penetrate through the skin. These results applied to both the formulations being developed during this study, as well as to the commercial product. Tape stripping studies were done to determine the concentration of drug present in the epidermis and dermis. The highest epidermal concentration of vitamin A acetate was obtained with the Pheroid emulgel (0.0045 ug/ml), whilst the emulgel formulation provided the highest vitamin A acetate concentration in the dermis (0.0029 ug/ml). Contrary, for the commercial product, the total concentration of vitamin A acetate in the epidermis was noticeably lower than for all the new formulations studied. Vitamin A acetate concentrations of the commercial product in the dermis were within the same concentration range as the newly developed formulations, with the exception of the emulgel that delivered approximately 31% more vitamin A acetate to the dermis, than the commercial product. Zinc acetate was able to diffuse through full thickness skin, although no flux values were obtained. To eliminate the possibility of endogenous zinc diffusion, placebo formulations (without zinc) were prepared for use as control samples during the skin diffusion investigation. The emulgel and Pheroid emulgel formulations were unable to deliver significant zinc acetate concentrations transdermally, although transdermal diffusion was attained from both the cream and Pheroid cream. Tape stripping experiments with placebo formulations relative to the formulated products revealed that zinc acetate concentrations in the epidermis and dermis were significantly higher when the placebo formulations were applied. However, the average zinc acetate concentration in the dermis, after application of the cream formulation, was significantly higher, compared to when the placebo cream was applied. It could therefore be concluded that no zinc acetate had diffused into the epidermis and dermis from the new formulations, except from the cream formulation. The zinc acetate concentration being measured in the epidermis thus rather represented the endogenous zinc acetate. The cream formulation, however, was probably able to deliver detectable zinc acetate concentrations to the epidermis. Stability of the formulated products was tested under a variety of environmental conditions to determine whether the functional qualities would remain within acceptable limits over a certain period of time. The formulated products were tested for a period of three months under storage conditions of 25°C/60% RH (relative humidity), 30°C/60% RH and 40°C/75% RH. Stability studies included stability indicating assay testing, the determination of rheology, pH, droplet size, zeta–potential, mass loss, morphology of the particles and physical assessment. The formulations were unstable over the three months stability test period. A change in viscosity, colour and concentration of the active ingredients were observed. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Non–melanoma skin cancer (NMSC) is the most common human malignancy and it is estimated that over 1.3 million cases are diagnosed each year in the United States (Neville et al., 2007:462). There are three main types of NMSC, which include basal–cell carcinoma (BCC), squamous–cell carcinoma (SCC) and cutaneous malignant melanoma (CMM). Exposure to ultra–violet (UV) radiation plays a major role in the aetiology of these three skin cancer types (Franceschi et al., 1996:24). 5–Fluorouracil is an antineoplastic pyrimidine analogue that functions as an anti–metabolite. It interferes with DNA (deoxyribonucleic acid), and to a lesser extent, with RNA (ribonucleic acid) synthesis by blocking the methylation of deoxyuridylic acid into thymidylic acid. It is used in topical preparations for the treatment of actinic keratosis (AK) and NMSC. The cure rate with topical 5–fluorouracil is partly reflected by the degree of erythema, erosions, and eventual crusting which develop at the sites of treatment. This reaction often attains the best clinical response, but in turn, frustrates patients, which may lead to patient incompliance (McGillis & Fein, 2004:175). Due to the hydrophilic nature of 5–fluorouracil, the transdermal permeation through the lipophilic stratum corneum is very low and trivial (Singh et al., 2005:99). Transdermal drug delivery is the delivery of a chemical substance across the skin to reach the systemic circulation (Prausnitz et al., 2004:115). This unique drug transport mechanism suggests many advantages that include safety, patient compliance, user–friendliness, efficiency and non–invasiveness (Fang et al., 2004:241). The stratum corneum is a specialised structure that forms part of several anatomically distinct layers of the skin. Seeing that it is the outermost layer, it provides protection to the skin. It is known as the main barrier to percutaneous absorption of compounds, as well as water loss, through the skin (Bouwstra et al., 2003:4). This study focussed on the formulation of six different types of semisolid formulations, containing 0.5% 5–fluorouracil. The formulations included: a cream, Pheroid cream, emulgel, Pheroid emulgel, lotion and Pheroid lotion. Pheroid refers to a delivery system which was incorporated in the formulations in an attempt to enhance the penetration of 5–fluorouracil into the skin. This drug delivery system consists of unique and stable lipid–based submicronand micron–sized structures, formulated in an emulsion. The dispersed Pheroid structures largely comprise of natural essential fatty acids, which have an affinity for the cell membranes of the human body (Grobler et al., 2008:284–285). These formulations were manufactured in large quantities and stored at three different temperatures, each with their respective relative humidity (RH): 25 °C/60% RH, 30 °C/60% RH and 40 °C/70% RH, for a period of six months. Stability tests were conducted on each of these formulations on the day of manufacture (month 0), and then after 1, 2, 3 and 6 months. The tests included: determination of concentration of the analytes (assay) by means of high performance liquid chromatography (HPLC); determination of zeta–potential and droplet size; pH measurement; viscosity; mass loss determination; physical appearance; and particle size distribution. Franz cell skin diffusion tests were performed with these six 5–fluorouracil containing semisolid formulations (0.5%), as well as with a 0.5% Pheroid solution, 0.5% non–Pheroid solution. A 5.0% Pheroid solution and a 5.0% non–Pheroid solution were also prepared in order to compare the skin diffusion test results to a 5.0% commercially available ointment. The data of the 0.5% formulations and solutions, as well as the 5.0% solutions and commercial ointment, were statistically compared and those formulations (and solutions) that yielded the best results, with regard to % diffused, epidermis and dermis concentrations, were identified. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Extra pulmonary tuberculosis makes up 10% of all tuberculosis cases and cutaneous tuberculosis (CTB) only a fraction of this 10%. CTB is caused by mainly Mycobacterium tuberculosis and can lead to scarring and deformities. The disease presents in different forms, from superficial granulomas to deeper ulceration and necrosis. Tissue cultures, polymerase chain reactions or purified protein derivative staining is used for the diagnosis of CTB (Barbagallo etal., 2002:320). Since the current treatment for CTB is oral anti-tubercular regimens and no topical treatment is available yet (Barbagallo et a!., 2002:320), this study aims to provide a topical preparation of isoniazide and rifampicin which will prevent the deformities and scarring caused by CTB and deliver quicker healing. This topical preparation is to be used in addition to oral treatment. Isoniazide and rifampicin are powerful first-line anti-tubercular drugs, active against both intra- and extracellular bacteria (SAMF, 2005:293). Human skin is a resistant and protective barrier against the external environment and the stratum corneum is the main barrier against diffusion of compounds through the skin (Williams, 2003:9). The physicochemical characteristics (lipophilicity and molecular size) of neither isoniazide nor rifampicin are optimal for penetration of the stratum corneum and the skin-friendly Pheroid™ delivery system was incorporated in two of the formulations to investigate the possibility of improving drug delivery. In this study the transdermal delivery of isoniazide and rifampicin was studied after formulation into four different topical preparations. The stability of these formulations were determined over a six month period under three different conditions of temperature and humidity (25°C/60% RH (relative humidity), 30°C/60% RH and 40°C/75% RH). Isoniazide and rifampicin were formulated into two Pheroid™ and two non-Pheroid™ spray formulations: lotion, Pheroid™ lotion, emulgel and Pheroid™ emulgel. Micrographs were taken with a confocal laser scanning microscope and it was seen that the formulations were homogenous and oil droplets were smaller than 10 urn, allowing permeation through skin. Vertical Franz diffusion cells were used for in vitro permeation studies, with cellulose acetate membranes, for 12 h periods at pH 7.4, to determine drug release. The donor phase was the formulation, with 5 mg/ml of isoniazide and 10 mg/ml of rifampicin. The actives were released from the formulations and small concentrations penetrated the membranes. Release for isoniazide was best from the Pheroid™ emulgel and for rifampicin from the Pheroid™ lotion. Thus it can be concluded that the Pheroid™ improved drug release. The diffusion study was repeated, substituting the membranes with female abdominal skin in order to investigate transdermal delivery. Isoniazide and rifampicin failed to permeate the skin from any of the formulations and no isoniazide or rifampicin could be found in the skin by means of tape stripping after 12 h. Stability tests performed at 4, 8, 12 and 24 weeks was the determination of drug concentrations, pH, weight loss, viscosity, particle size, physical appearance and colour change tests. In these emulsion-type formulations, rifampicin proved to be more stable than isoniazide and after 24 weeks minimal concentrations of isoniazide (20.2 ug/ml) was left. The Pheroid™ formulations were proven to be more stable than the non-Pheroid™ formulations. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Acne vulgaris is the single, most common disease that presents a significant challenge to dermatologists, due to its complexity, prevalence and range of clinical expressions. This condition can be found in 85% of teenage boys and 80% of girls (Gollnick, 2003:1580). Acne can cause serious psychological consequences (low self–esteem, social inhibition, depression, etc.), if left untreated, and should therefore be recognised as a serious disorder (Webster, 2001:15). The pathogenesis of acne is varied, with factors that include plugging of the follicle, accumulation of sebum, growth of Propionibacterium acnes (P. acnes), and inflammatory tissue responses (Wyatt et al., 2001:1809). Acne treatment focuses on the reduction of inflammatory and non–inflammatory acne lesions, and thus halts the scarring process (Railan & Alster, 2008:285). Non–inflammatory acne lesions can be expressed as open and closed comedones, whereas inflammatory lesions comprise of papules, pustules, nodules and cysts (Gollnick, 2003:1581). Acne treatment may be topical, or oral. Topical treatment is the most suitable first–line therapy for non–inflammatory comedones, or mildly inflammatory disease states, with the advantage of avoiding the possible systemic effects of oral medications (Federman & Kirsner, 2000:80). Topical retinoids were very successfully used for the treatment of acne in the 1980s. Their effectiveness in long–term therapies was limited though, due to local skin irritations that occurred in some individuals (Julie & Harper, 2004:S36). Vitamin A acetate presented a new approach in the treatment of acne, showing less side effects (Cheng & Depetris, 1998:7). In this study, vitamin A acetate and zinc acetate were formulated into semisolid, combination formulations for the possible treatment of acne. Whilst vitamin A controls the development of microcomedones, reduces existing comedones, diminishes sebum production and moderately reduces inflammation (Verschoore et al., 1993:107), zinc normalises hormone imbalances (Nutritional–supplements–health–guide.com, 2005:2) and normalises the secretion of sebum (Hostýnek & Maibach, 2002:35). Although the skin presents many advantages to the delivery of drugs, it unfortunately has some limitations. The biggest challenge in the transdermal delivery of drugs is to overcome the natural skin barrier. Its physicochemical properties are a good indication(s) of the transdermal behaviour of a drug. The ideal drug to be used in transdermal delivery would have sufficient lipophilic properties to partition into the stratum corneum, but it would also have sufficient hydrophilic properties to partition into the underlying layers of the skin (Kalia & Guy, 2001:159). Pheroid technology was also implemented during this study, in order to establish whether it would enhance penetration of the active ingredients across the skin. The Pheroid consists of vesicular structures that contain no phospholipids, nor cholesterol, but consists of the same essential fatty acids that are present in humans (Grobler et al., 2008:283). The aim of this study hence was to investigate the transdermal delivery of vitamin A acetate and zinc acetate, jointly formulated into four topical formulations for acne treatment. Vitamin A acetate (0.5%) and zinc acetate (1.2%) were formulated into a cream, Pheroid cream, emulgel and Pheroid emulgel. An existing commercial product, containing vitamin A acetate, was used to compare the results of the formulated products with. The transdermal, epidermal and dermal diffusion of the formulations were determined during a 6 h diffusion study, using Franz diffusion cells and tape stripping techniques. Experimental determination of the diffusion studies proved that vitamin A acetate did not penetrate through the skin. These results applied to both the formulations being developed during this study, as well as to the commercial product. Tape stripping studies were done to determine the concentration of drug present in the epidermis and dermis. The highest epidermal concentration of vitamin A acetate was obtained with the Pheroid emulgel (0.0045 ug/ml), whilst the emulgel formulation provided the highest vitamin A acetate concentration in the dermis (0.0029 ug/ml). Contrary, for the commercial product, the total concentration of vitamin A acetate in the epidermis was noticeably lower than for all the new formulations studied. Vitamin A acetate concentrations of the commercial product in the dermis were within the same concentration range as the newly developed formulations, with the exception of the emulgel that delivered approximately 31% more vitamin A acetate to the dermis, than the commercial product. Zinc acetate was able to diffuse through full thickness skin, although no flux values were obtained. To eliminate the possibility of endogenous zinc diffusion, placebo formulations (without zinc) were prepared for use as control samples during the skin diffusion investigation. The emulgel and Pheroid emulgel formulations were unable to deliver significant zinc acetate concentrations transdermally, although transdermal diffusion was attained from both the cream and Pheroid cream. Tape stripping experiments with placebo formulations relative to the formulated products revealed that zinc acetate concentrations in the epidermis and dermis were significantly higher when the placebo formulations were applied. However, the average zinc acetate concentration in the dermis, after application of the cream formulation, was significantly higher, compared to when the placebo cream was applied. It could therefore be concluded that no zinc acetate had diffused into the epidermis and dermis from the new formulations, except from the cream formulation. The zinc acetate concentration being measured in the epidermis thus rather represented the endogenous zinc acetate. The cream formulation, however, was probably able to deliver detectable zinc acetate concentrations to the epidermis. Stability of the formulated products was tested under a variety of environmental conditions to determine whether the functional qualities would remain within acceptable limits over a certain period of time. The formulated products were tested for a period of three months under storage conditions of 25°C/60% RH (relative humidity), 30°C/60% RH and 40°C/75% RH. Stability studies included stability indicating assay testing, the determination of rheology, pH, droplet size, zeta–potential, mass loss, morphology of the particles and physical assessment. The formulations were unstable over the three months stability test period. A change in viscosity, colour and concentration of the active ingredients were observed. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Non–melanoma skin cancer (NMSC) is the most common human malignancy and it is estimated that over 1.3 million cases are diagnosed each year in the United States (Neville et al., 2007:462). There are three main types of NMSC, which include basal–cell carcinoma (BCC), squamous–cell carcinoma (SCC) and cutaneous malignant melanoma (CMM). Exposure to ultra–violet (UV) radiation plays a major role in the aetiology of these three skin cancer types (Franceschi et al., 1996:24). 5–Fluorouracil is an antineoplastic pyrimidine analogue that functions as an anti–metabolite. It interferes with DNA (deoxyribonucleic acid), and to a lesser extent, with RNA (ribonucleic acid) synthesis by blocking the methylation of deoxyuridylic acid into thymidylic acid. It is used in topical preparations for the treatment of actinic keratosis (AK) and NMSC. The cure rate with topical 5–fluorouracil is partly reflected by the degree of erythema, erosions, and eventual crusting which develop at the sites of treatment. This reaction often attains the best clinical response, but in turn, frustrates patients, which may lead to patient incompliance (McGillis & Fein, 2004:175). Due to the hydrophilic nature of 5–fluorouracil, the transdermal permeation through the lipophilic stratum corneum is very low and trivial (Singh et al., 2005:99). Transdermal drug delivery is the delivery of a chemical substance across the skin to reach the systemic circulation (Prausnitz et al., 2004:115). This unique drug transport mechanism suggests many advantages that include safety, patient compliance, user–friendliness, efficiency and non–invasiveness (Fang et al., 2004:241). The stratum corneum is a specialised structure that forms part of several anatomically distinct layers of the skin. Seeing that it is the outermost layer, it provides protection to the skin. It is known as the main barrier to percutaneous absorption of compounds, as well as water loss, through the skin (Bouwstra et al., 2003:4). This study focussed on the formulation of six different types of semisolid formulations, containing 0.5% 5–fluorouracil. The formulations included: a cream, Pheroid cream, emulgel, Pheroid emulgel, lotion and Pheroid lotion. Pheroid refers to a delivery system which was incorporated in the formulations in an attempt to enhance the penetration of 5–fluorouracil into the skin. This drug delivery system consists of unique and stable lipid–based submicronand micron–sized structures, formulated in an emulsion. The dispersed Pheroid structures largely comprise of natural essential fatty acids, which have an affinity for the cell membranes of the human body (Grobler et al., 2008:284–285). These formulations were manufactured in large quantities and stored at three different temperatures, each with their respective relative humidity (RH): 25 °C/60% RH, 30 °C/60% RH and 40 °C/70% RH, for a period of six months. Stability tests were conducted on each of these formulations on the day of manufacture (month 0), and then after 1, 2, 3 and 6 months. The tests included: determination of concentration of the analytes (assay) by means of high performance liquid chromatography (HPLC); determination of zeta–potential and droplet size; pH measurement; viscosity; mass loss determination; physical appearance; and particle size distribution. Franz cell skin diffusion tests were performed with these six 5–fluorouracil containing semisolid formulations (0.5%), as well as with a 0.5% Pheroid solution, 0.5% non–Pheroid solution. A 5.0% Pheroid solution and a 5.0% non–Pheroid solution were also prepared in order to compare the skin diffusion test results to a 5.0% commercially available ointment. The data of the 0.5% formulations and solutions, as well as the 5.0% solutions and commercial ointment, were statistically compared and those formulations (and solutions) that yielded the best results, with regard to % diffused, epidermis and dermis concentrations, were identified. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

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.

Thesis (M.S.)--University of Michigan, 1983.

Thesis (M. Sc.)--Memorial University of Newfoundland, 1997. / Bibliography: leaves 95-108.

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.