The skin is the largest and most easily accessible organ of the human body thus making it the ideal route for systemic drug delivery. The transdermal route of drug delivery offers several advantages compared to the traditional routes including elimination of first pass metabolism and higher patient compliance. However, many drugs are topically and systemically ineffective when applied onto the skin, due to their almost complete failure to penetrate the skin. The main limitation lies in the stratum corneum, the barrier of the skin, which prevent the drug from reaching the deeper skin strata. 5-Fluorouracil is a polar hydrophilic drug and is therefore not a good penetrant through skin. A popular technique to increase transdermal permeation is to use a penetration enhancer, which reversibly reduce the permeability barrier of the stratum corneum. The primary aim of this study was to determine the effect of Brij 97 in the presence and absence of carrageenan on the transdermal delivery of 5-fluorouracil. The formulations were identified by means of confocal laser scanning microscopy and measurement of the particle size. The zeta-potential was measured to determine whether the formulations were stable and the pH was measured to determine if the internal structures of the formulations were affected by the drug. The drug released from the formulations was measured with a VanKel dissolution apparatus. In vitro transdermal diffusion studies were performed using vertical Franz diffusion cells with human epidermal skin. Histopathological studies were carried out on human epidermis skin to determine if the surfactant, Brij 97, had any effect on the skin. Through confocal laser scanning microscopy and particle size measurements, the 4 and 8% Brij 97 formulations without carrageenan could be identified as emulsions while the 15 and 25% Brij 97 formulations without carrageenan could be identified as microemulsions. The 4, 8, 15 and 25% Brij 97 formulations containing carrageenan could be identified as gels. The results obtained from the zeta-potential analysis indicated that the 4 and 8% Brij 97 formulations without carrageenan and 4% Brij 97 formulation with carrageenan are the most electronegative and thus the most stable. The pH measurements confirmed that the internal structure of the formulations was not influenced by the drug. 5-Fluorouracil was released from the formulations. The 4 and 8% Brij 97 formulations without carrageenan had an enhancing effect on the penetration of 5-fluorouracil while the 4, 8, 15 and 25% Brij 97 formulations with carrageenan and the 15 and 25% Brij 97 formulations without carrageenan had an hindering effect on the penetration of 5-fluorouracil. Although carrageenan led to good adhesiveness of the formulation on the skin, it did not lead to the enhancement of the penetration of 5-fluorouracil through the skin. When histopathological studies were carried out on female human abdominal skin, Brij 97, the surfactant, was found to have no damaging effect on the skin structure. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2006.

Thesis (Ph.D. (Pharmacy))--North-West University, Potchefstroom Campus, 2008.

Local anaesthetics have been implemented extensively in the case of a variety of painful superficial procedures, venipuncture, skin graft harvesting, anal or genital pruritus, poison ivy rashes, postherpetic neuralgia and several other dermatoses. The dilemma with commercially available local acting anaesthetics is that it may take well up to an hour to produce an anaesthetic effect. Anaesthetics have to traverse the highly efficient barrier, the stratum corneum, in order to reach the intended target site which is the free nerve endings located in the dermis. The objective of this study was to compare the transdermal delivery of an eutectic combination of two ionisable amide types of local anaesthetics, lidocaine HCI and prilocaine HCI, delivered with the novel Pheroid™ technology to that of a commercially available product in order to establish whether the lag time could be significantly reduced. Several techniques of promoting the penetration of these anaesthetics have previously been employed, including occlusive dressing, entrapment in liposomes and miscelles, iontophoretic delivery and so forth. The Pheroid™ delivery system is novel technology that entails improved delivery of several active compounds. It is a submicron emulsion type formulation that possesses the ability to be transformed in morphology and size, thereby affording it tremendous flexibility. Since it primarily consists of unsaturated essential fatty acids, it is not seen as foreign to the body but rather as a skin-friendly carrier. Vertical Franz cell diffusion studies were performed over a 12 hour period using Caucasian female abdominal skin obtained, with the consent of the donor, from abdominoplastic surgery. Comparison was made between the commercial product EMLA® cream, the active local anaesthetics dissolved in phosphate buffered solution (PBS) and the active ingredients entrapped within Pheroid™ vesicles. Distinct entrapment could be ascertained visually by confocal laser scanning microscopy (CLSM). The amount of drug that traversed the epidermal membrane into the receptor phase was then assayed by high performance liquid chromatography (HPLC). The results obtained with the Pheroid™ vesicles revealed a biphasic character with rapid permeation during the first two hours, followed by a plateau between 3 to 12 hours. The initial dramatic increase in percentage yield and flux indicates that the Pheroid™ carrier enhances the transdermal delivery of the actives in order to accelerate the onset of action. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2009.

Most individuals are influenced by pain at some stage in their lives. It can either be of acute or chronic nature. An acute pain condition initiates and is treated within a time span of 12 weeks. Chronic pain can, however, take substantially longer to treat. Chronic pain may last up to 6 months after the original injury was sustained. The after effects of chronic pain can, however, take years to heal, but physical and emotional scars may even last much longer than the initial chronic ailment. In this study the skin was chosen as an area for delivery of non-steroidal anti-inflammatory drugs for the treatment of pain at the joint and muscle tissue regions. The stratum corneum (the topmost horny layer of the skin), however bars the effective movement of chemical substances across the skin as it forms part of the skin's function to protect the superficial tissue of the body against the external environment. It furthermore plays an important role in regulation of the movement of chemicals across the skin. Sweat pores and hair follicles can be utilised as pathways for the movement of chemical substances through the stratum corneum. Physical deformation ie, hydration of the top layer of the skin, may also enhance the movement of chemicals The non-steroidal anti-inflammatory drug, diclofenac, has been evaluated for transdermal diffusion. Three different diclofenac salts were evaluated, namely diclofenac diethylamine, diclofenac hydroxyethyl pyrrolidine and diclofenac sodium. These salts have the potential to relieve systemic pain conditions. Diclofenac salts, however, possess physicochemical characteristics that are unfavourable for transdermal diffusion. Pheroid™ delivery technology, as patented by the Northwest-University, was implemented as a method to enhance transdermal delivery of the diclofenac salts. During the study each of the diclofenac salts was formulated in a Pheroid™ and non-Pheroid™ formulation. All the formulations as well as corresponding retail products containing similar diclofenac salts were evaluated in order to determine which preparation had the most effective transdermal diffusion. High performance liquid chromatograhphy was implemented in order to determine the concentration of each salt in their various preparations. The Pheroid™ and non-Pheroid™ formulations were also compared to retail products currently available. An active ingredient flux was determined by means of Franz cell diffusion studies. Membrane diffusion studies were utilised in order to determine whether the active ingredients were effectively released from the formulated preparations and market products. Membrane diffusion studies determined that Arthruderm (the retail product containing diclofenac sodium) had the most potential to effectively release the active ingredient from the formulation (median flux 28.36 ± 0.26 ug/cm2.h"1). Franz cell diffusion studies showed no flux values for any of the evaluated preparations, including the retail products. Concentrations obtained within the epidermis and dermis were determined through tape stripping of these areas. The largest concentration of active ingredient within the epidermis was obtained from the studies done on Voltaren® (the retail product containing diclofenac diethylamine) which was 7.27 |ig/cm2.h"1 the largest value in the dermis was obtained from a non-Pheroid™ formulation containing diclofenac sodium (4.47 ug/ml). Confocal laser scanning microscopy was utilised and the micrographs where evaluated to ensure that the diclofenac salts were effectively entrapped in the Pheroid™ delivery system. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Thesis (Ph.D. (Pharmacy))--North-West University, Potchefstroom Campus, 2008.

Most individuals are influenced by pain at some stage in their lives. It can either be of acute or chronic nature. An acute pain condition initiates and is treated within a time span of 12 weeks. Chronic pain can, however, take substantially longer to treat. Chronic pain may last up to 6 months after the original injury was sustained. The after effects of chronic pain can, however, take years to heal, but physical and emotional scars may even last much longer than the initial chronic ailment. In this study the skin was chosen as an area for delivery of non-steroidal anti-inflammatory drugs for the treatment of pain at the joint and muscle tissue regions. The stratum corneum (the topmost horny layer of the skin), however bars the effective movement of chemical substances across the skin as it forms part of the skin's function to protect the superficial tissue of the body against the external environment. It furthermore plays an important role in regulation of the movement of chemicals across the skin. Sweat pores and hair follicles can be utilised as pathways for the movement of chemical substances through the stratum corneum. Physical deformation ie, hydration of the top layer of the skin, may also enhance the movement of chemicals The non-steroidal anti-inflammatory drug, diclofenac, has been evaluated for transdermal diffusion. Three different diclofenac salts were evaluated, namely diclofenac diethylamine, diclofenac hydroxyethyl pyrrolidine and diclofenac sodium. These salts have the potential to relieve systemic pain conditions. Diclofenac salts, however, possess physicochemical characteristics that are unfavourable for transdermal diffusion. Pheroid™ delivery technology, as patented by the Northwest-University, was implemented as a method to enhance transdermal delivery of the diclofenac salts. During the study each of the diclofenac salts was formulated in a Pheroid™ and non-Pheroid™ formulation. All the formulations as well as corresponding retail products containing similar diclofenac salts were evaluated in order to determine which preparation had the most effective transdermal diffusion. High performance liquid chromatograhphy was implemented in order to determine the concentration of each salt in their various preparations. The Pheroid™ and non-Pheroid™ formulations were also compared to retail products currently available. An active ingredient flux was determined by means of Franz cell diffusion studies. Membrane diffusion studies were utilised in order to determine whether the active ingredients were effectively released from the formulated preparations and market products. Membrane diffusion studies determined that Arthruderm (the retail product containing diclofenac sodium) had the most potential to effectively release the active ingredient from the formulation (median flux 28.36 ± 0.26 ug/cm2.h"1). Franz cell diffusion studies showed no flux values for any of the evaluated preparations, including the retail products. Concentrations obtained within the epidermis and dermis were determined through tape stripping of these areas. The largest concentration of active ingredient within the epidermis was obtained from the studies done on Voltaren® (the retail product containing diclofenac diethylamine) which was 7.27 |ig/cm2.h"1 the largest value in the dermis was obtained from a non-Pheroid™ formulation containing diclofenac sodium (4.47 ug/ml). Confocal laser scanning microscopy was utilised and the micrographs where evaluated to ensure that the diclofenac salts were effectively entrapped in the Pheroid™ delivery system. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Local anaesthetics have been implemented extensively in the case of a variety of painful superficial procedures, venipuncture, skin graft harvesting, anal or genital pruritus, poison ivy rashes, postherpetic neuralgia and several other dermatoses. The dilemma with commercially available local acting anaesthetics is that it may take well up to an hour to produce an anaesthetic effect. Anaesthetics have to traverse the highly efficient barrier, the stratum corneum, in order to reach the intended target site which is the free nerve endings located in the dermis. The objective of this study was to compare the transdermal delivery of an eutectic combination of two ionisable amide types of local anaesthetics, lidocaine HCI and prilocaine HCI, delivered with the novel Pheroid™ technology to that of a commercially available product in order to establish whether the lag time could be significantly reduced. Several techniques of promoting the penetration of these anaesthetics have previously been employed, including occlusive dressing, entrapment in liposomes and miscelles, iontophoretic delivery and so forth. The Pheroid™ delivery system is novel technology that entails improved delivery of several active compounds. It is a submicron emulsion type formulation that possesses the ability to be transformed in morphology and size, thereby affording it tremendous flexibility. Since it primarily consists of unsaturated essential fatty acids, it is not seen as foreign to the body but rather as a skin-friendly carrier. Vertical Franz cell diffusion studies were performed over a 12 hour period using Caucasian female abdominal skin obtained, with the consent of the donor, from abdominoplastic surgery. Comparison was made between the commercial product EMLA® cream, the active local anaesthetics dissolved in phosphate buffered solution (PBS) and the active ingredients entrapped within Pheroid™ vesicles. Distinct entrapment could be ascertained visually by confocal laser scanning microscopy (CLSM). The amount of drug that traversed the epidermal membrane into the receptor phase was then assayed by high performance liquid chromatography (HPLC). The results obtained with the Pheroid™ vesicles revealed a biphasic character with rapid permeation during the first two hours, followed by a plateau between 3 to 12 hours. The initial dramatic increase in percentage yield and flux indicates that the Pheroid™ carrier enhances the transdermal delivery of the actives in order to accelerate the onset of action. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2009.

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.

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.