The objective of this research is the development of an electrically active microneedle array that can deliver biomolecules such as DNA and drugs to epidermal cells by means of electroporation. Properly metallized microneedles could serve as microelectrodes essential for electroporation. Furthermore, the close needle-to-needle spacing of microneedle electrodes provides the advantage of utilizing reduced voltage, which is essential for safety as well as portable applications, while maintaining the large electric fields required for electroporation. Therefore, microneedle arrays can potentially be used as part of a minimally invasive, highly-localized electroporation system for cells in the epidermis layer of the skin. This research consists of three parts: development of the 3-D microfabrication technology to create the microneedle array, fabrication and characterization of the microneedle array, and the electroporation studies performed with the microneedle array. A 3-D fabrication process was developed to produce a microneedle array using an inclined UV exposure technique combined with micromolding technology, potentially enabling low cost mass-manufacture. The developed technology is also capable of fabricating 3-D microstructures of various heights using a single mask. The fabricated microneedle array was then tested to demonstrate its feasibility for through-skin electrical and mechanical functionality using a skin insertion test. It was found that the microneedles were able to penetrate skin without breakage. To study the electrical properties of the array, a finite element simulation was performed to examine the electric field distribution. From these simulation results, a predictive model was constructed to estimate the effective volume for electroporation. Finally, studies to determine hemoglobin release from bovine red blood cells (RBC) and the delivery of molecules such as calcein and bovine serum albumin (BSA) into human prostate cancer cells were used to verify the electrical functionality of this device. This work established that this device can be used to lyse RBC and to deliver molecules, e.g. calcein, into cells, thus supporting our contention that this metallized microneedle array can be used to perform electroporation at reduced voltage. Further studies to show efficacy in skin should now be performed.

The aim of the present study was to assess the effectiveness of a cognitive-behavioral smoking cessation program combined with nicotine patches in a university student sample. Moreover, changes in self-efficacy judgments of both experimental and control group participants were examined. 37 students from various departments of Middle East Technical University participated in the study. Participants in the experimental group received a 6-week group based multicomponent smoking cessation program combined with nicotine patches, whereas those in the control group were provided with self-help booklets. Point prevalence abstinence was used as the main outcome measure, which was verified by CO-measurement in exhaled air both at post-treatment and follow-ups. Separate one-way ANOVAs and repeated measures ANOVAs were used in data analysis. Results showed that there were no significant differences between the experimental and control group in terms of their degree of motivation, readiness and decision to quit smoking, nicotine dependence, depression, self-efficacy, and perceived social support at pre-treatment. Results of the repeated measures ANOVA with CO-values showed that the CO-levels of experimental groups significantly declined from pre-treatment to post-treatment and to follow-ups. Abstinence rates for the experimental group were found to be 66.67%, 55.55% and 45.44% at post-treatment, 1-month follow-up and 2-months follow-up respectively. On the other hand, abstinence rates for the control group were found to be 11.76%, 5.88% and 5.88% at post-treatment, 1-month follow-up and 2-months follow-up respectively. Moreover, it was found that self-efficacy scores of experimental group participants significantly increased at post-treatment, whereas those of control group participants significantly decreased from pre-treatment to post-treatment. The findings were discussed in the light of the relevant literature. After discussing the limitations and implications of the study, directions for future studies were suggested.

The distinctive architecture of the stratum corneum with its unique nature of an interstitial lipoidal environment plays the major role in regulating the barrier function of the skin. The major problem with the transdermal delivery of 5-fluorouracil or idoxuridine is the permeation of sufficient amounts to the deeper layers of the skin and into the systemic circulation. In an attempt to enhance the transdermal permeability of 5-fluorouracil and idoxuridine, the aim of this study was to evaluate two lamellar gel phase systems (Physiogel dermaquadrille® and Physiogel NT®) and Emzaloids® as transdermal delivery vehicles for the two actives. Lamellar gel phase systems (LGPS) and Emzaloids® are both novel drug delivery systems. The epidermis of female abdominal skin was used in vertically mounted Franz diffusion cell experiments. An average amount of 250 mg of the 1% m/m LGPS was applied to cover the entire diffusion area of 1,075 cm2 of the skin, which contained 2,5 mg of the active. Samples of the actives in Emzaloids® were prepared and applied in the same way. The control solutions of the actives in water were prepared so that 1 ml of the applied solution contained the same amount of drug that was applied to the experimental cells. The entire receptor phase of the cells was removed at 2,4,6, 8, 10, 12 and 24 hours and was replaced with fresh 37°C receptor phase. The amount of active in the receptor phase was determined by HPLC analysis. Graphs of the cumulative amount of the active that permeated the skin over the 24 hour period were drawn and the slope of the graphs represented the flux in µg/ml/h. The average flux values of six experimental cells and six control cells were compared. Entrapment of the actives in the Emzaloid® vesicles was confirmed with the use of confocal laser scanning microscopy. Results for the LGPS indicate an enhancement ratio in the order of 4,2 for 5-fluorouracil and 1,7 for idoxuridine when compared to the control cells. There were no viscosity changes in the LGPS samples containing 1% m/m of the active when compared with the blank LGPS samples, suggesting that no change in the internal structure of the LGPS occurred after the addition of the actives to it. There were also no significant changes in the pH of the samples. Entrapment of the actives in the Emzaloid® vesicles occurred readily. The Emzaloid® vehicle showed a lower rate of release for idoxuridine than the LGPS did during the VanKel dissolution experiments. This suggests that higher flux values would be obtained with the LGPS for idoxuridine than with the Emzaloid® formulation, since more drug was available for permeation through the skin. This was, however, not the case. The Emzaloid® formulation showed much higher flux values, showing that even with a smaller amount of active available to permeate the skin higher flux values were obtained. Enhancement ratios of 20,33 and 3,50 were achieved with the Emzaloid® formulation for 5-fluorouracil and idoxuridine respectively. The internal LGPS structure which mimics the skins lipid components remained unchanged after the addition of the actives. Greater success might be achieved with the LGPS for different model drugs, since the drugs' physicochemical properties play an important part in its permeation through the skin. The Emzaloid® formulation, which is closely related to liposomes and transfersomes, showed great potential for commercially marketable formulations for the drugs tested but further research on the formulation has to be done. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.

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.

Naltrexone (NTX) is a drug used primarily in the management of alcohol dependence and opioid dependence. Based on several drawbacks associated with the oral and injectable intramuscular dosage forms of naltrexone currently available on the market, there is substantial interest in delivering naltrexone transdermally. Although naltrexone does not permeate skin at the rate sufficient to reach therapeutic plasma concentrations in humans, novel flux enhancement methods such as microneedles help address this challenge. Earlier work in humans has demonstrated that the use of microneedles achieves plasma concentrations in the lower end of expected therapeutic values. Further flux enhancement is desired to decrease the patch area while increasing drug transport rates. In the present work, several strategies aiming at in vitro flux maximization were employed including: formulation optimization, naltrexone salt screening, and naltrexone prodrug design. While naltrexone prodrugs did not reveal any improved permeation characteristics formulation optimization through decrease in vehicle microviscosity allowed a 5-fold increase in the percutaneous transport rates, and naltrexone glycolate salt selection provided an additional 1.5-fold enhancement in flux. One of the key observations was a good correlation (R2 = 0.99) between vehicle microviscosity and drug transport rates across the microchannel pathway. This finding alone allowed for formulation optimization and, at the same time, provided a potential explanation for the low permeation of high-concentration naltrexone salts and prodrugs. In vivo studies were carried out in Yucatan minipigs using a “poke and patch” microneedle method to deliver NTX•HCl. These studies demonstrated that initial plasma concentrations spiked to 2.5 ng/ml but rapidly dropped to a plateau of below 1 ng/ml. This pharmacokinetic profile could be explained by the use of a mathematical model which identified the importance of microchannel closure kinetics on drug transport. Also, an estimate of diffusional resistance of the viable tissue associated with percutaneous NTX•HCl delivery through microchannels was obtained. Its relatively large value suggests that the effect of diffusional resistance of the dermis in vivo should not be ignored and must be accounted for in order to obtain a good in vitro-in vivo correlation.

The aim of this study was to investigate the effect of different penetration enhancers containing essential fatty acids (EFAs) on the transdermal delivery of flurbiprofen. Flurbiprofen was used as a marker / model compound. Fatty acids were chosen as penetration enhancers for their ability to reversibly increase skin permeability through entering the lipid bilayers and disrupting their ordered domains. Fatty acids are natural, non-toxic compounds (Karande & Mitragotri, 2009:2364). Evening primrose oil, vitamin F and Pheroid™ technology all contain fatty acids and were compared using a cream based-formulation. This selection was to ascertain whether EFAs exclusively, or EFAs in a delivery system, would have a significant increase in the transdermal delivery of a compound. For an active pharmaceutical ingredient (API) to be effectively delivered transdermally, it has to be soluble in lipophilic, as well as hydrophilic mediums (Naik et al., 2000:319; Swart et al., 2005:72). This is due to the intricate structure of the skin, where the stratum corneum (outermost layer) is the primary barrier, which regulates skin transport (Barry, 2001:102; Moser et al., 2001:103; Venus et al., 2010:469). Flurbiprofen is highly lipophilic (log P = 4.24) with poor aqueous solubility. It has a molecular weight lower than 500 g/mol indicating that skin permeation may be possible, though the high log P indicates that some difficulty is to be expected (Dollery, 1999:F126; Hadgraft, 2004:292; Swart et al., 2005:72; Karande & Mitragotri, 2009:2363; Drugbank, 2012). In vitro transdermal diffusion studies (utilising vertical Franz diffusion cells) were conducted, using donated abdominal skin from Caucasian females. The studies were conducted over 12 h with extractions of the receptor phase every 2 h to ensure sink conditions. Prior to skin diffusion studies, membrane release studies were performed to determine whether the API was released from the formulation. Membrane release studies were conducted over 6 h and extractions done hourly. Tape stripping experiments were performed on the skin circles after 12 h diffusion studies to determine the concentration flurbiprofen present in the stratum corneum and dermisepidermis. The flurbiprofen concentrations present in the samples were determined using high performance chromatography and a validated method. Membrane release results indicated the following rank order for flurbiprofen from the different formulations: vitamin F > control > evening primrose oil (EPO) >> Pheroid™. The control formulation contained only flurbiprofen and no penetration enhancers. Skin diffusion results on the other hand, indicated that flurbiprofen was present in the stratum corneum and the dermisepidermis. The concentration flurbiprofen present in the receptor phase of the Franz cells (representing human blood) followed the subsequent rank order: EPO > control > vitamin F >> Pheroid™. All the formulations stipulated a lag time shorter than that of the control formulation (1.74 h), with the EPO formulation depicting the shortest (1.36 h). The control formulation presented the highest flux (8.41 μg/cm2.h), with the EPO formulation following the closest (8.12 μg/cm2.h). It could thus be concluded that fatty acids exclusively, rather than in a delivery system, had a significant increase in the transdermal delivery of flurbiprofen. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.

Local anaesthetics are used regularly in the medical world for a variety of different procedures. Topical anaesthetics are used largely in minor skin breaking procedures, laceration repair and minor surgical procedures such as laryngoscopy, oesophagoscopy or urethroscopy (Franchi et al., 2008:186e1). The topical means of application of a local anaesthetic is non-invasive and painless that results in a good patient acceptability profile (Little et al., 2008:102). An existing commercial topical anaesthetic product contains a eutectic mixture of the amide-type local anaesthetics lidocaine hydrochloride (HCl) and prilocaine hydrochloride (HCl). This commercial product takes up to an hour to produce an anaesthetic effect. This is considered as a disadvantage in the use of topical anaesthetics, an hour waiting time is not always ideal in certain medical circumstances (Wahlgren & Quiding, 2000:584). This study compared the lag times, transdermal and topical delivery of lidocaine HCl and prilocaine HCl from four different semi-solid formulations with the inclusion of a current commercial product. One of the formulated semi-solid formulations included Pheroid™ technology, a novel skin-friendly delivery system developed by the Unit for Drug Research and Development at the North-West University, Potchefstroom Campus, South Africa. The skin is the body’s first line of defence against noxious external stimuli. It is considered the largest organ in the body with an intensive and complex structure. It consists of five layers with the first outer layer, the stratum corneum, the most impermeable (Williams, 2003:1). The stratum corneum has excellent barrier function characteristics and is the cause for the time delay in the transdermal delivery of active pharmaceutical ingredients (API) (Barry, 2007:569). Local anaesthetics need to penetrate all the epidermal skin layers in order to reach their target site, the dermis. Skin appendages as well as blood vessels and skin nerve endings are located in the dermis. Local anaesthetics have to reach the free nerve endings in the dermis in order to cause a reversible block on these nerves for a local anaesthetic effect (Richards & McConachie, 1995:41). Penetration enhancement strategies for the transdermal delivery of lidocaine and prilocaine have been investigated and include methods like liposomal entrapment (Franz-Montan et al., 2010; Müller et al., 2004), micellisation (Scherlund et al., 2000), occlusive dressing (Astra Zeneca, 2006), heating techniques (Masud et al., 2010) and iontophoresis (Brounéus et al., 2000). The Pheroid™ delivery system has improved the transdermal delivery of several compounds with its enhanced entrapment capabilities. Pheroid™ consists mainly of unsaturated essential fatty-acids, non-harmful substances that are easily recognised by the body (Grobler et al., 2008:285). The morphology and size of Pheroid™ is easily manipulated because it is a submicron emulsion type formulation which provides it with a vast flexibility profile (Grobler et al., 2008:284). Vesicular entrapment was used to entrap lidocaine HCl and prilocaine HCl in the Pheroid™ and incorporated into an emulgel formulation. An emulgel without the inclusion of Pheroid™ was formulated for comparison with the Pheroid™ emulgel as well as with a hydrogel. Pheroid™ solution was prepared and compared to a phosphate buffer solution (PBS) without Pheroid™, both containing lidocaine HCl and prilocaine HCl as APIs. Franz cell type transdermal diffusion studies were performed on the four semi-solid formulations (emulgel, Pheroid™ emulgel, hydrogel and the commercial product) and two solutions (PBS and Pheroid™). The diffusion studies were performed over a 12 h period followed by the tape stripping of the skin after each diffusion study. Caucasian female abdominal skin was obtained with consent from the donors. The skin for the diffusion cells were prepared by using a Zimmer Dermatome®. PBS (pH 7.4) was prepared as the receptor phase of the diffusion studies. The receptor phase was extracted at certain pre-determined time intervals and analysed with high performance liquid chromatography (HPLC) to determine the amount of API that had traversed the skin. Stratum corneum-epidermis samples and epidermis-dermis samples were prepared and left over night at 4 °C and analysed the next day with HPLC. This was done to determine the amount of API that accumulated in the epidermis-dermis and the amount of API that were left on the outer skin layers (stratum corneum-epidermis). The results from the Franz cell diffusion studies indicated that the emulgel formulation without Pheroid™ shortened the lag time of lidocaine HCl and that the emulgel formulated with Pheroid™ shortened the lag time of prilocaine HCl, when compared to the commercial product. Pheroid™ did not enhance the flux of lidocaine HCl and prilocaine HCl into the skin. The hydrogel formulation demonstrated a high transdermal flux of prilocaine HCl due to the hydrating effect it had on the stratum corneum. The commercial product yielded high flux values for both APIs but it did not result in a high concentration of the APIs delivered to the epidermis-dermis. Pheroid™ technology did, however, enhance the epidermal-dermal delivery of lidocaine HCl and prilocaine HCl into the skin epidermis-dermis. The stability of the emulgel formulation, Pheroid™ emulgel formulation and the hydrogel formulation was examined over a 6 month period. The formulations were stored at 25 °C/60% RH, 30 °C/60% RH and 40 °C/75% RH. The API concentration, mass, pH, zeta potential, particle size, viscosity and visual appearance for each formulation at the different storage conditions were noted and compared at month 0, 1, 2, 3 and 6 to determine if the formulations remained stable for 6 months. The results obtained from the stability study demonstrated that none of the formulations were stable for 6 months. The emulgel remained stable for the first 3 months. At 6 months, large decreases in API concentration and pH occurred which could cause a loss of anaesthetic action in the formulations. The Pheroid™ emulgel formulation did not remain stable for 6 months. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.

The aim of this study was to investigate the effect of different penetration enhancers containing essential fatty acids (EFAs) on the transdermal delivery of flurbiprofen. Flurbiprofen was used as a marker / model compound. Fatty acids were chosen as penetration enhancers for their ability to reversibly increase skin permeability through entering the lipid bilayers and disrupting their ordered domains. Fatty acids are natural, non-toxic compounds (Karande & Mitragotri, 2009:2364). Evening primrose oil, vitamin F and Pheroid™ technology all contain fatty acids and were compared using a cream based-formulation. This selection was to ascertain whether EFAs exclusively, or EFAs in a delivery system, would have a significant increase in the transdermal delivery of a compound. For an active pharmaceutical ingredient (API) to be effectively delivered transdermally, it has to be soluble in lipophilic, as well as hydrophilic mediums (Naik et al., 2000:319; Swart et al., 2005:72). This is due to the intricate structure of the skin, where the stratum corneum (outermost layer) is the primary barrier, which regulates skin transport (Barry, 2001:102; Moser et al., 2001:103; Venus et al., 2010:469). Flurbiprofen is highly lipophilic (log P = 4.24) with poor aqueous solubility. It has a molecular weight lower than 500 g/mol indicating that skin permeation may be possible, though the high log P indicates that some difficulty is to be expected (Dollery, 1999:F126; Hadgraft, 2004:292; Swart et al., 2005:72; Karande & Mitragotri, 2009:2363; Drugbank, 2012). In vitro transdermal diffusion studies (utilising vertical Franz diffusion cells) were conducted, using donated abdominal skin from Caucasian females. The studies were conducted over 12 h with extractions of the receptor phase every 2 h to ensure sink conditions. Prior to skin diffusion studies, membrane release studies were performed to determine whether the API was released from the formulation. Membrane release studies were conducted over 6 h and extractions done hourly. Tape stripping experiments were performed on the skin circles after 12 h diffusion studies to determine the concentration flurbiprofen present in the stratum corneum and dermisepidermis. The flurbiprofen concentrations present in the samples were determined using high performance chromatography and a validated method. Membrane release results indicated the following rank order for flurbiprofen from the different formulations: vitamin F > control > evening primrose oil (EPO) >> Pheroid™. The control formulation contained only flurbiprofen and no penetration enhancers. Skin diffusion results on the other hand, indicated that flurbiprofen was present in the stratum corneum and the dermisepidermis. The concentration flurbiprofen present in the receptor phase of the Franz cells (representing human blood) followed the subsequent rank order: EPO > control > vitamin F >> Pheroid™. All the formulations stipulated a lag time shorter than that of the control formulation (1.74 h), with the EPO formulation depicting the shortest (1.36 h). The control formulation presented the highest flux (8.41 μg/cm2.h), with the EPO formulation following the closest (8.12 μg/cm2.h). It could thus be concluded that fatty acids exclusively, rather than in a delivery system, had a significant increase in the transdermal delivery of flurbiprofen. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.

Local anaesthetics are used regularly in the medical world for a variety of different procedures. Topical anaesthetics are used largely in minor skin breaking procedures, laceration repair and minor surgical procedures such as laryngoscopy, oesophagoscopy or urethroscopy (Franchi et al., 2008:186e1). The topical means of application of a local anaesthetic is non-invasive and painless that results in a good patient acceptability profile (Little et al., 2008:102). An existing commercial topical anaesthetic product contains a eutectic mixture of the amide-type local anaesthetics lidocaine hydrochloride (HCl) and prilocaine hydrochloride (HCl). This commercial product takes up to an hour to produce an anaesthetic effect. This is considered as a disadvantage in the use of topical anaesthetics, an hour waiting time is not always ideal in certain medical circumstances (Wahlgren & Quiding, 2000:584). This study compared the lag times, transdermal and topical delivery of lidocaine HCl and prilocaine HCl from four different semi-solid formulations with the inclusion of a current commercial product. One of the formulated semi-solid formulations included Pheroid™ technology, a novel skin-friendly delivery system developed by the Unit for Drug Research and Development at the North-West University, Potchefstroom Campus, South Africa. The skin is the body’s first line of defence against noxious external stimuli. It is considered the largest organ in the body with an intensive and complex structure. It consists of five layers with the first outer layer, the stratum corneum, the most impermeable (Williams, 2003:1). The stratum corneum has excellent barrier function characteristics and is the cause for the time delay in the transdermal delivery of active pharmaceutical ingredients (API) (Barry, 2007:569). Local anaesthetics need to penetrate all the epidermal skin layers in order to reach their target site, the dermis. Skin appendages as well as blood vessels and skin nerve endings are located in the dermis. Local anaesthetics have to reach the free nerve endings in the dermis in order to cause a reversible block on these nerves for a local anaesthetic effect (Richards & McConachie, 1995:41). Penetration enhancement strategies for the transdermal delivery of lidocaine and prilocaine have been investigated and include methods like liposomal entrapment (Franz-Montan et al., 2010; Müller et al., 2004), micellisation (Scherlund et al., 2000), occlusive dressing (Astra Zeneca, 2006), heating techniques (Masud et al., 2010) and iontophoresis (Brounéus et al., 2000). The Pheroid™ delivery system has improved the transdermal delivery of several compounds with its enhanced entrapment capabilities. Pheroid™ consists mainly of unsaturated essential fatty-acids, non-harmful substances that are easily recognised by the body (Grobler et al., 2008:285). The morphology and size of Pheroid™ is easily manipulated because it is a submicron emulsion type formulation which provides it with a vast flexibility profile (Grobler et al., 2008:284). Vesicular entrapment was used to entrap lidocaine HCl and prilocaine HCl in the Pheroid™ and incorporated into an emulgel formulation. An emulgel without the inclusion of Pheroid™ was formulated for comparison with the Pheroid™ emulgel as well as with a hydrogel. Pheroid™ solution was prepared and compared to a phosphate buffer solution (PBS) without Pheroid™, both containing lidocaine HCl and prilocaine HCl as APIs. Franz cell type transdermal diffusion studies were performed on the four semi-solid formulations (emulgel, Pheroid™ emulgel, hydrogel and the commercial product) and two solutions (PBS and Pheroid™). The diffusion studies were performed over a 12 h period followed by the tape stripping of the skin after each diffusion study. Caucasian female abdominal skin was obtained with consent from the donors. The skin for the diffusion cells were prepared by using a Zimmer Dermatome®. PBS (pH 7.4) was prepared as the receptor phase of the diffusion studies. The receptor phase was extracted at certain pre-determined time intervals and analysed with high performance liquid chromatography (HPLC) to determine the amount of API that had traversed the skin. Stratum corneum-epidermis samples and epidermis-dermis samples were prepared and left over night at 4 °C and analysed the next day with HPLC. This was done to determine the amount of API that accumulated in the epidermis-dermis and the amount of API that were left on the outer skin layers (stratum corneum-epidermis). The results from the Franz cell diffusion studies indicated that the emulgel formulation without Pheroid™ shortened the lag time of lidocaine HCl and that the emulgel formulated with Pheroid™ shortened the lag time of prilocaine HCl, when compared to the commercial product. Pheroid™ did not enhance the flux of lidocaine HCl and prilocaine HCl into the skin. The hydrogel formulation demonstrated a high transdermal flux of prilocaine HCl due to the hydrating effect it had on the stratum corneum. The commercial product yielded high flux values for both APIs but it did not result in a high concentration of the APIs delivered to the epidermis-dermis. Pheroid™ technology did, however, enhance the epidermal-dermal delivery of lidocaine HCl and prilocaine HCl into the skin epidermis-dermis. The stability of the emulgel formulation, Pheroid™ emulgel formulation and the hydrogel formulation was examined over a 6 month period. The formulations were stored at 25 °C/60% RH, 30 °C/60% RH and 40 °C/75% RH. The API concentration, mass, pH, zeta potential, particle size, viscosity and visual appearance for each formulation at the different storage conditions were noted and compared at month 0, 1, 2, 3 and 6 to determine if the formulations remained stable for 6 months. The results obtained from the stability study demonstrated that none of the formulations were stable for 6 months. The emulgel remained stable for the first 3 months. At 6 months, large decreases in API concentration and pH occurred which could cause a loss of anaesthetic action in the formulations. The Pheroid™ emulgel formulation did not remain stable for 6 months. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.

The distinctive architecture of the stratum corneum with its unique nature of an interstitial lipoidal environment plays the major role in regulating the barrier function of the skin. The major problem with the transdermal delivery of 5-fluorouracil or idoxuridine is the permeation of sufficient amounts to the deeper layers of the skin and into the systemic circulation. In an attempt to enhance the transdermal permeability of 5-fluorouracil and idoxuridine, the aim of this study was to evaluate two lamellar gel phase systems (Physiogel dermaquadrille® and Physiogel NT®) and Emzaloids® as transdermal delivery vehicles for the two actives. Lamellar gel phase systems (LGPS) and Emzaloids® are both novel drug delivery systems. The epidermis of female abdominal skin was used in vertically mounted Franz diffusion cell experiments. An average amount of 250 mg of the 1% m/m LGPS was applied to cover the entire diffusion area of 1,075 cm2 of the skin, which contained 2,5 mg of the active. Samples of the actives in Emzaloids® were prepared and applied in the same way. The control solutions of the actives in water were prepared so that 1 ml of the applied solution contained the same amount of drug that was applied to the experimental cells. The entire receptor phase of the cells was removed at 2,4,6, 8, 10, 12 and 24 hours and was replaced with fresh 37°C receptor phase. The amount of active in the receptor phase was determined by HPLC analysis. Graphs of the cumulative amount of the active that permeated the skin over the 24 hour period were drawn and the slope of the graphs represented the flux in µg/ml/h. The average flux values of six experimental cells and six control cells were compared. Entrapment of the actives in the Emzaloid® vesicles was confirmed with the use of confocal laser scanning microscopy. Results for the LGPS indicate an enhancement ratio in the order of 4,2 for 5-fluorouracil and 1,7 for idoxuridine when compared to the control cells. There were no viscosity changes in the LGPS samples containing 1% m/m of the active when compared with the blank LGPS samples, suggesting that no change in the internal structure of the LGPS occurred after the addition of the actives to it. There were also no significant changes in the pH of the samples. Entrapment of the actives in the Emzaloid® vesicles occurred readily. The Emzaloid® vehicle showed a lower rate of release for idoxuridine than the LGPS did during the VanKel dissolution experiments. This suggests that higher flux values would be obtained with the LGPS for idoxuridine than with the Emzaloid® formulation, since more drug was available for permeation through the skin. This was, however, not the case. The Emzaloid® formulation showed much higher flux values, showing that even with a smaller amount of active available to permeate the skin higher flux values were obtained. Enhancement ratios of 20,33 and 3,50 were achieved with the Emzaloid® formulation for 5-fluorouracil and idoxuridine respectively. The internal LGPS structure which mimics the skins lipid components remained unchanged after the addition of the actives. Greater success might be achieved with the LGPS for different model drugs, since the drugs' physicochemical properties play an important part in its permeation through the skin. The Emzaloid® formulation, which is closely related to liposomes and transfersomes, showed great potential for commercially marketable formulations for the drugs tested but further research on the formulation has to be done. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.