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.

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.

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.

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.

Malaria is one the world’s most devastating diseases. Several classes of drugs are used to treat malaria. Artemisinin combination therapy is the first line treatment of uncomplicated malaria. The artemisinin derivative, artemisone in conjunction with the Pheroid® drug delivery system, is the focus of this thesis. The impact of the Pheroid® on the bioavailability of artemisone was evaluated in vervet monkeys. The resulting artemisone plasma levels were much lower (Cmax of 47 and 114 ng/mL for reference and Pheroid® test formulations respectively) than expected for the dosages administered (60 mg/kg). The Pheroid® improved the pharmacokinetic profile of artemisone in a clinically significant manner. The metabolism of artemisone was assessed in vitro by using human and monkey liver and intestinal microsomes, and recombinant CYP3A4 enzymes. The Pheroid® inhibits the microsomal metabolism of artemisone. In addition, there is a species difference in artemisone metabolism between man and monkey since the in vitro intrinsic clearance of the reference formulation with monkey liver microsomes is ~8 fold higher in the monkey liver microsomes compared to the human liver microsomes and the estimated in vivo hepatic clearance for the monkey is almost twofold higher than in humans. Artemisone has potent antimalarial activity. Its in vitro efficacy was approximately twofold higher than that of either artesunate or dihydroartemisinin when evaluated against P. falciparum W2, D6, 7G8, TM90-C2B, TM91-C235 and TM93-C1088 parasite strains. The Pheroid® drug delivery system did not improve or inhibit the in vitro efficacy of artemisone or DHA. Artemisone (reference and Pheroid® test formulations) and metabolite M1 abruptly arrested the growth of P. falciparum W2 parasites and induced the formation of dormant ring stages in a manner similar to that of DHA. Interaction of artemisone with the p-glycoprotein (p-gp) efflux transporter was investigated. Artemisone stimulates ATPase activity in a concentration-dependent manner, whereas the Pheroid® inhibited this p-gp ATPase activity. P-gp ATPase activity stimulation was fourfold greater in human than cynomolgus monkey MDR1 expressed insect cell membranes. Artemisone alone and artemisone entrapped in Pheroid® vesicles showed moderate apical to basolateral and high basolateral to apical permeability (Papp) across Caco-2 cells. The Papp efflux ratio of artemisone and artemisone entrapped in Pheroid® vesicles were both >5, and decreased to ~1 when the p-gp inhibitor, verapamil, was added. Therefore, artemisone is a substrate for mammalian p-gp. The cytotoxic properties of Pheroid® on Caco-2 cells were assessed and the pro-Pheroid® seems to be non-toxic at concentrations of 1.25%. Vervet monkey plasma caused antibody-mediated growth inhibition of P. falciparum. Heat inactivated or protein A treatment proved useful in the elimination of the growth-inhibitory activity of the drug-free plasma. Plasma samples containing artemisone could not be analysed by the ex-vivo bioassay method. The dual labelling ROS assay did not prove to be useful in the evaluation of ROS production by artemisone and the Pheroid® delivery system. In conclusion, entrapment of artemisone in the Pheroid® delivery system improves the pharmacokinetic properties of artemisone, but does not improve or inhibit its antimalarial efficacy in vitro. The Pheroid® inhibited both the microsomal metabolism of artemisone and P-gp ATPase activity and was shown to be non-toxic at clinically usable concentrations. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Malaria is one the world’s most devastating diseases. Several classes of drugs are used to treat malaria. Artemisinin combination therapy is the first line treatment of uncomplicated malaria. The artemisinin derivative, artemisone in conjunction with the Pheroid® drug delivery system, is the focus of this thesis. The impact of the Pheroid® on the bioavailability of artemisone was evaluated in vervet monkeys. The resulting artemisone plasma levels were much lower (Cmax of 47 and 114 ng/mL for reference and Pheroid® test formulations respectively) than expected for the dosages administered (60 mg/kg). The Pheroid® improved the pharmacokinetic profile of artemisone in a clinically significant manner. The metabolism of artemisone was assessed in vitro by using human and monkey liver and intestinal microsomes, and recombinant CYP3A4 enzymes. The Pheroid® inhibits the microsomal metabolism of artemisone. In addition, there is a species difference in artemisone metabolism between man and monkey since the in vitro intrinsic clearance of the reference formulation with monkey liver microsomes is ~8 fold higher in the monkey liver microsomes compared to the human liver microsomes and the estimated in vivo hepatic clearance for the monkey is almost twofold higher than in humans. Artemisone has potent antimalarial activity. Its in vitro efficacy was approximately twofold higher than that of either artesunate or dihydroartemisinin when evaluated against P. falciparum W2, D6, 7G8, TM90-C2B, TM91-C235 and TM93-C1088 parasite strains. The Pheroid® drug delivery system did not improve or inhibit the in vitro efficacy of artemisone or DHA. Artemisone (reference and Pheroid® test formulations) and metabolite M1 abruptly arrested the growth of P. falciparum W2 parasites and induced the formation of dormant ring stages in a manner similar to that of DHA. Interaction of artemisone with the p-glycoprotein (p-gp) efflux transporter was investigated. Artemisone stimulates ATPase activity in a concentration-dependent manner, whereas the Pheroid® inhibited this p-gp ATPase activity. P-gp ATPase activity stimulation was fourfold greater in human than cynomolgus monkey MDR1 expressed insect cell membranes. Artemisone alone and artemisone entrapped in Pheroid® vesicles showed moderate apical to basolateral and high basolateral to apical permeability (Papp) across Caco-2 cells. The Papp efflux ratio of artemisone and artemisone entrapped in Pheroid® vesicles were both >5, and decreased to ~1 when the p-gp inhibitor, verapamil, was added. Therefore, artemisone is a substrate for mammalian p-gp. The cytotoxic properties of Pheroid® on Caco-2 cells were assessed and the pro-Pheroid® seems to be non-toxic at concentrations of 1.25%. Vervet monkey plasma caused antibody-mediated growth inhibition of P. falciparum. Heat inactivated or protein A treatment proved useful in the elimination of the growth-inhibitory activity of the drug-free plasma. Plasma samples containing artemisone could not be analysed by the ex-vivo bioassay method. The dual labelling ROS assay did not prove to be useful in the evaluation of ROS production by artemisone and the Pheroid® delivery system. In conclusion, entrapment of artemisone in the Pheroid® delivery system improves the pharmacokinetic properties of artemisone, but does not improve or inhibit its antimalarial efficacy in vitro. The Pheroid® inhibited both the microsomal metabolism of artemisone and P-gp ATPase activity and was shown to be non-toxic at clinically usable concentrations. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Acne is a multifactorial skin disease affecting about 80 % of people aged 11 to 30. Several systemic and topical treatments are used to treat existing lesions, prevent scarring and suppress the development of new lesions. Topical therapy is often used as first line treatment for acne, due to the location of the target organ, the pilosebaceous unit, in the skin. Retinoids are widely used as oral or topical treatment for this disease, with tretinoin and adapalene being two of the most used topical retinoids. The transdermal route offers several challenges to drug delivery, e.g. the excellent resistance of the stratum corneum to diffusion, as well as variable skin properties such as site, age, race and disease. Some additional difficulties are associated with the dermatological delivery of tretinoin and adapalene, which include suboptimal water solubility of the retinoids, isomerisation of tretinoin in the skin, mild to severe skin irritation, as well as oxidation and photo–isomerisation of tretinoin, even before crossing the stratum corneum. Researchers constantly strive to improve dermatological retinoid formulations in order to combat low dermal flux, skin irritation and instability. The release kinetics of tretinoin varies greatly according to the way in which it is incorporated into the formulation and according to the type of formulation used. Little research has been conducted regarding improved formulations for adapalene. Pheroid technology is a patented delivery system employed in this study in order to improve the dermal delivery of retinoids. Tretinoin and adapalene were separately incorporated into castor oil, vitamin F and Pheroid creams. The creams were evaluated in terms of their in vitro retinoid release, in vitro transdermal diffusion and stability. Castor oil and Pheroid creams were superior in terms of release and dermal delivery of adapalene. Tretinoin was best released and delivered to the dermis by castor oil cream. The castor oil creams were the most stable formulations, whereas the Pheroid creams were the most unstable. In terms of release, dermal diffusion and stability, castor oil cream proved to be the most suitable cream for both tretinoin and adapalene. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Acne is a multifactorial skin disease affecting about 80 % of people aged 11 to 30. Several systemic and topical treatments are used to treat existing lesions, prevent scarring and suppress the development of new lesions. Topical therapy is often used as first line treatment for acne, due to the location of the target organ, the pilosebaceous unit, in the skin. Retinoids are widely used as oral or topical treatment for this disease, with tretinoin and adapalene being two of the most used topical retinoids. The transdermal route offers several challenges to drug delivery, e.g. the excellent resistance of the stratum corneum to diffusion, as well as variable skin properties such as site, age, race and disease. Some additional difficulties are associated with the dermatological delivery of tretinoin and adapalene, which include suboptimal water solubility of the retinoids, isomerisation of tretinoin in the skin, mild to severe skin irritation, as well as oxidation and photo–isomerisation of tretinoin, even before crossing the stratum corneum. Researchers constantly strive to improve dermatological retinoid formulations in order to combat low dermal flux, skin irritation and instability. The release kinetics of tretinoin varies greatly according to the way in which it is incorporated into the formulation and according to the type of formulation used. Little research has been conducted regarding improved formulations for adapalene. Pheroid technology is a patented delivery system employed in this study in order to improve the dermal delivery of retinoids. Tretinoin and adapalene were separately incorporated into castor oil, vitamin F and Pheroid creams. The creams were evaluated in terms of their in vitro retinoid release, in vitro transdermal diffusion and stability. Castor oil and Pheroid creams were superior in terms of release and dermal delivery of adapalene. Tretinoin was best released and delivered to the dermis by castor oil cream. The castor oil creams were the most stable formulations, whereas the Pheroid creams were the most unstable. In terms of release, dermal diffusion and stability, castor oil cream proved to be the most suitable cream for both tretinoin and adapalene. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

The available literature indicates that to date, few research has been performed on oil powders for topical delivery. The aim of this project was to investigate the release characteristics of oil powder formulations, as well as their dermal and transdermal delivery properties. Whey protein-stabilised emulsions were used to develop oil powders. Whey protein was used alone, or in combination with chitosan or carrageenan. Nine oil powders, with salicylic acid as the active ingredient, were formulated by using the layer-by-layer method. Three different pH values (pH 4, 5 and 6) were used to prepare the formulations, because of the different charges that polymeric emulsifiers may have. The characteristics of the prepared oil powders were determined, including their droplet sizes, particle size distributions, loss on drying, encapsulation efficiencies, oil leakage and water dispersibility. Release studies (membrane diffusion studies) were conducted by utilising cellulose acetate membranes (0.2 μm pore size) and Franz-type diffusion cells over a period of eight hours. The release of the active ingredient was determined for all nine powders, their respective template emulsions, as well as their respective oil powders redispersed in water. The release of salicylic acid from the respective redispersed oil powders was then further compared to its release from the template emulsions and from the oil powders. The effect of pH and different polymer types used in preparing the oil powders, their respective redispersed oil powders and the template emulsions were determined with regards to the release of the active ingredient from all these preparations. The effect of pH and different polymers used was furthermore determined on the oil powders and their respective redispersed oil powders, with regards to their dermal and transdermal deliveries. Transdermal delivery and skin uptake were investigated on specifically selected powders only, based on the outcomes of the oil powder characterisation and release data. The qualifying formulations were chitosan pH 4, 5 and 6, whey and carrageenan pH 6 oil powders, together with their respective redispersed oil powders in water. Human abdominal skin was dermatomed (thickness 400 μm) for use in the diffusion studies. Franz-type diffusion cells were used over a period of 24 hours. The results of the membrane release studies indicated that the oil powders had achieved a significantly higher release than their respective redispersed oil powders. The release of salicylic acid from the redispersed oil powders and from their respective emulsions was similar. The transdermal delivery test outcomes showed that the effect of pH could have been influenced by the degree of ionisation, resulting in a decrease in permeation with increasing ionisation of salicylic acid, in accordance with the pH partition hypothesis. Furthermore, biopolymers, such as chitosan had demonstrated a penetration enhancing effect, which had led to the enhanced dermal and transdermal delivery of salicylic acid. A correlation was also found between the powder particle size and transdermal delivery. / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

The available literature indicates that to date, few research has been performed on oil powders for topical delivery. The aim of this project was to investigate the release characteristics of oil powder formulations, as well as their dermal and transdermal delivery properties. Whey protein-stabilised emulsions were used to develop oil powders. Whey protein was used alone, or in combination with chitosan or carrageenan. Nine oil powders, with salicylic acid as the active ingredient, were formulated by using the layer-by-layer method. Three different pH values (pH 4, 5 and 6) were used to prepare the formulations, because of the different charges that polymeric emulsifiers may have. The characteristics of the prepared oil powders were determined, including their droplet sizes, particle size distributions, loss on drying, encapsulation efficiencies, oil leakage and water dispersibility. Release studies (membrane diffusion studies) were conducted by utilising cellulose acetate membranes (0.2 μm pore size) and Franz-type diffusion cells over a period of eight hours. The release of the active ingredient was determined for all nine powders, their respective template emulsions, as well as their respective oil powders redispersed in water. The release of salicylic acid from the respective redispersed oil powders was then further compared to its release from the template emulsions and from the oil powders. The effect of pH and different polymer types used in preparing the oil powders, their respective redispersed oil powders and the template emulsions were determined with regards to the release of the active ingredient from all these preparations. The effect of pH and different polymers used was furthermore determined on the oil powders and their respective redispersed oil powders, with regards to their dermal and transdermal deliveries. Transdermal delivery and skin uptake were investigated on specifically selected powders only, based on the outcomes of the oil powder characterisation and release data. The qualifying formulations were chitosan pH 4, 5 and 6, whey and carrageenan pH 6 oil powders, together with their respective redispersed oil powders in water. Human abdominal skin was dermatomed (thickness 400 μm) for use in the diffusion studies. Franz-type diffusion cells were used over a period of 24 hours. The results of the membrane release studies indicated that the oil powders had achieved a significantly higher release than their respective redispersed oil powders. The release of salicylic acid from the redispersed oil powders and from their respective emulsions was similar. The transdermal delivery test outcomes showed that the effect of pH could have been influenced by the degree of ionisation, resulting in a decrease in permeation with increasing ionisation of salicylic acid, in accordance with the pH partition hypothesis. Furthermore, biopolymers, such as chitosan had demonstrated a penetration enhancing effect, which had led to the enhanced dermal and transdermal delivery of salicylic acid. A correlation was also found between the powder particle size and transdermal delivery. / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014