Acquired immunodeficiency syndrome (AIDS) has shown a rapid increase in incidence over the past 25 years. Many clinical manifestations occur in patients infected with human immunodeficiency virus (HIV) due to compromised immunity caused by this virus. Dermatological disorders are almost inevitable for individuals suffering from HIV/AIDS and are seen in approximately 90% of all infected patients (Cedeno-Laurent et al., 2011:5; Dlova & Mosam, 2004:12). Vulnerability of the skin causes impaired life quality by causing low self-esteem, depression or even suicide. The skin is regarded as the most visible organ due to its location and large surface area (Cedeno-Laurent et al., 2011:5). Cutaneous manifestations, including viral, fungal and bacterial pathogens, can serve as markers in HIV/AIDS progression or as indicators for commencing HIV/AIDS treatment (Vusadevan et al., 2012:20). Acyclovir is an anti-viral agent showing activity against herpes simplex virus type 1 and type 2, varicella-zoster virus and cytomegalovirus to a certain extent (King, 1988:176; Beers, 2006:1061). The anti-fungal agent, ketoconazole, shows activity against the majority of pathogenic fungal infections seen in HIV/AIDS including Candida spp, Cryptocococcus neoformans and Histoplasma capsulatum (Bennet, 2006:1225). Ketoconazole has shown to have in vitro inhibitory activity against certain Staphylococcus spp (Pottage, 1986:217). According to Bickers (1994:89), ketoconazole shows a synergistic anti-viral activity when used in combination with acyclovir. Using the mucosal route of administration may be beneficial for these compounds due to the location of occurrence as many of these diseases are found on mucosal surfaces such as the labial and vaginal areas. Compounds are mainly delivered via passive diffusion across epithelium membranes (Patel et al., 2011:107). In mucosal skin, the principle barrier function is removed by the absence of the keratinised stratum corneum as found in normal skin and is, thus, more permeable (Farage & Scheffler, 2011:117). In this study three different formulations containing acyclovir (5% w/w) and ketoconazole (2% w/w) were formulated for topical delivery on mucus membranes, which included a cream, gel and lip balm. Topical delivery is used to target specific sites on the skin by penetration of the skin layers, but has a minimal requirement for systemic effect (Dayan, 2005:67). The aim in this study was to formulate a stable product containing acyclovir and ketoconazole that would provide an efficient flux of both compounds when applied on mucosal membranes. In vitro studies were performed to determine skin permeation of acyclovir and ketoconazole by using a flow-through diffusion system. The formulated products were compared to Acitop® and Ketazol®, which are two products available on the South African market, containing acyclovir and ketoconazole, respectively. However, no product is yet available containing both acyclovir and ketoconazole. Results obtained for acyclovir released from the different formulations during the permeation studies depicted no statistical significant differences between the different formulations in the average cumulative amount of acyclovir released (p > 0.05). The cream, gel and lip balm formulations depicted a decreased average cumulative acyclovir amount released through the mucosa when compared to Acitop®. The following rank order could be established: Acitop® > gel > cream > lip balm. Furthermore, the gel formulation and Acitop® produced a relatively similar percentage of acyclovir diffused. A linear relationship (r2 = 0.9977) existed between the flux and the release rate of acyclovir from the different formulations, indicating that as the acyclovir was released, the flux increased correspondingly. Using the Higuchi model, the average cumulative amount of acyclovir released that permeated the mucosa per unit surface area was constructed against the square root of time (h½). All formulations depicted a correlation coefficient (r2) of 0.9644 – 0.9914 for acyclovir, indicating that the release of acyclovir from the different formulations could be described by the Higuchi model. No statistical significant differences could be obtained for acyclovir between any of the formulations for % diffused, apparent release constant (ARC), release rate (RR) and lag times. The amount of ketoconazole that permeated the mucosa from the gel and cream formulations exhibited a smaller average cumulative amount that permeated the mucosa when compared to Ketazol®. The lip balm was the only formulation that showed a statistically significant (p < 0.05) increase in permeation through the mucosa in comparison to Ketazol®. A rank order for the average cumulative amount of ketoconazole that permeated through the mucosa could be established namely: lip balm >>> Ketazol® > gel > cream. A linear relationship (r2 = 0.9991) was depicted between the average release constant and the average release rate from each of the different formulations for ketoconazole. This indicated that as the compound was released, the flux increased correspondingly which was in accordance with the acyclovir release tendency. The only statistically significant difference (p < 0.05) was seen for the release rate of ketoconazole from the lip balm formulation compared to that of the cream and gel formulations. Release rate and flux of ketoconazole was the highest from the lip balm formulation. The rate of ketoconazole released from all of the different formulations obeyed the Higuchi model as the amount of compound released from each formulation was a linear function of the square root of time (r2 = 0.9584 - 0.9899). Statistically significant (p < 0.05) differences were furthermore noted between the lip balm and both the cream and gel formulations when % diffused, ARC and RR were compared. The lip balm depicted the highest percentage diffused, the highest ARC as well as the fastest RR. However, no statistical differences were obtained between the cream and gel formulation even though the gel formulation performed slightly better. Considering the lag time, all the formulations presented with a relatively shorter initial time of release (less than an hour). Shorter lag time values indicate that the ketoconazole was preferentially released by the base of the formulations. Statistically significant differences (p < 0.05) were depicted between the lag times of Ketazol® and lip balm formulation, as well as between the lip balm and the cream and gel formulations. The stability of the formulated products was examined over a period of three months according to the standards of the International Conference of Harmonisation (ICH) Tripartite Guidelines (2003:12) and the Medicines Control Council (MCC) of South Africa (2011:12). Each of the formulated products was stored at three different temperatures and humidities. Stability tests conducted included visual appearance, mass variation, assay, pH determination, viscosity, particle size observation, and zeta potential. Due to the different properties of the formulations, some tests could not be conducted on the gel and lip balm formulations. The outcomes of the stability tests showed that all three formulations presented acceptable results for some of the tests conducted. No significant changes were noted in the visual appearance, mass variation and pH values of all tested formulations at the specified storage conditions. Acyclovir is slightly soluble in water and has a solubility of 1.3 mg/ml at 25 ºC according to Bethesda (2010). Low solubility often causes crystal formation in products. All of the formulations developed in this study presented crystals on the surface. Due to non-homogenous sample preparation differences in concentrations could be obtained as the amount and size of crystals may differ. Ketoconazole did, however, not depict any significant changes in concentration for any of the formulations at all storage conditions. The cream depicted variable changes in viscosity over the three months, showing no clear trend, whereas, the viscosity measurement results of the gel formulation depicted a definite trend. The sodium carboxymethylcellulose (Na-CMC) used as the thickening agent in this formulation was responsible for this trend obtained in the results, due to the effects of pH, hydration and temperature on this excipient (Aqualon, 1996:10). Results obtained from zeta potential determination for the cream formulation depicted no significant change and the values remained below 25 mV. Zeta potential values below 25 mV present the risk of coalescence due to the lower repelling forces between particles (Jelvehgari et al., 2010:1240). The average size of the particles in dispersion was also observed and could be linked to zeta potential values. The cream depicted an increase in particle size over the three months stability testing. Due to the low zeta potential depicted in the cream formulation it was expected that coalescence would occur over time. From results obtained in this study it was clear that manufacturing different formulations containing both acyclovir and ketoconazole proved difficult due to the significant differences between their physicochemical properties, which in turn influenced the stability of the formulation. Furthermore, it was evident that formulation at specific pH values, as well as the incorporation of certain excipients, played a significant role in the stability of formulations. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013

Acquired immunodeficiency syndrome (AIDS) has shown a rapid increase in incidence over the past 25 years. Many clinical manifestations occur in patients infected with human immunodeficiency virus (HIV) due to compromised immunity caused by this virus. Dermatological disorders are almost inevitable for individuals suffering from HIV/AIDS and are seen in approximately 90% of all infected patients (Cedeno-Laurent et al., 2011:5; Dlova & Mosam, 2004:12). Vulnerability of the skin causes impaired life quality by causing low self-esteem, depression or even suicide. The skin is regarded as the most visible organ due to its location and large surface area (Cedeno-Laurent et al., 2011:5). Cutaneous manifestations, including viral, fungal and bacterial pathogens, can serve as markers in HIV/AIDS progression or as indicators for commencing HIV/AIDS treatment (Vusadevan et al., 2012:20). Acyclovir is an anti-viral agent showing activity against herpes simplex virus type 1 and type 2, varicella-zoster virus and cytomegalovirus to a certain extent (King, 1988:176; Beers, 2006:1061). The anti-fungal agent, ketoconazole, shows activity against the majority of pathogenic fungal infections seen in HIV/AIDS including Candida spp, Cryptocococcus neoformans and Histoplasma capsulatum (Bennet, 2006:1225). Ketoconazole has shown to have in vitro inhibitory activity against certain Staphylococcus spp (Pottage, 1986:217). According to Bickers (1994:89), ketoconazole shows a synergistic anti-viral activity when used in combination with acyclovir. Using the mucosal route of administration may be beneficial for these compounds due to the location of occurrence as many of these diseases are found on mucosal surfaces such as the labial and vaginal areas. Compounds are mainly delivered via passive diffusion across epithelium membranes (Patel et al., 2011:107). In mucosal skin, the principle barrier function is removed by the absence of the keratinised stratum corneum as found in normal skin and is, thus, more permeable (Farage & Scheffler, 2011:117). In this study three different formulations containing acyclovir (5% w/w) and ketoconazole (2% w/w) were formulated for topical delivery on mucus membranes, which included a cream, gel and lip balm. Topical delivery is used to target specific sites on the skin by penetration of the skin layers, but has a minimal requirement for systemic effect (Dayan, 2005:67). The aim in this study was to formulate a stable product containing acyclovir and ketoconazole that would provide an efficient flux of both compounds when applied on mucosal membranes. In vitro studies were performed to determine skin permeation of acyclovir and ketoconazole by using a flow-through diffusion system. The formulated products were compared to Acitop® and Ketazol®, which are two products available on the South African market, containing acyclovir and ketoconazole, respectively. However, no product is yet available containing both acyclovir and ketoconazole. Results obtained for acyclovir released from the different formulations during the permeation studies depicted no statistical significant differences between the different formulations in the average cumulative amount of acyclovir released (p > 0.05). The cream, gel and lip balm formulations depicted a decreased average cumulative acyclovir amount released through the mucosa when compared to Acitop®. The following rank order could be established: Acitop® > gel > cream > lip balm. Furthermore, the gel formulation and Acitop® produced a relatively similar percentage of acyclovir diffused. A linear relationship (r2 = 0.9977) existed between the flux and the release rate of acyclovir from the different formulations, indicating that as the acyclovir was released, the flux increased correspondingly. Using the Higuchi model, the average cumulative amount of acyclovir released that permeated the mucosa per unit surface area was constructed against the square root of time (h½). All formulations depicted a correlation coefficient (r2) of 0.9644 – 0.9914 for acyclovir, indicating that the release of acyclovir from the different formulations could be described by the Higuchi model. No statistical significant differences could be obtained for acyclovir between any of the formulations for % diffused, apparent release constant (ARC), release rate (RR) and lag times. The amount of ketoconazole that permeated the mucosa from the gel and cream formulations exhibited a smaller average cumulative amount that permeated the mucosa when compared to Ketazol®. The lip balm was the only formulation that showed a statistically significant (p < 0.05) increase in permeation through the mucosa in comparison to Ketazol®. A rank order for the average cumulative amount of ketoconazole that permeated through the mucosa could be established namely: lip balm >>> Ketazol® > gel > cream. A linear relationship (r2 = 0.9991) was depicted between the average release constant and the average release rate from each of the different formulations for ketoconazole. This indicated that as the compound was released, the flux increased correspondingly which was in accordance with the acyclovir release tendency. The only statistically significant difference (p < 0.05) was seen for the release rate of ketoconazole from the lip balm formulation compared to that of the cream and gel formulations. Release rate and flux of ketoconazole was the highest from the lip balm formulation. The rate of ketoconazole released from all of the different formulations obeyed the Higuchi model as the amount of compound released from each formulation was a linear function of the square root of time (r2 = 0.9584 - 0.9899). Statistically significant (p < 0.05) differences were furthermore noted between the lip balm and both the cream and gel formulations when % diffused, ARC and RR were compared. The lip balm depicted the highest percentage diffused, the highest ARC as well as the fastest RR. However, no statistical differences were obtained between the cream and gel formulation even though the gel formulation performed slightly better. Considering the lag time, all the formulations presented with a relatively shorter initial time of release (less than an hour). Shorter lag time values indicate that the ketoconazole was preferentially released by the base of the formulations. Statistically significant differences (p < 0.05) were depicted between the lag times of Ketazol® and lip balm formulation, as well as between the lip balm and the cream and gel formulations. The stability of the formulated products was examined over a period of three months according to the standards of the International Conference of Harmonisation (ICH) Tripartite Guidelines (2003:12) and the Medicines Control Council (MCC) of South Africa (2011:12). Each of the formulated products was stored at three different temperatures and humidities. Stability tests conducted included visual appearance, mass variation, assay, pH determination, viscosity, particle size observation, and zeta potential. Due to the different properties of the formulations, some tests could not be conducted on the gel and lip balm formulations. The outcomes of the stability tests showed that all three formulations presented acceptable results for some of the tests conducted. No significant changes were noted in the visual appearance, mass variation and pH values of all tested formulations at the specified storage conditions. Acyclovir is slightly soluble in water and has a solubility of 1.3 mg/ml at 25 ºC according to Bethesda (2010). Low solubility often causes crystal formation in products. All of the formulations developed in this study presented crystals on the surface. Due to non-homogenous sample preparation differences in concentrations could be obtained as the amount and size of crystals may differ. Ketoconazole did, however, not depict any significant changes in concentration for any of the formulations at all storage conditions. The cream depicted variable changes in viscosity over the three months, showing no clear trend, whereas, the viscosity measurement results of the gel formulation depicted a definite trend. The sodium carboxymethylcellulose (Na-CMC) used as the thickening agent in this formulation was responsible for this trend obtained in the results, due to the effects of pH, hydration and temperature on this excipient (Aqualon, 1996:10). Results obtained from zeta potential determination for the cream formulation depicted no significant change and the values remained below 25 mV. Zeta potential values below 25 mV present the risk of coalescence due to the lower repelling forces between particles (Jelvehgari et al., 2010:1240). The average size of the particles in dispersion was also observed and could be linked to zeta potential values. The cream depicted an increase in particle size over the three months stability testing. Due to the low zeta potential depicted in the cream formulation it was expected that coalescence would occur over time. From results obtained in this study it was clear that manufacturing different formulations containing both acyclovir and ketoconazole proved difficult due to the significant differences between their physicochemical properties, which in turn influenced the stability of the formulation. Furthermore, it was evident that formulation at specific pH values, as well as the incorporation of certain excipients, played a significant role in the stability of formulations. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013

Preformulation studies of two naturally occurring compounds, sulforaphane and myricetin, are presented. Both compounds have shown promise as chemoprevention agents throughout the literature. Despite this evidence, minimal information is available to guide the progression of formulations designed for future drug development. The presented work describes solubility, stability, and solid-state characterization of these compounds. Additionally, a mathematical model based on the ideal solubility equation, which reasonably estimates the solubility of a hydrate is described. This model accounts for the dehydration energetics of the solute as it transforms from hydrate to anhydrous prior to melting and conversion to a hypothetical super-cooled liquid (HSL). This model will lend itself to the appreciation of the solubility differences that can exist between hydrate and anhydrous drug forms. By improving the accuracy of solubility estimation, drug development studies involving hydrates can be designed more accurately.

Acne affects as many as 80% of young adults and adolescents all over the world. This detrimental condition can be classified into four stages: (a) open comedo (blackhead), (b) closed comedo (whitehead), (c) papule and (d) pustule (Russell, 2000:357-366). There are various factors that can lead to acne outbreaks which include: (a) hormone level changes during the menstrual cycle in women, (b) certain drugs (i.e. lithium), (c) certain cosmetics and (d) environmental conditions such as humidity (University of Maryland, 2009:1). The skin performs a variety of functions which include the two major functions: (a) the containment and (b) the protection of the internal organs of the body. The containment function relates specifically to the ability of the skin to confine the underlying tissues and restrain their movement from place to place. The protective function, on the other hand, relates to the ability of the skin to act as a microbiological barrier to most micro-organisms; a chemical barrier to exogenous chemical compounds; barrier to radiation and electrical shock; and mechanical barrier to impact (Danckwerts, 1991:315). Niacinamide and salicylic acid were chosen in combination, due to the beneficial effects that they have on acne. Niacinamide has an anti-inflammatory action on acne; which reduces redness, dryness and irritation caused by Propioni-bacterium acnes that live in the clogged pores of pimples (Acnetreatmentlab, 2008:1). Salicylic acid is a keratolytic and keratoplastic agent. It is used in combination with other ingredients to enhance the shedding of corneocytes. This causes penetration into the skin to be very difficult (SAMF, 2005:177). The solubility of niacinamide and salicylic acid in PBS (pH 7.4 at 32°C) were 212.95 mg/ml and 4.07 mg/ml, respectively. The log D values of niacinamide and salicylic acid were determined to be -0.32 and 0.33, respectively. According to the solubility of niacinamide and salicylic acid it was expected that both of the active ingredients would permeate through the skin. However, it is expected that niacinamide will depict enhanced permeation with respect to salicylic acid. The results of the log D for both of the active ingredients indicate that there would not be optimal permeation. This study involved the formulation of four different acne preparations (Pheroid™cream, Pheroid™gel, cream and gel), combining niacinamide and salicylic acid. The evaluation of stability parameters for the different formulations indicated that none of the formulations was stable under the different storage conditions determined by the Medicines Control Council. Nevertheless, the cream and gel were the most stable of the four formulations. Visual assessment of the Pheroid™ formulations with the confocal laser scanning microscopy (CLMS) was conducted and inconclusive evidence to whether the active substances were entrapped within the Pheroids™, was obtained. Franz cell diffusion studies indicated that the cream (in the case of niacinamide) and gel (in the case of salicylic acid) depicted the highest average and median flux from hours 6 to 12. Results of the tape stripping studies showed that with the gel formulation, concentrations of 2.060 ug/ml and 44.749 ug/ml niacinamide were obtained in the epidermis and dermis respectively. After the Pheroid™ gel was applied, tape stripping depicted only 1.587 ug/ml niacinamide in the epidermis with respect to 22.764 ug/ml niacinamide in the dermis. The cream formulation, on the other hand, showed niacinamide concentrations of 2.001 ug/ml in the epidermis and 13.363 ug/ml in the dermis, whereas with the Pheroid™ cream formulation, concentrations of 1.097 ug/ml and 18.061 ug/ml were obtained in the epidermis and dermis respectively. Tape stripping results depicted that with the gel formulation, concentrations of 2.113 ug/ml and 49.519 ug/ml salicylic acid were obtained in the epidermis and dermis respectively, whereas the Pheroid™ gel formulation showed salicylic acid, concentrations of 1.114 ug/ml in the epidermis and 95.360 ug/ml in the dermis. The cream formulation, however, depicted salicylic acid concentrations of 0.758 ug/ml in the epidermis and 44.729 ug/ml in the dermis. Lastly, after the Pheroid™ cream was applied, salicylic acid concentrations of 0.411 ug/ml and 48.424 ug/ml in the epidermis and dermis respectively, were measured. It could, therefore, be concluded that both niacinamide and salicylic acid tend to concentrate more in the dermis, irrespective of the formulation. This may be an advantage since acne is usually targeted in the dermis and epidermis. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

The aim of this in vitro study was to investigate the efficacy of the novel Pheroid™ technology system in a semi-solid dosage form, for the topical delivery of acyclovir (5% w/w), an anti-viral agent and ketoconazole (2% w/w) an anti-fungal agent. The human immununodeficiency virus (HIV) had an immense impact on the spectrum of diagnosis of cutaneous diseases since its first manifestation in the late 1970's (Yen-More et al., 2000:432). The skin is the most commonly affected organ in HIV infected individuals with skin manifestations present in up to 92% of HIV-positive patients. According to Ramdial (2000:113) the skin may also be the first or the only organ affected throughout the course of the HIV/AIDS disease. HIV/AIDS patients are more susceptible to infections due to their compromised immune systems (Durden & Elewski, 1997:200) and an exceptionally wide range of infectious skin manifestations presents in HIV/AIDS infected individuals, some of which are viral and fungal. Acyclovir is an anti-viral active against herpes simplex virus type 1 and type 2, varicella-zoster virus, Epstein-Barr virus and the cytomegalovirus (Hayden, 2001:1317). The anti-fungal drug, ketoconazole has activity against the majority of pathogenic fungi which include Candida species and Histoplasma capsulatum (Bennett, 2001:1301). It is appropriate to formulate a topical product containing both acyclovir and ketoconazole because viral and fungal cutaneous manifestations are regularly encountered in combination in HIV/AIDS infected individuals,. This combination topical product may be useful in the treatment of viral and fungal opportunistic skin manifestations. Curing these skin lesions may also assist to improve the state of mind and wellbeing of infected individuals. The skin, however, acts as a barrier against diffusion of substances through the underlying tissue. The main problem in transdermal and dermal delivery of actives is to overcome the stratum corneum, the skin's natural barrier (Menon, 2002:4). The Pheroid™ delivery system can promote the absorption and increase the efficacy of a selection of active ingredients in dermatological preparations (Grobler et al., 2008:284). The aim of this study was to formulate a stable semi-solid product containing Pheroid™ to determine whether Pheroid™ technology would enhance the flux and/or delivery of acyclovir and ketoconazole to the epidermal and dermal layers of the skin. In vitro studies and tape stripping were used to determine the effect that the Pheroid™ delivery system had on skin permeation of acyclovir and ketoconazole in semi-solid formulations. The formulae containing no Pheroid™ were used as a control against which the efficacy of the formulations containing Pheroid™ was measured. The stability of the formulated semi-solid products was examined over a period of 6 months according to the International Conference of Harmonisation (ICH) Tripartite Guidelines (2003) and the Medicines control council (MCC) of South Africa (2006). The formulated products were stored at three different temperatures. The stability tests included the assay of the actives and other attributes in the formulation, pH, viscosity, mass loss and particle size observation. These tests were conducted at 0, 1, 2, 3 and 6 months. The results demonstrated that the transdermal flux, epidermal and dermal penetration of acyclovir was enhanced by the Pheroid™ cream formulation. Ketoconazole's transdermal flux as well as delivery to the epidermal and dermal layers of the skin was improved by the Pheroid™ emulgel formula. The topical delivery of ketoconazole and acyclovir was thus enhanced by Pheroid™ technology. The Pheroid™ formulations, however, did not meet the requirements for stability according to the ICH and MCC. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Acne affects as many as 80% of young adults and adolescents all over the world. This detrimental condition can be classified into four stages: (a) open comedo (blackhead), (b) closed comedo (whitehead), (c) papule and (d) pustule (Russell, 2000:357-366). There are various factors that can lead to acne outbreaks which include: (a) hormone level changes during the menstrual cycle in women, (b) certain drugs (i.e. lithium), (c) certain cosmetics and (d) environmental conditions such as humidity (University of Maryland, 2009:1). The skin performs a variety of functions which include the two major functions: (a) the containment and (b) the protection of the internal organs of the body. The containment function relates specifically to the ability of the skin to confine the underlying tissues and restrain their movement from place to place. The protective function, on the other hand, relates to the ability of the skin to act as a microbiological barrier to most micro-organisms; a chemical barrier to exogenous chemical compounds; barrier to radiation and electrical shock; and mechanical barrier to impact (Danckwerts, 1991:315). Niacinamide and salicylic acid were chosen in combination, due to the beneficial effects that they have on acne. Niacinamide has an anti-inflammatory action on acne; which reduces redness, dryness and irritation caused by Propioni-bacterium acnes that live in the clogged pores of pimples (Acnetreatmentlab, 2008:1). Salicylic acid is a keratolytic and keratoplastic agent. It is used in combination with other ingredients to enhance the shedding of corneocytes. This causes penetration into the skin to be very difficult (SAMF, 2005:177). The solubility of niacinamide and salicylic acid in PBS (pH 7.4 at 32°C) were 212.95 mg/ml and 4.07 mg/ml, respectively. The log D values of niacinamide and salicylic acid were determined to be -0.32 and 0.33, respectively. According to the solubility of niacinamide and salicylic acid it was expected that both of the active ingredients would permeate through the skin. However, it is expected that niacinamide will depict enhanced permeation with respect to salicylic acid. The results of the log D for both of the active ingredients indicate that there would not be optimal permeation. This study involved the formulation of four different acne preparations (Pheroid™cream, Pheroid™gel, cream and gel), combining niacinamide and salicylic acid. The evaluation of stability parameters for the different formulations indicated that none of the formulations was stable under the different storage conditions determined by the Medicines Control Council. Nevertheless, the cream and gel were the most stable of the four formulations. Visual assessment of the Pheroid™ formulations with the confocal laser scanning microscopy (CLMS) was conducted and inconclusive evidence to whether the active substances were entrapped within the Pheroids™, was obtained. Franz cell diffusion studies indicated that the cream (in the case of niacinamide) and gel (in the case of salicylic acid) depicted the highest average and median flux from hours 6 to 12. Results of the tape stripping studies showed that with the gel formulation, concentrations of 2.060 ug/ml and 44.749 ug/ml niacinamide were obtained in the epidermis and dermis respectively. After the Pheroid™ gel was applied, tape stripping depicted only 1.587 ug/ml niacinamide in the epidermis with respect to 22.764 ug/ml niacinamide in the dermis. The cream formulation, on the other hand, showed niacinamide concentrations of 2.001 ug/ml in the epidermis and 13.363 ug/ml in the dermis, whereas with the Pheroid™ cream formulation, concentrations of 1.097 ug/ml and 18.061 ug/ml were obtained in the epidermis and dermis respectively. Tape stripping results depicted that with the gel formulation, concentrations of 2.113 ug/ml and 49.519 ug/ml salicylic acid were obtained in the epidermis and dermis respectively, whereas the Pheroid™ gel formulation showed salicylic acid, concentrations of 1.114 ug/ml in the epidermis and 95.360 ug/ml in the dermis. The cream formulation, however, depicted salicylic acid concentrations of 0.758 ug/ml in the epidermis and 44.729 ug/ml in the dermis. Lastly, after the Pheroid™ cream was applied, salicylic acid concentrations of 0.411 ug/ml and 48.424 ug/ml in the epidermis and dermis respectively, were measured. It could, therefore, be concluded that both niacinamide and salicylic acid tend to concentrate more in the dermis, irrespective of the formulation. This may be an advantage since acne is usually targeted in the dermis and epidermis. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

The aim of this in vitro study was to investigate the efficacy of the novel Pheroid™ technology system in a semi-solid dosage form, for the topical delivery of acyclovir (5% w/w), an anti-viral agent and ketoconazole (2% w/w) an anti-fungal agent. The human immununodeficiency virus (HIV) had an immense impact on the spectrum of diagnosis of cutaneous diseases since its first manifestation in the late 1970's (Yen-More et al., 2000:432). The skin is the most commonly affected organ in HIV infected individuals with skin manifestations present in up to 92% of HIV-positive patients. According to Ramdial (2000:113) the skin may also be the first or the only organ affected throughout the course of the HIV/AIDS disease. HIV/AIDS patients are more susceptible to infections due to their compromised immune systems (Durden & Elewski, 1997:200) and an exceptionally wide range of infectious skin manifestations presents in HIV/AIDS infected individuals, some of which are viral and fungal. Acyclovir is an anti-viral active against herpes simplex virus type 1 and type 2, varicella-zoster virus, Epstein-Barr virus and the cytomegalovirus (Hayden, 2001:1317). The anti-fungal drug, ketoconazole has activity against the majority of pathogenic fungi which include Candida species and Histoplasma capsulatum (Bennett, 2001:1301). It is appropriate to formulate a topical product containing both acyclovir and ketoconazole because viral and fungal cutaneous manifestations are regularly encountered in combination in HIV/AIDS infected individuals,. This combination topical product may be useful in the treatment of viral and fungal opportunistic skin manifestations. Curing these skin lesions may also assist to improve the state of mind and wellbeing of infected individuals. The skin, however, acts as a barrier against diffusion of substances through the underlying tissue. The main problem in transdermal and dermal delivery of actives is to overcome the stratum corneum, the skin's natural barrier (Menon, 2002:4). The Pheroid™ delivery system can promote the absorption and increase the efficacy of a selection of active ingredients in dermatological preparations (Grobler et al., 2008:284). The aim of this study was to formulate a stable semi-solid product containing Pheroid™ to determine whether Pheroid™ technology would enhance the flux and/or delivery of acyclovir and ketoconazole to the epidermal and dermal layers of the skin. In vitro studies and tape stripping were used to determine the effect that the Pheroid™ delivery system had on skin permeation of acyclovir and ketoconazole in semi-solid formulations. The formulae containing no Pheroid™ were used as a control against which the efficacy of the formulations containing Pheroid™ was measured. The stability of the formulated semi-solid products was examined over a period of 6 months according to the International Conference of Harmonisation (ICH) Tripartite Guidelines (2003) and the Medicines control council (MCC) of South Africa (2006). The formulated products were stored at three different temperatures. The stability tests included the assay of the actives and other attributes in the formulation, pH, viscosity, mass loss and particle size observation. These tests were conducted at 0, 1, 2, 3 and 6 months. The results demonstrated that the transdermal flux, epidermal and dermal penetration of acyclovir was enhanced by the Pheroid™ cream formulation. Ketoconazole's transdermal flux as well as delivery to the epidermal and dermal layers of the skin was improved by the Pheroid™ emulgel formula. The topical delivery of ketoconazole and acyclovir was thus enhanced by Pheroid™ technology. The Pheroid™ formulations, however, did not meet the requirements for stability according to the ICH and MCC. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Aims Novel low toxicity formulations using biomaterial (i.e. gelatin) for triggered release and controlled manner of formulated therapeutic agent for treatment of immuno-inflammatory disease on the skin were studied in the PhD project. It is a challenging concept because of difficulties in targeting and controlling for the releases that is tailored to disease severity or lesional inflammation extent. Background Psoriasis is a complicated disease with multi-factorial pathogenesis. Potent anti-psoriatic drugs are available but for managing the symptoms of the disease. Due to the toxicity of the therapeutic agents, different strategies have been suggested to avoid severe side effects from long term or high dose usage. Psoriasis is an optimal representative for this investigation in terms of the toxicities of recognized drugs, unpredictable or relapsed nature of the disease or even life threatening developments if generalised symptoms develop as they can in some types. Method Using the rheometry in temperature sweep mode, a series of concentrations of pure gelatin and gelatin mixture were developed. In addition, using tryptic enzyme, their action was studied rheologically. A Petri dish observational method was used to investigate the permeability of formulations chosen on the basis of the rheometric performance. Then, combining the Copley diffusion cell kit and UV/VIS spectrophotometer, the release of the model drug was investigated in porous artificial membranes and porcine skin for one or more of the formulations. The preliminary part using porous artificial membranes was to investigate the amount of the release of tartrazine from a candidate gel into the circulation system. In this part, alternatives were considered for dealing with gelatin or gelatin/carbomer swelling by using mechanical stress approach or changing to octanol solvent. For the latter a dye, rhodamine, which would partition into octanol had to be substituted for tartrazine (which has iv negligible organic solubility). In the final part, using skin membrane, the amount of the release tartrazine to the skin was measured because in this, skin staining, rather than partition was needed. Results Promising results were observed in each stage. The rheological investigation on the developed gelatin/water system and gelatin/carbomer intimate system in absence and presence of tryptic enzyme showed that a responsive but convenient formulation was possible and was independent of the presence of tartrazine. Analysis of these resulting rheological profiles suggested a prediction for the best gelatin/carbomer formulations to select for the permeability tests. The latter used Petri dishes to compare differential diffusion of these candidates showed the carbomer was able to stop three-dimensional spreading of the dye through the pure gelatin or its residue (after enzyme action). The drug release studies using artificial porous membranes for preliminary work showed significant differential release between enzyme free and enzyme treated versions of the 20% gelatin/0.9% carbomer formulation. The final success was the in vitro skin experiment in which the result was obtained for the pure gelatin and shown to deliver very substantially more to areas with applied enzyme s a simulated lesion.

In Thailand, Acanthus ebracteatus Vahl and Clerodendrum petasites S. Moore have been prescribed to treat skin diseases, such as rash, abscess, and urticaria, for at least 30 years. However, there is limited scientific support and no clinical trials that identify and verify the compounds that elicit useful pharmacological effects following their topical delivery. Vanillic acid was identified for the first time in A. ebracteatus together with verbascoside; furthermore, nine phenolic compounds, vanillic acid, 4-coumaric acid, ferulic acid, verbascoside, nepetin, luteolin, chrysin, naringenin, and hesperetin, and two reported, apigenin and hispidulin, were found in C. petasites. C. petasites (CP) was therefore chosen as the principal plant to be studied in this thesis. Hispidulin was quantified as a predominant compound, being present at 39 μmol/g (1.2% w/w) in a dried ethanolic extract. Various formulations of CP extracts were examined (a) in in vitro skin penetration experiments using Franz diffusion cells, and (b) in vivo using the tape-stripping method. Hispidulin penetrated through the skin within 3 hours; vanillic acid and nepetin were absorbed after 6 hours. In contrast, verbascoside was only taken up into the superficial layers of SC. There was no difference in the permeation of hispidulin, nepetin and vanillic acid from 10% w/w CP cream and lotion formulations. Hispidulin was percutaneously absorbed through the skin and taken up into the stratum corneum in the greatest amount, followed by vanillic acid and nepetin. It was found that the in vitro model was useful for preliminary formulation development, and that the tape-stripping method was robust and effective. Verbascoside, although a poor penetrant, was well released from the formulations in an in vitro release test, suggesting that it might be a potential skin surface-active compound, such as an antimicrobial. Hispidulin, nepetin and vanillic acid, based on their uptake and penetration into the skin, together with their known biological activities, may be considered as feasible candidates for the development of novel and effective antimicrobial, anti-inflammatory, and antioxidant formulations.

Aging can be described as an extremely complex occurrence from which no organism can be excluded. Intrinsic and extrinsic aging make out the two components of skin aging and they differ on the macromolecular level while sharing specific molecular characteristics which include elevated levels of reactive oxygen species (ROS) and matrix metalloproteinase (MMP) while collagen synthesis decreases. The skin functions as a protective barrier against the harsh environment and is essential for regulating body temperature. The stratum corneum (SC) is responsible for the main resistance to the penetration of most compounds; nevertheless the skin represents as an appropriate target for delivery. The target site for anti-aging treatment includes the epidermal and dermal layers of the skin. Calendula oil and L-carnitine L-tartrate was utilised as the cosmeceutical actives as they can be classified as a mixed category of compounds/products that lie between cosmetics and drugs. Both show excellent properties which can prove valuable during anti-aging treatment, whether it is due to the scavenging of ROS (calendula oil), moisturising effects (calendula oil and L-carnitine L-tartrate) or the improvement of the skin turnover rate (L-carnitine L-tartrate). The Pheroid™ delivery system can enhance the absorption of a selection of active ingredients. The aim of this study was to determine whether the Pheroid™ delivery system will enhance the flux and/or delivery of the named actives to the target site by performing Franz cell diffusion studies over an 8 h period, followed by tape stripping experiments. The Pheroid™ results of the actives were compared to the results obtained when 1 00 % calendula oil was applied and the L-carnitine L-tartrate was dissolved in phosphate buffer solution (PBS), respectively. In the case of calendula oil only a qualitative gas chromatography mass spectrometry (GC/MS) method could be employed. No calendula oil was observed to permeate through the skin, but linoleic acid (marker compound) was present in the epidermis and dermis layers. Components in the Pheroid™ delivery system hampered the results as the marker compound identified is a fundamental component of the Pheroid™, making it difficult to determine whether or not the Pheroid™ delivery system enhanced calendula oil's penetration. The aqueous solubility and log D partition coefficient of L-carnitine L-tartrate was determined. Inspection of the log D value of -1.35 indicated that the compound is unfavourable to penetrate the skin, whereas the aqueous solubility of 16.63 mg/ml in PBS at a temperature of 32º C indicated favourable penetration. During the Franz cell diffusion and tape stripping studies it was determined by liquid chromatography mass spectrometry (LC/MS) that carnitine may be inherent to human skin. Pheroid™ enhanced the flux (average of 0.0361 µg/cm2.h, median of 0.0393 µg/cm2.h) of the L-carnitine L-tartrate when compared to PBS (average of 0.0180 µg/cm2.h, median of 0.0142 µg/cm2.h ) for the time interval of 2 -8 h. The PBS was more effective in delivering the active to the target site (0.270 µg/ml in the epidermis and 2.403 µg/ml in the dermis) than Pheroid™ (0.111 µg/ml and 1.641 µg/ml in the epidermis and dermis respectively). Confocal laser scanning microscopy (CLSM) confirmed the entrapment of L-carnitine L-tartrate in the Pheroid™ vesicle, while in the case of calendula oil it was impossible to differentiate between the oil and the Pheroid™ components. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2009.