No description available.

Two specific goals were addressed for this dissertation. First to investigate and identify the mechanistic profile of ketoconazole (KT)-induced hepatotoxicity by utilizing in vivo and in vitro approaches determining the mechanism of action for the hepatotoxicity incurred. To date, there has not been a mechanistic determination of the hepatotoxicity associated with KT in vivo. This dissertation evaluates the possible metabolic bioactivation of KT by cytochrome-P450 (CYP) or flavin-containing monooxygenases (FMO) resulting in covalent binding with hepatic macromolecules. The hypothesis of this study was to reveal whether covalent binding by the parent compound, KT, and/or reactive metabolites produces hepatic damage associated with increased serum alanine aminotransaminase (ALT) release and decreased hepatic glutathione (GSH). The first objective was determination of in vivo covalent binding in a dose-time response comparison in Sprague-Dawley (SD) rat ALT and GSH levels. Increased ALT and reduced hepatic GSH levels occurred. The second objective was an in vitro comparison of covalent binding with GSH levels utilizing SD microsomal protein with incubations of KT. Covalent binding decreased with added GSH to microsomal incubations. Thirdly, correlate in vivo with in vitro findings. Covalent binding of KT in vivo and in vitro occurred with increased doses and time. The final objective was to determine the bioactivation pathway utilizing heat inactivation and no NADPH in vitro. Covalent binding of KT decreased in the absence of NADPH and deactivation of FMO. The second goal was to determine and quantitate in vitro the presence of FMO isozymes in microsomes of the human intestinal duodenum, jejunum, ileum, and colon as well as the Caco-2 (HTB-37), epithelial intestinal (CCL-241) and colon (CRL1790) cell lines. The presence of FMO could result in a first-pass effect decreasing the bioavailability of soft nucleophiles or a toxicity effect due to inhibition or modulation of the enzyme from co-administration. To date, this is the first evaluation of FMO isoforms in human intestine and cell lines. Western blot techniques were utilized for detection of human FMO1, FMO3, and FMO5 using human FMO-expressed recombinant cDNA from a baculovirus system. / Graduation date: 2003

Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

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

Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior / The aim of this work was to study the electrochemical behavior of antifungal ketoconazole on polished Silver Solid Amalgam Electrode (p-AgSAE).The study began with the evaluation of the best electrolyte for ketoconazole (KC) electrochemical reduction and the BrittonâRobinson buffer solution at pH 12 was selected as the best support electrolyte. In the following, with a constant ketoconazole concentration (1.0x10-5 mol L-1) the square wave voltammetric parameters were optimized for the p-AgSAE. The best experimental responses were achieved with 100 s-1 frequency, 25 mV of amplitude and 2 mV of scan increment. The results showed that ketoconazole is reduced in a quasi-reversible process, with one reduction peak at -1.50 V vs. Ag/AgCl/Cl- reference system. After optimized the SWV parameters, the analytical studies were developed in accord to ANVISA for validation the methodology. Linearity range, detection and quantification limits, precision, robustness and accuracy were evaluated. An analytical curve was constructed, that presented a linear region to 4.97x10-7 a 4.30x10-6 mol L-1 with a correlation coefficient to 0.9989. The detection limits for the concentration range were determined as 63.4 &#956;g L-1 while the quantification limits were to 211.5 &#956;g L-1. Studies of accuracy of the methodology were made in different formulations: tablet, cream and shampoo. The values obtained were to 100.8% for the electrolyte, 91% for the tablet, 104% for the cream and 103% for the shampoo. The Relative Standard Deviation (RSD) for the accuracy was less than 5.0%. Quantum chemical calculations were also made with the aim of studying the electronic characteristics of the molecule, and predicting which region of the molecule occurs a electrochemical reduction. It was investigated the distribution of charge on the molecule and the molecular orbital (HOMO and LUMO), which are possible sites of oxidation and reduction, respectively. The LUMO was located on the imidazole ring. In the sequence of the mechanistic elucidation, it was made an exhaustive electrolysis (E = -1,8V during six hours) with monitoring by UV-Vis, being used in the studies that identify the products, the technique of nuclear magnetic resonance espectroscopy, NMR H1. In accord to the study, the reduction of KC occur between the C-N bond on the imidazole ring. / No presente trabalho foi investigado o comportamento eletroquÃmico do antifÃngico Cetoconazol (CTZ) sobre o Eletrodo SÃlido de AmÃlgama de Prata (p-AgSAE). A otimizaÃÃo das condiÃÃes de reduÃÃo foi obtida por voltametria de onda quadrada (VOQ), onde foram analisadas as condiÃÃes mais adequadas para a realizaÃÃo dos experimentos. O meio de trabalho escolhido foi TampÃo BR 0,04 mol L-1. Foi avaliada a influÃncia do pH, onde o valor escolhido para estudar a reduÃÃo do analito foi 12. Os parÃmetros da VOQ otimizados foram frequÃncia (100 s-1), amplitude (25 mV) e incremento de potencial (2 mV). De acordo com os resultados, foi observado que o CTZ sofre um processo de reduÃÃo em -1,5 V vs. Ag/AgCl/Cl-. A concentraÃÃo de CTZ utilizada nos estudos de otimizaÃÃo foi de 1,0x10-5 mol L-1. ApÃs estabelecimento dos parÃmetros experimentais, foram estudadas as figuras de mÃrito especificadas pela ANVISA para validaÃÃo de mÃtodos analÃticos na anÃlise de fÃrmacos. Assim, foram avaliados regiÃo de linearidade (4,97x10-7 a 4,30x10-6 mol L-1 com R = 0,9993), limites de detecÃÃo(1,19x10-7 mol L-1 - 63,4 &#956;g L-1) e de quantificaÃÃo (3,98x10-7 mol L-1 - 211,5 &#956;g L-1), precisÃo e robustez. Os estudos de exatidÃo da metodologia foram feitos em diferentes produtos comerciais: comprimido, creme e xampu. Para fins de comparaÃÃo e avaliaÃÃo de possÃvel influÃncia do meio eletroquÃmico na resposta, foi feito o estudo de exatidÃo utilizando curvas de recuperaÃÃo para o eletrÃlito de suporte, onde o valor da taxa de exatidÃo foi de 100,1%. Assim, os valores das taxas de exatidÃo para as amostras foram de 91% para a amostra de comprimido, 104% para a amostra de creme e 103% para a amostra de xampu. Os valores de RSD para as amostras foram inferiores a 5%. CÃlculos quÃmico-quÃnticos tambÃm foram feitos com o objetivo de estudar as caracterÃsticas eletrÃnicas da molÃcula, e prever qual regiÃo tem maior probabilidade de sofrer a reduÃÃo. De fato, foram investigadas as distribuiÃÃes de carga na molÃcula, bem como os orbitais de fronteira (HOMO e LUMO), que sÃo possÃveis sÃtios de oxidaÃÃo e reduÃÃo, respectivamente. O LUMO foi localizado sobre o anel imidazÃlico. Na sequÃncia da elucidaÃÃo mecanÃstica, foi feita uma eletrÃlise exaustiva (E = -1,8V durante seis horas) com acompanhamento por espectroscopia UVVis, sendo utilizada nos estudos de identificaÃÃo do produto a tÃcnica de espectroscopia de ressonÃncia magnÃtica nuclear, RMN H1. Com base neste estudo, foi constatado que o CTZ sofreu uma reduÃÃo na dupla ligaÃÃo entre C-N do anel imidazÃlico da molÃcula de CTZ.

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.

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.