Malaria is currently one of the most imperative parasitic diseases of the developing world. Current effective treatment options are limited because of increasing drug resistance, treatment cost effectiveness and treatment availability. Novel drug delivery systems are a new approach for increased efficacy in the treatment of the disease. Pheroid™ technology, a proven drug delivery system, in combination with anti-malarial drugs was evaluated in this study. The aim of this study was to evaluate the possible enhancement of the efficacy of the existing anti-malarial drugs in combination with Pheroid™ technology. The efficacy of existing anti-malarial drugs in combination with Pheroids was investigated in vitro with a chloroquine RB-1-resistant strain of P. falciparum. Two different Pheroid formulations, vesicles and microsponges, were used and the control medium consisted of sterile water for injection. Parasitaemia levels were determined microscopically and expressed as a percentage. An in vivo pilot study was also conducted using the P. berghei mouse model. The mice were grouped into seven batches of three mice each. The control group was treated with a Pheroid vesicle formulation only. Three of the groups were treated with three different concentrations of chloroquine dissolved in water namely 2 mg/kg; 5 mg/kg and 10 mg/kg bodyweight (bw) respectively, while the other three groups received the same three concentrations of chloroquine entrapped in Pheroid vesicle formulations. The measure of parasite growth inhibition (percentage parasitaemia), the survival rates and the percentage chemosuppresion was determined. In the in vivo study, all concentrations of chloroquine entrapped in Pheroid vesicles showed suppressed parasitaemia levels up to 11 days post infection. From day 11, the parasitaemia increases rapidly and becomes higher than that in groups treated with chloroquine in water. Chloroquine entrapped in Pheroid vesicles showed improved activity against a chloroquine resistant strain (RB-1) in vitro. The efficacy was enhanced by 1544.62%. The efficacy of mefloquine, artemether and artesunate in Pheroid microsponges were enhanced by 314.32%, 254.86% and 238.78% respectively. It can be concluded that Pheroid™ technology has potential to enhance the efficacy of anti-malaria drugs. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

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

Malaria is currently one of the most imperative parasitic diseases of the developing world. Current effective treatment options are limited because of increasing drug resistance, treatment cost effectiveness and treatment availability. Novel drug delivery systems are a new approach for increased efficacy in the treatment of the disease. Pheroid™ technology, a proven drug delivery system, in combination with anti-malarial drugs was evaluated in this study. The aim of this study was to evaluate the possible enhancement of the efficacy of the existing anti-malarial drugs in combination with Pheroid™ technology. The efficacy of existing anti-malarial drugs in combination with Pheroids was investigated in vitro with a chloroquine RB-1-resistant strain of P. falciparum. Two different Pheroid formulations, vesicles and microsponges, were used and the control medium consisted of sterile water for injection. Parasitaemia levels were determined microscopically and expressed as a percentage. An in vivo pilot study was also conducted using the P. berghei mouse model. The mice were grouped into seven batches of three mice each. The control group was treated with a Pheroid vesicle formulation only. Three of the groups were treated with three different concentrations of chloroquine dissolved in water namely 2 mg/kg; 5 mg/kg and 10 mg/kg bodyweight (bw) respectively, while the other three groups received the same three concentrations of chloroquine entrapped in Pheroid vesicle formulations. The measure of parasite growth inhibition (percentage parasitaemia), the survival rates and the percentage chemosuppresion was determined. In the in vivo study, all concentrations of chloroquine entrapped in Pheroid vesicles showed suppressed parasitaemia levels up to 11 days post infection. From day 11, the parasitaemia increases rapidly and becomes higher than that in groups treated with chloroquine in water. Chloroquine entrapped in Pheroid vesicles showed improved activity against a chloroquine resistant strain (RB-1) in vitro. The efficacy was enhanced by 1544.62%. The efficacy of mefloquine, artemether and artesunate in Pheroid microsponges were enhanced by 314.32%, 254.86% and 238.78% respectively. It can be concluded that Pheroid™ technology has potential to enhance the efficacy of anti-malaria drugs. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

Yes / Artemether (ARTM) is a very effective antimalarial drug with poor solubility and consequently low bioavailability. Smart nanocrystals of ARTM with particle size of 161±1.5 nm and polydispersity index of 0.172±0.01 were produced in <1 hour using a wet milling technology, Dena® DM-100. The crystallinity of the processed ARTM was confirmed using differential scanning calorimetry and powder X-ray diffraction. The saturation solubility of the ARTM nanocrystals was substantially increased to 900 µg/mL compared to the raw ARTM in water (145.0±2.3 µg/mL) and stabilizer solution (300.0±2.0 µg/mL). The physical stability studies conducted for 90 days demonstrated that nanocrystals stored at 2°C-8°C and 25°C were very stable compared to the samples stored at 40°C. The nanocrystals were also shown to be stable when processed at acidic pH (2.0). The solubility and dissolution rate of ARTM nanocrystals were significantly increased (P<0.05) compared to those of its bulk powder form. The results of in vitro studies showed significant antimalarial effect (P<0.05) against Plasmodium falciparum and Plasmodium vivax. The IC50 (median lethal oral dose) value of ARTM nanocrystals was 28- and 54-fold lower than the IC50 value of unprocessed drug and 13- and 21-fold lower than the IC50 value of the marketed tablets, respectively. In addition, ARTM nanocrystals at the same dose (2 mg/kg) showed significantly (P<0.05) higher reduction in percent parasitemia (89%) against P. vivax compared to the unprocessed (27%), marketed tablets (45%), and microsuspension (60%). The acute toxicity study demonstrated that the LD50 value of ARTM nanocrystals is between 1,500 mg/kg and 2,000 mg/kg when given orally. This study demonstrated that the wet milling technology (Dena® DM-100) can produce smart nanocrystals of ARTM with enhanced antimalarial activities.

A nanotecnologia tem sido empregada como plataforma para o desenvolvimento de formas farmacêuticas com maior eficácia e segurança. A redução do tamanho de partículas em escala nanométrica permite conferir ao material propriedades inovadoras que têm sido exploradas em inúmeras aplicações, principalmente na indústria farmacêutica. Essa nova característica permite aumentar a biodisponibilidade oral de fármacos pouco solúveis em água. Os nanocristais apresentam como vantagens o aumento da solubilidade de saturação e da velocidade de dissolução. Tais propriedades são decorrentes da sua maior área superficial. Além disso, os nanocristais apresentam excelente adesão em superfícies biológicas. Essa característica resulta não apenas em uma melhor biodisponibilidade, mas também em redução na variação da biodisponibilidade de fármacos pouco solúveis em água. A malária é uma doença negligenciada prevalente nos países emergentes e afeta mais de 210 milhões de pessoas no mundo. Dentre as terapias medicamentosas para o tratamento da malária, o artemeter, derivado da artemisinina, apresenta potente atividade esquizonticida na fase hepática e na fase eritrocítica. Esse fármaco, amplamente utilizado no tratamento da malária, apresenta baixa solubilidade em água limitando sua biodisponibilidade oral. Tendo em vista a melhoria dessa característica, foram utilizados os métodos de moagem a alta energia, homogeneização a alta pressão e moagem via úmida, em escala reduzida para a obtenção de nanocristais. Esse último método foi aquele que permitiu a redução das partículas em escala nanométrica. O método por moagem a alta energia (MAE) revelou, nas condições experimentais do presente trabalho, 10% (D0,1) da população das partículas com diâmetro menor ou igual a 3,504 &#177; 0,19 &#181;m, 50% (D0,5) menor ou igual a 14,225 &#177; 0,34 &#181;m e 90% (D0,9) menor ou igual a 57,306 &#177; 5,72 &#181;m. O diâmetro hidrodinâmico médio foi 25,01 &#177; 2,08 &#181;m, sendo que o fator limitante na redução do tamanho da partícula foi a densidade do artemeter. Resultados similares foram obtidos empregando método de homogeneização a alta pressão. Diferentes tensoativos foram avaliados empregando o método selecionado, a moagem via úmida em escala reduzida. O agente estabilizante soluplus® foi aquele que favoreceu a redução do tamanho das partículas. Tal característica foi observada por meio de análise térmica. Essa análise permitiu determinar o grau de amorfização mínima, assim como, a presença de fortes ligações moleculares entre o fármaco e diferentes polímeros. A utilização do método por moagem via úmida em escala reduzida permitiu a obtenção de nanocristais de artemeter (formula R2-MUR), com diâmetro hidrodinâmico médio (DHM) igual a 342 &#177; 16,3 nm, índice de polidispersão (IP) de 0,23 &#177; 0,01 e distribuição monomodal de tamanho. Essa preparação otimizada foi obtida por meio de planejamento de experimentos por superfície de resposta tendo como variáreis independentes as concentrações de artemeter e do agente estabilizante (Soluplus®) além do tempo de moagem. As respostas foram o DHM e o IP, determinados utilizando espalhamento de luz dinâmica (DLS). Adicionalmente, as avaliações empregando calorimetria exploratória diferencial (DSC) e difração de raio X (DRX) revelaram que não houve alteração na estrutura cristalina do artemeter e interação entre o fármaco e os excipientes. O presente trabalho permitiu a obtenção de nanocristais de artemeter com solubilidade de saturação até 2,0 e 1,8 vezes maior em água e tampão McIlvaine (pH 2,5) respectivamente, comparada ao fármaco micronizado. Além disso, a preparação liofilizada foi estável após armazenamento por três meses a temperatura de 25 e 4 °C. / Nanotechnology has been used as a platform for the development of pharmaceutical forms with greater effectiveness and safety. The reduction of particle size on a nanometric scale enables innovative properties to the material. These properties have been exploited in numerous applications, mainly in the pharmaceutical industry. This novel feature allows increasing the oral bioavailability of poorly water-soluble drugs. Nanocrystals have advantages such as increased saturation solubility and dissolution rate. These properties are due to their greater surface area. In addition, nanocrystals exhibit excellent adhesion on biological surfaces. This characteristic results not only in a better bioavailability but also in a reduction in the bioavailability variation of poorly water-soluble drugs. Malaria is a neglected disease prevalent in emerging countries and affects more than 210 million people worldwide. Among the medicinal therapies for the treatment of malaria, artemisinin-derived, artemether has potent schizonticidal activity in the liver and erythrocyte phases. This drug, widely used in the treatment of malaria, presents low solubility in water limiting its oral bioavailability. In order to improve this characteristic, the methods of high energy milling, high-pressure homogenization and wet milling on a reduced scale were used to obtain nanocrystals. This last method was the one that allowed the reduction of the artemether particles in nanoscale. The high energy milling method revealed, in the experimental conditions of the present study, 10% (D0,1) of the population of particles with a diameter less than or equal to 3,504 &#177; 0,19 &#181;m, 50% (D0,5) less than or equal to 14.225 &#177; 0.34 &#181;m and 90% (D0.9) less than or equal to 57.306 &#177; 5.72 &#181;m. The mean hydrodynamic diameter was 25.01 &#177; 2.08 &#181;m, being the limiting factor in the reduction of particle size the density of the artemether. Similar results were obtained using a high-pressure homogenization method. Different surfactants were evaluated using the selected method, wet milling on a reduced scale. The stabilizing agent soluplus® was the one that favored the reduction of the particle size. This characteristic was observed by thermal analysis. This analysis allowed determining the degree of minimum amorphization, as well as the presence of strong molecular bonds between the drug and some polymers. The wet milling on a reduced scale method allowed obtaining artemether nanocrystals (formula R2-MUR) with a mean hydrodynamic diameter (MHD) of 342 ± 16.3 nm, polydispersity index (PdI) of 0,23 &#177; 0.01 and monomodal distribution. These preparations were obtained through the response surface methodology (RSM) having as independent variables the concentrations of artemether and stabilizing agent (Soluplus®) and the milling time. MHD and PdI were performed using dynamic light scattering (DLS). In addition, evaluations using differential scanning calorimetry (DSC) and X-ray diffraction (XRD) revealed that there was no change in the crystal structure of the artemether and interaction between the drug and the excipients. The present work allowed obtaining of artemether nanocrystals with saturation solubility up to 2.0 and 1.8 times higher in water medium and McIlvaine buffer (pH 2.5), respectively, compared to the micronized drug. In addition, the lyophilized preparation was stable after storage for three months at 25 and 4 ° C.

Malaria is still an epidemic in many parts of the world-about 220 million people are still infected with malaria worldwide and about 700 thousand people die from this disease per year. Most of the drugs used to treat malaria work well if they are used as required and they contain the right amounts of the active ingredient; however, it is estimated that more than 10% of drugs traded worldwide are counterfeits including 38% to 53% of antimalarial tablets produced in China and India. Due to the lack of data covering the extent of counterfeit antimalarial drugs in Ghana, the purpose of this quantitative study was to determine the percentage of counterfeit antimalarial drugs sold in Ghana by assessing the amounts of the 2 most common antimalarial drugs, artemether (ATMT) and lumefantrine (LMFT) in drugs sold in Ghana retail outlets. These drugs were purchased from retail outlets in Ghana and analyses at the Mayo Clinic Pharmacology core lab (Rochester, MN). The quality of the drugs were characterized by comparing the actual amount of ATMT & LMFT in each tablet to the expected amount. Using explanatory theory along with dose response-response occupancy theory, the researcher addressed quantitative solutions to questions related to the percentage and distribution of counterfeit ATMT and LMFT tablets. The results revealed that overall 20% of the drugs are counterfeit; this is not dependent on the location or kind of outlet but rather depends on whether the tablets were imported or locally manufactured and whether the tablets had a pedigree scratch panel. This study provides a better understanding of how much antimalarial medication is counterfeit in Ghana, which will aid interventions to minimize the adverse effects of counterfeit antimalarial medication in Ghana

A nanotecnologia tem sido empregada como plataforma para o desenvolvimento de formas farmacêuticas com maior eficácia e segurança. A redução do tamanho de partículas em escala nanométrica permite conferir ao material propriedades inovadoras que têm sido exploradas em inúmeras aplicações, principalmente na indústria farmacêutica. Essa nova característica permite aumentar a biodisponibilidade oral de fármacos pouco solúveis em água. Os nanocristais apresentam como vantagens o aumento da solubilidade de saturação e da velocidade de dissolução. Tais propriedades são decorrentes da sua maior área superficial. Além disso, os nanocristais apresentam excelente adesão em superfícies biológicas. Essa característica resulta não apenas em uma melhor biodisponibilidade, mas também em redução na variação da biodisponibilidade de fármacos pouco solúveis em água. A malária é uma doença negligenciada prevalente nos países emergentes e afeta mais de 210 milhões de pessoas no mundo. Dentre as terapias medicamentosas para o tratamento da malária, o artemeter, derivado da artemisinina, apresenta potente atividade esquizonticida na fase hepática e na fase eritrocítica. Esse fármaco, amplamente utilizado no tratamento da malária, apresenta baixa solubilidade em água limitando sua biodisponibilidade oral. Tendo em vista a melhoria dessa característica, foram utilizados os métodos de moagem a alta energia, homogeneização a alta pressão e moagem via úmida, em escala reduzida para a obtenção de nanocristais. Esse último método foi aquele que permitiu a redução das partículas em escala nanométrica. O método por moagem a alta energia (MAE) revelou, nas condições experimentais do presente trabalho, 10% (D0,1) da população das partículas com diâmetro menor ou igual a 3,504 &#177; 0,19 &#181;m, 50% (D0,5) menor ou igual a 14,225 &#177; 0,34 &#181;m e 90% (D0,9) menor ou igual a 57,306 &#177; 5,72 &#181;m. O diâmetro hidrodinâmico médio foi 25,01 &#177; 2,08 &#181;m, sendo que o fator limitante na redução do tamanho da partícula foi a densidade do artemeter. Resultados similares foram obtidos empregando método de homogeneização a alta pressão. Diferentes tensoativos foram avaliados empregando o método selecionado, a moagem via úmida em escala reduzida. O agente estabilizante soluplus® foi aquele que favoreceu a redução do tamanho das partículas. Tal característica foi observada por meio de análise térmica. Essa análise permitiu determinar o grau de amorfização mínima, assim como, a presença de fortes ligações moleculares entre o fármaco e diferentes polímeros. A utilização do método por moagem via úmida em escala reduzida permitiu a obtenção de nanocristais de artemeter (formula R2-MUR), com diâmetro hidrodinâmico médio (DHM) igual a 342 &#177; 16,3 nm, índice de polidispersão (IP) de 0,23 &#177; 0,01 e distribuição monomodal de tamanho. Essa preparação otimizada foi obtida por meio de planejamento de experimentos por superfície de resposta tendo como variáreis independentes as concentrações de artemeter e do agente estabilizante (Soluplus®) além do tempo de moagem. As respostas foram o DHM e o IP, determinados utilizando espalhamento de luz dinâmica (DLS). Adicionalmente, as avaliações empregando calorimetria exploratória diferencial (DSC) e difração de raio X (DRX) revelaram que não houve alteração na estrutura cristalina do artemeter e interação entre o fármaco e os excipientes. O presente trabalho permitiu a obtenção de nanocristais de artemeter com solubilidade de saturação até 2,0 e 1,8 vezes maior em água e tampão McIlvaine (pH 2,5) respectivamente, comparada ao fármaco micronizado. Além disso, a preparação liofilizada foi estável após armazenamento por três meses a temperatura de 25 e 4 °C. / Nanotechnology has been used as a platform for the development of pharmaceutical forms with greater effectiveness and safety. The reduction of particle size on a nanometric scale enables innovative properties to the material. These properties have been exploited in numerous applications, mainly in the pharmaceutical industry. This novel feature allows increasing the oral bioavailability of poorly water-soluble drugs. Nanocrystals have advantages such as increased saturation solubility and dissolution rate. These properties are due to their greater surface area. In addition, nanocrystals exhibit excellent adhesion on biological surfaces. This characteristic results not only in a better bioavailability but also in a reduction in the bioavailability variation of poorly water-soluble drugs. Malaria is a neglected disease prevalent in emerging countries and affects more than 210 million people worldwide. Among the medicinal therapies for the treatment of malaria, artemisinin-derived, artemether has potent schizonticidal activity in the liver and erythrocyte phases. This drug, widely used in the treatment of malaria, presents low solubility in water limiting its oral bioavailability. In order to improve this characteristic, the methods of high energy milling, high-pressure homogenization and wet milling on a reduced scale were used to obtain nanocrystals. This last method was the one that allowed the reduction of the artemether particles in nanoscale. The high energy milling method revealed, in the experimental conditions of the present study, 10% (D0,1) of the population of particles with a diameter less than or equal to 3,504 &#177; 0,19 &#181;m, 50% (D0,5) less than or equal to 14.225 &#177; 0.34 &#181;m and 90% (D0.9) less than or equal to 57.306 &#177; 5.72 &#181;m. The mean hydrodynamic diameter was 25.01 &#177; 2.08 &#181;m, being the limiting factor in the reduction of particle size the density of the artemether. Similar results were obtained using a high-pressure homogenization method. Different surfactants were evaluated using the selected method, wet milling on a reduced scale. The stabilizing agent soluplus® was the one that favored the reduction of the particle size. This characteristic was observed by thermal analysis. This analysis allowed determining the degree of minimum amorphization, as well as the presence of strong molecular bonds between the drug and some polymers. The wet milling on a reduced scale method allowed obtaining artemether nanocrystals (formula R2-MUR) with a mean hydrodynamic diameter (MHD) of 342 ± 16.3 nm, polydispersity index (PdI) of 0,23 &#177; 0.01 and monomodal distribution. These preparations were obtained through the response surface methodology (RSM) having as independent variables the concentrations of artemether and stabilizing agent (Soluplus®) and the milling time. MHD and PdI were performed using dynamic light scattering (DLS). In addition, evaluations using differential scanning calorimetry (DSC) and X-ray diffraction (XRD) revealed that there was no change in the crystal structure of the artemether and interaction between the drug and the excipients. The present work allowed obtaining of artemether nanocrystals with saturation solubility up to 2.0 and 1.8 times higher in water medium and McIlvaine buffer (pH 2.5), respectively, compared to the micronized drug. In addition, the lyophilized preparation was stable after storage for three months at 25 and 4 ° C.

Malaria is the most important parasitic disease in man and it kills approximately 2,000 people each day. Pregnant women are especially vulnerable to malaria with increased incidence and mortality rates. There are indications that pregnancy alters the pharmacokinetic properties of many antimalarial drugs. This is worrisome as lower drug exposures might result in lowered efficacy and lower drug exposures can also accelerate the development and spread of resistant parasites. The aim of this research was to study the pharmacokinetics and pharmacodynamics of the most commonly used drugs for the treatment of uncomplicated Plasmodium falciparum malaria during the second and third trimester of pregnancy using a pharmacometric approach. This thesis presents a number of important findings that increase the current knowledge of antimalarial drug pharmacology and that may have an impact in terms of drug efficacy and resistance. (1) Lower lumefantrine plasma concentrations at day 7 were evident in pregnant women compared to that in non-pregnant patients. Subsequent in-silico simulations with the final pharmacokinetic-pharmacodynamic lumefantrine/desbutyl-lumefantrine model showed a decreased treatment failure rate after a proposed extended artemether-lumefantrine treatment. (2) Dihydroartemisinin exposure (after intravenous and oral administration of artesunate) was lower during pregnancy compared to that in women 3 months post-partum (same women without malaria). Consecutive in-silico simulations with the final model showed that the underexposure of dihydroartemisinin during pregnancy could be compensated by a 25% dose increase. (3) Artemether/dihydroartemisinin exposure in pregnant women was also lower compared to literature values in non-pregnant patients. This further supports the urgent need for a study in pregnant women with a non-pregnant control group. (4) Quinine pharmacokinetics was not affected by pregnancy trimester within the study population and a study with a non-pregnant control group is needed to evaluate the absolute effects of pregnancy. (5) Finally, a data-dependent power calculation methodology using the log likelihood ratio test was successfully used for sample size calculations of mixed pharmacokinetic study designs (i.e. sparsely and densely sampled patients). Such sample size calculations can contribute to a better design of future pharmacokinetic studies. In conclusion, this thesis showed lower exposures for drugs used to treat uncomplicated Plasmodium falciparum malaria during the second and third trimester of pregnancy. More pharmacokinetic studies in pregnant women with a non-pregnant control group are urgently needed to confirm the current findings and to enable an evidence-based dose optimisation. The data-dependent power calculation methodology using the log likelihood ratio test can contribute to an effective design of these future pharmacokinetic studies.