A acne vulgaris é uma patologia cutânea crônica que acomete a unidade pilossebácea resultando em hiperqueratinização, aumento da produção de sebo, inflamação e proliferação bacteriana nos folículos pilosos. Diversos fármacos estão disponíveis para o tratamento da acne, entretanto a combinação de tratamentos tópicos, com diferentes mecanismos de ação, apresentam uma melhor eficácia. Desse modo, o presente trabalho visa o desenvolvimento de um sistema nanocarreador contendo adapaleno e dapsona no intuito de promover melhor seletividade, aumentando a eficiência do tratamento e minimizando efeitos adversos. Neste contexto, desenvolveu-se e caracterizou-se físico-quimicamente uma formulação de nanocápsulas de núcleo lipídico contendo adapaleno e dapsona. A suspensão contendo 0,025 % de adapaleno e 0,07 % de dapsona apresentou diâmetro médio de 194,9 ± 0,42 nm, índice de polidispersão de 0,12 ± 0,02, potencial zeta -15 ± 1,2 mV, pH 5,1 ± 0,1 e eficiência de encapsulação próximos a 100 %. A avaliação da morfologia por microscopia eletrônica de transmissão demonstrou partículas esféricas, homogêneas de dimensões nanométricas. Através da análise de retroespalhamento de luz dinâmico (Turbiscan®) não se detectou fenômenos de instabilidade na formulação. Uma nanoemulsão, similarmente preparada, mas sem o uso do polímero, foi desenvolvida para comparação a fim de estabelecer o mecanismo de encapsulação dos fármacos. As suspensões foram incorporadas em veículos semissólidos, hidrogéis de Carpobol® 940, e os seguintes estudos foram realizados: comportamento reológico, pH, perfil de liberação, potencial de irritação (HET-CAM) e permeação cutânea in vitro. A determinação quantitativa dos ativos foi realizada por cromatografia líquida de alta eficiência (CLAE), e os métodos analíticos foram desenvolvidos e validados de acordo com os códigos oficiais vigentes. As formulações apresentaram perfil não-Newtoniano pseudoplástico. No estudo de liberação in vitro, não houve diferença significativa entre as formulações contendo dapsona (p>0,05). Já para o adapaleno, não foi possível estabelecer o perfil de liberação in vitro por membrana de diálise. As formulações foram avaliadas como não irritantes pela técnica de HET-CAM. Através dos estudos de permeação cutânea foi possível quantificar os fármacos na epiderme e na derme, e quantidade não-significativa foi detectada no fluído receptor (p>0,05). Comparando as formulações de nanocápsula de núcleo lipídico e nanoemulsão, as quantidades de adapaleno e dapsona em cada camada da pele foi significativamente diferente (p<0,05). Em conclusão, os resultados obtidos até o presente momento demonstram que as nanocápsulas de núcleo lipídico são um sistema promissor para aplicação cutânea de adapaleno e dapsona. Contudo, estudos clínicos fazem-se necessários a fim de avaliar a efetividade da formulação no tratamento da acne. / Acne vulgaris is a chronic skin condition that affects the pilosebaceous unit resulting in hyperkeratinization, increased sebum production, inflammation and bacterial proliferation in hair follicles. Several drugs are available for treating acne, however the combination of topical treatments with different mechanisms of action presents greater effectiveness. Therefore, this study aims to develop a nanocarrier system containing adapalene and dapsone in order to promote better selectivity, increasing efficiency of treatment and minimizing adverse side effects. In this study, a suspension of lipid-core nanocapsules containing adapalene and dapsone was prepared by interfacial deposition of preformed polymer and characterized physicochemically. The suspension containing 0.025 % of adapalene and 0.07 % of dapsone showed an average diameter of 194.9 ± 0.42 nm, a polydispersity index of 0.12 ± 0.02, zeta potential -15 mV ± 1.2, pH 5.1 ± 0.1 and encapsulation efficiency approaching 100 %. The assessment of morphology by transmission electron microscopy showed spherical particles of homogeneous nanometric dimensions. No detectable instability phenomena in the formulation was observed by dynamic light scattering analysis (Turbiscan®). A nanoemulsion, similarly prepared but omitting the polymer, was developed to establish the mechanism of drug encapsulation. The suspensions were incorporated into semisolid vehicles, hydrogels of Carpobol® 940, and the following studies were performed: rheological behavior, pH, release profile, irritation potential (HET-CAM) and skin permeation in vitro. Drug quantification was carried out by high-performance liquid chromatography (HPLC) and analytical methods were developed and validated according to current official guidelines. The formulations exhibited non-Newtonian pseudoplastic profile. In the in vitro release study, no significant difference was found between the formulations containing dapsone (p>0.05). However, for adapalene, it was not possible to establish the in vitro release profile by dialysis membrane. The formulations were evaluated as non-irritant by HET-CAM technique. Through the skin permeation studies, it was possible to quantify the drug in epidermis and dermis, and non-significant quantity was detected in the receptor fluid (p>0.05). Comparing the lipid-core nanocapsules and nanoemulsion formulations, the amount of adapalene and dapsone in each skin layer was significantly different (p<0.05). In conclusion, the results obtained show that the lipid-core nanocapsules are a promising system for cutaneous application of adapalene and dapsone. However, clinical studies are required in order to evaluate the effectiveness of the formulation in the treatment of acne.

Orientador: Anita Jocelyne Marsaioli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-25T07:45:46Z (GMT). No. of bitstreams: 1 Martins_LucasGelain_D.pdf: 5948717 bytes, checksum: d64f37183bfefec1cedc88b263d32340 (MD5) Previous issue date: 2014 / Resumo: Nesta tese consiste no estudo de interações supramoleculares utilizando diferentes metodologias de Ressonância Magnética Nuclear de hidrogênio (RMN de 1H), tais como ROESY 1D, RMN-DOSY e RMN-STD. Os sistemas supramoleculares foram abordados em dois casos de estudo diferentes. O Capítulo I tem como objeto de estudo interações do fármaco Dapsona com diferentes carreadores de fármacos (ß-CD, SBE-ß-CD e lipossoma de EPC), com a finalidade de encontrar formulações nas quais a Dapsona seja mais solúvel. Os complexos binários e ternário formados foram determinadas por medidas de difusão molecular. Foram observadas as formações dos complexos Dap/ß-CD, Da-/SBE-ß-CD, Dap/EPC e o ternário Dap/ß-CD/EPC, os quais contribuem para o aumento de solubilidade do fármaco. O objeto de estudo apresentado no Capítulo II é a inibição da enzima acetilcolinesterase por dois alcaloides, a Fisostigmina e a Crinina. Para determinação das constantes de dissociação aparentes foram utilizados os crescimentos iniciais das curvas de saturação obtids por RMN-STD para construção das Isotermas de Langmuir. De acordo com os valores de constantes obtidos foi possível concluir que a AchE tem mais afinidade com a Fisostigmina do que com a Crinina / Abstract: This thesis consists of the supramolecular interactions study applying different Nuclear Magnetic Resonance methodologies (1H NMR) such as 1D ROESY, DOSY-NMR and STD-NMR. The supramolecular systems were addressed in two different case studies. In chapter I Dapsone solubility was the case study. To solve the solubility problem the interactions between Dapsone and various drug carriers (ß-CD , SBE-ß-CD and EPC liposome) were characterized in terms of the binary and ternary complexes structure using NMR method, such as 1D ROESY and STD-NMR and apparent association constants were determined by measuring molecular diffusion using DOSY-NMR. Dap/ß-CD, Dap/SBE-ß-CD, Dap/EPC and Dap/ß-CD/EPC complexes were observed and Dapsone water solubility was increased. The case study in Chapter II is the inhibition of acetylcholinesterase by two alkaloids, Physostigmine and Crinina. The apparent dissociation constants were determined using the initial growth saturation curves obtained by STD-NMRto construct the Langmuir isotherms. The constants showed that the AChE has more affinity for the Physostigmine than Crinine / Doutorado / Quimica Organica / Doutor em Quimica

Dapsone has been shown to be an effective agent against Pneumocystis carinii pneumonia, an opportunistic infection in AIDS patients. Oral administration of dapsone is associated with several adverse effects, including methemoglobinemia, hemolytic anemia and photosensitivity reactions. To reduce the adverse effects associated with oral dapsone, an alternative would be to administer the prodrug diacetyldapsone (DADDS) into the lung, which may be hydrolyzed to monoacetyldapsone and the active metabolite dapsone. The purpose of this investigation was to determine the effect of cyclodextrindiacetyldapsone (CD-DADDS) complex upon the cultured lung cells and whether or not cultured lung cells could activate DADDS into dapsone, the active metabolite. The effect of the CD-DADDS complex upon the growth of cultured CRL 7272 lung cells was assessed by the trypan blue dye exclusion technique. There was no significant reduction in cell number as compared to the control for incubations with three different concentrations of CD-DADDS complex. The amount of arylamine produced by hydrolysis was initially monitored by the Bratton-Marshall diazotization technique. Only incubation with 0.01% DADDS in 1% CD showed a significant time dependent hydrolysis of DADDS over a period of 72 hours due to insensitivity of the assay method. Over the same period, cultured lung cells produced 1.65 μmoles of metabolite/106 cells. However interfering substances could contribute to this value. To provide additional evidence for hydrolysis and to quantitatively estimate the amount of dapsone, a more sensitive HPLC method was used. The results obtained from HPLC analysis demonstrated a significant concentration and time dependent increase in the amount of dapsone with 0.001% DADDS, 0.005% DADDS and 0.01% DADDS incubations, respectively. Over a period of 48 hours, 255ng of dapsone/ 106 cells was formed in an incubation containing 0.01% DADDS.

A dapsona, fármaco de escolha no tratamento da hanseníase, na prevenção da malária e no da pneumonia pelo Pneumocystis carinii vem sendo associada a casos clinicamente freqüentes, caracterizadas por metemoglobinemia e anemia hemolítica. Essa hemotoxicidade está diretamente relacionada à N-hidroxilação sofrida pelo fármaco. Com o objetivo de se verificar a inibição da hemotoxicidade acarretada pelos produtos de biotransformação reativos, a arginina, fármaco antioxidante, precursor do óxido nítrico, foi administrado concomitantemente à dapsona em ratos Wistar, em estudo de doses únicas e múltiplas, por gavage: Grupo I: 40 mg/kg de dapsona. Grupos II, III, IV, V e VI; administração de 0.5%, 1.5%, 3%, 6% e 18% de arginina. Grupo VII, 0.5% de arginina antes de 40 mg/Kg de dapsona. Grupo VIII, 1.5% de arginina antes de 40 mg/Kg de dapsona, Grupo IX, 3,0% de arginina antes de 40 mg/kg de dapsona. Grupo X, 6,0% de arginina antes de 40 mg/kg de dapsona. Grupo XI, 18,0% de arginina antes de 40 mg/kg de dapsona. Os parâmetros hematológicos e bioquímicos serão correlacionados com a concentração plasmática de dapsona, determinada por CLAE, na exposição à dapsona em monoterapia e na associação com a com a arginina. O resultado mostrou que a interação com a arginina e dapsona não protegeu da hemotoxicidade da dapsona, principalmente a metemoglobinemia e anemia hemolítica. / The dapsone, medicine used in the treatment of Hansen\'s disease, in the malaria prevention and in pneumonia caused by Pneumocystis carinii is being associated to the clinically frequents cases, characterized by methemoglobinemia and hemolytic anemia. This hemotoxicity is directly related to the N-hidroxidation suffered by the medicine. With the target to verify the inhibition of the hemotoxicity occurred by the products of biotransformation reactive, the arginine, antioxidant, forerunner of the nitric oxide, will be dosed concurrently with dapsone in Wistar mice, with only one and multiple dose, per gavage: Group I: 40 mg/Kg of dapsone. Groups II, III, IV, V and VI: management the just one dose of 0,5%, 1,5%, 3,0%, 6,0% and 18,0% de arginine. Group VII: arginine 0,5% before of 40 mg/Kg dapsone. Group VIII: arginine 1,5% before of 40 mg/Kg dapsone. Group IX: arginine 3,0% before of 40 mg/Kg dapsone, Group X: arginine 6,0% before of 40 mg/Kg dapsone. Group XI: arginine 18,0% before of 40 mg/Kg dapsone The hematologyc and biochemical parameters are related to the plasmatic concentration of dapsone, determined by CLAE, in the exposition to the dapsone in monotherapic and in the association with arginine. The result showed that the interaction with arginine and dapsone did not protect the hemotoxicity of the dapsone, mainly the methemoglobinemia and hemolytic anemia.

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2016-09-21T19:19:52Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Gaya Freitas.pdf: 1529179 bytes, checksum: c9caac96378af20cf153b0fd3adead1b (MD5) / Approved for entry into archive by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2016-09-21T19:20:09Z (GMT) No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Gaya Freitas.pdf: 1529179 bytes, checksum: c9caac96378af20cf153b0fd3adead1b (MD5) / Made available in DSpace on 2016-09-21T19:20:09Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Gaya Freitas.pdf: 1529179 bytes, checksum: c9caac96378af20cf153b0fd3adead1b (MD5) Previous issue date: 2015-08-12 / A dapsona é uma sulfona com atividade antibiótica utilizada para doenças crônicas de pele como a psoríase, contudo seu uso pela via oral apresenta elevada incidência de eventos adversos. Uma abordagem para reduzir os efeitos colaterais é a aplicação da dapsona diretamente na área afetada, o que pode ser feito com a utilização de nanocápsulas (NC), visando aumentar a permeabilidade do fármaco na pele. Dentre os componentes que podem ser utilizados como núcleo oleoso de NC, está o óleo de arroz (Oryza sativa), devido a suas propriedades hidratantes, umectantes, antioxidantes e de proteção à radiação UV. Desta maneira, este trabalho teve por objetivo desenvolver e caracterizar NC de dapsona com diferentes polímeros - poli-ε-caprolactona (NC-P) e Eudragit® RS100 (NC-E) - utilizando diferentes quantidades de óleo de arroz e fármaco. As NC apresentaram pH levemente ácido, diâmetro de partícula inferior a 334 nm, distribuição granulométrica estreita, potencial zeta negativo (-9,9 a -33,7 mV) e eficiência de encapsulação superior a 83%. O estudo da liberação in vitro, realizado em sacos de diálise, demonstrou que as NC foram eficientes em controlar a liberação da dapsona, sendo o modelo monoexponencial o mais adequado para descrever os perfis de liberação. A nanoencapsulação diminuiu a degradação fotolítica da dapsona frente à luz UVA, obtendo-se percentuais de fármaco residual de 80,6%; 91,9% e 1,4% para NC-P1, NC-E e fármaco livre, respectivamente. Além disso, hidrogéis preparados com NC-P1 (HG-NCP1) e NC-E (HG-NCE) apresentaram pH adequado para aplicação cutânea, teor próximos a 100% e comportamento não-newtoniano pseudoplástico (HG-NCE) e plástico (HG-NCP1). Na avaliação da oclusão in vitro, observou-se que o HG-NCP1 aumentou consideravelmente a oclusão quando comparado ao HG-NCE e ao hidrogel contendo fármaco livre. Assim, estas formulações apresentam-se como sistemas promissores para aplicação cutânea de dapsona, com potencial para constituir-se em um tratamento tópico eficaz para a psoríase. / Dapsone is a sulfone with antibiotic activity used for chronic skin diseases such as psoriasis. The use of dapsone by oral route presents high incidence of adverse events. An approach to reduce side effects is the application of dapsone directly into the skin, which can be done by use of nanocapsules (NC), in order to increase the skin permeability of the drug. The rice (Oryza sativa) oil is a component that can be used as NC oil core due to its moisturizing, humectant, antioxidant and UV protection properties. Thus, this study aimed to develop and characterize dapsone-loaded NC using different polymers - poly-ε-caprolactone (NC-P) and Eudragit® RS100 (NC-E) - using different rice oil and drug concentration. The NC showed slightly acidic pH, particle diameter less than 334 nm, narrow particle size distribution, negative zeta potential (-9.9 to -33.7 mV) and encapsulation efficiency higher than 83%. The in vitro release study, carried out in dialysis bags, showed that both NC were effective in controlling the release of dapsone. The monoexponential equation was the most appropriate model to describe the release profiles. The nanoencapsulation decreases photolytic degradation of dapsone in UVA light, yielding drug remaining percentage of 80.6%, 91.9% and 1.4% for NC-P1, NC-E and free drug, respectively. In addition, hydrogels prepared with NC-P1 (HG-NCP1) and NC-E (HG-NCE) showed pH suitable for cutaneous application, content close to 100% and non-Newtonian pseudoplastic (HG-NCE) or plastic (HG-NCP1) behavior. In vitro occlusion evaluation showed that the HG-NCP1 significantly increased the occlusion factor when compared to HG-NCE and the free drug hydrogel. Thus, these formulations are promising systems for topical application of dapsone, with the potential to constitute in an effective topical treatment for psoriasis.

A dapsona, fármaco de escolha no tratamento da hanseníase, na prevenção da malária e no da pneumonia pelo Pneumocystis carinii vem sendo associada a casos clinicamente freqüentes, caracterizadas por metemoglobinemia e anemia hemolítica. Essa hemotoxicidade está diretamente relacionada à N-hidroxilação sofrida pelo fármaco. Com o objetivo de se verificar a inibição da hemotoxicidade acarretada pelos produtos de biotransformação reativos, a arginina, fármaco antioxidante, precursor do óxido nítrico, foi administrado concomitantemente à dapsona em ratos Wistar, em estudo de doses únicas e múltiplas, por gavage: Grupo I: 40 mg/kg de dapsona. Grupos II, III, IV, V e VI; administração de 0.5%, 1.5%, 3%, 6% e 18% de arginina. Grupo VII, 0.5% de arginina antes de 40 mg/Kg de dapsona. Grupo VIII, 1.5% de arginina antes de 40 mg/Kg de dapsona, Grupo IX, 3,0% de arginina antes de 40 mg/kg de dapsona. Grupo X, 6,0% de arginina antes de 40 mg/kg de dapsona. Grupo XI, 18,0% de arginina antes de 40 mg/kg de dapsona. Os parâmetros hematológicos e bioquímicos serão correlacionados com a concentração plasmática de dapsona, determinada por CLAE, na exposição à dapsona em monoterapia e na associação com a com a arginina. O resultado mostrou que a interação com a arginina e dapsona não protegeu da hemotoxicidade da dapsona, principalmente a metemoglobinemia e anemia hemolítica. / The dapsone, medicine used in the treatment of Hansen\'s disease, in the malaria prevention and in pneumonia caused by Pneumocystis carinii is being associated to the clinically frequents cases, characterized by methemoglobinemia and hemolytic anemia. This hemotoxicity is directly related to the N-hidroxidation suffered by the medicine. With the target to verify the inhibition of the hemotoxicity occurred by the products of biotransformation reactive, the arginine, antioxidant, forerunner of the nitric oxide, will be dosed concurrently with dapsone in Wistar mice, with only one and multiple dose, per gavage: Group I: 40 mg/Kg of dapsone. Groups II, III, IV, V and VI: management the just one dose of 0,5%, 1,5%, 3,0%, 6,0% and 18,0% de arginine. Group VII: arginine 0,5% before of 40 mg/Kg dapsone. Group VIII: arginine 1,5% before of 40 mg/Kg dapsone. Group IX: arginine 3,0% before of 40 mg/Kg dapsone, Group X: arginine 6,0% before of 40 mg/Kg dapsone. Group XI: arginine 18,0% before of 40 mg/Kg dapsone The hematologyc and biochemical parameters are related to the plasmatic concentration of dapsone, determined by CLAE, in the exposition to the dapsone in monotherapic and in the association with arginine. The result showed that the interaction with arginine and dapsone did not protect the hemotoxicity of the dapsone, mainly the methemoglobinemia and hemolytic anemia.

Malaria is a life–threatening disease caused by Plasmodium spp and causes over one million deaths annually. The complex life cycle of the malaria parasite offers several points of attack for the antimalarial drugs. The rapid spread of resistance against antimalarial drugs, especially chloroquine and pyrimethamine–sulphadoxine, emphasises the need for new alternatives or modification of existing drugs. Artemisinin–based combination therapies (ACT’s) with different targets prevent or delay the development of drug resistance and therefore have been adopted as first–line therapy by all endemic countries. Proguanil–dapsone, an antifolate combination is more active than pyrimethamine–sulphadoxine and is being considered as an alternative to pyrimethamine–sulphadoxine. Artesunate–proguanil–dapsone is a new ACT that has wellmatched pharmacokinetics and is relatively rapidly eliminated; therefore there is a reduced risk of exposure to any single compound and potentially a decreasing risk of resistance. A few studies have been done on a triple fixed–dose combination therapy for malaria treatment and such a combination for artesunate, proguanil and dapsone are not currently investigated, manufactured or distributed. The aim of this study was to develop a triple fixed–dose combination for artesunate, proguanil and dapsone. The formulation was developed in three phases; basic formulation development, employing factorial design to obtain two possible optimised formulations and evaluating the optimised formulations. During the formulation development the most suitable manufacturing procedure and excipients were selected. A full 24 factorial design (four factors at two levels) was used to obtain the optimised formulations. As end–points to identify the optimised formulations, weight variation, friability, crushing strength and disintegration of the tablets, were used. Statistical analysis (one way ANOVA) was used to identify optimal formulations. To identify any interaction between the active pharmaceutical ingredients (API’s) and the API’s and excipients, differential scanning calorimetry was done. Flow properties of the powder mixtures (of the optimised formulations) were characterised by means of angle of repose; critical orifice diameter (COD); bulk density and tapped density; and flow rate. Tablets of the two optimised powder formulations were compressed. The tablets were evaluated and characterised in terms of weight variation, friability, crushing strength, disintegration and dissolution behaviour. Initial formulation development indicated that wet granulation was the most suitable manufacturing method. The results from the factorial design indicated that different amounts (% w/w) of the lubricant and binder as well as two different fillers influenced the weight variation, crushing strength and disintegration statistically significant. Two formulations containing two different fillers (microcrystalline cellulose or Avicel® PH 101, and lactose or Granulac® 200) were found to be within specifications and ideal for manufacturing. Tablets prepared from the FA formulation (formulation containing Avicel® PH 101) complied with the standards and guidelines for weight variation, friability, crushing strength and disintegration as set by the British Pharmacopoeia (BP). Tablets had an average crushing strength of 121.56 ± 0.022 N. Tablets disintegrated within 52.00 seconds and a maximum weight loss of 0.68% occurred during the friability test. Weight variation of the tablets prepared from the FG formulation (formulation containing Granulac® 200) complied with the standards. Average crushing strength was 91.99 ± 6.008 N and the tablets disintegrated within 140.00 seconds. Percentage friability (1.024%) did not comply with the guideline of a percentage friability of less than 1%, however, no cracked or broken tablets were seen. Dissolution showed that 98, 93 and 94% of artesunate, proguanil and dapsone were respectively released (of the label value) within 15 minutes for the FA formulations. Release of artesunate, proguanil and dapsone for the FG formulation was 62, 85 and 92% for the same time period. The release of the three API’s (the FG formulation) increased to 78, 89 and 92%, respectively, after 45 minutes. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2012.

Malaria is a life–threatening disease caused by Plasmodium spp and causes over one million deaths annually. The complex life cycle of the malaria parasite offers several points of attack for the antimalarial drugs. The rapid spread of resistance against antimalarial drugs, especially chloroquine and pyrimethamine–sulphadoxine, emphasises the need for new alternatives or modification of existing drugs. Artemisinin–based combination therapies (ACT’s) with different targets prevent or delay the development of drug resistance and therefore have been adopted as first–line therapy by all endemic countries. Proguanil–dapsone, an antifolate combination is more active than pyrimethamine–sulphadoxine and is being considered as an alternative to pyrimethamine–sulphadoxine. Artesunate–proguanil–dapsone is a new ACT that has wellmatched pharmacokinetics and is relatively rapidly eliminated; therefore there is a reduced risk of exposure to any single compound and potentially a decreasing risk of resistance. A few studies have been done on a triple fixed–dose combination therapy for malaria treatment and such a combination for artesunate, proguanil and dapsone are not currently investigated, manufactured or distributed. The aim of this study was to develop a triple fixed–dose combination for artesunate, proguanil and dapsone. The formulation was developed in three phases; basic formulation development, employing factorial design to obtain two possible optimised formulations and evaluating the optimised formulations. During the formulation development the most suitable manufacturing procedure and excipients were selected. A full 24 factorial design (four factors at two levels) was used to obtain the optimised formulations. As end–points to identify the optimised formulations, weight variation, friability, crushing strength and disintegration of the tablets, were used. Statistical analysis (one way ANOVA) was used to identify optimal formulations. To identify any interaction between the active pharmaceutical ingredients (API’s) and the API’s and excipients, differential scanning calorimetry was done. Flow properties of the powder mixtures (of the optimised formulations) were characterised by means of angle of repose; critical orifice diameter (COD); bulk density and tapped density; and flow rate. Tablets of the two optimised powder formulations were compressed. The tablets were evaluated and characterised in terms of weight variation, friability, crushing strength, disintegration and dissolution behaviour. Initial formulation development indicated that wet granulation was the most suitable manufacturing method. The results from the factorial design indicated that different amounts (% w/w) of the lubricant and binder as well as two different fillers influenced the weight variation, crushing strength and disintegration statistically significant. Two formulations containing two different fillers (microcrystalline cellulose or Avicel® PH 101, and lactose or Granulac® 200) were found to be within specifications and ideal for manufacturing. Tablets prepared from the FA formulation (formulation containing Avicel® PH 101) complied with the standards and guidelines for weight variation, friability, crushing strength and disintegration as set by the British Pharmacopoeia (BP). Tablets had an average crushing strength of 121.56 ± 0.022 N. Tablets disintegrated within 52.00 seconds and a maximum weight loss of 0.68% occurred during the friability test. Weight variation of the tablets prepared from the FG formulation (formulation containing Granulac® 200) complied with the standards. Average crushing strength was 91.99 ± 6.008 N and the tablets disintegrated within 140.00 seconds. Percentage friability (1.024%) did not comply with the guideline of a percentage friability of less than 1%, however, no cracked or broken tablets were seen. Dissolution showed that 98, 93 and 94% of artesunate, proguanil and dapsone were respectively released (of the label value) within 15 minutes for the FA formulations. Release of artesunate, proguanil and dapsone for the FG formulation was 62, 85 and 92% for the same time period. The release of the three API’s (the FG formulation) increased to 78, 89 and 92%, respectively, after 45 minutes. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2012.