Malaria is an infectious disease caused by various forms of the Plasmodium parasite. It is responsible for thousands of deaths yearly with 90 % of those deaths being in sub-Saharan Africa, thus making it a disease of global importance. The global burden of malaria is worsened by resistance to current treatment, a lack in funding and limited research outputs. More alternative ways of treatment must be explored and may include the co-formulation of antimalarial drug substances as well as alternative ways of drug delivery. Antifolates are drugs which interfere with an organism’s folate metabolism by inhibiting dihydropteroate synthase (DHPS) or dihydrofolate reductase (DHFR). Dapsone is a synthetic sulfone which has a mechanism of action that is very similar to that of sulphonamides. The mechanism of action is characterised by the inhibition of folic acid synthesis through the inhibition of dihydropteroate synthase (DHPS). Another antifolate drug, proguanil, is the prodrug of cycloguanil. Its mechanism involves the inhibition of dihydrofolate reductase (DHFR), thus inhibiting the malaria parasite to metabolise folates and therefore stunting its growth. Unfortunately, dapsone has a serious side-effect in people with a deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) causing oxidative stress on the red blood cells leading to the rupturing of these cells. The main objective of this study was to formulate and characterise TMC-TPP microparticles loaded with the effective but toxic drug combination of dapsone and proguanil and to determine if these drug-containing microparticles had in vivo efficacy against malaria. N-trimethyl chitosan chloride (TMC), a partially quaternised chitosan derivative, shows good water solubility across a wide pH range thus having mucoadhesive properties and excellent absorption enhancing effects even at neutral pH. A faster, more efficient microwave irradiation method was developed as an alternative to the conventional synthesising method of TMC. TMC with the same degree of quaternisation (DQ), ± 60 %, was obtained in a quarter of the reaction time (30 min) by using the newly developed method. The TMC synthesised with the microwave irradiation method also exhibited less degradation of the polymer structure, thus limiting the chance for the formation of any unwanted by-products (Omethylation, N,N-dimethylation and N-monomethylation). The formation of complexes by ionotropic gelation between TMC and oppositely charged macromolecules, such as tripolyphosphate (TPP), has been utilised to prepare microparticles which are a suitable drug delivery system for the dapsone-proguanil combination. Both these drugs were successfully entrapped. These particles were characterised and the in vivo efficacy against the malaria parasites was determined. The microparticles with both the drugs, separately and in combination, displayed similar or better in vivo efficacy when compared to the drugs without the TMC microparticles. An in vitro dissolution study was also performed by subjecting the dapsone and proguanil TMC formulations to 0.1N HCl dissolution medium. Samples were withdrawn after predetermined time points and the drug concentration was determined with HPLC. It was found that the TMC microparticles resulted in a sustained release profile since only 73.00 ± 1.70 % (dapsone) and 55.00 ± 1.90 % (proguanil) was released after 150 minutes. The in vivo bioavailability of the dapsone and proguanil TMC formulations was evaluated in mice by collecting blood samples at predetermined time points and analysing the samples with a sensitive and accurate LC-MS/MS method. The in vivo bioavailability of the dapsone TMC formulation relative to the normal dapsone formulation was found to be 244 % and 123 % for the proguanil TMC formulation relative to the normal proguanil formulation. These TMC-TPP microparticles formulations showed better in vivo efficacy and bioavailability when compared to the normal formulation. Together with the sustained release, these formulations may be a promising cheaper and more effective treatment against malaria. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2015

Oxidative stress is a pathophysiological condition defined by an increased production of reactive oxygen species (ROS), which can result in the growth arrest of cells followed by cell disintegration or necrosis. A number of small molecule antioxidants (e.g. curcumin, quercetin and resveratrol) are capable of directly scavenging ROS, thereby short-circuiting the self-propagating oxidative stress state. However, poor solubility and rapid 1st pass metabolism results in overall low bioavailability and acts as a barrier for its use as a drug to suppress oxidative stress efficiently. To overcome this limitation, these small molecule antioxidants were covalently conjugated into poly(β-amino ester) (PβAE) cross-linked networks to formulate prodrug gel microparticles and nanoparticles (nanogels). Being hydrolytically degradable in nature, these PβAE crosslinked systems released antioxidants in their original structural form in a sustained controlled fashion. Both quercetin and curcumin-PβAE nanogels showed prolonged suppression of cellular oxidative stress induced by H2O2. Curcumin PβAE nanogels also demonstrated protection against mitochondrial oxidative stress induced by H2O2 and polychlorinated biphenyls. Curcumin-PβAE gel microparticles were also developed as a platform to treat oral mucositis through a local antioxidant delivery route. The same synthesis chemistry was transferred to formulate resveratrol PβAE gel microparticles for topical applications, to treat UV radiation induced oxidative stress. Both formulations showed suppression of induced oxidative stress. An in vivo trial with curcumin-PβAE microparticles further showed relatively reduced the severity of induced oral mucositis (OM) in hamster check pouch as compared to placebo.

Thesis (PhD (Process Engineering))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: The ongoing trend in papermaking industries is to lower production costs by increasing the low cost filler content in the sheets. However, the disruption of inter-fibre bonding is accompanied by a deterioration of paper stiffness and mechanical properties if filler content exceeds 18 wt%. Polysaccharide solutions, such as starch, are often used as a low cost biodegradable additive to improve internal sheet strength when added to the wet-end of production. The amount of starch that can be added is however limited as only a small percentage will be retained in the paper web. A dual additive multifunctional polysaccharide system was developed to allow higher filler loading levels without detrimental deterioration in paper properties. In order to achieve a larger surface area for fibre/filler interaction and to reduce drainage losses, at least one of these additives was in particulate form. Anionic, cationic, and unsaturated derivatives were prepared using sodium monochloroacetate, 3-chloro-2-hydroxypropyltrimethylammonium chloride, and allyl bromide, respectively. The degree of substitution was determined by 1H-NMR spectroscopy and back titration methods and the interaction of the ionic modified derivatives with paper components was determined using fluorescence microscopy. Anionic modified polysaccharide particles were prepared using techniques such as macrogel ultrasonification, water-in-water emulsification, and in-situ cross-linking and carboxymethylation of granular starch. A process of adding sequential layers of oppositely charged polyelectrolyte layers onto the filler particles was also investigated. A novel approach of preparing modified particles with tailored size and distribution using microfluidics was studied and modelled using response surface methodology. Hand sheets were prepared using the dual additive system and improvements in stiffness, tear resistance, breaking length, and folding endurance were observed. The modified granular maize starch particles had a pre-eminent effect on improving stiffness at higher filler loadings (14% improvement at 30 wt% filler loading), while bulky particles prepared using microfluidics showed a more consistent improvement (between 6% and 10%) across the loading range. Overall improvements gained by the introduction of multi-layered soluble polymers onto fillers suggest that the introduction of nanotechnology to the papermaking process should be of potential benefit to the industry. Furthermore, the dual additive system developed during the course of this study should also be tested on a continuous pilot plant papermaking process. / AFRIKAANSE OPSOMMING: Die papierindustrie neig voortdurend daarna om produksiekostes te verlaag deur die persentasie lae koste vulstof wat gebruik word te verhoog. Aangesien die vulstof vesel kontak belemmer, gaan hoër vlakke (> 18 wt%) egter gepaard met ’n verlaging in papier styfheid en meganiese eienskappe. Polisakkaried oplossings, soos byvoorbeeld stysel, word dikwels gebruik as lae koste vergaanbare bymiddel om papier intern te versterk wanneer dit voor die vormingsproses bygevoeg word. Slegs ’n beperkte hoeveelheid stysel word egter behou in die papier matriks en oormatige oplossings ontsnap tydens dreinering in die afvalwater. ’n Dubbele multi-funksionele polisakkaried bymiddelsisteem was ontwikkel wat ongewensde verwakking in papiereienskappe verminder tydens vulstof verhogings. Ten minste een van die bymiddels was in partikelvorm om sodoende ’n groter oppervlak te bied vir vesel/vulstof interaksie en om dreineringsverliese te verminder. Anioniese, kationiese, sowel as onversadigde derivate was berei deur onderskeidelik gebruik te maak van natrium monochloroasetaat, 3-chloro-2-hidroksiepropieltrimetielammonium chloried, en alliel bromied. Die graad van substitutiese was bepaal met behulp van 1H-KMR spektroskopie sowel as titrasie tegnieke terwyl die ioniese interaksie van die gemodifiseerde stysels met die papierkomponente ondersoek was met behulp van fluoressensie mikroskopie. Anioniese polisakkaried partikels was berei met tegnieke soos makro-jel ultrasonifikasie, water-in-water emulsifikasie, en in-situ kruisbinding en karboksiemetielasie van stysel granulate. ’n Proses was ook ondersoek waar vulstof partikels omhul was in verskeie lae poliëlektroliet oplossings. ’n Nuwe benadering was toegepas waar gemodifiseerde partikels met voorafbepaalde grootte en verspreiding berei is deur gebruik te maak van mikrofluïdika en gemodelleer met behulp van oppervlakte ontwerp metodeleer. Papier toetse was uitgevoer met die bymiddelsisteem en algehele verbetering in styfheid, skeurweerstand, breeklengte, en voulydsaamheid is waargeneem. Die gemodifiseerde stysel granulate het die grootste verbetering in styfheid by hoë vulstofladings getoon (14% verbetering by 30 wt% vulstoflading) terwyl die groter mikrofluïdika-bereide partikels algehele verbetering (tussen 6% en 10%) getoon het oor die hele vulstoflading reeks. Die verbeteringe in styfheid sowel as meganiese eienskappe van papier voorberei met poliëlektroliet omhulde vulstof toon dat aanwending van nanotegnologie in hierdie bedryf potensieel voordelig kan wees. Opskalering van die polisakkaried bymiddels ontwikkel gedurende hierdie studie behoort uitgevoer te word vir verdere toetse op ’n kontinue papier loodsaanleg.

No description available.

Les analogues de nucléosides (AN), sont des agents importants dans le traitement d’hémopathies malignes et de certaines tumeurs solides. Le catabolisme rapide, la résistance cellulaire au traitement et le grand volume de distribution dans le corps limitent potentiellement l’efficacité thérapeutique des AN. Notre objectif est de concevoir un vecteur permettant un ciblage de ces molécules vers les tissus cancéreux, assurant son internalisation cellulaire et sa protection dans les milieux biologiques. Trois types de vecteurs de taille micronique, submicronique et moléculaire ont été élaborés et caractérisés : microparticules polymériques à base de poly(ε-caprolactone) (PCL), liposomes multilamellaires et complexes d’inclusion de la prodrogue de la cytarabine (Ara-C), qui est active sur certaines lignées cellulaires résistantes à l’Ara-C, l’AraC-SATE (bis(tbutyl-S-acyl-2-thioethyl)-cytidine monophosphate).Les microparticules ont été préparées par la méthode de « double émulsion - évaporation de solvant » en utilisant comme surfactants des copolymères amphiphiles composés de blocs biodégradables de PCL et de blocs bio-éliminables de polyéthylène glycol (PEG). Une série de copolymères mPEG-PCL avec des blocs PCL de différents poids moléculaires a été synthétisée et l’effet de la longueur de chaînes de PCL sur les caractéristiques physico-chimiques des particules a été étudié. Une efficacité d’encapsulation satisfaisante a pu être obtenue, qui a été dix fois plus importante que celle des microparticules à base de PCL seul. Les liposomes ont été préparés par la méthode d’injection d’éthanol. Une étude de formulation a été réalisée afin de sélectionner la formule permettant d’obtenir la meilleure efficacité d’encapsulation. Le test d’internalisation cellulaire et du comportement aérodynamique des liposomes nébulisés ont montré la pertinence des liposomes élaborés pour le ciblage des cellules pulmonaires qui pourrait être d'un grand intérêt pour le traitement des métastases au niveau des poumons.L’encapsulation moléculaire de l’AraC-SATE dans l’hydroxyporpyl-β-cyclodextrine a été réalisée pour augmenter la solubilité apparente de la prodrogue. L’évaluation des complexes sur des cultures de cellules leucémiques murines a montré une activité cytotoxique comparable à celle de la prodrogue indiquant que l’inclusion moléculaire ne modifie pas l’activité biologique de la prodrogue. / Nucleoside analogues (NA) are important agents in the treatment of haematological malignancies and solid tumours. Their rapid catabolism, cell resistance and overdistribution in the body jeopardize the NA chemotherapy. Our objective is to design a vector for these molecules targeting cancerous tissue and ensuring its cellular internalization and protection in the biological media. Micro-sized, nano-sized and molecular vectors were developed and characterized: polymeric microparticles of poly (ε-caprolactone) (PCL), multilamellar liposomes and inclusion complexes of the prodrug of cytarabine (Ara-C), which is active on some cell types resistant to treatment, the AraC-SATE (bis(tbutyl-S-acyl-2-thioethyl)-cytidine monophosphate).The microparticles were prepared by the "double emulsion - solvent evaporation" method using as surfactants, amphiphilic copolymers consisting of biodegradable blocks (PCL) and bio-removable blocks (polyethylene glycol, PEG). A series of copolymers mPEG-PCL with PCL blocks of different molecular weights was synthesized and the effect of PCL chain length on the particle physico-chemical properties was studied. Satisfactory encapsulation efficiency could be obtained, which was 10 times greater than that of microparticles prepared with PCL alone. Liposomes were prepared by the ethanol injection method. A formulation study was conducted in order to select the formula having the optimal encapsulation efficiency. Investigations about the cell internalization and the aerodynamic behaviour of the nebulized liposomes showed the relevance of developed liposomes for targeting lung cells that could be of great interest for the treatment of metastases in the lungs. The molecular encapsulation of the AraC-SATE in the hydroxyporpyl-β-cyclodextrin was carried out in order to increase the apparent solubility of the prodrug. The evaluation of inclusion complexes on murine leukemic cell cultures showed a cytotoxic activity comparable to that of the prodrug indicating that the molecular inclusion does not alter the biological activity of the prodrug.

Les microparticules (MP) sont des vésicules de la membrane plasmique émises après stress cellulaire. Nous avons étudié le rôle des MPs leucocytaires extraites de la rate de rats comme marqueur du vieillissement et effecteurs de la senescence et de la dysfonction endothéliales induites par les fortes concentrations de glucose (HG). L’émission basale de MP augmente avec l’âge qui favorise leur génération en réponse au LPS ou au PMA/ionophore A23187 (MPLPS, MPPMA/I). Les MP de rats âgés mais pas de jeunes induisent la sénescence de cellules endothéliales primaires d’artères coronaires (AC) de porc. MPLPS ou MPPMA/I de rats jeunes, mais pas MPCTL (cellules non traitées) réduisent la relaxation dépendante de l’endothélium d’anneaux d’AC en réponse à la bradykinine avec sous-expression de eNOS, surexpression de COX2, ICAM-1, VCAM-1. HG favorise l’émission des MP de rate. Dans les AC en HG, la vasoconstriction en réponse au U46619l est diminuée de manière dépendante du SGLT1/2 et de l’EDHF. / Microparticles (MP) are plasma membrane vesicles shed from stimulated cells. We investigated whether leukocyte MP extracted from rat spleen are reliable markers of aging and effectors of high glucose (HG)-induced endothelial senescence and dysfunction. Data indicate that ageing enhances MP shedding from spleen cells of middle-age and aged rats and raises MP release in response to LPS, or to PMA and ionophore A23187. Of note, MP from aged but not young rats induced senescence of porcine coronary artery primary endothelial cells. In young rats, MPLPS, MPPMA/I but not from resting cells (MPCTL) reduced the endothelial-dependent relaxation of coronary artery rings (CAR) in response to bradykinin with down-regulation of eNOS, up-regulation of COX-2, ICAM-1, VCAM-1. HG enhanced early and late MP release from spleen cells. Prolonged exposure to HG potentiated endothelial dysfunction in CAR and altered vasoconstriction in response to U46619l in a SGLT1/2 and EDHF dependent manner.

Orientador: Leonardo Fernandes Fraceto / Resumo: A demanda pelo uso de produtos para uma agricultura sustentável com um menor impacto no ambiente tem sido cada vez maior. Sendo assim, a utilização do controle biológico é uma alternativa para diminuir o uso dos agrotóxicos e os consequentes riscos. O fungo Trichoderma harzianum é um exemplo de controle biológico eficaz contra o patógeno Sclerotinia sclerotiorum (mofo branco), o qual atinge diversas culturas e traz perdas na produção que podem chegar até 100 %. Porém, a utilização desse fungo de controle biológico pode encontrar alguns problemas como, por exemplo, estresse do fungo por fatores bióticos e abióticos. Uma possível solução para esse tipo de problema é a microenpcaulação. Desta maneira, este trabalho teve por objetivo desenvolver micropartículas de alginato de cálcio e de quitosana como sistema carreador de fungos, caracterizar o sistema de micropartículas através de métodos físico-químicos, avaliação molecular da microbiota do solo, antagonismo contra o fitopatógeno S. sclerotiorum e o efeito das micropartículas em plantas. O tamanho médio das micropartículas de alginato de cálcio e quitosana foi de 2000 μm e 2500 μm, respectivamente. A microscopia eletrônica de varredura confirmou a morfologia esférica das micropartículas após o processo de desidratação. O ensaio de fotoestabilidade revelou uma maior proteção do fungo Trichoderma harzianum quando encapsulado nas micropartículas de alginato de cálcio. Os ensaios de Calorimetria Diferencial de Varredura (DSC) e Es... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor

Nous avons mis au point par atomisation-séchage un système vecteur innovant de corticostéroïdes destiné à être administré par voie pulmonaire pour le traitement des maladies inflammatoires des voies respiratoires dont la plus fréquente est l’asthme. Cette forme pharmaceutique appelée "grosse particule poreuse" consiste en une matrice de deux excipients biocompatibles et biodégradables, la 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) et l'acide hyaluronique (AH) encapsulant le palmitate de dexaméthasone (DXP). La première partie de ce travail a consisté à optimiser l’encapsulation d’un glucocorticoïde modèle, la DXP, une prodrogue lipophile de la dexaméthasone (DXM) au sein de microparticules poreuses par atomisation séchage. Les résultats des tests physicochimiques ont permis d’isoler la poudre à 5% de DXP dont les propriétés morphologiques et aérodynamiques répondent bien aux critères des grosses particules poreuses. La cinétique de libération in vitro a montré une libération relativement lente avec moins de 5% de DXP dans le surnageant après 21 jours. Nous avons ensuite mis au point une méthode d’extraction et de de dosage de la DXP et de son métabolite actif, la DXM dans le plasma et le liquide de lavage bronchoalveolaire (BALF). La dernière partie de notre travail a été consacrée à l’étude pharmacocinétique après administration pulmonaire de la formulation optimisée chez le rat sain. Les résultats in vivo montrent une libération relativement lente de la DXP dans le BALF tandis que la concentration en DXM diminue rapidement en 4 heures. En revanche les concentrations dans le plasma restent faibles. Ces résultats indiquent une bonne distribution pulmonaire de la DXP et la DXM avec une faible absorption sanguine de ces molécules ce qui est prometteur pour le traitement local de l’asthme avec la possibilité de réduire le nombre d’administrations et d’améliorer l’observance thérapeutique des patients. / We have developed by spray drying an innovative carrier system of corticosteroids to be administered by pulmonary route for the treatment of airway inflammatory diseases, among which the most common is asthma. This pharmaceutical form known as "large porous particles" consists of a matrix composed of two biocompatible and biodegradable excipients, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and hyaluronic acid (HA) encapsulating dexamethasone palmitate (DXP). The first part of this work was to optimize the encapsulation of a model glucocorticoid, DXP, a lipophilic prodrug of dexamethasone (DXM) within porous microparticles by spray drying. The results of the physicochemical characterization allowed to isolate microparticles loaded with 5% DXP for which morphological and aerodynamic properties meet the criteria of large porous particles. In vitro release kinetics showed a relatively slow release with less than 5% of DXP in the supernatant after 21 days. Then we developed an extraction method and a HPLC method for the determination of DXP and its active metabolite, DXM in plasma and bronchoalveolar lavage fluid (BALF). In vivo results show a relatively slow release of DXP in BALF while the DXM concentration decreases rapidly in 4 hours. By contrast, the plasma concentrations remained low. These results indicate good pulmonary delivery of DXP and DXM with low blood absorption of these molecules which is promising for the local treatment of asthma with the possibility of reducing the number of administrations and improve patient compliance.

Diante da hipótese de que micropartículas poliméricas podem atravessar a barreira epidérmica através da rota transfolicular, e baseado na evidência de que a iontoforese é um método que consegue direcionar a liberação de fármacos para os folículos pilosos, este trabalho teve como objetivo estudar in vitro a permeação cutânea do minoxidil sulfato (MXS), fármaco utilizado no tratamento da alopecia androgênica, tanto em sua forma microencapsulada como não encapsulada utilizando ou não a iontoforese, na tentativa de aumentar, controlar e direcionar a sua liberação tópica para o folículo piloso. O MXS foi primeiramente incorporado em um gel hidrofílico contendo 2,0% (m/m) do ativo e sua permeação e retenção cutânea in vitro verificada com e sem a presença de corrente elétrica durante 6 h, utilizando células de difusão e pele de orelha de porco. A quantidade de MXS retida no EC da pele foi determinada e diferenciada daquela retida nos folículos pilosos utilizando-se a técnica denominada tape stripping diferencial. Foi observado que o fluxo passivo de fármaco através da pele aumentou 150 vezes com aplicação de iontoforese anódica e que o aumento do pH da formulação de 3,5 para 5,5 restringiu 3 vezes essa permeação iontoforética e aumentou a retenção do MXS no EC e folículos pilosos. Estes resultados mostram que a iontoforese do MXS nestas condições é capaz de promover a liberação folicular do fármaco de maneira bastante significativa. Uma série de micropartículas de quitosana contendo MXS foi obtida por spray drying modificando quantidades e proporções de polímero e fármaco. O sistema selecionado para estudo foi obtido a partir de 1,50 g de polímero e 0,75 g de MXS, e apresentou alta eficiência de encapsulação (~82%), diâmetro médio igual a 3,05 µm, morfologia esférica e sem porosidades, e potencial zeta igual a + 5,87 mV. Quando incorporadas a uma formulação hidroalcoólica, essas micropartículas sofreram intumescimento, aumentando 1,5 vezes o seu diâmetro médio, mas não tiveram sua morfologia esférica alterada. Experimentos de liberação in vitro mostraram que as micropartículas obtidas foram capazes de sustentar 3,5 vezes a liberação do MXS. As micropartículas ainda restringiram a permeação passiva do fármaco, reduzindo 2 vezes seu fluxo de permeação e aumentando em 5 vezes a retenção de fármaco na região folicular, apesar das partículas em si não penetrarem a pele após administração passiva. Assim, este sistema foi capaz de promover uma liberação mais sustentada do fármaco, o que deve reduzir o número de aplicações do produto pelo paciente ao longo do dia, e garantiu a entrada de grandes quantidades do fármaco nos folículos pilosos, seu alvo de ação. A iontoforese dessas micropartículas, apesar de também não fazê-las penetrar a pele, conseguiu direcioná-las mais rapidamente para as aberturas foliculares, como mostrou os estudos de microscopia confocal de varredura a laser das micropartículas marcadas. Adicionalmente, a iontoforese aumentou 6 vezes a quantidade de MXS retida nos folículos já nas primeiras 3 h de aplicação, garantindo assim que grandes quantidades do fármaco atingissem seu local de ação mais rapidamente que quando as partículas foram aplicadas passivamente sobre a pele. / Given the hypothesis that polymeric microparticles can penetrate the skin barrier along the transfollicular route, and based on the evidence that iontophoresis is a method that can direct the delivery of drugs to the hair follicles, this work aimed to study the in vitro skin permeation of minoxidil sulfate (MXS), a drug used to treat androgenic alopecia, both in its micro-encapsulated and non-encapsulated form, using or not iontophoresis, in an attempt to increase, control and direct its topical delivery to the hair follicle. The MXS was first incorporated in a hydrophilic gel containing 2.0% (w/w) MXS and its skin permeation and retention was in vitro observed with and without the presence of electric current for 6 h, using diffusion cells and skin of porcine\'s ears. The amount of MXS retained in EC was determined and differentiated from that retained in the hair follicles using the technique called differential tape stripping. It was observed that the passive flux of drug through the skin was increased 150-fold with the application of anodal iontophoresis and, by increasing the pH of the formulation from 3.5 to 5.5, iontophoretic permeation of MXS was 3-fold restricted, whereas it increased its retention in stratum corneum and hair follicles. These results show that iontophoresis of MXS in these conditions can promote the follicular delivery of the drug quite significantly. A series of chitosan microparticles containing MXS was obtained by spray drying, modifying quantities and proportions of polymer and drug. The system selected for study was obtained from 1.50 g of polymer and 0.75 g of MXS, and showed high encapsulation efficiency (~ 82%), mean diameter of 3.05 µm, spherical morphology without porosities, and zeta potential equal to + 5.87 mV. When incorporated into a hydro ethanolic formulation, these microparticles suffered swelling, increasing 1.5 times its diameter, but their spherical morphology was not modified. Permeation experiments showed in vitro that the microparticles obtained were able to sustain 3.5 times the release of MXS. The microparticles also restricted the passive permeation of the drug, reducing 2-fold its permeation flux and increasing by 5-fold the retention of drug in the follicular region, although the microparticles themselves did not penetrate the skin after passive administration. Thus, this system was able to promote a more sustained release of the drug, which must reduce the number of product applications by the patient throughout the day, and ensured the entry of large amounts of drug in hair follicles, their target. Iontophoresis of microparticles, although not making them penetrate the skin either, was able to direct them quickly to the follicular openings, as shown by laser confocal scanning microscopy studies of the labeled microparticles. In addition, iontophoresis increased 6-fold the amount of MXS retained in the follicles within the first 3 h of application, thereby ensuring that large quantities of the drug achieved its site of action more quickly than when the particles were applied passively to the skin.

Os carreadores micro e nanoparticulados como os lipossomos, nanoparticulas polimericas e microparticulas e nanoparticulas lipidicas solidas sao investigadas por suas vantagens em relacao as formulacoes tradicionais, tais como: liberacao sustentada dos ativos, minimizar efeitos colaterais, aumentar estabilidade fisico-quimica das moleculas labeis, diminuir a toxicidade entre outras. As microparticulas lipidicas solidas produzidas neste trabalho sao compostas de cera de abelha e oleo de cafe verde, este oleo e um produto rico em acidos graxos, esterois, di e triterpenos e tocoferois. Para a producao destas microparticulas foi escolhida a tecnica de spray congealing, que e considerada rapida e ambientalmente correta, uma vez que nao utiliza nenhum tipo de solvente. As misturas fundidas contendo concentracoes determinadas de oleo de cafe verde e cera de abelha foram atomizadas numa camara de resfriamento onde houve a solidificacao e formacao das microparticulas. Foi utilizado um planejamento experimental do tipo Box-Behnken, que auxiliou na avaliacao dos resultados obtidos, verificando a influencia das diversas variaveis do processo. As microparticulas foram caracterizadas por analise termica, microscopia de varredura eletronica, tamanho, atividade fotocatalitica, eficiencia de encapsulacao e estabilidade. A avaliacao das microparticulas mostrou que a concentracao do oleo de cafe verde foi a variavel que mais influenciou no processo. Em concentracoes maiores, este oleo aumenta a viscosidade da mistura fundida atomizada, aumentando o tamanho da particula formada e provocando maiores imperfeicoes em sua superficie, o que foi confirmado por um estudo reologico das misturas de cera de abelhas e oleo de cafe verde. Os tamanhos das microparticulas obtidas em diferentes condicoes de spray congealing variaram de 50 a 140 ?Êm, e estao adequadas para que nao ocorra a sua penetracao cutanea. O estudo de atividade fotocatalitica demonstrou que o oleo de cafe verde microencapsulado apresenta propriedades de protecao antioxidante ao oleo de ricino muito maiores do que o oleo puro. A composicao do oleo de cafe verde em relacao ao acido linoleico, palmitico, oleico e estearico, determinada por cromatografia a gas com espectrometria de massa esta de acordo com o encontrado na literatura. As microparticulas formadas a partir de misturas contendo 40% de oleo de cafe verde apresentaram melhor estabilidade e melhor acao na protecao de outras substancias contra a oxidacao. No teste de estabilidade acelerada, usando o acido linoleico como marcador quimico, as perdas corresponderam a 27, 6 e 3% para as microparticulas encapsuladas com 20, 30 e 40% de oleo de cafe verde, respectivamente. No mesmo teste, a perda de acido linoleico foi de 45% para o oleo nao encapsulado. Os resultados demonstram que a microencapsulacao do oleo de cafe verde pode ser uma excelente alternativa para a protecao deste contra a oxidacao e que o processo de spray congealing, bem como a cera de abelhas foram escolhas adequadas para a sua preparacao. / The micro and nanoparticulate carriers such as liposomes, polymeric nanoparticles and solid lipid nanoparticles and microparticles are investigated for their advantages over traditional formulations such as sustained release of the drugs, minimize side effects, increase physical and chemical stability of labile molecules, decrease toxicity among others. The solid lipid microparticles produced in this work are composed of beeswax and green coffee oil, this oil is a product rich in fatty acids, sterols, tocopherols and di and triterpenes. For the generation of microparticles was chosen spray congealing technique, which is considered fast and environmentally friendly, since it does not use any type of solvent. The molten mixtures containing certain concentrations of green coffee oil and beeswax were atomized in a cooling chamber where there was solidification and formation of microparticles. We used an experimental design like Box-Behnken, who assisted in the evaluation of the results, checking the influence of various process variables. The microparticles were characterized by thermal analysis, scanning electron microscopy, size, photocatalytic activity, encapsulation efficiency and stability. The evaluation of the microparticles showed that the green coffee oil concentration was the variable that most influenced the process. At higher concentrations, this oil increases the viscosity of the molten mixture atomized, increasing the size of the particle formed and causing major imperfections on its surface, which was confirmed by a study of the rheological mixture of beeswax and green coffee oil. The sizes of the microparticles obtained at different spray congealing conditions ranged from 50 to 140 ?Ým, and are not suitable for your skin penetration occurs. The study showed that the photocatalytic activity of green coffee oil microencapsulated has properties antioxidant protection to castor oil much higher than the pure oil. The composition of green coffee oil relative to linoleic, palmitic, oleic and stearic acids, determined by gas chromatography with mass spectrometry is consistent with findings in the literature. The microparticles formed from mixtures containing 40% of green coffee oil showed better stability and better action in protecting other substances from oxidation. In accelerated stability test, using linoleic acid as a chemical marker, the losses amounted to 27, 6 and 3% for the microparticles containing 20, 30 and 40% green coffee oil, respectively. In the same test, the loss of linoleic acid was 45% for the unencapsulated oil. The results show that the microencapsulation of green coffee oil can be an excellent alternative for protection against this oxidation and that the spray congealing process, as well as beeswax were appropriate choices for their preparation.