A hipovitaminose de vitamina D é um problema global de saúde e a sua deficiência compromete funções importantes ao corpo humano. A suplementação oral, políticas de fortificação em alimentos e mudanças dos hábitos de vida são medidas efetivas para solucionar este problema. Porém, pessoas com doença de Crohn, celíaca, fibrose cística, bypass gástrico e que fazem uso de medicamentos sequestradores de ácido biliares possuem a absorção intestinal de vitamina D comprometida. A via transdérmica pode ser uma alternativa de administração de vitamina D3, porém poucas referências bibliográficas abordam sobre o assunto. A proposta do presente estudo é o desenvolvimento de sistemas transdérmicos com a combinação de promotores de permeação químicos: lecitina de soja, palmitato de isopropila, etoxidiglicol (Transcutol® CG), propilenoglicol e etanol, acrescidos do ingrediente ativo vitamina D3, a validação analítica para quantificação do ativo em Cromatografia Líquida de Alta Eficiência (CLAE), a avaliação da estabilidade, segurança, retenção e permeação cutânea. A validação do método analítico de quantificação da vitamina D3 em CLAE foi considerada específica, linear, precisa e exata. O limite de detecção foi 20 ng/mL e de quantificação 40 ng/mL. Os testes de estabilidade foram realizados (preliminar, acelerado e normal) e a melhor condição de armazenamento foi a geladeira (5,0 ± 2,0 ºC) durante 90 dias. A condição de radiação luminosa foi a menos adequada, o que indica que o armazenamento deve ser realizado em frascos protegidos da luz (âmbar). No teste de segurança de irritação (HET-CAM) as formulações testadas foram consideradas não irritantes. No teste de retenção e permeação cutânea a solubilidade da vitamina D3 foi avaliada para garantir a sink condition do líquido receptor escolhido: Phosfate Buffer Saline (PBS) com etanol a 50% e a integridade da pele foi garantida com o teste de perda de água transepidérmica (TEWL). A formulação desenvolvida com a presença de todos os promotores de permeação avaliados (F1) e o controle, apenas com a presença do etanol e o propilenoglicol, foram avaliados. A F1 permaneceu na superfície da pele, por possuir maior afinidade com a fase oleosa da formulação e houve tendência de hidratação desta formulação. O controle demonstrou uma retenção cutânea em 4 h no estrato córneo e em 24 h na epiderme e derme. Concluiu-se que a formulação desenvolvida é estável, segura e a vitamina D3 ficou retida na pele, o que indica o uso tópico da mesma. A alta lipofilicidade foi a justificativa dos resultados apresentados e futuros estudos podem ser realizados com derivados menos lipofílicos da vitamina D para avaliar a via transdérmica. / Hypovitaminosis D is a global health issue and vitamin D deficiency compromises important functions to the human body. Oral supplementation, fortification food and changes in live style are effective measures to solve this problem. However, people with Crohn\'s disease, celiac disease, cystic fibrosis, gastric bypass and who use bile acid-binding medications have compromised intestinal vitamin D absorption. The transdermal route may be an alternative for vitamin D3 administration, but few references refer to the subject. The purpose of the present study is the development of transdermal systems with the combination of penetrations enhancers (soybean lecithin, isopropyl palmitate, ethoxydiglycol (Transcutol® CG), propylene glycol and ethanol) with vitamin D3, the analytical validation for quantification of the active in High Performance Liquid Chromatography (HPLC), stability assessment, safety, skin retention and permeation. The validation of the analytical method for quantification of vitamin D3 in HPLC was considered specific, linear, precise and accurate. The limit of detection was 20 ng/mL and 40 ng/mL. Stability assessment was performed and the appropriate storage condition was the refrigerator (5.0 ± 2.0 ° C) for 90 days. The indirect solar radiation condition was not adequate, which indicates that the storage should be performed in light-protected bottles (amber). In the irritation safety test (HET-CAM) the formulations tested were considered non-irritant. In the skin permeation and retention test the solubility of vitamin D3 was evaluated to guarantee the sink condition of the receptor fluid: Phosfate Buffer Saline (PBS) with 50% ethanol and skin integrity was guaranteed with Transepidermal Water Loss (TEWL). The developed formulation with the presence of all penetrations enhancers evaluated (F1) and the control formulation with the presence of ethanol and propylene glycol were assessed. F1 remained on the surface of the skin, because it had greater affinity with the oily phase of the formulation and there was tendency of hydration to this formulation. The control formulation demonstrated skin retention in 4 hours in the stratum corneum and in 24 hours in the epidermis and dermis. The study concluded that the formulation developed is stable, safe and vitamin D3 was retained in the skin, which indicates the topical use. High lipophilicity was the explanation of the presented results and future studies can be carried out with less lipophilic derivatives of vitamin D to evaluate the transdermal route.

A influência do ultra-som terapêutico na transmissão transcutânea (sonoforese) do diclofenaco sódico como gel tópico (Voltaren Emulgel) foi investigada em 14 voluntários humanos sadios (dez mulheres, quatro homens; 26,4 anos de idade, 62 Kg de peso corporal e 1,7 m de altura, em média). Foi realizada irradiação ultra-sônica prévia da pele (modo contínuo, 1 MHz de freqüência, intensidade de 0,5 W/centímetro quadrado) por 5 minutos em duas áreas de 225 centímetros quadrados (15 x 15 cm) de cada lado da região dorsal dos voluntários usando um gel comum para acoplamento do cabeçote, com subseqüente aplicação do gel de diclofenaco (2,5 g) em cada uma das áreas pré-determinadas e deixado por três horas. Os mesmos voluntários participaram desse procedimento duas vezes com um mês de intervalo, em média, sendo que na segunda vez com o equipamento desligado (procedimento placebo), para controle. Amostras de sangue (3 ml) foram coletadas de veias do antebraço imediatamente antes e com 60, 120 e 180 minutos do procedimento, para análise da massa plasmática do diclofenaco, por meio da cromatografia líquida de alta eficiência (HPLC). Os resultados demonstraram que a massa plasmática do diclofenaco estava significativamente mais elevada (p=0,01) aos 60 e 120 minutos após a irradiação com o ultra-som do que após o procedimento placebo. Dentro das condições em que este estudo foi realizado, os resultados permitem concluir que a irradiação prévia da pele com ultra-som terapêutico facilita a penetração transcutânea de diclofenaco sódico na forma de gel tópico / The influence of therapeutic ultrasound on the transdermal transmission (sonophoresis) of sodium diclofenac as a gel of topic application (Voltaren Emulgel) was investigated in 14 human healthy volunteers (ten women, four men, 26,4 years of age, 62 Kg of body weight and 1,7 m of height on average). Therapeutic ultrasound (continuous mode, 1 MHz frequency, 0,5 W/square centimeter) was applied for 5 minutes on two 225 square centimeters (15 x 15 cm) areas on each side of the dorsum of the volunteers using ultrasound transmission gel as a coupling agent. Following ultrasonic irradiation, the gel was removed and gloves were used to apply 2,5 g on each two defined areas. The same volunteers participated in procedures twice at one-month interval on average, however the second time with the equipment turned off (sham procedure) for control. Blood samples (3 ml) were withdrawn from forearm veins, near the elbow flexure, immediately before and at 60, 120 and 180 minutes from the procedure, for analysis of the plasmatic diclofenac mass by means of high performance liquid chromatography (HPLC). The results showed that the plasmatic diclofenac mass was significantly higher (p=0,01) at 60 and 120 minutes following the ultrasound irradiation than the sham procedure. The results presented in this study support that therapeutic ultrasound applied prior to application of sodium diclofenac gel does lead to enhanced penetration of the drug across the skin under the conditions of the investigation

La perméabilité de la peau ne permet pas la diffusion passive de grandes molécules, comme l'insuline ou encore les plasmides d'ADN, au travers de l'épiderme dans le but d'atteindre les vaisseaux sanguins. Cela est uniquement possible pour des molécules de plus petite taille comme la nicotine par exemple. Il existe différentes voies alternatives (électrique, mécanique, thermique) de délivrance transdermique permettant d'éviter l'utilisation de la seringue d'injection, qui pourraient améliorer la qualité de vie des patients atteints de maladies comme le diabète. Ces méthodes incluent par exemple les micro-aiguilles, l'électro-perméabilisation, et l'iontophorèse. L'électroperméabilisation permet, via l'application d'un champ électrique, d'augmenter momentanément la perméabilité de la peau et par conséquent de permettre le passage transdermique de molécules de haut poids moléculaire. L'objectif de ces travaux de thèse était de concevoir et de réaliser un patch nanocomposite à base de nanotubes de carbone permettant de stocker, mais également de relarguer un médicament lorsque qu'il est soumis à une électrostimulation. Pour ce faire, différents polymères ainsi que différentes techniques de mise en forme ont été explorées et développées pour permettre de démontrer la faisabilité de notre approche. Les études ont permis de proposer et de développer un hydrogel nanocomposite biocompatible comportant une matrice polymère agarose et contenant de nanotubes de carbone biparois dans le but d'améliorer les propriétés à la fois électriques et mécanique du matériau. Nous en avons étudié les différentes caractéristiques telles que la microstructure, la capacité de stockage et de relargage, ainsi que les propriétés électriques. Dans le contexte général de précaution en relation avec la mise en œuvre de nanoparticules, et sur la base de travaux antérieurs démontrant l'innocuité des nanotubes utilisés lorsqu'ils ne sont pas en contact direct avec des cellules. Nous avons aussi démontré qu'il n'y a pas de relargage des nanotubes dans des conditions extrêmes (sans électrostimulation) de température en milieu sueur artificielle. L'avancée de ces travaux a permis d'effectuer les premiers tests de délivrance transdermique ex-vivo sur peau de souris et a démontré ainsi la faisabilité et l'intérêt d'utiliser les nanotubes de carbones biparois dans une matrice en polymère pour la délivrance transdermique électrostimulée de molécules de masse molaire de l'ordre de celle de l'insuline. Cette thèse en co-direction alliant la Science des Matériaux (CIRIMAT) et la Science du Vivant (IPBS) a réuni différentes compétences lui donnant un véritable contexte interdisciplinaire. Elle s'est intégrée dans un projet de plus grande ampleur associant la Sociologie et le Droit (Défi Nano CNRS), centré sur le cas du diabète. Ceci a permis de démontrer l'intérêt de développer un tel dispositif (du point de vue des médecins et des patients), mais aussi en nous orientant vers un dispositif médical afin d'éviter de futurs écueils juridiques en termes d'application. / The permeability of skin does not allow the passive diffusion across epidermis to reach blood vessels for large molecular weight molecules such as insulin or DNA plasmids. This is possible only for small molecules such as nicotine, for example. Alternative routes of transdermal delivery exist (thermal, electrical, mechanical) that avoid injections and improve the quality of life of patients suffering of diseases like diabetes. These methods known as "Transdermal Drug Delivery" (TDD) technologies, include for example electroporation, iontophoresis and micro needles. In particular, electropermeabilisation is known to temporarily increase the permeability of the skin, consequently allowing transdermal passage of molecules of high molecular weight. The aim of this work was to conceive and elaborate an innovative needle-free device for transdermal drug delivery, made of a nanocomposite material containing carbon nanotubes to improve both electrical and mechanical properties of the biocompatible polymer matrix. This nanocomposite device aims at permeabilising the skin and delivering drug molecules simultaneously when electrically stimulated. To reach this goal, we investigated different biocompatible polymers and shaping processes, finally demonstrating the feasibility of the fabrication of such a device. We have developed a bio-sourced and biocompatible nanocomposite hydrogel with an agarose matrix and containing double-walled carbon nanotubes, and characterized it in terms of microstructure, storage and release capacity, as well as electrical properties. In the general context of precaution in relation to the implementation of nanoparticles, and on the basis of previous work demonstrating the safety of nanotubes used when they are not in direct contact with cells, we have also demonstrated that there is no release of the nanotubes under extreme conditions of temperature (without electrostimulation) in an artificial sweat medium. Finally, we have demonstrated the feasibility of its first use as a TDD system using an ex vivo mouse skin model. These results provide good evidence that the use of double-walled carbon nanotubes makes possible the transdermal delivery of large molecules with a molecular weight similar to insulin with such a nanomaterial. This thesis was in co-direction, combining Materials Science (CIRIMAT) and Life Science (IPBS) in order to gather different skills, giving it a real interdisciplinary context. Moreover, this work was integrated into a larger project (CNRS, "Nano challenge"), also including Sociology and Law, focusing on diabetes. This has demonstrated the actual demand for such a device from both the medical doctors and the patients, but also directed our work towards a medical device thanks from the juridical point of view.

Meloksikamas, (4-hidroksi-2-metil-N-(5-metil-2-tiazolil)-2H-1,2-benzotiazin-3-karboksamid-1,1-dioksidas), yra nesteroidinis vaistas nuo uždegimo (NVNU), selektyvus ciklooksigenazės-II (COX-II) inhibitorius ir naudojamas reumatoidiniam artritui, osteoartritui ir kitoms sąnarių ligoms gydyti. Jis yra žymiai efektyvesnis ir sukelia mažiau šalutinių poveikių virškinamąjam traktui lyginant su kitais tradiciniais nesteroidiniais vaistais nuo uždegimo (NVNU). Gydomoji meloksikamo paros dozė (15 mg) yra viena mažiausių lyginant su kitais tradiciniais nesteroidiniais vaistais nuo uždegimo (NVNU). Europoje ir Lietuvoje yra registruotos tik peroralinės ir parenteralinės meloksikamo vaistų formos. Todėl siekiama sukurti transdermalines meloksikamo vaistų formas. Šio darbo tikslas – sukurti meloksikamo išsiskyrimo iš tirpalų pro dializės membraną in vitro metodą ir įvertinti išsiskyrusio meloksikamo kiekį. Tyrimo metu buvo naudojamas 1 proc. meloksikamo propileno glikolio tirpalas. Dializės membrana - regeneruotos celiuliozės. Akceptorinis tirpalas – buferinis tirpalas, kurio pH reikšmė 8,5. Palaikoma temperatūra - 37°C. Bandiniai buvo imami po 15, 30, 60, 120, 180 ir 300 minučių. Išsiskyręs meloksikamo kiekis iš bandinių kiekybiškai buvo vertinamas efektyviosios skysčių chromatografijos (HPLC) metodu. Didžiausias meloksikamo srautas (346, 963 µg/cm²/h) buvo po 15 minučių nuo eksperimento pradžios. Vėliau meloksikamo srautas mažėjo. Mažiausias meloksikamo srautas (67,401 µg/cm²/h)... [toliau žr. visą tekstą] / Meloxicam, (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1, 2-benzothiazine-3-carbox-amide-1, 1-dioxide), a non-steroidal anti-inflammatory drug (NSAID) and selective cyclooxygenase-II (COX-II) inhibitor, is used in the treatment of rheumatoid arthritis, osteoartritis and other joint diseases. It has comparable efficiency and greater gastric tolerability in comparison to conventional non-steroidal anti-inflammatory drugs (NSAIDs). The efficiency dose of meloxicam (15 mg/day) is one of the lowest in the non-steroidal anti-inflammatory drugs (NSAIDs). There are registered only oral and parenteral formulations of meloxicam in Europe and Lithuania. So it is strive to create transdermal formulations of meloxicam. The aim of the present work was to develop in vitro meloxicam release through dialysis membrane method and measure the amount of released meloxicam. On release of meloxicam from 1 % meloxicam propylene glycol solution was used regenerated cellulose dialysis membrane. As acceptor fluid was used buffer pH 8,5. Temperature was controlled at 37°C. Samples 1 ml were withdrawn at intervals of 15, 30, 60, 120, 180 and 300 min. The quantitative determination of meloxicam in samples was performed by high performance liquid chromatography (HPLC). The maximum flux of meloxicam (346,963 µg/cm²/h) was after 15 min from the beginning of the experiment. Later on meloxicam flux was on the decrease. The minimum flux of meloxicam (67,401 µg/cm²/h) was after 300 min from the beginning of... [to full text]

The progression of skin ageing in individuals is multifaceted and provoked by various aspects, including hereditary and a variety of environmental causes, for instance UV (ultra violet) radiation, resulting in the morphological modifications in the dermal layer of the skin (Makrantonaki & Zouboulis, 2007:40) Transformations caused by ageing skin, in which degenerative alterations exceed regenerative alterations are recognised by the thinning and wrinkling of the epidermis in conjunction with the appearance of lines, creases, crevices and furrows, particularly emphasised in lines of facial expressions (Aburjai & Natsheh, 2003:990). For human beings to continue to exist in a terrestrial atmosphere, the loss of water from the skin must be cautiously synchronised by the epidermis, a task dependent on the multifaceted character of the stratum corneum (Rawlings & Harding, 2004:43). The stratum corneum (SC) is responsible for the main resistance to the penetration of most compounds; nevertheless the skin represents as an appropriate target for delivery. The target site for anti-ageing treatment includes the epidermal and dermal layers of the skin. Therefore, the need to apply fatty materials to the skin is practically intuitive and may perhaps be as old as man’s existence itself (Lodén, 2005:672). Natural therapies have been used for several decades for taking care of skin illnesses and a wide variety of dermatological disorders, such as inflammation, phototoxicity, atopic dermatitis and alopecia areata (Aburjai & Natsheh, 2003:988). Using the skin as an alternative route for the administration of honeybush extracts for the treatment of ageing skin may be beneficial. Tea contains more than 500 chemical compounds, including, tannins, flavonoids, amino acids, vitamins, caffeine and polysaccharides. Tea polyphenols (flavonoids) have proven anti-inflammatory, antioxidant, antiallergic, antibacterial and antiviral effects (Aburjai & Natsheh, 2003:990). Unfortunately using the skin as an alternative route for administering drugs (transdermal drug delivery) has numerous limitations. One of these limitations is the barrier function of the skin (Naik et al., 2000:319). Because of the skin’s outstanding ability to protect the body against unwanted substances from its surroundings, it is necessary to use methods to enhance drug penetration through the skin. The aim of this study was to formulate two 2% semisolid formulations containing two different honeybush extracts as the active ingredient, and to determine which of the formulations deliver mangiferin and hesperidin best to the target site (dermis). Cosmetic formulations of a natural origin, is designed to protect the skin against exogenous or endogenous harmful agents, as well as to balance the dermal homeostatis lipids altered by dermatosis and ageing (Aburjai & Natsheh, 2003:988). Stability tests over a three month period were also performed on the different formulations. To determine the stability of the different semi-solid formulations, the formulated products were stored at 25 °C/60% RH (relative humidity), 30 °C/60% RH and 40 °C/75% RH. HPLC analysis was used to determine the concentrations of the ingredients in all the formulated products. Other stability tests included appearance, pH, viscosity, mass loss, zeta potential and particle size determination. Unfortunately a change in colour, viscosity, zeta potential, mass loss, particle size and concentration of the ingredients in both the formulations, indicated that the products were unstable from the first month of stability testing. A 2% Cyclopia maculata cream as well as a 2% Cyclopia genistoides cream was formulated. Franz cell diffusion studies as well as membrane release studies were performed over a 12 h period, followed by tape stripping experiments to determine which semi-solid formulation delivered mangiferin and hesperidin the best to the dermal layer of the skin. The results of the different formulations were compared. Unfortunately there was no significant penetration by any of the honeybush extracts. Results were inconclusive and unquantifiable due to unconvincing penetration results. The antioxidant properties of both the extracts and the active ingredients were calculated. Antioxidant studies by the use of the TBA-assay method were done to determine whether the honeybush extracts, mangiferin and hesperidin as well as their semisolid formulations had any antioxidant activities. Both the honeybush extracts and the semisolid formulations showed promising results. Mangiferin and hesperidin did not show any antioxidant activity on their own, therefore the assumption can be confirmed that plants do function synergistically. A clinical study was also conducted to see whether honeybush extracts have the potential to hydrate the skin, counteracting the symptoms and signs of skin ageing. Clinical efficacy studies were done to determine whether the honeybush formulations had any skin hydrating effects in the treatment against skin ageing. The results were statistically inconclusive and variations between the subjects were very high due to skin variations at different skin sites. There was however a trend that Cyclopia genistoides performed the best. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.

The progression of skin ageing in individuals is multifaceted and provoked by various aspects, including hereditary and a variety of environmental causes, for instance UV (ultra violet) radiation, resulting in the morphological modifications in the dermal layer of the skin (Makrantonaki & Zouboulis, 2007:40) Transformations caused by ageing skin, in which degenerative alterations exceed regenerative alterations are recognised by the thinning and wrinkling of the epidermis in conjunction with the appearance of lines, creases, crevices and furrows, particularly emphasised in lines of facial expressions (Aburjai & Natsheh, 2003:990). For human beings to continue to exist in a terrestrial atmosphere, the loss of water from the skin must be cautiously synchronised by the epidermis, a task dependent on the multifaceted character of the stratum corneum (Rawlings & Harding, 2004:43). The stratum corneum (SC) is responsible for the main resistance to the penetration of most compounds; nevertheless the skin represents as an appropriate target for delivery. The target site for anti-ageing treatment includes the epidermal and dermal layers of the skin. Therefore, the need to apply fatty materials to the skin is practically intuitive and may perhaps be as old as man’s existence itself (Lodén, 2005:672). Natural therapies have been used for several decades for taking care of skin illnesses and a wide variety of dermatological disorders, such as inflammation, phototoxicity, atopic dermatitis and alopecia areata (Aburjai & Natsheh, 2003:988). Using the skin as an alternative route for the administration of honeybush extracts for the treatment of ageing skin may be beneficial. Tea contains more than 500 chemical compounds, including, tannins, flavonoids, amino acids, vitamins, caffeine and polysaccharides. Tea polyphenols (flavonoids) have proven anti-inflammatory, antioxidant, antiallergic, antibacterial and antiviral effects (Aburjai & Natsheh, 2003:990). Unfortunately using the skin as an alternative route for administering drugs (transdermal drug delivery) has numerous limitations. One of these limitations is the barrier function of the skin (Naik et al., 2000:319). Because of the skin’s outstanding ability to protect the body against unwanted substances from its surroundings, it is necessary to use methods to enhance drug penetration through the skin. The aim of this study was to formulate two 2% semisolid formulations containing two different honeybush extracts as the active ingredient, and to determine which of the formulations deliver mangiferin and hesperidin best to the target site (dermis). Cosmetic formulations of a natural origin, is designed to protect the skin against exogenous or endogenous harmful agents, as well as to balance the dermal homeostatis lipids altered by dermatosis and ageing (Aburjai & Natsheh, 2003:988). Stability tests over a three month period were also performed on the different formulations. To determine the stability of the different semi-solid formulations, the formulated products were stored at 25 °C/60% RH (relative humidity), 30 °C/60% RH and 40 °C/75% RH. HPLC analysis was used to determine the concentrations of the ingredients in all the formulated products. Other stability tests included appearance, pH, viscosity, mass loss, zeta potential and particle size determination. Unfortunately a change in colour, viscosity, zeta potential, mass loss, particle size and concentration of the ingredients in both the formulations, indicated that the products were unstable from the first month of stability testing. A 2% Cyclopia maculata cream as well as a 2% Cyclopia genistoides cream was formulated. Franz cell diffusion studies as well as membrane release studies were performed over a 12 h period, followed by tape stripping experiments to determine which semi-solid formulation delivered mangiferin and hesperidin the best to the dermal layer of the skin. The results of the different formulations were compared. Unfortunately there was no significant penetration by any of the honeybush extracts. Results were inconclusive and unquantifiable due to unconvincing penetration results. The antioxidant properties of both the extracts and the active ingredients were calculated. Antioxidant studies by the use of the TBA-assay method were done to determine whether the honeybush extracts, mangiferin and hesperidin as well as their semisolid formulations had any antioxidant activities. Both the honeybush extracts and the semisolid formulations showed promising results. Mangiferin and hesperidin did not show any antioxidant activity on their own, therefore the assumption can be confirmed that plants do function synergistically. A clinical study was also conducted to see whether honeybush extracts have the potential to hydrate the skin, counteracting the symptoms and signs of skin ageing. Clinical efficacy studies were done to determine whether the honeybush formulations had any skin hydrating effects in the treatment against skin ageing. The results were statistically inconclusive and variations between the subjects were very high due to skin variations at different skin sites. There was however a trend that Cyclopia genistoides performed the best. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.

Στην παρούσα διατριβή, μελετήθηκε η χρήση ελαστικών λιποσωμάτων στη διαδερμική χορήγηση υδατοδιαλυτών ουσιών και πραγματοποιήθηκαν επίσης μελέτες προ-μορφοποίησης αντιϋπερτασικών βιοδραστικών ενώσεων για διαδερμική χορήγηση. Αρχικά, πραγματοποιήθηκαν μελέτες της φυσιολογίας του δέρματος με τεχνικές μικροσκοπίας και μέτρησης της απώλειας ύδατος μέσω της επιδερμίδας (TEWL) με σκοπό να διαπιστωθεί η λειτουργία του φραγμού της κεράτινης στοιβάδας, καθώς και η ορθότητα χρήσης των σχετικών τεχνικών προετοιμασίας των δειγμάτων δέρματος που χρησιμοποιήθηκαν. Η οπτική μικροσκοπία ειδικά μας έδωσε πληροφορίες ως προς τη δομή της επιδερμίδας και ως προς τον πιθανό μηχανισμό μεταφοράς ουσιών μέσω της χρήσης λιποσωμάτων. Στη συνέχεια πραγματοποιήθηκε μελέτη και σύγκριση των διαφόρων φυσικοχημικών χαρακτηριστικών ελαστικών λιποσωμάτων που μπορεί να χρησιμοποιηθούν ως πρώτοι δείκτες για πρόγνωση της διαδερμικής απορρόφησης (in vivo) των υδρόφιλων βιοδραστικών ενώσεων. Ως μοντέλα υδρόφιλων βιοδραστικών ενώσεων χρησιμοποιήθηκαν οι φθορίζουσες χρωστικές καλσεΐνη και καρβοξυφλουορεσκεΐνη. Όλες οι λιποσωμικές διασπορές (τόσο τα συμβατικά λιποσώματα-CLs, όσο και τα ελαστικά λιποσώματα τύπου transfersome-TRs και τύπου invasomes-INVs) χαρακτηρίστηκαν ως προς τα εξής φυσικοχημικά χαρακτηριστικά: Την κατανομή μεγέθους, το ζ-δυναμικό, το σφαιρικό σχήμα και τη μορφολογία τους, την ικανότητα εγκλωβισμού υδρόφιλων ουσιών, τη σταθερότητά τους (ως προς τα μορφολογικά χαρακτηριστικά, τη διασπορά μεγέθους και το φορτίο επιφανείας, και τη συγκράτηση της εγκλωβισμένης σε αυτά ουσίας) σε σχέση με το χρόνο, την ελαστικότητα και τέλος ως προς τη δυνατότητα διαπέρασης εγκλωβισμένων σε αυτές υδρόφιλων ουσιών μέσω ανθρώπινου δέρματος in vitro. Το μέγεθος των λιποσωμάτων ήταν παρόμοιο και αρκετά ομοιογενές, ενώ η προσθήκη διαφορετικών τύπων ενισχυτικών διαπέρασης στα ελαστικά λιποσώματα, στα συνήθη εύρη συγκεντρώσεων που χρησιμοποιούνται, δεν επηρεάζει καθόλου το επιφανειακό φορτίο των παραχθέντων λιποσωμάτων. Αύξηση του μεγέθους και αστάθεια ως προς τη συγκράτηση της εγκλωβισμένης ουσίας παρατηρήθηκε στην περίπτωση προσθήκης μεγαλύτερης ποσότητας ενισχυτικού διαπέρασης, η οποία αλλάζει και τα φυσικοχημικά χαρακτηριστικά των λιποσωμάτων. Τα TRs που περιείχαν χολικό νάτριο ήταν πιο ελαστικά από τα αντίστοιχα με Tween 80, τα οποία είχαν συγκριτικά χαμηλές τιμές ελαστικότητας (<40mg/s∙cm2). Οι υψηλότερες τιμές ελαστικότητας από όλους τους τύπους ελαστικών λιποσωμάτων που παρασκευάστηκαν στα πλαίσια αυτής της διατριβής, παρατηρήθηκε στην περίπτωση των INVs με 1% w/w PE και 1% w/w LIM. Επιπλέον, τα περισσότερα λιποσώματα τύπου INVs είχαν υψηλότερες τιμές ελαστικότητας σε σχέση με τα αντίστοιχα χωρίς τερπένια (INVs αναφοράς), εκτός από την περίπτωση των INVs με citral και cineol, όπου η ελαστικότητα σημείωσε μείωση σε σχέση με τα INVs χωρίς τερπένια. Οι διάφοροι τύποι λιποσωμάτων φαίνεται να μεταβάλλουν τη διαπέραση της χρωστικής με την εξής σειρά: Διάλυμα<CLs<TRs<<INVs. H διαπερατότητα (permeability), η ροή (flux) και ο λόγος προσαύξησης (ER) δείχνουν ότι τα συμβατικά λιποσώματα αύξησαν ελάχιστα τη ροή της καλσεΐνης, ενώ τα TRs και INVs κατά 1.8 και 7.2 φορές, αντίστοιχα. Τα αποτελέσματα αυτά επιβεβαιώνουν το γεγονός ότι τα συμβατικά λιποσώματα είναι ανεπαρκή συστήματα μεταφοράς υδρόφιλων μορίων μέσω του δέρματος, ενώ παράλληλα δείχνουν ότι τα ελαστικά λιποσώματα με τη μεγαλύτερη τιμή ελαστικότητας είναι πιο αποτελεσματικά στη μεταφορά της ουσίας μέσω του δέρματος. Σε επόμενα πειράματα μελετήθηκε η δυνατότητα διείσδυσης τόσο υδρόφιλων όσο και λιπόφιλων μορίων στις στοιβάδες του δέρματος, σε μια προσπάθεια να διερευνηθεί ο μηχανισμός αύξησης της διαδερμικής διαπέρασης των υδρόφιλων χρωστικών από τους διάφορους τύπους ελαστικών λιποσωμάτων. Ως μοντέλο υδρόφιλης ουσίας χρησιμοποιήθηκε η φθορίζουσα χρωστική καλσεΐνη, ενώ η λιπιδική ροδαμίνη χρησιμοποιήθηκε ως μοντέλο λιπόφιλης ουσίας (που δεν φεύγει από τα λιποσώματα και ουσιαστικά μας δείχνει το βάθος εις το οποίο εισχωρούν μέσα στο δέρμα τα αντίστοιχα είδη λιποσωμάτων). Τα λιποσώματα τύπου TR φαίνεται ότι επάγουν τη διαπέραση με το να βοηθούν τη χρωστική να προχωρά (υπό μορφή λιποσωμάτων που την εγκλωβίζουν) σε βαθύτερα στρώματα της κεράτινης στιβάδας σε σχέση με τα συμβατικά λιποσώματα όπου σε μεγάλο ποσοστό διαρρηγνύονται και απελευθερώνουν την υδρόφιλη ουσία η οποία στη συνέχεια διέρχεται μόνη της, ως ελεύθερο μόριο, στις στιβάδες του χορίου. Αντίθετα, τα λιποσώματα τύπου INV αποδείχτηκε ότι εισδύουν σε βαθύτερες στιβάδες της επιδερμίδας, φθάνοντας σε αρκετά υψηλά ποσοστά σε στιβάδες του χορίου, παρασύροντας μαζί τους και τα μόρια του εγκλωβισμένου σε αυτά υδρόφιλου φαρμάκου. Τέλος, μελετήθηκε η δυνατότητα μορφοποίησης ενός πειραματικού φαρμάκου με ανάλογη δομή γνωστού φαρμάκου προκειμένου για διαδερμική αντιϋπερτασική θεραπεία. Αρχικά, μελετήσαμε το πειραματικό φάρμακο ως προς τις φυσικοχημικές του ιδιότητες (διαλυτότητα σε διάφορα μέσα, σύνδεση με πρωτεΐνες) και στη συνέχεια μελετήσαμε τη δυνατότητα χορήγησης μιας φαρμακοτεχνικής μορφής μέσω του δέρματος σε κατάλληλο σύστημα διαλυτών. Αφού βρέθηκαν οι κατάλληλες συνθήκες, χρησιμοποιήθηκαν ενισχυτικά διαπέρασης στη φαρμακοτεχνική μορφή για να επιταχυνθεί η διαδερμική απορρόφηση του φαρμάκου, όσο είναι δυνατόν, και να ευρεθεί η βέλτιστη φαρμακοτεχνική μορφή. Τέλος, πραγματοποιήθηκαν πειράματα σύγκρισης μεταξύ του πειραματικού φαρμάκου και γνωστού αντιϋπερτασικού (Los) ως προς τις φυσικοχημικές ιδιότητες και την ικανότητα μεταφοράς τους διαδερμικά. Τα αποτελέσματα έδειξαν ότι το ΠΦ παρουσίασε μεγαλύτερη διαπέραση υπό μορφή ουδέτερου μορίου (σε σχέση με την αντίστοιχη του άλατος με TFA (όπως φάνηκε από τα αρχικά πειράματα αυτής της σειράς) ή του μετά Καλίου άλατος (όπως προκύπτει μετά από σύγκριση των σχετικών τιμών Ροής και Συντελεστή Διαπερατότητας (P). Συγκρίνοντας λοιπόν τις τιμές διαπερατότητα και ροής διαμέσου ανθρώπινης επιδερμίδας με τις αντίστοιχες τιμές του φαρμάκου Los θα πρέπει να λάβουμε υπ’ όψη και τις τιμές για το ουδέτερο μόριο. Η διαπέραση του ουδέτερου μορίου του ΠΦ είναι σημαντικά χαμηλότερη από την αντίστοιχη του μετά καλίου άλατος της los. / In this study, we investigated the use of elastic liposomes in transdermal delivery of hydrophilic substances and we studied the possibility of formulating a new antihypertensive drug for transdermal delivery. Primarily, morphological studies of human skin were conducted by the use of optical microscopy and transepidermal water loss measurements (TEWL), in order to assess the barrier function of stratum corneum (SC), and the integrity of the techniques used in this study. By optical microscopy, in particular, data concerning the skin structure and the possible mechanism by which substances can be delivered through / into the skin, were obtained. Secondly, we studied and compared various physicochemical characteristics of two different types of elastic liposomes, which could help us predict the transdermal absorption (in vivo) of hydrophilic molecules. Fluorescent markers calcein and carboxyfluorescein were used as hydrophilic model drugs. All liposomal dispersions (conventional liposomes CLs, and elastic liposomes i.e. transfersomes TRs and invasomes INVs) were evaluated in means the following physicochemical properties: size distribution, z-potential, stability upon storage, morphology by cryo-electron microscopy and membrane elasticity. Moreover, their ability to encapsulate and also to retain aqueous soluble markers, was investigated. Finally, the permeation of calcein through human skin was tested and compared by use of elastic and conventional rigid liposomes. The mean diameter was found relatively homogenous, similar for most liposomal dispersions, while the addition of different penetration enhancers during the preparation did not influence z-potential. Increase of size average and instability – as far as the retention of the encapsulated substance is concerned – was observed at higher concentrations of penetration enhancers used. Sodium cholate containing TRs were found more elastic compared to Tween 80 containing TRs, which showed relatively low elasticity values (<40mg/s∙cm2). The highest elasticity values among all types of elastic liposomes prepared, were found in the case of INVs with 1%w/w PE and 1% w/w LIM. Furthermore, most INVs showed higher elasticity values compared to the ones without terpenes (control INVs), except from citral and cineol INVs, where elasticity decreased compared to the control ones. It appears that different types of liposomes can alter fluorescent permeation in the following order: Solution<CLs<TRs<<INVs. Permeability, flux and enhancement ratio (ER) show that conventional liposomes increased slightly calcein flux, while TRs and INVs 1.8 and 7.2 times respectively. These findings confirm the fact that CLs are inefficient drug delivery systems for water soluble molecules through human skin, and show that elastic liposomes having the highest elasticity value are more efficient in delivering CF transdermally. In further experiments, the penetration of both hydrophilic and lipophilic molecules in human skin was studied, in order to investigate the mechanism of action by which liposomes could enhance the drug delivery in skin. Fluorescent marker calcein was used as a hydrophilic drug model, while lipid rhodamine-PE was used as a lipophilic model (it shows us how deeply the liposomes penetrate into the skin). Liposomes TRs seem to enhance skin permeation by helping the marker to penetrate (through liposomes) in deeper stratum corneum layers while conventional liposomes the hydrophilic substance which penetrates the skin layers as a free molecule. In contrast, INV liposomes were proved to be able to penetrate in deeper skin layers, and deliver relatively high amounts of the encapsulated substance. In the end, experiments with a new molecule with similar structure to losartan were conducted. This study aimed at discovering a new formulation for this experimental drug in order to be used as a transdermal antihypertensive. First, we studied the physicochemical properties (solubility in PBS, BSA etc, and protein binding). Secondly, we investigated the possibility of preparing a formulation to be used transdermally. After establishing the techniques and drug properties we used penetration enhancers in order to increase the transdermal absorption as possible and help find the right skin formulation. Last, we compared the experimental drug and losartan in terms of physicochemical properties and their ability to be transported through human skin. The results showed that the experimental drug had better permeation rate as a neutral molecule compared to TFA salt, (as shown in preliminary experiments) or K+ (as shown after comparing P and flux values). Therefore, the values given for the neutral molecule should be taken into consideration when comparing the two drugs. (losartan and experimental drug). The permeation of the neutral molecule nevertheless is significantly lower than the one for losartan.

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No. of bitstreams: 1 coelho_gm_me_bot.pdf: 3704223 bytes, checksum: 1913a08655010052736bb490b0ed492f (MD5) Previous issue date: 2017-12-01 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Bases científicas: A laparotomia é um procedimento invasivo que causa grande dano tecidual e provoca dor no período pós-operatório. Embora a analgesia seja um procedimento padrão em cirurgia, a terapêutica ideal para o controle deste sintoma ainda necessita ser investigada. Estudos mostram que há uma correlação significativa entre a queda da impedância tecidual e a dor manifestada por pacientes que sofrem lesões teciduais, sugerindo que a reparação da integridade dos tecidos pode restaurar o equilíbrio bioelétrico das células e controlar a dor dos pacientes. A corrente elétrica contínua (CEC), todavia, quando aplicada em tecidos lesados é capaz de promover a migração direcionada e o alinhamento de células epiteliais, particularmente de fibroblastos, favorecendo o processo de regeneração tecidual. Este tipo de corrente elétrica, porém, não tem sido usado na prática clínica com finalidades analgésicas, o mesmo ocorrendo com a iontoforese transdérmica (ITD), que visa à absorção de íons solúveis através da pele, como o zinco, que participa ativamente da formação do colágeno e da cicatrização. Assim, este estudo se fundamentou na hipótese de que a ação benéfica da CEC sobre a cicatrização poderia aumentar a impedância tecidual e, por consequência, modular inibitoriamente a dor apresentada pelos pacientes. Objetivo: Avaliar os efeitos da CEC isolada e da ITD+Zn sobre o consumo de analgésicos e a intensidade de dor na parede abdominal de pacientes submetidos à laparotomias eletivas. Métodos: Foi realizado um estudo prospectivo envolvendo 45 pacientes adultos, de ambos os sexos, internados no HC/FMB-UNESP, para tratamento cirúrgico eletivo de enfermidades do abdome, através da laparotomia. Pacientes impossibilitados de realizar a eletroterapia ou com riscos maiores de apresentar efeitos adversos ou complicações foram excluídos. Os pacientes foram distribuídos, por sorteio, em 3 grupos experimentais, com 15 pacientes cada: GC – Grupo Controle, com tratamento simulado das incisões abdominais; GCEC, com incisões tratadas com corrente elétrica contínua isolada; GITD+Zn, com incisões tratadas com CEC e administração tópica de sulfato de zinco, através da iontoforese transdérmica. A eletroterapia foi aplicada uma vez ao dia, em 4 sessões de tratamento, respectivamente, no 1º, 2º, 3º e 4º PO. Pacientes dos 3 grupos experimentais também receberam analgesia pós-operatória, com tramadol, usando bombas de PCA, e também foram submetidos a testes de ansiedade e depressão no pré-operatório. O efeito dos tratamentos foi avaliado pela frequência de doses de analgésico solicitadas e liberadas, quantidade de analgésicos consumida e pela intensidade de dor na parede abdominal, medida pelas escalas de avaliação Verbal (VRS), Numérica (NRS) e Visual Analógica (VAS), aplicadas no pré-operatório e nos 4 dias de pós-operatório, antes e após a movimentação/deambulação. Os dados obtidos foram analisados pela Análise de Variância, com nível de significância nos testes de comparações definido para P<0,05 ou 5%. Resultados: Apesar da predominância de mulheres obesas na amostra, não houve diferenças significantes (P>0,05) entre indivíduos dos 3 grupos experimentais em relação à: idade, escolaridade, índice de massa corpórea, níveis de ansiedade e depressão, porte da cirurgia, duração da cirurgia e anestesia, tamanho da incisão, prevalência de complicações da ferida operatória e tempo de internação. Também não houve variações estatísticas entre homens vs mulheres e obesos vs não-obesos, antes da eletroterapia ter-se iniciado (POI), em relação à frequência de solicitações de analgésico à bomba de PCA, doses efetivamente liberadas e dose total diária de analgésico administrada aos pacientes. Iniciada a eletroterapia, pacientes do GCEC e GITD+Zn tiveram frequência de solicitações de analgésico à bomba de PCA e dose total diária de analgésico significantemente menor (P<0,05) que pacientes do GC, a partir do 2º PO, não havendo diferenças significantes entre os dois tratamentos. Um número menor de doses de analgésico efetivamente liberadas pela bomba também foi observado em pacientes do GCEC e GITD+Zn, nos 4 dias de pós-operatório, porém, as diferenças foram estatisticamente significantes (P<0,05), somente no 2º e 3º PO. Na avaliação da intensidade de dor observou-se que homens vs mulheres e obesos vs não-obesos apresentaram respostas diferentes, antes do início da eletroterapia (POI), onde percentual significantemente maior de mulheres (P<0,05) sentiu dor classificada como “moderada”, enquanto homens a classificaram como “leve”, e percentual significantemente maior de obesos (P<0,05) referiu sentir dor de intensidades “moderada”, “intensa” ou “muito intensa” quando comparado com não-obesos. Estas diferenças, porém, não foram observados com as escalas NRS e VAS. Iniciada a eletroterapia, em geral, observou-se que uma percentagem significantemente maior (P<0,05) de pacientes do GCEC e GITD+Zn, avaliados pela escala VRS, referiu não sentir dor ou ter dor leve, tanto no repouso como após a movimentação, nos 4 períodos do pós-operatório, quando comparado com o GC. Com raras exceções, observadas no 1º PO, os resultados obtidos com a CEC não diferiram estatisticamente (P>0,05) daqueles observados com a ITD+Zn. Quando foram aplicadas as escalas NRS e VAS, pacientes do GCEC e GITD+Zn tiveram uma intensidade de dor menor que a observada entre os pacientes do GC, em todos os períodos do PO, tanto em repouso, como após a movimentação. Porém, as diferenças só foram estatisticamente significantes (P<0,05) a parir do 2º PO, após a movimentação do paciente. Não foram observados eventos adversos ou quaisquer complicações com a aplicação da eletroterapia. Conclusões: A aplicação de CEC e ITD+Zn reduz a frequência de doses solicitadas ou liberadas de analgésico, o consumo de analgésico e, também, a intensidade de dor de pacientes submetidos à laparotomia, principalmente nas fases mais tardias do pós-operatório. Os benefícios, em geral, foram mais evidentes a partir do 2º dia de pós-operatório, após a movimentação do paciente. Com raras exceções, a eficácia de ambos os tratamentos no controle da intensidade de dor foi similar. No entanto, amostra maior de pacientes e o uso de outras metodologias de avaliação da intensidade de dor tornam-se necessárias para validar o real efeito da CEC e ITD+Zn como terapêuticas alternativas e/ou de suporte à analgesia convencional. / Purpose: To evaluate the effects of continuous electrical current (CEC) and zinc sulphate administered by transdermal iontophoresis (TDI+Zn) on the analgesic consumption and intensity of pain in patients submitted to elective laparotomies. Methods: 45 adult patients of both genders were randomly assigned to 3 experimental groups, with 15 patients each: CG - Control Group, with simulated treatment of abdominal incisions; GCEC, incisions treated with CEC alone; GTDI+Zn, incisions treated with CEC plus topical administration of zinc sulfate, through TDI. Electrotherapy was applied once a day in the morning, in a total of 4 treatment sessions, during 4 postoperative days. All patients also received postoperative analgesia with tramadol, using PCA pumps. Pain intensity was evaluated by the frequency and analgesic consumption, and by Verbal (VRS), Numerical (NRS) and Visual Analogue (VAS) scales, applied in the preoperative period and in the 4 postoperative days, before and after the movement/walking. Results: There were no statistically significant differences (P>0.05) among groups in relation to: age, schooling, body mass index, anxiety and depression levels, preoperative pain, surgery/anesthesia duration, incision size, prevalence of surgical wound complications, inpatient time, frequency of analgesic requested or released to/by the PCA pump, and total daily dose of analgesic administered in pre-, and immediate postoperative period. GCEC and GTDI+Zn patients had a frequency of analgesic requests to PCA pump and total daily dose of analgesic significantly lower (P <0.05) than CG patients, from the 2nd PO. A smaller number of analgesic doses effectively released by the pump were also observed in GCEC and GTDI+Zn patients in the 4 postoperative days, but the differences were statistically significant (P<0.05), only in the 2nd and 3rd PO. A significantly higher percentage (P<0.05) of GCEC and GTDI+Zn patients reported no pain or mild pain in VRS scale, and when NRS and VAS scales were applied they also had a lower pain intensity than that observed among CG patients, both at rest and after movement, in all periods of PO. However, the differences were only statistically significant (P<0.05) from the 2nd PO, after patient movement. Conclusion: CEC and TDI+Zn reduce analgesic consumption and pain intensity of patients undergoing laparotomy, especially in the later phases of the postoperative period. However, a larger sample of patients becomes necessary to validate the real effect of CEC and TDI+Zn as alternative and/or support for conventional analgesia. There were no differences between the two electrotherapeutic methods in reducing the pain intensity of patients.

Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Rutin is a flavonoid widely reported in the literature for its antioxidant properties, anti-inflammatory, vasoprotective, antithrombogen, among others. However, its low solubility in aqueous media reduces its bioavailability orally and, therefore, transdermal administration proves to be promising. Thus, the present work aimed to obtain, characterize and evaluate an activity and antioxidant activity of a gel. PLO (Pluronic Lecithin Organogel) containing rutin for transdermal administration.The analytical methodology for rutin quantification was developed and validated by high performance liquid chromatography (HPLC). Initially it was evaluated as an influence of the concentration of Polaxamer 407, obtained by the extrusion method with the aid of syringes, in front of the centrifugation test. The formulation that remained stable after the test was characterized by partical size determination, in vitro release study, in vitro skin penetration study, in vitro skin adhesion study. Also assessed for stability for 60 days at varying temperatures and at predetermined times, physico-chemical characteristics such as pH, density, viscosity and spreadability, as well as organoleptic characteristics, were evaluated. The antioxidant activity of the formulation was evaluated by the TRAP and TAR methods, comparing it with a positive control, Trolox. The results demonstrate that a formulation with higher concentration of Polaxamer is more stable and that is why it was characterized. The partical size were perfect for dermal administration. The formulation demonstrated controlled release of the drug after 24 hours, being able to permeate as deeper layers of the skin and to be absorbed into the systemic circulation, in addition to good adhesion to the skin surface. During the accelerated stability study, as formulations stored at low temperature, they underwent small variations in density, viscosity and spreadability relative to those stored at room temperature, while the pH remained stable throughout and favorable for application in skin. However, as observed variations were not sufficient to cause visual signs of instability. As for the antioxidant activity, a formulation showed greater activity in relation to the Trolox control and the free rutin, but it was not able to sustain an activity for a longer time, presenting a lower TAR value than Trolox. Thus, a chosen formulation has been shown capable of promoting a permeation of the rutin by transdermal route in a controlled manner, as well as being stable at an ambient temperature and having more significant antioxidant activity than the free rutin, and is therefore promising to administration of rutin by this route. / A rutina é um flavonoide bastante estudado devido principalmente as suas propriedades antioxidantes, anti-inflamatória, vasoprotetora e antitrombogência. No entanto, sua baixa solubilidade em meio aquoso reduz sua biodisponibilidade por via oral e, portanto, a administração por via transdérmica pode ser uma alternativa promissora. Dessa forma, o presente trabalho teve por objetivo obter, caracterizar e avaliar a estabilidade e a atividade antioxidante de um gel contendo Pluronic Lecithin Organogel (PLO) contendo rutina, para administração pela via transdérmica. A metodologia analítica para quantificação de rutina foi desenvolvida e validada por cromatografia líquida de alta eficiência (CLAE). Inicialmente foi avaliado qual a influência da concentração do Polaxamer 407, obtidos pelo método de extrusão com auxílio de seringas, frente ao teste de centrifugação. A formulação que permaneceu estável após o teste foi caracterizada através da determinação do tamanho de partícula, estudo de liberação, penetração cutânea e adesão à pele, todos in vitro. Foi também avaliada a estabilidade do produto durante 60 dias em variadas temperaturas em tempos pré-determinados, além das análises físico-químicas, como pH, densidade, viscosidade e espalhabilidade, bem como características organolépticas. A atividade antioxidante da formulação foi determinada pelos métodos TRAP e TAR, em comparação com um controle positivo, o Trolox. Os resultados demonstraram que a formulação contendo maior concentração de Polaxamer é mais estável e por isso esta foi caracterizada. O tamanho de partícula encontrado foi 4,33 μm e o sistema se mostrou homogêneo, ideal para administração cutânea. A formulação demonstrou liberação controlada do fármaco após 24 horas, sendo capaz de permear as camadas mais profundas da pele e ser absorvida para circulação sistêmica, além de boa adesão à superfície da pele. Durante o estudo de estabilidade acelerada, as formulações armazenadas em baixa e alta temperatura, sofreram pequenas variações na densidade, na viscosidade e na espalhabilidade, em relação àquelas armazenadas a temperatura ambiente, enquanto que o pH se manteve estável durante todo o tempo e favorável à sua aplicação na pele. Além disso, as variações observadas não foram suficientes para provocar alterações visuais de instabilidade. Quanto à atividade antioxidante, a formulação demonstrou maior atividade em relação ao controle Trolox e à rutina livre, porém de forma não duradoura, apresentando valor de TAR menor que o Trolox. Sendo assim, a formulação escolhida, demonstrou-se capaz de promover a permeação da rutina por via transdérmica de forma controlada, bem como estabilidade a temperatura ambiente e com atividade antioxidante significativa, sendo considerada então promissora a administração da rutina por esta via. / São Cristóvão, SE

O objetivo do presente trabalho foi de analisar, experimentalmente, a variação do índice de transmissão e o coeficiente de atenuação ultra-sônica no meio diclofenaco gel, bem como, a penetração do fármaco em amostras de gelatina semelhante a pele humana através da fonoforese. A variação destes parâmetros foi investigada em 120 amostras de agar-agar, (modo contínuo, 1 MHz de freqüência, nas intensidades de 1,0 e 1,5 W/\'CM POT.2\'), por 5 minutos. Os corpos de prova forma divididos em grupos referentes as intensidades de ultra-som utilizadas, e cada um destes grupos, foi subdividido em sub-grupos correspondendo aos diferentes meios utilizados para irradiação. A investigação da transmissão ultra-sônica foi medida a partir de um dosímetro de precisão ULTRASONIC POWER METER, modelo UPM-DT 10. O cálculo do coeficiente de atenuação foi realizado a partir dos dados de leitura da transmissão ultra-sônica. A penetração ou não da droga foi estudada por análise macroscópica e microscópica. Segundo os resultados obtidos não houve variação significativa nos índices de transmissão e nos coeficientes de atenuação do diclofenaco gel em comparação ao gel neutro. A penetração do medicamento foi de 3 mm para as amostras irradiadas com a intensidade de 1,0 W/\'CM POT.2\' e de 5 mm para as amostras irradiadas com 1,5 W/\'CM POT.2\', não houve evidência de penetração do fármaco no grupo controle. Os resultados obtidos neste estudo sugerem que a fonoforese do diclofenaco gel é efetiva nas intensidades 1,0 e 1,5 W/\'CM POT.2\'. / The objective of the present work was of analyzing, experimentally, the variation of the transmission index and the coefficient of ultrasonic reduction in the half diclofenaco gel, as well as, the penetration of the drug in samples of similar jelly the human skin through the phonophoresis. The variation of these parameters was investigated in 120 agar-agar samples, (continuous way, 1 MHz of frequency, in the intensities of 1,0 and 1,5 W/\'CM POT.2\'), for 5 minutes. The proof bodies form divided in referring groups the ultrasound intensities used, and each one of these groups, it was subdivided in sub-groups corresponding to the different means used for irradiation. The investigation of the ultrasonic transmission was measured starting from a ULTRASONIC POWER METER, model UPM-DT 10. The calculate it of the reduction coefficient was accomplished starting from the data of reading of the ultrasonic transmission. The penetration or not of the drug it was studied for it analyzes macroscopic and microscopic. According to the obtained results there was not significant variation in the transmission indexes and in the coefficients of reduction of the diclofenaco gel in comparison with the neutral gel. The penetration of the medicine went of 3 mm to the samples irradiated with the intensity of 1,0 W/\'CM POT.2\' and of 5 mm for the samples irradiated with 1,5 W/\'CM POT.2\', there was not evidences of penetration of the drug in the group control. The results obtained in this study suggest that the phonophoresis of the diclofenaco gel is effective in the intensities 1,0 and 1,5 W/\'CM POT.2\'.