Desenvolvimento e caracterização de sistemas líquido-cristalinos para aplicação tópica de metotrexato: estudos de liberação, retenção e permeação in vitro

Widely used in the treatment of some types of cancer, the methotrexate (MTX) is a chemotherapeutic, structurally analog of the folic acid, although its effectiveness, presents a series of adverse effect, being the most serious hepatotoxicity. Currently, the liquid crystal lamellar phase is being used of devices for modified release of drug demonstrated to be advantageous in the release topic of some substances, given to the characteristics of interaction with the stratum corneun and other layers of the skin, avoiding systemic adverse effects. The aims of this research had been to develop and to characterize liquid crystalline nanostructure systems of lamellar phase, increased of MTX of the physical point of view, also carry through the structural analysis of the formulations through by polarized light microscopy (PLM), small-angle X-ray scattering (SAXS) and rheological properties. Perform stability studies of the chosen formulations, validate the analytical method of quantification of MTX for High Performance Liquid Chromatography (HPLC) and carry through release assay, cutaneous permeation and skin retention in vitro for the chosen formulations. The formulations prepared by the mixture of polyether functional siloxane as surfactant, with silicone polyether copolymer as oily phase and phosphate buffer 0,01M pH 7,4 as aqueous phase demonstrating lamellar liquid-crystalline phases, confirmed by assays of PLM and SAXS. The stability studies showed that formulations A, B and C remained stable throughout the period of the study. The study of the rheological behavior of the formulations presented as not Newtonian pseudoplastic fluid and thixotropic ...Amplamente utilizado no tratamento de vários tipos de câncer e na psoríase, o metotrexato (MTX) é um quimioterápico, estruturalmente análogo do ácido fólico, que apesar de sua eficácia apresenta uma série de efeitos adversos, sendo a hepatotoxicidade o mais grave. Atualmente os sistemas nanoestruturados líquido-cristalinos de fase lamelar estão sendo utilizados como dispositivos para liberação modificada de fármacos, sendo vantajosos na liberação tópica de várias substâncias, conforme suas características de interação com o estrato córneo e as outras camadas da pele, evitando assim efeitos adversos sistêmicos. Os objetivos deste trabalho foram desenvolver sistemas nanoestruturados líquido-cristalinos de fase lamelar, acrescidos de MTX, caracteriza-los do ponto de vista físico, realizar a análise estrutural das formulações, através de microscopia de luz polarizada (MLP), espalhamento de raios-X a baixo ângulo (SAXS) e suas propriedades reológicas, executar os testes de estabilidade preliminar (TEP) das formulações, validar o método analítico para a quantificação de MTX por CLAE e executar ensaios de liberação, permeação e retenção in vitro. As formulações preparadas a partir da mistura do poliéter funcional siloxano (Dow Corning® 5329) como tensoativo, com silicone fluido de co-polímero glicol (Dow Corning® 193C) como fase oleosa titulados em fase aquosa, composta por tampão fosfato de potássio monobásico 0,01M pH 7,4, apresentaram fases líquido-cristalinas do tipo lamelar, confirmados pelos ensaios de MLP e SAXS. Os TEPs evidenciaram que as formulações A, B e C mantiveram-se estáveis durante o período do estudo. Os estudos do comportamento reológico das formulações apresentaram-se como fluidos pseudoplásticos não–newtonianos tixotrópicos ...Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Bioadhesive Surfactant Systems for Methotrexate Skin Delivery

Methotrexate (MTX) is an immunosuppressive drug for systemic use in the treatment of skin diseases, however, MTX presents a number of side effects, such as hepatotoxicity. To overcome this limitation, this study developed skin MTX delivery surfactant systems, such as a microemulsion (ME) and a liquid crystalline system (LCS), consisting of a glycol copolymer-based silicone fluid (SFGC) as oil phase, polyether functional siloxane (PFS) as surfactant, and carbomer homopolymer type A (C971) dispersion at 0.5% (wt/wt) as aqueous phase. Polarized light microscopy and small-angle X-ray scattering evidenced the presence of hexagonal and lamellar LCSs, and also a ME. Texture profile and in vitro bioadhesion assays showed that these formulations are suitable for topical application, showing interesting hardness, adhesiveness and compressibility values. Rheology analysis confirmed the Newtonian behaviour of the ME, whereas lamellar and hexagonal LCSs behave as pseudoplastic and dilatant non-Newtonian fluids, respectively. In vitro release profiles indicated that MTX could be released in a controlled manner from all the systems, and the Weibull model showed the highest adjusted coefficient of determination. Finally, the formulations were not cytotoxic to the immortalized human keratinocyte line HaCaT. Therefore, these bioadhesive surfactant systems established with PFS and C971 have great potential as skin delivery systems

Hydroxyethylcellulose-Based Hydrogels Containing Liposomes Functionalized with Cell-Penetrating Peptides for Nasal Delivery of Insulin in the Treatment of Diabetes

Liposomes functionalized with cell-penetrating peptides are a promising strategy to deliver insulin through the nasal route. A hydrogel based on hydroxyethylcellulose (HEC) aqueous solution was prepared, followed by a subsequent addition of liposomes containing insulin solution functionalized with trans-activator of transcription protein of HIV-1 (TAT) or Penetratin (PNT). The formulations were characterized for rheological behavior, mucoadhesion, syringeability, in vitro release and in vivo efficacy. Rheological tests revealed non-Newtonian fluids with pseudoplastic behavior, and the incorporation of liposomes (HLI, HLITAT and HLIPNT) in hydrogels did not alter the behavior original pseudoplastic characteristic of the HEC hydrogel. Pseudoplastic flow behavior is a desirable property for formulations intended for the administration of drugs via the nasal route. The results of syringeability and mucoadhesive strength from HEC hydrogels suggest a viable vehicle for nasal delivery. Comparing the insulin release profile, it is observed that HI was the system that released the greatest amount while the liposomal gel promoted greater drug retention, since the liposomal system provides an extra barrier for the release through the hydrogel. Additionally, it is observed that both peptides tested had an impact on the insulin release profile, promoting a slower release, due to complexation with insulin. The in vitro release kinetics of insulin from all formulations followed Weibull’s mathematical model, reaching approximately 90% of release in the formulation prepared with HEC-based hydrogels. Serum insulin levels and the antihyperglycemic effects suggested that formulations HI and HLI have potential as carriers for insulin delivery by the nasal pathway, a profile not observed when insulin was administered by subcutaneous injection or by the nasal route in saline. Furthermore, formulations functionalized with TAT and PNT can be considered promoters of late and early absorption, respectively