Vitamin E TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate), the water-soluble derivative of the naturally occurring d-a-tocopherol, was used initially to overcome malabsorption and correct severe vitamin E deficiency in cholestatic children. The observation that its administration increased the absorption of vitamin D focused attention on its amphiphilic properties as nonionic surfactant and applications in solubilizing lipophilic and poorly soluble compounds and enhancing their absorption and bioavailability. Further research has evaluated its safety and efficacy which combines solubilization and formation of micelle-like particles with inhibition of P-glycoprotein-mediated efflux, the key mechanism to the development of drug resistance. These properties expanded its applications in pharmaceuticals and dietary, disease-specific, supplements for malabsorbing patients. Emerging research on major nutraceuticals and the developing field of cannabinoids have shown that poor water solubility and extensive first-pass metabolism cause poor absorption and bioavailability. This chapter describes the properties, safety, and efficacy of vitamin E TPGS with a focus on its applications in nutraceuticals and cannabinoids.

Apesar da aparente acessibilidade, a pele é bem protegida contra a absorção de materiais estranhos. Esta função barreira é exercida principalmente pelo estrato córneo. Dessa forma, a administração cutânea de fármacos precisa transpor esta barreira para atingir uma concentração efetiva. Uma maneira de tornar o tratamento eficaz é o uso de injeções, forma de administração muito invasiva e desconfortável para o paciente. A administração tópica é uma forma simples e confortável para a administração cutânea de fármacos. As doenças cutâneas, em geral, são doenças estigmatizadas. Assim, o desenvolvimento de uma formulação capaz de transpor as barreiras impostas a esta via de administração e um novo tratamento para estas doenças complexas, com componentes genéticos, devem ser estudados. O siRNA veiculado com nanocarreadores foi aplicado a esta via de administração. O nanocarreador possibilita um maior tempo de permanência na superfície da pele devido às propriedades adesivas, além de proteger o siRNA contra a degradação. O siRNA visa o bloqueio específico da expressão de genes, por isso é capaz de agir em diferentes caminhos de uma doença. A maior limitação para o uso de siRNA é a incapacidade de difundir-se através das membranas celulares devido a carga negativa, o que gera uma repulsão eletrostática da membrana celular. Portanto, a complexação com um carreador torna a liberação do siRNA no interior celular mais efetiva. É amplamente aceito que o desenvolvimento de um sistema de liberação eficiente é um dos principais obstáculos para transformar siRNA em terapêutica. Consequentemente, o objetivo deste trabalho foi o desenvolvimento farmacotécnico de um nanocarreador capaz de liberar o siRNA de maneira efetiva na aplicação tópica cutânea, respeitando as peculiaridades desta via. As formulações de monoleína (MO), polietilenoimina (PEI) e diferentes concentrações de vitamina E TPGS, contendo ou não ácido oléico (AO), foram caracterizadas como fases líquido cristalinas com tamanho de partícula e potencial zeta desejado, mostrando-se eficazes em complexar o siRNA. As nanodispersões desenvolvidas foram efetivas na complexação do siRNA, na estabilização deste ácido nucléico frente a degradação enzimática, e na efetiva internalização celular in vitro em células de fibroblastos de camundongos L929. As nanodispersões contendo maior quantidade de vitamina E TPGS, ou contendo o AO foram as formulações que promoveram um maior aumento da penetração cutânea de siRNA in vitro em peles de modelo animal. Logo, os resultados obtidos permitiram concluir que as formulações desenvolvidas são sistemas de liberação nanotecnológicos, contendo cristais líquidos, promissores para a administração tópica de siRNA, no tratamento de patologias cutâneas na terapia gênica / Despite its apparent easy accessibility, the skin is, in fact, well protected against the absorption of foreing materials. The barrier function is imposed, mainly, by the stratum corneum. Thus, the cutaneous administration of drugs needs to overcome this barrier to reach an effective concentration. One way to make an effective treatment is the use of injections, mode of administration very invasive and uncomfortable for the patient. Topical administration is simple and comfortable for cutaneous administration of drugs. Skin diseases, in general, are stigmatized diseases. Therefore, the development of a formulation capable of overcoming the barriers of this route of administration and a new treatment for these complex diseases, with the genetic components, shall be studied. The siRNA in nanocarriers has been applied to this route of administration. The nanocarrier allows siRNA to stay longer on the skin surface because of its adhesive properties, while also protects siRNA against degradation. The siRNA is directed for producing gene-specific inhibition, so it is able to act in different ways to the same disease. The most critical factor limiting the use of siRNA as therapeutics is delivering siRNA to its intracellular target site due to their negative charge, which cause an electrostatic repulsion of the cell membrane. Therefore, complexation with a carrier makes the release of siRNA inside the cells more effective. It is widely accepted that the development of an efficient delivery system is a major obstacle to change siRNA into therapeutics. Consequently, the objective of this work was the pharmacotechnical development of a nanocarrier capable of releasing the siRNA effectively in topical skin, respecting the peculiarities of this pathway. The formulations of monoolein (MO), polyethylenimine (PEI) and different concentrations of vitamin E TPGS, with or without oleic acid (OA), were characterized as liquid crystalline phases with particles size and zeta potential desired, proving to be effective in complexing the siRNA. The nanodispersions developed were effective for the complexation of siRNA, for the stabilization of nucleic acid against enzymatic degradation, and for the effective in vitro cellular uptake into cells of mouse fibroblast L929. The nanodispersions containing higher amounts of vitamin E TPGS, or containing OA, have been the formulations which promoted a greater increase in skin penetration of siRNA in vitro in animal model skin. Therefore, the results obtained allowed one to conclude that the formulations developed are delivery systems based on nanotechnology, with liquid crystalline phase, promising for topical administration of siRNA, for the treatment of cutaneous diseases in gene therapy

Tocopheryl Polyethylene Glycol Succinate 1000 (TPGS 1000) can inhibit P-glycoprotein (P-gp); TPGS 1000 was not originally designed to inhibit an efflux pump. Recent work from our laboratories demonstrated that TPGS activity has a rational PEG chain length dependency. In other recent work, inhibition mechanism was investigated and appears to be specific to the ATPase providing P-gp energy. Based on these observations, we commenced rational surface-active design. The current work summarizes new materials tested in a validated Caco-2 cell monolayer model; rhodamine 123 (10 μM) was used as the P-gp substrate. These results demonstrate that one may logically construct non-ionic surfactants with enhanced propensity to inhibit in vitro efflux. One new surfactant based inhibitor, Tocopheryl Polypropylene Glycol Succinate 1000 (TPPG 1000), approached cyclosporine (CsA) in its in vitro efflux inhibitory potency. Subsequently, TPPG 1000 was tested for its ability to enhance the bioavailability of raloxifene - an established P-gp substrate - in fasted male rats. Animals dosed with raloxifene and TPPG 1000 experienced an increase in raloxifene oral bioavailability versus a control group which received no inhibitor. These preliminary results demonstrate that one may prepare TPGS analogs that possess enhanced inhibitory potency in vitro and in vivo.