Desenvolvimento, caracterização e avaliação de nanocápsulas poliméricas contendo ácido ursólico com modificadores de superfície em modelo de cicatrização de feridas

Abstract

The increasing numbers of elderly people worldwide has been accompanied by rising levels of concern regarding the maintenance of quality of life. These concerns include combating the signs of skin aging by using active ingredients that help to minimize the harmful effects of free radicals and the inflammatory process triggered by aging. Ursolic acid has been used for this purpose; however, its clinical use is limited due to its low aqueous solubility. For this reason, it is necessary to study technological alternatives that can overcome this limitation and improve the action of ursolic acid. Surface modifiers have been utilized to optimize the action of particles in the organism; in addition to contributing to the permanence of these particles in the organism they provide more efficient interaction with cells. Thus, the objectives of this study were to synthesize poly (lactic acid) polymer (PLA) and to produce lipid core nanocapsules containing ursolic acid (UA) with different surface modifications using polyethylene glycol (PEG) and sialic acid (SA); and also to evaluate these particles in a healing model in oophorectomized animals to investigate collagen synthesis. The nanocapsules were prepared by the interfacial deposition method of the preformed polymer and were characterized in terms of particle size, polydispersity index, zeta potential, infrared spectroscopy, X-ray diffraction and morphology. The stability test and the validation of an analytical method using UHPLC were performed. An in vivo healing model was used to evaluate the retraction of the lesion. The following were evaluated: histological skin thickness; neutrophil count; macrophages; angiogenesis; collagen synthesis; and toxicity. The nanocapsules showed adequate characteristics in relation to particle size, polydispersity index, and zeta potential. There was no appearance of chemical interactions in the infrared spectroscopy after nanoencapsulation; however, this process led to an amorphization of the system. The stability study revealed that the best storage condition was under refrigeration. It was shown that UA had collagenase-inhibiting activity. The evaluation of in vivo activity demonstrated that the nanocapsules containing UA and UA-SA had a more accelerated retraction, with modulation of the inflammatory process and macrophage stimulation, increased angogenesis, and stimulation of type I collagen synthesis. The treatments with the nanocapsules showed no signs of toxicity. In summary, these data show that UA encapsulation using lipid core nanocapsules and SA coating were appropriate approaches to circumvent UA's low water solubility, improve the drug's pharmacological effect when used intradermally, and to provide an better resolution of the wound healing process.