Desenvolvimento de nanopartículas lipídicas sólidas para o tratamento tópico da acne vulgaris

Abstract

All-trans retinoic acid (RA, tretinoin) has shown to be efficient in the topical treatment of patients presenting mild to moderate inflammatory acne. Nevertheless, topical use of RA is followed by a high incidence of side-effects such as: irritation, erythema varying from mild to severe, as well as dryness and scaling. These occurrences diminish the patient compliance, compromising the efficacy of the therapy. In order to overcome these disadvantages, without compromising efficiency, new systems to delivery RA have been developed and evaluated.Among these systems, solid lipid nanoparticles (SLN), which have shown potential for controlled release, would be an interesting alternative to lipophilic drugs such as RA. However, the encapsulation rate of RA in SLN is usually low (< 1% in comparison to the lipid mass), unless a high surfactant/lipid ratio is used. This favors interface location of RAand compromises the benefits of encapsulation in the lipid matrix. Thus, this study aims to develop, characterize and evaluate the in vivo comedolytic activity of SLN as RA delivery system. SLN were prepared by hot melt homogenization method using an emulsificationultrasound.The increase of the surfactant/lipid ratio or cholesterol concentration improved the encapsulation efficiency and reduced the mean particle size of SLN. However, this favors interfacial location of the drug. Then, the formation of an ion pairing between RA and various amines was evaluated with the aim of increasing its incorporation into the lipid matrix of the SLN. The incorporation of amines provided a significant increase in the encapsulation rate, which was proportional to the lipophilic properties of these substances. The stearilamine (STE), a lipophilic amine, provided an encapsulation rate of RA in SLN that was higher than 90%. The stability of the SLN loaded with the ion pairing RA-STE was higher than that observed for the SLN without the amine. The SLN containing RA were characterized by differential scanning calorimetry (DSC), wide angle X-ray scattering (WAXS) and small angle X-ray scattering (SAXS). The DSC thermograms and the WAXS and SAXS diffractograms showed the presence of the RA crystals outside the lipid matrix in the SLNwithout amine, and the absence of the crystalline state of the RA and STE outside the lipid matrix of SLN with the ion pairing RA-STE, suggesting an extensive combination between the constituents of the ion pairing and the SLN. Subsequently, studies of efficacy and skin irritation, conducted in rhino mice, showed that the SLN presented efficacy at least equal tothe conventional commercial formulation in the various parameters evaluated (utricle diameter reduction, thickness of the epidermis and the granular layer), but with lower irritation index (redness and flaking) and inflammatory infiltrates in the dermis. Additionally, the increased cell proliferation in the granular layer of the animals treated with the SLNprovided an evidence of epidermal targetting. In summary, we demonstrated that the encapsulation of the RA in SLN through the formation of an ion pairing is feasible in terms of production, stability and encapsulation rate. Moreover, this system was able to reduce theadverse reactions characteristic of the topical application of RA without compromising effectiveness.