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Development of lipid nanodispersions containing insulin for the topical treatment of dry eye disease

Grant number: 15/04008-1
Support type:Scholarships in Brazil - Master
Effective date (Start): May 01, 2016
Effective date (End): February 28, 2017
Field of knowledge:Health Sciences - Pharmacy - Pharmaceutical Technology
Principal Investigator:Renata Fonseca Vianna Lopez
Grantee:Francieli Pereira
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Dry eye disease is a multifactorial disorder that affects the tear film and the ocular surface; it is associated with several causes such as autoimmune diseases, hormone deficiencies and population aging. It is known that the pathophysiology of the disease is related to an inflammatory process in the ocular structures, which leads to symptoms as discomfort, eye irritation, blurred vision, and ocular pain, which may impact in life quality of the patients. Although the conventional treatment consists of the use of lubricants eye drops, it's a symptomatic therapy that demonstrates low efficacy, which justifies the necessity of drug alternatives with efficacy and clinical relevance. Recent researches indicate that insulin enhances the healing of corneal wounds and it seems to restore the tear film in diabetic rats. However insulin is a macromolecule which can be very quickly metabolized and degraded by enzymes present on the ocular surface. In order to overcome such problems related to its bioavailability and to provide a convenient topical administration to the patient in terms of comfort and dosage, the development of appropriate delivery systems for the ocular use is necessary. The delivery system must have low toxicity, to be able to increase the drug retention time in the ocular surface, and, if possible, to avoid the tear film evaporation, which may be restored with the treatment. Therefore, the aim of this study is to develop lipid nanodispersions containing insulin for the topical treatment of dry eye disease. For this purpose, the developed formulations will be characterized by size, morphology and Zeta potential, using techniques as Transmission Electronic Microscopy (TEM), Atomic Force Microscopy (AFM), Differential Scanning Calorimetry (DSC) and Ray-X Diffraction. The insulin integrity in the developed nanoparticles will be evaluated by immunoassay and by Circular Dichroism. The formulations will be tested in epithelial corneal cell cultures and in lacrimal glands acinar cells, as to cytotoxicity, cell viability, proinflammatory cytokines (IL- 1², IL-6 , TNF- ± ) , nitric oxide (NO) and extracellular matrix metalloproteinases (MMP -9 ) dosage, in order to evaluate its influence on the expression of these cell mediators. In vivo and ex vivo studies will be performed in order to verify the release profile, penetration and retention of insulin, both in membranes and in porcine corneas. (AU)