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Comparative study of the clinical efficiency of dimethyl fumarate in gelatin capsules and dimethyl fumarate in solid lipid nanoparticles administered by the oral and subcutaneous routes, respectively

Grant number: 16/14264-8
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): November 01, 2016
Effective date (End): October 31, 2017
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Fabio de Lima Leite
Grantee:Gisela Bevilacqua Rolfsen Ferreira da Silva
Supervisor abroad: João José Fernandes Cardoso de Araujo Cerqueira
Home Institution: Centro de Ciências e Tecnologias para a Sustentabilidade (CCTS). Universidade Federal de São Carlos (UFSCAR). Sorocaba , SP, Brazil
Local de pesquisa : Universidade do Minho (UMinho), Portugal  
Associated to the scholarship:13/22141-5 - Development of solid lipid nanoparticles containing dimethyl fumarate intranasal for multiple sclerosis, BP.PD

Abstract

The SLN is an alternative in the attempt to develop a new dosage form for transport by dimethylfumarate because presents structure basically composed of lipid, and is therefore capable of carrying the dimethylfumarate, highly lipophilic drug. The subcutaneous route is a very common approach in the treatment of MS. Several drugs are administered by this route, such as: interferon-beta and glatiramer acetate. This route can cause adverse effects due to the high frequency of administration (daily or even 3 times a week), and these effects include pain, inflammation and induration at the site of application. However, to associate the subcutaneous form of a pharmaceutical controlled release can be obtained reduction in frequency of administration. Thus, the development of a delivery system controlled to dimethylfumarate, such as solid lipid nanoparticles, concomitantly with the subcutaneous route of administration, would result in reducing the frequency of administration, reduction or absence of adverse gastrointestinal effects and redness in the skin and targeting of the drug to the CNS without suffering DMF hepatic first-pass metabolism. All these factors are favorable when compared to oral administration marketed today. In the initial project (process FAPESP n ° 2013 / 22141-5), presented as a proposal the development and characterization of NLS with DMF, in addition to analyzes in vitro and in vivo. But one of the goals was that the NLS was studied for intranasal administration. The in vivo experiments are in the process of progress and have already obtained preliminary results. Of these, we obtained consistent and encouraging results, where the analysis of clinical signs showed that NLS containing DMF administered via the intranasal route in mice with EAE were able to slow the development of disease when compared to animals that received NLS free of DMF. Moreover, some results were not consistent, especially those related to around the 29th day of treatment. Animals that received NLS with DMF started having cardiac arrest. No one knows for sure, and this is what is being studied at the moment, what was causing the cardiac arrest. At the moment we speculated that the fact may be related to some potential toxicity of the drug with the nasal administration, which could take a fraction of drug to the lungs, or even both simultaneously. For this reason it has been suggested to use an alternative route for administration of NLS as the subcutaneous or oral, since the results of both physical-chemical characterization and the in vivo experiment, compared to slow down or even preventing the disease during the experiment conducting time period, they are suitable to allow continued research. In addition to the alternative route of administration, Professor Dr. João José Cerqueira, a researcher responsible for the student internship abroad, presents initial studies with dimethyl fumarate and receives industry BG-12 medicine. In Portugal, the product is already marketed more time there than in Brazil. Taking into consideration these facts, with this project, we can join our research with the NLS with DMF developed by the student in his ongoing project and BG-12 drug given to Professor João José Cerqueira. In this way, will be possible perform the dimethylfumarate administration comparison between subcutaneous and oral, through the EAE mouse model. The main goal of this proposal is to compare the efficacy of orally administered dimethylfumarate (BG-12 capsules) with dimethylfumarate incorporated in solid lipid nanoparticles administered subcutaneously. (AU)