y Rational design of oral flubendazole-loaded nanoemulsion for brain delivery in cryptococcosis

Autor(es):Mostrar menos -

Yukuyama, Megumi Nishitani ^[1] ; Ishida, Kelly ^[2] ; Barros de Araujo, Gabriel Lima ^[1] ; Spadari, Cristina de Castro ^[2] ; de Souza, Aline ^[1] ; Lobenberg, Raimar ^[3] ; Bazan Henostroza, Mirla Anali ^[1] ; Folchini, Beatriz Rabelo ^[1] ; Peroni, Camilla Midori ^[1] ; Camasmie Peters, Maria Christina ^[1] ; de Oliveira, Isabela Fernandes ^[1] ; Saito Miyagi, Mariana Yasue ^[1] ; Bou-Chacra, Nadia Araci ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Pharm, Prof Lineu Prestes Ave 508, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Prof Lineu Prestes Ave 508, Sao Paulo, SP - Brazil

^[3] Univ Alberta, Div Pharmaceut Sci, Fac Pharm & Pharmaceut Sci, Katz Grp Rexall Ctr Pharm & Hlth Res, 11361-87 Ave, Room 3-142-K, Edmonton, AB T6G 2E1 - Canada

• Tipo de documento: Artigo Científico
• Fonte: COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS; v. 630, DEC 5 2021.
• Citações Web of Science: 0

Resumo

Cryptococcal meningitis is caused by Cryptococcus spp. and predominantly affects patients with acquired immunodeficiency syndrome. However, an increase in the number of nonHIV patients diagnosed with cryptococcosis raises concerns worldwide. The current antifungal therapy has some limitations such as being unavailable in some countries, high cost, toxicity, and the need for trained professionals for intravenous administration, which compromises patient compliance, resulting in treatment withdrawal and increased fungal resistance. In this regard, new alternative drugs, especially those administered orally and at affordable cost are desired. However, these drugs face challenges due to the gastrointestinal (GI) and blood-brain barriers (BBB). In this present work, we developed a new oil-in-water nanoemulsion containing flubendazole (FLZ) for oral administration using a unique low-energy process for treating cryptococcosis. The combination of D-phase emulsification (DPE) process and design of experiment (DoE) resulted in a stable FLZ-loaded nanoemulsion with 35-nm mean particle size, 60.0% oil phase with 3.0% surfactant phase (both % w/w), at 25 degrees C process temperature without using specific equipment. The careful selection of components for developing this nanoemulsion as a drug carrier is thoroughly discussed herein, including the interaction of lipid components with brain transporters, the type of surfactant as a permeability enhancer through BBB, as well as the choice of the drug. The use of statistical design combined with the DPE process, and selection of components, resulted in reducing approximately 30% of fungal burden in mice brain, and safety testing in an invertebrate model showed nontoxicity by this nanoemulsion. This work reports a step-by-step alternative process for designing a nanoemulsion with improved efficacy and safety, even containing a drug at a significantly reduced concentration compared to previously published works. This nanoemulsion provides multiple benefits - overcoming GI and BBB barriers, and affordable production cost delivering a new antifungal alternative for treating cryptococcosis. (AU)

• Processo FAPESP: 18/12149-2 - Nanopartículas como carreadores de miltefosina para tratamento de meningite criptocócica.
• Beneficiário: Cristina de Castro Spadari
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 17/19374-9 - Equinocandinas no controle de infecções associadas a biofilmes polimicrobianos de Candida spp. e bactérias como Stapholococcus aureus e Pseudomonas aeruginosa
• Beneficiário: Kelly Ishida
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/22713-2 - Estudo do reposicionamento do flubendazol para o tratamento de câncer de pulmão e meningoencefalite empregando nanossistema lipídico oral
• Beneficiário: Megumi Nishitani Yukuyama
• Modalidade de apoio: Bolsas no Brasil - Doutorado