[Co-tutorship Thesis]: Overcoming Central Nervous System-barriers by the development of hybrid structured systems for nose-to-brain drug delivery using clean technologies by Vanessa S.S. Gonçalves

Thesis Vanessa Gonçalves

Dr. Vanessa S.S. Gonçalves defended her thesis on friday 30th September 2016 at the Instituto de Tecnologia Quimica e Biologica – Universidade Nova de Lisboa. This is a co-tutorship thesis between Universidad de Valladolid and Universidade Nova de Lisboa.

The effective delivery of therapeutics into the brain is challenging since drugs or drug delivery systems (DDS) candidates are not able to cross the blood-brain barrier (BBB), making the development of new drugs alone not enough to ensure progresses in Central Nervous System (CNS) drug therapy. Due to several problems related with other routes of brain drug administration, the interest has increased towards exploring the possibility of intranasal administration. The nose-to-brain transport and the therapeutic viability of this route have been investigated for rapid and effective transport of drugs to CNS, but the development of nasal drug products for brain targeting is still faced with many challenges. Nasal to brain delivery requires solid-based particulate formulations capable to provide drug deposition in the olfactory region and prolonged residence time with high local drug concentration. Face to this, core-shell or layered solid particles that combine different carrier materials could be considered an attractive alternative to single carriers, which still present limitations. There are several conventional techniques to produce hybrid delivery systems, however, these have many post-processing steps, are time-consuming and use organic solvents.

The goal of this dissertation was to use Supercritical fluid (SCF)-based precipitation and drying technologies to produce hybrid particulate structures with improved features for efficient nose-to brain drug administration.

Particles from gas saturated solutions (PGSS®) technique, a precipitation method that avoids completely the use of organic solvents, was explored in this thesis to prepare novel hybrid particles such as Glyceryl monoolate (GMO): glycerolipid structured lipid particles and Gelucire 43/01™ core- polyethylene glycol (PEG) 4000 shell particles. Structured lipid particles developed in this thesis (Chapter 2) presented increased storage stability, higher encapsulation efficiency and fast release of model drug (ketoprofen) with higher drug permeation through a mucous-membrane model (Strat-MR membrane impregnated with mucin) in comparison with single glycerolipid particles. Another PGSS® application was the precipitation from a CO2-saturated O/W emulsion with ketoprofen, constituted by Gelucire 43/01™ as the discontinuous phase and an aqueous solution containing PEG 4000 as continuous phase, that led to the development of novel hybrid particles constituted by lipid multicores involved by the polymeric shell (Chapter 3). Fundamental research was essential to be performed before each PGSS®-precipitation work.

Figure 1 - Microstructure of PEG-GEL hybrid particles: FIB micrographs at a) 5000x and b) 10000x magnification and c-d) TEM images.
Figure 1 – Microstructure of PEG-GEL hybrid particles: FIB micrographs at a) 5000x and b) 10000x magnification and c-d) TEM images.

The production and application of hybrid biopolymer aerogels as carriers for nose-to-brain delivery of drugs was also explored and investigated in this thesis (Chapter 4). Low methoxyl pectin and κ-carrageenan were co-gelled with alginate and further dried with supercritical-CO2, yielding spherical mesoporous microparticles with high specific surface area and mucoadhesive properties. Drugs with different polarities were successfully loaded in amorphous state, presenting a fast release from the polysaccharide matrix.

Figure 2 - SEM micrographs of aerogel microparticles prepared at HLB 5: alginate/pectin (a, b); alginate/κ-carrageenan (c, d).
Figure 2 – SEM micrographs of aerogel microparticles prepared at HLB 5: alginate/pectin (a, b); alginate/κ-carrageenan (c, d).

The purpose of this thesis was not only to show the versatility of SCF technology in the development of hybrid particles but also to preliminary evaluate their application as effective DDS for nose-to-brain administration. Thus, structured lipid particles and aerogel formulations were evaluated in terms of cytotoxicity and drug permeation using RPMI 2650 as human nasal epithelial cell line model (Chapter 5). None of the solid formulations showed cytotoxicity, whereas aerogel microparticles exhibited the highest permeation-enhancing effect compared to the pure model drug, which can be attributed to the mucoadhesive characteristics of the carrier materials, being this the most interesting formulation for nasal drug delivery.

Figure 3 - Effect of different types of formulation (ketoprofen or ketoprofen-loaded microparticles) on ketoprofen apparent permeability coefficients through RPMI 2650 multilayer when applied as solution, dispersion or powder+KRB, after 60 min of incubation (mean ± SD, n≥3); Statistical differences in relation with pure ketoprofen when administered in the same form are denoted as *P < 0.05; ***P < 0.001.
Figure 3 – Effect of different types of formulation (ketoprofen or ketoprofen-loaded microparticles) on ketoprofen apparent permeability coefficients through RPMI 2650 multilayer when applied as solution, dispersion or powder+KRB, after 60 min of incubation (mean ± SD, n≥3); Statistical differences in relation with pure ketoprofen when administered in the same form are denoted as *P < 0.05; ***P < 0.001.

The data presented throughout the chapters of this thesis clearly show that the endless combination of polymers and/or lipids using SCF methodologies allows the development of new delivery systems for more efficient nose-to-brain delivery of drugs. Due to the promising data and innovative results obtained in this dissertation, it is possible that the sustainable technologies used allied with the hybrid approach could play an especial role as pharmaceutical technology alternatives in the future.

 

President

  •  Dr. Maria Arménia Abreu Fonseca de Carvalho Teixeira Carrondo, Cathedratic Professor at Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Portugal.

Thesis Supervisors

  • Dr. Catarina Maria Martins Duarte, Scientific Researcher at Instituto Tecnologia Química e Biológica António Xavier, Universidade Nova Lisboa, Portugal.
  • Dr. Ana Alexandra Figueiredo Matias, Scientific Researcher at Instituto Biologia Experimental e Tecnologica, Portugal.
  • Dr. Soraya Rodriguez-Rojo, Scientific Researcher at Grupo de Investigación en Procesos a Alta Presión, Departamento de Ingeniería Química y Tecnología del Medio Ambiente, Universidad de Valladolid, Spain.

Thesis Examiners

  • Dr. María Concepción Domingo Pascual, Scientific Researcher at Institut de Ciència de Materials de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Universitat Autònoma de Barcelona, Spain.
  • Dr. António José Leitão Neves Almeida, Cathedratic Professor of Pharmaceutical Technology, Faculdade de Farmácia, Universidade de Lisboa, Portugal.
  • Dr. Manuel Luís de Magalhães Nunes da Ponte, Cathedratic Professor at Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Portugal.
  • Dr. Carlos Alberto García-González, Scientific Researcher at Farmácia e Tecnoloxía Farmacéutica, Facultade de Farmácia, Universidade de Santiago de Compostela, Spain.
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