New molecule-based nanostructured drug carriers prepared using compressed fluids

Resumen

In the past 30 years, the explosive growth of nanotechnology has promoted challenging innovations in pharmacology, which is currently revolutionizing the delivery of biologically active compounds. Indeed, some existing drugs and new therapeutic compounds emerging from drug discovery processes present special delivery challenges, pushing nanotechnology towards the development of new drug nanocarriers that enhance the bioavailability of drugs. Such nanocarriers, of which vesicles and polymeric particles are probably the most thoroughly studied, are intended not only to protect drugs from degradation but also to achieve their temporal and spatial site-specific delivery. Although having proved to be more efficient than conventional treatments involving the use of free drugs, the employment of such sophisticated formulations as daily therapies depends on the development of efficient and environmentally respectful technologies that allow their industrial manufacturing with controlled structural characteristics. Compressed fluid (CF)-based methodologies, which emerged in the early 90's as an alternative to the use of conventional liquid solvents in the production of micro- and nanoparticulate materials, have been recently exploited for the preparation of diverse drug nanocarriers. Reduced use of harmful organic solvents, lower temperatures, less operational steps, easier scale-up and more uniform products are some of the advantages offered by these emerging technologies. Indeed, the special characteristics of CFs, between those of liquids and gases, enable the straightforward achievement of materials with high degree of structural homogeneity, which is of vital importance for optimum performance of functional materials, such as vesicles and polymeric particles as drug nanocarriers. Combining the enhanced performance of the emerging formulations for drug delivery with the enormous potential that CF-based technologies present for their processing at large scale, this Thesis has been devoted to expand the goodness of such methodologies for the preparation of drug nanocarriers, based on vesicles and nanostructured polymeric particles. Moreover, the capability of these processes for controlling supramolecular organization in non-crystalline ordered molecular materials has also been analysed. Concretely, the first part of this work has been focused on the comparison of the structural characteristics of a vesicular system prepared by DELOS-susp, a CF-based method, and a conventional multi-step process usually employed for the production of liposomes. The superior homogeneity presented by vesicles prepared using DELOS-susp has been confirmed not only in terms of size and morphology, but also regarding the membrane supramolecular organization of these self-assembled entities. In a further step towards the application of DELOS-susp for the production of drug-loaded vesicular systems, the second part of the present Thesis was dedicated to studying the feasibility of this CF-based process for the encapsulation of water-soluble drugs inside small unilamellar vesicles. Using gentamicin sulphate as a poorly bioavailable model drug, DELOS-susp proved to be a scalable method for the one-step production of gentamicin-loaded small unilamellar vesicles. Profiting from the goodness of CF-based processes for the production of micro- and nanoparticulate materials, the last part of this Thesis was devoted to the preparation and in depth characterization of nanostructured polymeric microparticles to be used in drug delivery. This work explored, for the first time, the suitability of CF-based methods for the processing of bioadhesive and biodegradable poly (methyl vinyl ether-co-maleic anhydride), PVM/MA, which presents good properties for oral drug delivery. PVM/MA-based nanostructured microparticles either non-, or highly gentamicin-loaded, were successfully prepared using CFs, providing a new platform for processing actives to be orally delivered.