Author(s): Azevedo, Cristiana Maria Rodrigues de
Date: 2017
Persistent ID: http://hdl.handle.net/10362/27866
Origin: Repositório Institucional da UNL
Subject(s): Controlled Drug Release; Burst; PLGA; nano- and microparticles; rational design; modeling; Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química
The controlled release of a drug from a carrier into a medium over a defined period of time is referred to as Controlled Drug Release (CDR). A major challenge for a sustainable and reproducible CDR is the unintentional initial burst, which occurs in the first hours/days of immersion and during which a large amount of drug is released. Also it can have deleterious effects on the host. Burst release happens with both small drug molecules and large proteins and for both drug-loaded PLGA micro- and nanoparticles. Particle design can, in principal, be used to control the amount of burst but no systematic methods are to date available and the design process is governed by trial and error. One reason might be that the available models for burst release do not explicitly account for the particle design parameters. This thesis proposes novel methodologies that allow for rational design of drug-loaded PLGA micro- and nanoparticles. It is divided in three main parts. Firstly, a quantitative analysis of the physicochemical factors that impact on the amount of burst release and the burst release rate using partial least squares and decision tree methods is performed. The factors with the greatest impact are selected for the subsequent modelling activities. Next, a bootstrap aggregated hybrid model (HM) is developed, which can successfully predict the cumulative drug release of an independent set of CDR experiments. Lastly, a new rational design method is presented for the optimization of the formulation characteristics of protein-loaded PLGA nanoparticles. The method is successfully applied to design the carrier of a mock-protein, α- chymotrypsin, yielding a close to desired release profile. The method can also help to judge upon the similarity of the mock protein with a target protein in terms of their similarities in burst release behavior. This thesis proposes the first rational PLGA particle design method requiring only the specification of the drug and the desired burst release profile. The application of the method can be expected to significantly reduce the time for PLGA particle development. With the increasing availability of CDR data the predictive power of the method can be further improved towards a systematic and reliable tool. The engine of the method is the hybrid model which links the release profile to the design parameters and is the first of its kind in drug release modeling.
