Mucoadhesive microcontainers for oral drug delivery

Oral administration is the preferred administration route by patients and is often associated with high patient compliance. The oral route is a challenging administration route as the gastrointestinal tracts physiological properties often hampers drug absorption. Microcontainers as a drug delivery system have been introduced to improve oral absorption of drugs. Microcontainers are cylindrical micrometer-sized reservoirs, facilitating unidirectional drug release. The unidirectional drug release of the microcontainers is believed to enhance absorption, as the drug can be delivered directly into the mucosa. It has been shown that microcontainers embed themselves into mucus in the small intestine, which might explain the enhanced oral bioavailability of drugs. The characteristics of the unidirectional release and the microcontainers behavior in mucus require investigated, in order to clarify their effect on drug absorption.
In this work, we explore the microcontainers behavior in the small intestine in relation to mucoadhesion and their orientation of unidirectional drug release. Different mucoadhesion strategies have been investigated in this PhD project, including microcontainers with different functionalized polymers, surface topography and morphology. The strategies have been evaluated in relation to mucoadhesion, impact on unidirectional drug release and how the drug release profile is affected. In order to determine the impact of different strategies on mucoadhesion a new ex vivo perfusion setup was developed, to enable evaluation of the microcontainers behavior in the small intestine. A texture analyzer was used to determine the adhesion forces of different topographies. From repeating measurements it was observed that the force measurements were strongly affected by disturbing factors such as tissue variations and the time interval between measurements. A statistical design was then developed in order to correct for the disturbing factors and enable a reproducible and reliable evaluation of the topographies adhesion force to mucosa. Microcontainers are fabricated in epoxy-based SU-8 and therefore not suitable for oral intake. For this reason, fabricating microcontainers in biocompatible and biodegradable polymers has been crucial to demonstrate the versatility of microcontainers. In this PhD, I investigated the impact of using different polymeric materials for microcontainers, in relation to their behavior in the small intestine, including mucoadhesion, orientation and degradation.
This thesis presents novel experimental models and validation strategies to improve investigation of mucoadhesive microcontainers. This approach led to a number of interesting conclusion. First and foremost, this work attests to microcontainers strong ability to adhere to mucosa, with only minor improvements observed when varying the size, shape and material of the microcontainer. Interestingly, applying mucoadhesive polymers onto the microcontainers cavity shows great potential for improved adhesion to mucosa ex vivo. Additionally, we were able to conclude that biodegradable and biocompatible microcontainers fabricated in poly(lactic-co-glycolic acid) (PLGA) and poly-ε-caprolactone (PCL) show similar adhesion to the mucosal lining as the SU-8 fabricated microcontainers. While the results indicated a slightly stronger ability to adhere for SU-8 microcontainers compared to the biodegradable and biocompatible microcontainers, this was not supported statistically.
The overall conclusion is that, microcontainers show strong adhesion to mucosa and modifying the microcontainers in terms of functionalized polymeric coatings and varying morphology appears to only show minor improvements of the abilities to adhere to the mucosal surface in the small intestine.