Fabrication and in vitro in vivo evaluation of small polymeric devices for oral drug delivery

Oral dosage forms are the preferred solution for systemic treatment and prevention of disease conditions. However, the gastrointestinal (GI) tract presents many obstacles for successful drug delivery, including pH variations, enzymes, peristalsis and continuously regenerating mucus barriers covering the inner surface. This challenges the oral delivery of drug compounds, which are sensitive to degradation in these conditions and/or present poor permeability across the epithelial barrier.
Engineered ingestible devices have been exploited as carriers to overcome the challenges related to oral drug delivery. These polymeric devices could be classified based on their proximity to the GI epithelium for enhanced drug absorption. This includes mucus-embedding devices (via adhesive forces), mucus-penetrating devices (via mechanical forces) and GI auto-injectors. These approaches have shown promise for enhanced drug bioavailability due to their localized controlled drug release in close proximity to the epithelial barrier.
In this PhD thesis, the potential of different devices based on mucus-embedding and mucus-penetrating strategies to improve drug absorption is assessed. Additionally, methodologies are investigated for the production of suitable devices in this subject, ensuring drug encapsulation and controlled release. Mucus-embedding devices, such as microcontainers, are polymeric devices with a compartment for drug-loading until targeted unidirectional drug release. To assess sequential co-delivery, dual-compartment microcontainers (DCMCs) made in SU-8 were developed, which could be relevant for co-presentation of therapeutics and excipients that promote the drug absorption. As a proof-of-concept, the respective compartments were loaded with two model drugs, furosemide and propranolol, and coated with the pH-sensitive polymers Eudragit® S100 (ES100) and Eudragit® L100 (EL100). With this delivery system, we obtained a sequential release of the two drugs in vitro, and a difference in the absorption profile in vivo, according to the respective compartments. Microcontainers are commonly produced in SU-8, which is a biocompatible material, but it is relevant to scale up the production in biodegradable materials. A few approaches have been proposed for this purpose, but they present limitations regarding shapes and materials. Therefore, a novel scalable approach based on ultrasonic spray coating and microcutting is presented. Microcontainers were successfully producted in polycaprolactone (PCL) and poly(lactic-co-glycolic acid) (PLGA). After loading, the cavities were spray coated with Kollicoat® Protect (KPRO) or EL100 for targeted immediate or enteric drug release, respectively, which was confirmed in vitro and in vivo. Additionally, an enhanced drug uptake was observed from microcontainers compared to a powder suspension after oral dosing to rats.
Mucus-penetrating devices have shown a particular potential to enhance the absorption of poorly permeable drugs such as peptides, which often benefit from encapsulation to avoid acidic and enzymatic degradation. An example of these devices is self-unfolding foils (SUFs). SUFs consist of an array of microcontainers comprised in an elastic foil, which unfolds upon capsule disintegration in the GI tract. This allows intimate contact with the epithelium during drug release by the application of mechanical forces relying on the elastomeric properties of the foil material, polydimethylsiloxane (PDMS). To assess the drug encapsulation from SUFs in vitro, a model drug, paracetamol, was loaded and sealed with different pH-sensitive mixtures. Among all the coatings evaluated, Eudragit® EFL30D-55 (EFL) seemed the most suitable material in this respect. Finally, the impact of the distance between the device and the GI epithelium, and the incorporation of mucus-penetrating microneedles, on the drug permeation was assessed in vitro with biosimilar mucus (BM). It was observed that the proximity to the apical membrane enhanced the permeation of a model macromolecule. Nevertheless, the incorporation of mucus-penetrating microneedles s did not result in an improved effect.
In conclusion, this thesis highlights the potential of mucus-embedding and mucus-penetrating devices as a future strategy in oral drug delivery. This could be useful for the delivery of drug compounds that currently present a low bioavailability and are commonly delivered by other routes such as injections. Especially, if the presented platforms are intended to achieve an increased proximity and retention time in the GI epithelium. Future studies should include further research in the formulations utilized as well as further understanding of the device-epithelium interactions. One example of potential new formulations could be small peptide molecules and potential co-presentation with different excipients enhancing their absorption and/or inhibit the enzymatic degradation.