Fabrication and loading of microcontainers for oral drug delivery

Oral drug delivery is considered as the most patient compliant delivery route. However, it faces many obstacles, especially due to the ever-increasing number of drugs that are poorly soluble and barely absorbed in the gastro-intestinal tract. Moreover, drugs can degrade in the harsh acidic environment of stomach before they reach the intestine. These issues lead to reduced bioavailability of active ingredients. To combat that novel oral drug delivery systems have been developed. Some of these systems that have gained significant interest in this field are reservoir based drug delivery microdevices. These microreservoir based-systems have dimension ranging from 10 μm to 500 μm. Additional functionalities are added to control the site and profile of drug release through mucoadhesive layers, asymmetric geometry and unidirectional drug release. Most of these devices have been fabricated using microfabrication methods with materials such as Si and photoresists. However, there is a need to shift from these materials towards biocompatible and biodegradable polymers such as poly-l-lactic acid (PLLA) or poly-e-caprolactone (PCL). Hot embossing is one of the most viable and matured methods to fabricate microstructures in such biopolymers. However, hot embossing is unable to produce discrete 3D microdevices due to the inherent problem of a residual layer that connects all the microdevices to each other. Therefore, hot punching which is combination of hot embossing and mechanical punching has been developed in this project. This process utilizes a stamp in connection with the ability to apply heat and pressure to transfer the stamp pattern to a film. Processes have been optimized for fabrication of nickel stamps with two layered, high aspect ratio microstructures. Bosch deep reactive ion etching of Silicon producing sloped sidewalls required for stamp production has been developed. The sloped sidewalls ensure a successful separation of stamp and film after patterning. High aspect ratio, 3D, discrete microcontainers in PLLA and PCL are fabricated using hot punching. High throughput and replication fidelity is achieved. Characterization of spin coating of drug-polymer films is thoroughly performed using microscopy, profilometry, differential scanning calorimetry, Raman spectroscopy, X-ray diffraction and microdissolution release tests. These films are applied for loading of microcontainers. Furosemide which is an important loop diuretic drug with low solubility and permeability is used as a model drug and embedded in a PCL matrix. The crystallinity of the drug is tailored by the process parameters of spin coating. Release profiles ranging from rapid burst release to sustained zero-order release are obtained by tuning spin coating. The hot punching technique is then applied for loading of microcontainers with the spin coated drug-polymer matrix. It has been demonstrated that hot punching is a fast, parallel, single step process that can load containers with high yield. Furthermore, the drug-polymer matrix loaded in the containers is characterized using the above mentioned techniques. Finally, zero-order sustained release of furosemide drug from microcontainers is successfully demonstrated.