Multi‐Reservoir Bioadhesive Microdevices for Independent Rate‐Controlled Delivery of Multiple Drugs

Abstract

A variety of oral administrative systems such as enterically coated tablets, capsules, particles, and liposomes have been developed to improve oral bioavailability of drugs. However, they suffer from poor intestinal localization and therapeutic efficacy due to the various physiological conditions and high shear fluid flow. Fabrication of novel microdevices combined with the introduction of controlled release, improved adhesion, selective targeting, and tissue permeation may overcome these issues and potentially diminish the toxicity and high frequency of conventional oral administration. Herein, thin, asymmetric, poly(methyl methacrylate); PMMA microdevices were fabricated with multiple reservoirs using photolithography and reactive ion etching. They were loaded with different individual model drug in each reservoir. Enhanced bioadhesion of the microdevices was observed in the presence of a conjugated of targeting protein; tomato lectin to the PMMA surface. As compared to drug encompassing hydrogels, an increase in drug permeation across the caco-2 monolayer was noticed in the presence of a microdevice loaded with the same drug-hydrogel system. Also, the release of multiple drugs from their respective reservoirs was found to be independent from each other. The use of different hydrogel systems in each reservoir showed differences in the controlled release of the respective drugs over the same period of release. These results suggest that in the future, the microfabricated unidirectional multi-drug releasing devices will have an impact over the oral administration of a broad range of therapeutics.

Planar Bioadhesive Microdevices: A New Technology for Oral Drug Delivery

“…Finally, to address the third major barrier to oral drug uptake - drug degradation, microdevices are fabricated to include drug reservoirs that allow for sustained release of drug, thereby decreasing the exposure of drugs to harsh conditions of the GI relative to a bolus dose [26]. With a variety of sustained drug release systems developed in the recent past for oral delivery including pH-sensitive hydrogels [30–32], enteric coating [33], and degradable polymers, well established microfabrication techniques can be effectively used to incorporate microdevice reservoirs with these drug systems [27, 34–36]. …”

“…In order to overcome this issue, microdevice fabrication shifted towards the use of relatively non-toxic polymers, including hydrogels and biodegradable materials. Poly(methyl methacrylate) (PMMA), an FDA-approved polymeric material [47] used in contact lenses and bone cement and also known to be stable at low pH values [26], has been utilized in numerous oral microdevice designs [34–35, 48–51]. Microdevices have also been fabricated from SU-8, an epoxy-based negative photoresist originally developed as an ultra-thick photoresist [36, 52].…”

“…The use of micro- and nanofabrication techniques for biological applications has been reviewed in detail elsewhere [63–65], but this review will highlight a selection of techniques that are particularly useful for oral microdevice fabrication. Many studies to this date have utilized conventional photolithography techniques originally developed by the microchip industry for the fabrication of microdevices [27, 34, 36, 40, 50–52, 62, 64–67]. Photolithography involves selective UV exposure of a photosensitive material, termed a photoresist, and is often followed by an etching step to transfer the photoresist pattern to a substrate.…”

pH-triggered drug release from biodegradable microwells for oral drug delivery

“…Innovative drug delivery systems have the potential to facilitate an improvement in oral bioavailability compared to current drug formulations. Novel approaches such as mucoadhesive gastrointestinal (GI) patches and micro fabricated devices have been suggested as oral delivery systems for drug compounds (Chirra and Desai 2012;Colombo et al 2009;Eaimtrakarn et al 2001). In particular, microfabricated wells have been proposed as promising oral drug delivery systems (Ahmed et al 2002;Ainslie et al 2009;Tao et al 2003).…”

“…This allows for unidirectional drug release, and also for protection of the drug in harsh environments, such as that occurring in the stomach (Ahmed et al 2002;Ainslie et al 2009;Eaimtrakarn et al 2001;Tao et al 2003). Microwells have previously been fabricated using various materials, including silicon (Ahmed et al 2002), poly(methyl methacrylate) (Chirra and Desai 2012;Tao and Desai 2005) and SU-8 (Tao and Desai 2007). The authors have previously presented processes for fabrication of microstructured wells using the polymers polycaprolactone (PCL) and poly-L-lactic acid (PLLA) (Nagstrup et al 2011).…”