Planar bioadhesive microdevices: a new technology for oral drug delivery

Abstract

The oral route is the most convenient and least expensive route of drug administration. Yet, it is accompanied by many physiological barriers to drug uptake including low stomach pH, intestinal enzymes and transporters, mucosal barriers, and high intestinal fluid shear. While many drug delivery systems have been developed for oral drug administration, the physiological components of the gastro intestinal tract remain formidable barriers to drug uptake. Recently, microfabrication techniques have been applied to create micron-scale devices for oral drug delivery with a high degree of control over microdevice size, shape, chemical composition, drug release profile, and targeting ability. With precise control over device properties, microdevices can be fabricated with characteristics that provide increased adhesion for prolonged drug exposure, unidirectional release which serves to avoid luminal drug loss and enhance drug permeation, and protection of a drug payload from the harsh environment of the intestinal tract. Here we review the recent developments in microdevice technology and discuss the potential of these devices to overcome unsolved challenges in oral drug delivery.

Figure 1

A. Physiological barriers to oral drug delivery. After encountering digestive enzymes and the low pH of the stomach, drugs enter the small intestine, the primary site of drug uptake where drugs encounter additional metabolic and proteolytic enzymes. Drugs must then pass through the motile and adherent mucus layers, the cellular monolayer through either a paracellular or transcellular route and finally pass through the interstitium and basement membrane to enter the capillary from which they are shuttled to the liver before entering systemic circulation. B. Advantages of asymmetric microdevice design for oral drug delivery include 1) reduced shear force per mass, increasing residence time, 2) unidirectional drug release toward endothelial tissue, increasing drug permeation, and 3) sustained release, reducing drug exposure to the harsh conditions of the GI tract and decreasing drug degradation.

Figure 2

Photolithography-based techniques for microfabrication of multi-reservoir PMMA devices. A. PMMA and, subsequently, photoresist are spin-cast onto a silicon wafer. B. A circular pattern is transferred from a UV-blocking photomask to the photoresist through UV-induced cleavage. C. Reactive ion etching with oxygen plasma directionally destroys PMMA not protected by the photoresist pattern. D. Following photoresist removal and re-coating of a fresh resist layer, a reservoir-containing pattern is transferred to the photoresist by UV-exposure. E. Reactive ion etching is used to partially etch the PMMA layer to form drug reservoirs. F. Photoresist is chemically removed. Adapted with permission from [34].

Figure 3

Soft lithography-based techniques for microdevice fabrication. A. Microcontact printing can be utililized for fabrication of microdevices in regions of contact of PVA with micropillar stamp with subsequent dissolution of PVA in water for device release [59]. B. Fabrication of microdevices from recessed regions of microwell stamp. The stamp was brought into contact with glass to remove PPMA from non-microwell regions before bringing the remaining PPMA into contact with PVA [59]. C. Discontinuous dewetting utilized to selectively collect resin before UV-induced polymerization. Microdevices were then brought into contact with PVA with subsequent dissolution in water for device release. [56]. Adapted with permission.

Figure 4

Chemical and structural modifications to enhance microdevice adhesion and increase residence time. A. Fluorescence micrograph of FITC-lectin (green) asymmetrically coated onto the drug-releasing side of microdevices for targeted bioadhesion to the intestinal mucosa with fluorescently labeled BSA shown in blue [34]. B. Microdevices with microposts designed to penetrate the mucus membrane surrounding a drug reservoir [57]. C. Planar nanowire-coated microparticles dramatically increase surface area and enhance microdevice adhesion through increased non-covalent interactions [76]. D. Self-folding microdevices shown before (i) and after (ii) exposure to water are designed to mechanically attach to intestinal tissue [60]. Reproduced with permission.

Figure 5

Current techniques for drug loading of microdevices with images of drug-loaded devices for each approach. A. Photolithography can be utilized to selectively induce crosslinking of drug-laden hydrogels in device reservoirs [34]. B. Discontinuous dewetting utilizes a hydrophilic material to selectively collect drug solution in device reservoirs before the drying the solvent to load drug into the device reservoir [56]. C. Inkjet printing can be utilized to deposit droplets of drug solution into device reservoirs, which later dries, leaving solidified drug [100]. D. Supercritical impregnation first utilizes inkjet printing to deposit a polymer solution into device reservoirs. After drying, the polymer is exposed to drug dissolved in supercritical carbon dioxide gas, allowing for drug incorporation of hydrophobic drugs without the use of organic solvent [101]. All scale bars are 100 µm. Adapted and reproduced with permission.

Figure 6

Microdevices loaded with multiple drugs with separate release profiles. A. Fluorescent image demonstrating separate drug loading of each microdevice reservoir with device shape outlined in white. Scale bar is 100 µm. B. Custom release profiles for each drug controlled by hydrogel crosslinking density. Reproduced with permission from [34].