Planar microdevices for enhanced in vivo retention and oral bioavailability of poorly permeable drugs

Abstract

The development of novel oral drug delivery platforms for administering therapeutics in a safe and effective manner through the harsh gastrointestinal environment is of great importance. Here, the use of engineered thin planar poly(methyl methacrylate) (PMMA) microdevices is tested to enhance oral bioavailability of acyclovir, a poorly permeable drug. Acyclovir is loaded into the unidirectional drug releasing microdevice reservoirs using a drug entrapping photocross-linkable hydrogel matrix. An increase in acyclovir permeation across in vitro caco-2 monolayer is seen in the presence of microdevices as compared with acyclovir-entrapped hydrogels or free acyclovir solution. Cell proliferation studies show that microdevices are relatively nontoxic in nature for use in in vivo studies. Enhanced in vivo retention of microdevices is observed as their thin side walls experience minimal peristaltic shear stress as compared with spherical microparticles. Unidirectional acyclovir release and enhanced retention of microdevices achieve a 4.5-fold increase in bioavailability in vivo as compared with an oral gavage of acyclovir solution with the same drug mass. The enhanced oral bioavailability results suggest that thin, planar, bioadhesive, and unidirectional drug releasing microdevices will significantly improve the systemic and localized delivery of a broad range of oral therapeutics in the near future.

Keywords: acyclovir; oral bioavailability; oral drug delivery; planar microdevices; retention.

Figure 1

a) Schematic representation of the advantages of using thin, planar microdevices over symmetric microparticles of same surface area—microdevices experience lower intestinal shear stress, release drug unidirectionally toward the epithelia, and can release multiple drugs independently and b) a scanning electron microscopic image of a microdevice loaded with acyclovir entrapping hydrogel in its reservoirs. The scale bar represents 50 µm.

Figure 2

The enhanced permeation of acyclovir-loaded microdevices as compared with its respective acyclovir-loaded hydrogel bolus (control: without devices) and conventional oral acyclovir solution through a caco-2 epithelial monolayer on collagen-treated Transwells (N = 3).

Figure 3

In vitro MTT viability data showing that both empty and acyclovir-loaded microdevices are nontoxic in nature as compared with negative control DMSO (N = 3).

Figure 4

In vivo mouse study showing the enhanced retention of thin, planar microdevices in the upper portion of the small intestine as compared with spherical microparticles of same surface area, which are pushed downstream to the colon by the high intestinal shear fluid flow. Also shown, is the further enhancement of retention by using bioadhesive lectin onto microdevices (N = 3).

Figure 5

Pharmacokinetic plot showing the increased in vivo bioavailability of acyclovir using microdevices as compared with an orally gavaged solution of same acyclovir concentration. Enhanced microdevice retention/drug residence time and increased drug permeation from microdevices result in increased oral bioavailability. Also shown for comparison, is the pharmacokinetic profile of a 5× concentrated (4 mg kg⁻¹) solution of orally gavaged acyclovir (N = 3).