Single compartment drug delivery

Abstract

Drug design is built on the concept that key molecular targets of disease are isolated in the diseased tissue. Systemic drug administration would be sufficient for targeting in such a case. It is, however, common for enzymes or receptors that are integral to disease to be structurally similar or identical to those that play important biological roles in normal tissues of the body. Additionally, systemic administration may not lead to local drug concentrations high enough to yield disease modification because of rapid systemic metabolism or lack of sufficient partitioning into the diseased tissue compartment. This review focuses on drug delivery methods that physically target drugs to individual compartments of the body. Compartments such as the bladder, peritoneum, brain, eye and skin are often sites of disease and can sometimes be viewed as "privileged," since they intrinsically hinder partitioning of systemically administered agents. These compartments have become the focus of a wide array of procedures and devices for direct administration of drugs. We discuss the rationale behind single compartment drug delivery for each of these compartments, and give an overview of examples at different development stages, from the lab bench to phase III clinical trials to clinical practice. We approach single compartment drug delivery from both a translational and a technological perspective.

Keywords: Controlled release drug delivery; Local therapy; Microfabrication; Noninvasive; Single compartment; Targeted therapy.

Figure 1

Deployment of LiRIS® through a specially designed catheter-like inserter with 1 cm markings. The sequences are from (A) to (E). Two devices are shown in (F) with a 5 cm strip; the devices on the left and the right contain approximately 300 mg and 900 mg of mini-tablets, respectively.

Figure 2

Schematic diagram of IV and IP drug delivery routes. Weight of arrows illustrates relative rates. Adapted from [81].

Figure 3

Ovarian tumors preferentially metastasize to adjacent tissues throughout the peritoneal cavity. Reproduced with permission from [90].

Figure 4

Sketch Illustrating the irregular distribution resulting from CED infusion. The drug preferentially follows white matter tracts (illustrated in orange). B, C) T1 weighted MRI image after infusion of Gd-DTPA into pig brain. The infusion pattern has an irregular shape due to motion along lower resistance white matter tracts. Reproduced with permission from [129].

Figure 5

Drug delivery compartments in the brain. Drugs and compounds can partition in a variety of different compartments in the brain. Drugs need to reside in the intracellular or interstitial fluids in order to exert intended pharmacologic effects. Major drug clearance mechanisms from the sites of action include crossing the BBB into the systemic circulation or into the CSF where it makes its way into the venous blood pool. Line weight represents relative magnitude of traffic between each compartment. Adapted from [141].

Figure 6

Schematic of potential treatment approach utilizing multiple passive diffusion devices implanted using a large biopsy needle. Overlapping diffusion profiles (depicted in yellow) around the tumor dissection site could be used to achieve a larger drug distribution. Right image reproduced with permission from [144].

Figure 7

Diagram of the eye showing various ocular drug delivery approaches. Reproduced with permission from [148].

Figure 8

Various techniques to achieve dermal drug delivery. Reproduced with permission from [186].