Progress in intra-articular therapy

Abstract

Diarthrodial joints are well suited to intra-articular injection, and the local delivery of therapeutics in this fashion brings several potential advantages to the treatment of a wide range of arthropathies. Possible benefits over systemic delivery include increased bioavailability, reduced systemic exposure, fewer adverse events, and lower total drug costs. Nevertheless, intra-articular therapy is challenging because of the rapid egress of injected materials from the joint space; this elimination is true of both small molecules, which exit via synovial capillaries, and of macromolecules, which are cleared by the lymphatic system. In general, soluble materials have an intra-articular dwell time measured only in hours. Corticosteroids and hyaluronate preparations constitute the mainstay of FDA-approved intra-articular therapeutics. Recombinant proteins, autologous blood products and analgesics have also found clinical use via intra-articular delivery. Several alternative approaches, such as local delivery of cell and gene therapy, as well as the use of microparticles, liposomes, and modified drugs, are in various stages of preclinical development.

Figures

Figure 1

How soluble molecules get into and out of joints. Macromolecules in the circulation enter the joint via the synovial capillaries and are sieved by the fenestrated endothelium of the capillaries (see figure 2). Small molecules also enter via the capillaries, but the major resistance to their entry is provided by the ECM of the synovial interstitum. Intra-articular injection by-passes both of these constraints to entry. However, both large and small molecules rapidly exit the joint via the lymphatics and small blood vessels, respectively

Figure 2

Concentration ratios of proteins between serum and synovial fluid. Entry of macromolecules into the synovial fluid from the systemic circulation is normally impeded as a function of molecular size (see also Figure 1)