Controlled release for local delivery of drugs: barriers and models

Abstract

Controlled release systems are an effective means for local drug delivery. In local drug delivery, the major goal is to supply therapeutic levels of a drug agent at a physical site in the body for a prolonged period. A second goal is to reduce systemic toxicities, by avoiding the delivery of agents to non-target tissues remote from the site. Understanding the dynamics of drug transport in the vicinity of a local drug delivery device is helpful in achieving both of these goals. Here, we provide an overview of controlled release systems for local delivery and we review mathematical models of drug transport in tissue, which describe the local penetration of drugs into tissue and illustrate the factors - such as diffusion, convection, and elimination - that control drug dispersion and its ultimate fate. This review highlights the important role of controlled release science in development of reliable methods for local delivery, as well as the barriers to accomplishing effective delivery in the brain, blood vessels, mucosal epithelia, and the skin.

Keywords: Controlled release; Local delivery; Pharmacokinetics; Polymer systems; Wound healing.

Figure 1

Mechanisms of transport and elimination of an agent during controlled release from a polymeric device into a local region of tissue. The solid circles represent the therapeutic agent and the arrows represent the modes of transport and reactions that occur after release from the device (top). Release from a controlled release device to the extracellular space (ECS) (arrow a), diffusion through the tortuous ECS due to concentration gradients (b), convective movement in the interstitial fluid within the ECS (c), internalization by a cell via passive, active, or facilitated transport to the intracellular space (ICS), which involves crossing through the cellular membrane (CM) (d), metabolism within the ECS (e), metabolism within a cell (f), diffusion across the semipermeable capillary walls (g), and the subsequent systemic transport or elimination via the capillary blood flow (h).

Figure 2

Concentration of an agent as a function of distance from the controlled release device, where transport of the agent depends on diffusion only with first-order elimination under steady state conditions. Each curve represents a different value of the modulus Ø, from 0 to 30: if L = 1 cm and D is 10⁻⁷ cm²/s, a typical diffusion coefficient for an agent in tissue (see Chapter 4 of [46]) these modulus values correspond to k values of 0 (no elimination), 10⁻⁸, 10⁻⁶, and 10⁻⁴ s⁻¹.

Figure 3

Concentration profiles in the vicinity of a BCNU- releasing polymer implant. Autoradiographic techniques were used to obtain the experimental results (open circles). These experimental data were compared to model predictions, represented by the solid lines, obtained from steady-state diffusion/elimination or transient diffusion/convection models. Adapted from Saltzman [46].

Figure 4

The extent of agent penetration into a tissue as a function of the agent’s properties. This prediction is based on a one-dimensional model in a rectangular coordinate system, but can be extended to other geometries [43].

Figure 5

Predicted heparin penetration through an arterial wall after release from a perivascular controlled release device. The device is on the adventitial side of the artery. Here, Eq. (6) was used to simulate heparin concentrations assuming no convection (v = 0) and no elimination (k = 0). Appropriate boundary conditions allowed the investigators to predict heparin concentrations in the tissue as a function of time, and interpret experimental data on the biological response of the tissue to heparin delivery. Adapted from Lovich and Edelman [79], with permission.

Figure 6

Mechanisms of transport and elimination of an agent during controlled release from a drug-eluting stent implanted in an artery. The solid circles represent the therapeutic agent and the arrows represent the modes of transport and reactions that occur after release from the device’s struts. Release from a controlled release device to the extracellular space (ECS), either the intima, media, or lumen (arrow a), diffusion through the ECS due to concentration gradients or convective transport (b), partition from intima to media (c), metabolism within a cell (d), drug may be bound by protein binding in vessel wall (e) partition from media to adventitia (f), and the subsequent systemic transport or elimination from the adventitia (g).

Figure 7

a) An example of numerical modeling of local drug release from the struts of a drug-eluting stent. Each of the white circular regions in the main image represents a stent strut, which is surrounded by vascular tissue. The lines indicate the mesh structure that is generated for numerical modeling of transport in the tissue surrounding the struts. The top image shows the global mesh and the zoomed image below shows more detail of the mesh resulting from the tighter spatial mapping adjacent to each strut. Adapted from Mongrain et al. [90], with permission. b) Geometry of a polymer-coated strut, partially embedded in an idealized arterial wall. Adapted from Zhu et al. and Davia et al. [91, 94].

Figure 8

a) Schematic of compartmental model for antibody biodistribution after local controlled release from a vaginal ring. b) Predicted concentrations for antibody in the vaginal mucus (top) and blood (bottom) as a function of rate of release from the vaginal ring (the diffusion coefficient for antibody diffusion in vaginal ring—the controlling parameter for antibody release—varied from 0.3 to 30 × 10⁻⁹ cm²/sec). Adapted from Saltzman et al. [39]

Figure 9

Antibody penetration through the vaginal epithelium depends on diffusion. These plots compare local antibody concentrations, measured by autoradiography, to steady-state solutions of the transport equations, as in Eq. (9), which are shown as solid lines. Concentrations measured in tissues from the nine mouse experiment at 16, 24, or 48 hr after insertion of an antibody-loaded vaginal ring are shown as open squares. Distance into tissue was measured relative to the tissue/mucus interface. Redrawn from original data presented in Kuo et al. [98].

Figure 10

Mechanisms of drug transport and elimination during controlled release from a topical device on the skin. The solid circles represent the therapeutic agent and the arrows represent the modes of transport and reactions that occur after release from the device. Release and subsequent diffusion via transcellular, intercellular, or follicular routes (arrow a) to the extracellular space (ECS), drug may be reversibly bound by protein binding (b), diffusion through the ECS due to concentration gradients or convective transport (c), metabolism within a cell (d), partition through tissue layers (e), and the subsequent systemic transport or elimination (f). The thickness of the stratum corneum is represented by H.