Mechanisms of controlled drug release from drug-eluting stents☆
Introduction
A stent is a small, expandable wire mesh in a tube form that is used to maintain an artery open after balloon angioplasty. Stent implantation, however, tends to cause injury to the blood vessel resulting in neointimal proliferation, known as in-stent restenosis, which continues to hamper initial procedural success in 10% to 50% of patients undergoing coronary intervention [1], [2], [3]. Recently, the concept of using coronary stents for localized delivery of antiproliferative drugs with programmed pharmacokinetics has emerged as an appealing solution to overcome the restenosis problem [4], [5], [6]. The aim of such localized drug delivery is to control, or reduce, smooth muscle cell growth and migration as well as to prevent inflammatory response, which are the predominant causes of neointimal proliferation and in-stent restenosis [7].
Localized drug delivery from drug-eluting stents (DESs) has been shown to be quite effective and accepted as one of the most promising treatment methods for preventing restenosis after stenting procedures. DESs ensure maximum delivery of the pharmacological agent directly to the target site, since they are in immediate contract with the coronary artery wall [8]. The DES approach has several advantages. Biologically active agents can be directly delivered to the target site, resulting in therapeutically effective drug concentrations in the surrounding tissues with the minimal systemic release of the drug and thus, negligible risk of systemic toxicity [9], [10].
Despite its relatively short history, DESs have already made seminal impacts in the interventional cardiology. While a few DESs are clinically available, many more DESs are expected to be developed in the near future. Currently, only two drugs, sirolimus and paclitaxel, are used in DESs approved by the Food and Drug Administration. There are many other drugs that are potentially useful for treating restenosis. Selection of a controlled drug delivery technology suitable for each drug depends on many factors, including physicochemical properties of the drug, duration of release and the release profiles. It is important to understand the currently available drug delivery technologies and how they can be applied to optimize the existing DESs and to develop new DESs. This article reviews the current DES formulations and their drug release kinetics, so that it can serve as a useful source of information for those who are involved in the DES area.
Section snippets
Drug delivery mechanisms
To appreciate the technologies associated with the current DESs and to develop new formulations, it would be beneficial to briefly review the drug delivery technologies. The controlled release technologies have been advanced during the last four decades. As a result, hundreds of commercial products have been developed based on the controlled drug delivery technologies. Despite such a large number of clinical products, there are only several distinct mechanisms for controlled drug release. Many
Drugs used in controlling restenosis
The drugs that are released from DESs are expected to inhibit inflammation and neiointimal formation after stent implantation. Since the inflammatory and proliferative responses are results of the complex cascade of events, various cells and tissue components involved in the vascular reparative process are all potential targets of therapeutic approaches [20]. For this reason, various drugs with widely different properties can be used for the same purpose of reducing neointimal proliferation [21]
Coating strategies for prevention of restenosis
Many different approaches have been used for drug delivery from stents, and the duration of drug delivery has been varied. It has been suggested that vascular smooth muscle cells start proliferation only a day after the injury resulting from balloon angioplasty/stent deployment for about 2 weeks [25]. Thus, it is believed that antirestenotic drugs need to be delivered for at least 3 weeks after stent deployment to prevent smooth muscle cell migration and proliferation [26], [27]. It is
Coating strategies for improving biocompatibility
In addition to prevention of restenosis, another important requirement of DESs is absence of inflammation and thrombogenicity [20], [21]. Selection of noninflammatory, nonthrombogenic coating materials has been a major obstacle in the development of DESs. This problem has been compounded by the possibility that delivery of unnecessarily high drug dose may result in delayed wound healing and endothelialization, which would increase thrombogenicity. The Cypher stent and the Taxus stent, the two
Some issues in the development of drug-eluting stents
Drug delivery from stents has become a very important research area that has shown immediate, huge benefits in clinical applications. The fact that there are a few DESs in clinical applications should not mask the importance and need of continued research on drug delivery from stents. There are still a few issues to be resolved in the development of DESs.
Summary
Despite the phenomenal advances in stent design, incidence of restenosis of bare metal stents remains unacceptably high. The interventional cardiology has been rapidly evolving and DESs have emerged as a breakthrough technology. The localized delivery of a drug directly to the target site resulted in prevention of restenosis without side effects associated with systemic delivery of the same drug at much higher concentrations. A number of different controlled drug delivery technologies can be
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Drug-Eluting Stents: an Innovative Multidisciplinary Drug Delivery Platform”, Vol. 58/3, 2006.