Abstract

Combination products, which comprise a medical device and a drug or a medical device and a biologic agent(s), represent a new trend in implantable therapeutics that is drawing a lot of interest from both the pharmaceutical industry and medical device companies. Many drug–device combination products, such as drug eluting stents, antimicrobial central venous catheters, and orthopedic device-based drug delivery systems, have demonstrated clinical success and result in a significant improvement in the quantity of patients’ life. This chapter describes the various types of drug–device combination products, focusing on the technology and the benefits underlying the development of these products.

Key words

combination products

drug enhanced devices

device-based drug delivery systems

technology utilization

benefits

1.1 Introduction

Combination products (drug–device, biologic–device or drug–device–biologic), supported by their powerful demonstration of clinical success, are emerging as a trend in implantable therapeutics and gaining increasing attention from both pharmaceutical and medical device companies as a strategy to overcome some long-standing clinical problems involving complications associated with conventional medical devices. According to the US Food and Drug Administration’s (FDA) definition, combination products comprise two or more regulated components that are either physically or chemically combined or mixed [1]. These components can be produced as a single entity, or otherwise two or more products can be packaged together as a unit in a single package. Based on the classification of their components, combination products can be categorized into four groups: traditional drug delivery systems, novel drug delivery systems, drug-enhanced devices, and regenerative medical products [2].

This chapter elaborates on the various types of drug–device combination products, focusing on the technology and the benefits underlying the development of drug–device combination products. The chapter is divided into three major sections: (1) rationale for drug–device combination applications; (2) drug-enhanced devices; and (3) device-based drug delivery systems. The first section involves a comparison between conventional drug administration and local drug delivery. The rationale for and benefits of drug–device combination products design are discussed. Different drug-enhanced devices and device-based drug delivery systems, the combination technologies used as well as the advantages and disadvantages of these products are discussed in the second and third sections.

1.2 Rationale for drug–device combination applications

In recent years, various medical devices (stents, biosensors, catheters, scaffolds for tissue engineering, endotracheal tubes, heart valves, vascular grafts, etc.) have been developed for implantation into patients to enhance as well as increase the efficiency of treatment. However, implanted medical devices induce foreign body responses that start with an acute inflammatory response, then turn into a chronic inflammatory phase, and finally the whole device becomes encapsulated by fibrosis [3]. Besides the foreign body response, acute or chronic infections associated with the device application are of great concern as in addition to the serious risk to patients, such infections decrease the efficacy and functional lifespan of the device [4–6]. Usually, device-associated infections are bacterial and can occur by different mechanisms: (i) contamination from the local environment, the skin, instruments used for or the procedure of device implantation; (ii) injury caused by device implantation, which instantly induces inflammation and edema, so altering the microenvironment and causing it to become suitable for bacterial growth and create a biomaterial–tissue interface that promotes adherence of bacteria to the device surfaces [6]. Both ‘foreign body responses’ and ‘device associate infection’ can cause device failure.

In order to ensure patient safety and device functionality, drug therapy is being used in combination with medical devices. To be effective in controlling the implantation site, the ideal drug therapy should provide effective drug doses with continuous drug release to the target site over prolonged durations (necessary to treat infection and/or control inflammation and fibrosis). Conventional drug therapy, administered intravenously, intramuscularly, subcutaneously, or orally (most common) usually does not maintain drug concentrations within the desired concentration at the target site for extended periods, since the drug is distributed systemically. In addition, conventional drug therapy can result in unwanted systemic side effects.

Compared with conventional drug administration, a local drug delivery system requires lower drug doses, increases bioavailability, can achieve extended durations of release, avoids systemic drug exposure, and hence offers better control over toxicity, and in the case of antibiotics reduces susceptibility to promoting antibiotic resistance. Accordingly, drug–device combination products have been designed in a coordinated strategy using local drug delivery to represent a promising new opportunity, which offers greater therapeutic benefits than drugs or devices acting alone. Drugs are released from the surfaces of the devices at the implantation site, for direct mitigation of device-associated infection and inflammation and this strategy also provides the possibility to combine both local and systemic drug delivery. Drug–device combination products can improve the acceptance and functional life of implantable devices, as well as reduce drug toxicity and side effects via local drug delivery. The manufacture and production of a qualified drug–device combination product requires consideration of issues, such as the dimensions of the device, physicochemical properties of the drug and excipients, which vary from device to device. More details of different drug–device combination products are provided in the following two sections.

1.3 Drug-enhanced device products

1.3.1 Drug eluting stents

The first stent – an expandable metal mesh in a tube form or ‘scaffold’ – was brought about to prevent vessel recoil associated with balloon angioplasty for the treatment of occlusive coronary artery disease in 1977. Since this first clinical introduction, the utilization of bare metal stents has been limited by the occurrence of re-blockage (restenosis) in about 10–50% of cases, which necessitates a repeat procedure. Moreover, the efficiency of most systemically administered drugs intended to prevent in-stent restenosis is disappointing, and this is generally due to poor drug bioavailability, insufficient drug concentration and toxicity at the target site [7]. Therefore, therapy has moved away from these purely mechanical devices toward testing and optimization of novel drug eluting stents (DES), a technology that combines stents with medication that is slowly eluted to overcome restenosis. The aim of this new combination product is to inhibit the growth of scar tissue in the artery lining as well as to prevent the inflammatory response, which are the main causes of in-stent restenosis.

Generally, a DES consists of three main components: (1) the stent backbone that carries the drug coating; (2) the drug that prevents restenosis; and (3) a polymer carrier from which the drug is eluted. The first DES was invented by J&J, in early 2000. Even though the clinical history is relatively short, DES have already produced a significant clinical impact. Since there are several different biologic responses involved in the restenosis process, it is very critical to deliver sufficient drug over the required timeframe. Since the pharmacokinetic profile of drugs released from stents is impacted by various factors, it is imperative to fully understand these factors (such as the physicochemical properties of the drug, the effective therapeutic drug concentration, the duration of drug release from the polymer coating, and interactions between the polymer carriers and drug). It is also very important to fully understand how to properly utilize the available controlled drug delivery technologies and to understand the mechanism of controlled drug release. A qualified DES should be capable of withstanding processing, including sterilization during manufacturing and should maintain its mechanical integrity throughout storage and clinical deployment.

Currently, there are four drugs that have been approved by the FDA for use in DES: sirolimus (rapamycin) and paclitaxel that work by inhibiting smooth muscle cell proliferation and migration, as well as zotarolimus, and everolimus that are immunosuppressive drugs. All of these drugs have demonstrated beneficial effects in clinical trials. Recently, a variety of different types of drugs, including vascular...