Preface
Ask not only what devices can do for drugs or what drugs can do for devices; ask also what new things that drugs and devices can do together.
Drugs treat diseases through chemical reactions. Devices treat diseases through physical actions. The differing technical challenges in developing molecules and macroscale devices are obvious. As such, drugs and medical devices have traditionally been developed and used separately. Pharmaceutical companies and device manufacturers operate in different markets and with different goals and business models. Whereas drug companies tend to focus on blockbuster products that are administered repetitively to patients, many medical devices, especially implants, involve long-term use of a single unit. Pharmaceutical companies can expect a relatively long period of profit from a successful drug, as there are few ways to "upgrade" therapy based on a particular molecule, and it is difficult to predict the success of related molecules. Generally speaking, all drugs must go through the same discovery, development, and approval process. Devices, on the other hand, either must undergo a full cycle of research, development, and approval if they are the first of their kind on the market, or they represent incremental changes to predicate products. It is a constant effort for devices to remain at the cutting edge, and many products can only maintain their market share for relatively short periods.
The regulatory paths for the two kinds of therapies have traditionally been separate, with differing sets of hurdles to overcome. Whereas any new drug must be considered on its own, and undergo an exacting and expensive set of phases of study, the path for approval of a device is somewhat less arduous if it is shown to be related to similar products that are already on the market. Original devices, especially those that could have impacts on patients' safety, however, require thorough studies to be performed to win premarket approval. Devices often have numerous components, all of which are subject to extensive studies in order to control and minimize possible mechanical, biocompatibility, electrical, or chemical failure modes following implantation.
Recently, there has been a trend toward drug-device convergence. A number of drug-device combination products have been developed to enable or enhance each other's functions and achieve improved or even new therapies. During 2008-2012, over 1000 new applications of combination products were submitted to U.S. FDA for review, all having drug or biological delivery components. Currently, these types of products represent a market of tens of billions of dollars. However, the definition of drug-device combination products has not been clear. Typically, it refers to products containing both drug and device components that act in concert to achieve functions that otherwise are difficult or impossible to achieve by either component alone. Such synergy is needed to justify the effort in producing combination products.
Drug-device combination products are recent innovation, but drug delivery products can be tracked back to tablet, capsules, and syringes that have long been used and may be considered as early "devices." While these products are still dominant as means for administering drugs, their utility, if not their design, is rather straightforward. Advanced drug delivery for improved efficacy, low toxicity, and convenient uses started in the 1960s. With advances in bioanalytical chemistry and the mathematical and physiological understanding of pharmacokinetics and pharmacodynamics, and the recognition of localized receptors as sites for drug action, it became clear that targeted delivery of drugs could improve therapy and reduce unwanted side effects. Of particular interest was control of the rate and locale of drug release. Rate control could smooth the concentration profile of drug in the blood over time, maintaining drug concentration within its "therapeutic window," wherein the drug is efficacious and nontoxic. On the other hand, release rate could be modulated by need, as in the case of insulin, which should be delivered in concert with intake of carbohydrate. By controlling the location of delivery, the drug could be focused at the site of action and hopefully avoid issues associated with toxicity. Moreover, direct delivery could lessen drug degradation that occurs as it passes through the harsh environment of the gastrointestinal tract and the liver (first pass metabolism).
Based on these considerations, devices designed specifically for drug delivery were developed. Such devices include implantable and externally worn drug pumps, transdermal patches, implantable drug-loaded tubes or rods, injectable drug depots, implantable and resorbable drug-loaded polymer wafers, drug-eluting eye inserts and intrauterine devices, devices for intranasal and inhalation delivery of liquids and dry powders, and a diverse collection of pen injectors, microneedle arrays, and buccal patches. Besides these innovative methods of delivery, there has been a steady improvement in traditional drug delivery devices. For example, syringe needles are now so sharp that they are much less painful, and extended release tablets, capsules, and other oral drug delivery "devices" such as osmotic pumps have stabilized and improved the therapeutic value of drugs. IV catheters can be directed to very specific sites, such as the loci of embolisms, where local administration of streptokinase or tissue plasminogen activator can dissolve the clots.
A more recent development has been the utilization of drugs to improve the function of implanted devices. The "trivial" way to do this is to administer drugs systemically, including antibiotics, blood thinners, and anti-inflammatories, following implantation. However, systemic administration leads to systemic effects, which are often undesirable. By localizing the drug delivery to the site of implantation, these systemic effects can often be reduced or eliminated. By incorporating the drug as a component of the device, not only can such localized delivery be achieved, but also delivery can be controlled in concert with the device's action to achieve synergistic therapeutic outcomes. Steroid-releasing cardiac pacing leads, heparin-coated vascular grafts, drug-eluting stents, antimicrobial pouches, and so on are a few successful examples.
The aim of this book is to summarize general principles surrounding synergistic combination of drugs and devices, to improve the performance of either the drug or the device. Emphasis is placed on the recognition of unmet needs that motivate the development of combination systems, the research and development required to introduce specific products, including recognition of special issues that arise when combining drugs and devices, and in certain cases the special regulatory hurdles that need to be overcome.
An overview of the general issues surrounding the development of drug-device combinations is provided by Avula and Grainger in Chapter 1. This chapter also summarizes progress in particular classes of devices, "case studies" of which are presented in later chapters. In Chapter 2, Peppas et al. provide a historical review of drug delivery devices, with emphasis on general principles and applications. This chapter shows the remarkable progress that has been made in the past 50 years, and demonstrates the ingenuity involved in combining physics, chemistry, engineering, and understanding of anatomy and physiology to create a vast variety of devices for drug delivery. The field has seen a rapid evolution from the relatively crude devices of the 1960s to present systems whose manufacture requires advanced techniques. Many of the latter devices are described in Chapter 3 by Stevenson and Langer.
Chapter 4 by Lyu and Siegel discusses practical aspects of developing and manufacturing drug-device combination products. The chapter starts with a discussion of tests required for combination products that go beyond those needed for simple devices and pharmaceutical products, due to possible interactions between the drug and the device. Selection of materials for combination products is then considered, first in general, and then specifically for drug delivery coatings and catheters. Several physical and chemical interactions between the drug and the device, which play a major role in a products' performance, are then identified. Finally, commonly used technologies for manufacturing combination products are reviewed, including dip coating, spray coating, impregnation, extrusion, molding, powder molding, and reservoir filling.
Chapter 5 by McVenes and Stokes reviews steroid-releasing cardiac pacing leads, which lower the pacing threshold, increasing the safety margin and the battery life of the pacemaker devices. The first such product received FDA approval in 1983. A historical trail describing how engineers and scientists learned that inflammatory reactions result in pacing threshold increase, and how they solved the problem, is presented, including a description of a large animal study to screen drugs for reducing pacing threshold. The chapter also presents the results of studies of steroid release over 7 years. These studies are important since the long-term release of steroid is necessary for certain patient populations.
Chapter 6 by Begovac et al. describes the development of the PROPATEN® Vascular Graft, which is composed of an expanded PTFE vascular graft functionalized with a heparin surface coating. The heparin coating...
