Breaking Through the Stent-Coating Process
According to the American Heart Association, heart disease is the leading cause of death in the United States, killing almost double the number of people killed by cancer, car accidents and AIDS combined.1 For this reason, innovative therapies and devices to treat heart disease are in high demand. This article describes a new coating technology which optimizes drug-eluting stents and other medical devices.
In 2003, drug-eluting stents emerged as a breakthrough solution for Acute Coronary Syndrome (ACS), one of the many causes of heart disease. This technology was anticipated to use drug therapy to address the persistence of early restenosis with bare metal stents, and the injury to vessel walls associated with traditional percutaneous coronary intervention (PCI) treatments (such as balloon angioplasties). Drug-eluting stents were rapidly adopted by physicians, and account for over five billion of the biomedical device market’s annual sales in 2006.2
Recently, drug-eluting stents have been plagued by concerns regarding long-term product safety. Although the FDA issued a statement in 2006 stating that drug-eluting stents are safe, they noted recent data suggesting a small but significant increase in the rate of death and myocardial infarction possibly due to late stent thrombosis.3
Micell Technologies, Inc. has developed a unique, proprietary, multi-layered coating technology that can create drug-eluting coatings for medical devices with better uniformity, enhanced control over drug placement, morphology and elution, and improved manufacturing process control. These improvements have the potential to provide substantial clinical benefits to future generations of drug-eluting stents. Micell partnered with the Commercial Equipment Group of Foster-Miller, Inc. to develop an automated, commercial-scale manufacturing process that would incorporate the new coating technology into drug-eluting stents faster and more effectively.
Current Challenges with Drug-Eluting Stents
Patients suffering from ACS have long been treated with PCI. By inserting a stent into an occluded or narrowed coronary artery, it is possible to restore blood flow to the heart while avoiding exposing already vulnerable heart patients to invasive open heart surgery, and achieve the same therapeutic effects. Patients benefit from reduced surgical risk, faster recovery, and a less painful procedure.
While first-generation bare-metal stents virtually eliminated many of the complications associated with abrupt artery closure after balloon angioplasty, issues with restenosis (or reblocking) persisted. Restenosis can occur through several mechanisms, but most importantly, it is thought to result from an inflammatory cellular response in the vessel wall that induces tissue proliferation around the angioplasty site. Although the rates were somewhat lower, bare-metal stents still experienced reblocking (typically at six-months) in about 25% of cases, necessitating a repeat procedure.4 Although drug-eluting stents have been successful in eliminating early restenosis, doctors have recently become concerned about the rising number of cases of patients experiencing complications from late stent thrombosis (typically years after stent implantation).
A number of factors (including potential polymer/drug toxicity, physician placement, off-label use, and lack of compliance with anti-platelet therapy post-stent implantation) have all been considered as contributing factors to the recent increases in late stent thrombosis. In September 2006, the FDA released a statement regarding their position on the public’s growing concerns with drug eluting stents. At the time of the statement, they defended their approval by stating that they still believe that drug-eluting stents are safe when used in patients that fit the same anatomic features as those used in the pivotal trials.
The clinical trials for both Boston Scientific’s Taxus, and Cordis / Johnson & Johnson’s Cypher (currently the only two approved drug-eluting stents on the market) were performed on a certain type of patient. These patients had only one untreated blockage in a single vessel. The positive results of this treatment led to the FDA approval of Taxus and Cypher for use in the situations in the clinical trials. Many cardiologists today use these devices outside of the manufacturer’s label guidelines; this is called “off-label” usage. Physicians often feel the patient with the higher risk is better served by newer devices that show less restenosis. As the stents were placed in these off-label patients, the incidence of late stent thrombosis has grown.
In December 2006, the FDA held a public meeting of the Circulatory System Devices Advisory Panel, where they provided recommendations and comments. It recommended further studies to insure the safety of the products, and noted that both approved drug-eluting stents are associated with a small increase in stent thrombosis when compared to bare metal stents.
Now that the issues associated with TAXUS and CYPHER are being publicly addressed, there is a need in the market to create new drug-eluting stents that are more efficient and reduce the risks of drug-eluting stents. It was thought that the drug-eluting stents completely prevented restenosis, when in actuality, it seems to delay it. Improved technologies that address thickness and uniformity of polymer coatings, together with control over drug morphology, elution and placement within the coating, will play an important role in the ability of future generations of drug-eluting stents to address the current clinical challenges.
An Improved Coating Process for Improved Patient Care
Micell Technologies has created a unique, proprietary, multi-layered coating technology that is designed for delivering advanced therapeutics to the surface of medical devices, and has the potential to create clinically superior next-generation drug-eluting stents.
First, Micell’s patented process can create coatings that allow for independent placement of multiple drugs into microenvironments inside the surface coating of devices. This feature enables the drug to be “dialed-in,” meaning that the distribution of the drug in the coating can be manipulated to control the elution profile.
In addition, multiple drug combinations, such as anti-restenosis and anti-coagulant therapies, can be added in a single drug-eluting stent, providing the opportunity for sequential therapies and potential improved clinical efficacy.
Using benign supercritical fluids, Micell’s technology provides a more gentle coating process that does not expose the drugs to harsh environments. Entirely dry and solvent-free, Micell’s technology uses moderate temperatures to retain the structure, morphology, and potency of therapeutic agents. Additionally, more uniform, flexible, and adherent polymer coatings can be created using Micell’s solvent-free system, due to the elimination of lengthy drying times and lack of exposure to harsh solvents.
Lastly, Micell’s unique process reduces exposure to potential solvent hazards and minimizes hazardous waste disposal issues.
Keeping Manufacturing in Mind
The features of Micell’s stent-coating process were designed to facilitate improved clinical efficacy and safety in the next-generation of drug-eluting stents; as such, a feasible manufacturing process was essential to enable commercialization of this technology. For this reason, Micell partnered with the design and engineering firm, Foster-Miller, early in the development process so that manufacturing needs would be considered from the initial stages of the project.
Combining Micell’s expertise with Foster-Miller’s engineering, materials and manufacturing know-how created a powerful team with a wealth of information about regulatory and quality standards, emerging technologies and manufacturability. This reduced the risk of designing an un-manufacturable device, and facilitated the development of an efficient, novel process.
Foster-Miller capitalized on several unique features of Micell’s technology in order to design a proprietary manufacturing process that would coat one or more stents in less than five minutes. The homogenous, unidirectional process developed by the Foster-Miller/ Micell team decreases production time and streamlines operations. This accelerates product time-to-market and offers advantages in terms of manufacturing throughput and associated costs.
Process control is also enhanced in this proprietary system, allowing the coating process to be monitored and measured at multiple points. The drug dosage can be metered in real-time to maximize the quality and consistency of drug placement.
The companies’ partnership created a seamless transition from design to manufacturing, moving the project from the laboratory to a process platform that could support both pre-clinical and clinical trials, and ultimately commercial product manufacturing. Foster-Miller also helped its partner secure intellectual property protection by assigning Micell all rights to the manufacturing process.
Looking to the Future
Preliminary data suggest that Micell’s unique drug-eluting stent technology may provide improved clinical benefits to ACS patients. Although coronary drug-eluting stents have been targeted as the first application for Micell’s proprietary technology, the process’ flexibility shows promise for future applications. The technology can be applied to a variety of combination devices, and is compatible with numerous drugs and a wide range of durable and bioabsorbable polymers. Small molecules, peptides, proteins, hormones and other heat sensitive agents can be used with Micell’s proprietary process, providing new therapeutic options for drug-eluting coatings. The next applications may include drug-eluting orthopedic devices and novel drug-delivery systems.
In the competitive medical market, drug coating will continue to be an important part of creating safer and more effective medical devices. Micell’s unique coating process offers significant advances in technology and has the potential to redefine surface modification of medical devices using drug-eluting coatings.
Robert R. Andrews is medical division manager for the commercial group at Foster-Miller Inc., and can be reached at 781-684-4639 or firstname.lastname@example.org. James B. McClain serves as Chief Technology Officer and is one of the co-founders of Micell Technologies, and can be contacted at 919-313-2111 or email@example.com.