Medical Device Link.

Originally Published EMDM May/June 2003

Product Update

The sirolimus-eluting Cypher stent from Cordis Corp. is coated with a polymeric matrix that slowly releases the drug over a period of 90 days.

With the drug-eluting stent (DES) market growing steadily, more surface treatment options are becoming available to OEMs worldwide. Some coatings are already on the market, while others are still in the research phase. This article highlights recent developments in the DES market, and offers an overview of some leading suppliers of drug-eluting coatings. 

Drug-eluting stents have been commercially available in the United States for only about a year. To date, the only drug-eluting stent that has been granted US FDA approval is the Cypher sirolimus-eluting coronary stent from Cordis Corp. (Miami Lakes, FL, USA). Medtronic (Minneapolis, MN, USA) aspires to bring another drug-eluting device to the US market by late 2004. The company received US FDA conditional approval in February to continue the third phase of clinical trials for its investigational Endeavor drug-eluting coronary stent. 

Unencumbered by US FDA oversight, the European DES market has expanded more rapidly. The Cypher stent received the CE mark almost two years ago, and two other DES products are also commercially available. The Dexamet dexamethasone-eluting stent by Abbott Vascular Devices (Redwood City, CA, USA) became available in December 2002, and the Taxus paclitaxel-eluting coronary stent system from Boston Scientific (Natick, MA, USA) was launched in Europe and other international markets in February 2003. 

Stents are commonly used to hold arteries open after angioplasty procedures. However, inflammation, foreign body reactions with the stent material, and cell growth can cause an artery to clog again. This condition, called restenosis, sends a high percentage of patients back to the operating table within a year. “There is a limited critical period after bare metal stenting, which lasts about six months in poststenting patients,” says Ingolf Schult, marketing manager at coating supplier Hemoteq (Würselen, Germany). 

Drug-eluting stents have the potential to virtually eliminate such problems. A special coating on the stent can prevent reclogged arteries, releasing drugs at a controlled rate for a duration of minutes to months.

A stainless-steel coronary stent is coated with Hemoteq’s polymer matrix containing paclitaxel.

The first task for a DES manufacturer is to find the right drug. Cordis chose sirolimus for Cypher because of its anti-inflammatory and antiproliferative properties. “When administered locally in microgram quantities from a stent coating, sirolimus prevents the exuberant smooth muscle proliferative response that can lead to luminal narrowing and restenosis,” says Bob Falotico, senior research fellow at Cordis. 

To ensure controlled drug delivery, Cordis coated the device with a polymeric matrix developed by SurModics Inc. (Eden Prairie, MN, USA) that slowly releases the drug. The polymer that comprises the coating matrix is a stable biocompatible elastomer whose components have already been used in human implantable devices. “It was selected for its physical-chemical compatibility with sirolimus and the ability to meet the functional requirements of the stent, namely durability, stretchability, and flexibility,” says Falotico. “The architecture of the coating as well as the materials contribute to the controlled drug delivery of Cypher,” he adds. The stent releases all of its sirolimus over a period of 90 days with most of the eluting taking place in the first 30 days. “Based on the clinical results, this elution period appears to be long enough to control restenosis.”

Following closely in the race to market drug-eluting stents is Medtronic. The third phase of its clinical trials will evaluate the safety and efficacy of the Endeavor stent by comparing it to the Cypher. “Our clinical strategy remains on track to meet our stated goal of a European product approval…in late 2004 and product approval in the United States in late 2005,” says Bill Hawkings, president of Medtronic Vascular. The company has used a phosphorylcholine coating technology, a polymer copy of the outside surface of a red blood cell. The coating mimics the structure of the natural cell membrane and is designed to reduce the body’s response to implanted devices. Serving as a delivery matrix, it controls the elution of the drug directly into the arterial wall, and remains on the stent after the drug has been released. 

Hemoteq has been offering Ouverture, a dual-layer stent coating, since the end of 2002. This high-performance drug-eluting stent platform is designed to overcome restenosis and thrombosis. Ouverture combines Hemoteq’s proprietary antirestenotic and haemocompatible coatings, Repulsion and Camouflage, respectively. Repulsion is a biodegradable and biocompatible matrix that ensures controlled release for a range of drugs. Camouflage is a covalently bonded synthetic carbohydrate that masks the stent surface as endothelial cells. “Many doctors feel more comfortable with a bioresorbable coating that will disappear after the drug-eluting phase,” says Schult. “That is why Hemoteq selected biodegradable polymers for Ouverture.” 

STS Biopolymers Inc. (Henrietta, NY, USA), recently acquired by Angiotech Pharmaceuticals Inc. (Vancouver, BC, Canada), also offers a drug-eluting coating technology, a patented polymer system called MediCoat. The drugs are entrapped in patented mixtures of hydrophilic and hydrophobic polymers. According to the firm, the ratio of hydrophilic to hydrophobic polymers can be easily adjusted, ensuring controlled elution of the drug-coated surfaces. 

In the past, the company would combine its coating formula with the drug provided by the OEM. Angiotech plans to continue doing so, but also hopes to provide the manufacturers with the appropriate drug. “We want to go to the manufacturer and say, ‘Here is what we think the clinical problem is, and here is the drug that we think will work,’” says Bill Hunter, president and CEO of Angiotech. “We’re providing the whole package by bringing the drug and the coating.”

NAMSA/Biomatech S.A.

A multinational company offers a complete sterility assurance programme from sterilization and packaging validation to environmental monitoring and shelf life studies. Sterilization-monitoring products supplied by NAMSA/Biomatech S.A. (Chasse-sur-Rhône, France) are used by medical device and pharmaceutical manufacturers and by contract sterilizers. Some of these products include biological indicators for steam, EtO, dry-heat, gamma, and E-beam radiation sterilization. “Our biological indicators are used to ensure the adequate sterilization of products and instruments,” says Joel Gorski, director of the products business unit and business development at NAMSA’s US headquarters in Northwood, Ohio. NAMSA also offers chemical process indicators for use with steam, EtO, and gamma and E-beam radiation sterilization processes. 

In addition, the company has developed an H-BAC coating solution that imparts thromboresistant properties to surfaces. “It is usually used in short-term applications such as catheters, guidewires, and other blood-contact devices,” says Gorski. The nonpyrogenic coating is applied to finished products by flushing, dipping, or wiping. “After the alcohol evaporates, a waxy coating remains on the device.” This waxy coating retains heparin activity on the surface of a device. “Other coatings require covalent links or surface treatment to adhere. H-BAC is not chemically bonded to the surface. All you really need to do is dip the device in the solution,” according to Gorski.

The solution contains 700–900 units of heparin activity per millilitre by USP assay. It carries a low bioburden and has a shelf life of 18 months.

Linac Technologies

E-beam accelerators are designed and manufactured in France and installed in service centers around the world, integrated in a production line or simply placed at the manufacturer’s site, depending on their size, throughput, and purpose. Offered by Linac Technologies (Orsay, France), these machines range from the high-energy (10-MeV) Circle, with up to 20 kW of beam power, to the low-energy (200-keV) KeVAC and medium-energy (3–5 MeV) MeVAC. In the medical sector, they are used in a variety of applications ranging from the complete sterilization of boxed nonwoven products to the surface sterilization of tubs containing syringes. 

Molnlycke Health Care A.B. (Waremme, Belgium) uses Linac’s accelerators to sterilize 50,000 pallets of medical supplies per year. High throughput is achieved by double-sided treatment. “Instead of having one accelerator treating the product from one side, you have two, one sterilizing the top and the other the bottom,” says Fiona Malcolm, marketing manager at Linac. “This way, the product is treated on both sides simultaneously and goes through the system faster, increasing throughput.”

Recently the company developed a smaller, lighter machine, called MeVAC. “We wanted to design a compact machine that could satisfy a demand for small treatment systems,” says Malcolm. The beam power ranges from 3 to 5 kW. Total size and throughput depend on the product and the machine power selected by the client. 

Linac also offers self-shielded E-beam sterilization units for surface decontamination of products entering a Class A area. These units contain one to three low-energy accelerators placed inside a lead shield with a stainless-steel housing and inner tunnel. The KeVAC accelerators produce a continuous E-beam that delivers 10–200 keV of energy and up to 10 mA of electric current. 

SurModics Inc. 

A company employs surface modification technology to create unique surfaces on medical devices. In addition to providing lubricious and haemocompatible coatings for medical devices, SurModics Inc. (Eden Prairie, MN, USA) can engineer surfaces to deliver therapeutic or antimicrobial agents. 

The company’s drug-delivery polymeric matrices incorporate unbound therapeutic or antimicrobial agents. “The therapeutic agents can be released from the matrix at a controlled rate,” says Jane Nichols, vice president of marketing at SurModics. Because the coatings are very thin, users can combine any number of surface characteristics without affecting the physical properties and dimensions of the devices being processed. “These coating matrices are able to deliver a variety of pharmaceutical agents and can be customized to deliver drugs for durations ranging from minutes to months,” according to Nichols.

For added flexibility and versatility, SurModics offers its copolymer matrix technology. This polymer blend is currently commercialized with the Cypher Sirolimus-eluting coronary stent from Cordis Corp. (Miami Lakes, FL, USA). “We can do a lot with polymer blends,” says Nichols. “Depending in part on what drug we’re delivering and how long it needs to be delivered, the ratio of the polymers and the way they are applied can be changed in order to give the appropriate elution profile.” 

The company has other matrices in its development pipeline that will allow the delivery of other types of drugs, such as small-molecule hydrophobic and hydrophilic agents, and macromolecules. 

SurModics also offers its PhotoLink surface modification technology to coat medical device substrates. Photoactivated polymer matrix formations can be used in applications that require lubricity, haemocompatibility, and biocompatibility, such as stents and cooling catheters. Biopolymer matrices are also available. These coatings are suitable for encapsulating and immune-shielding specialized cells for the secretion and delivery of therapeutic agents. 

Comelec S.A.

Parylene coating services are offered for medical applications such as cardiac assist devices, electronic circuits, pipettes, needles, and catheters. Comelec S.A. (La Chaux-de-Fonds, Switzerland) offers two variants, Parylene N and C, which are particularly suitable for medical applications. Parylene C features a combination of electrical and physical properties, including very low permeability to moisture and corrosive gases. Parylene N provides high dielectric strength and a dielectric constant that is independent of frequency with a high penetrating power.

“The main advantage of the parylene polymerization process is that it takes place at room temperature under vacuum,” says Laurent Morisset, marketing manager at Comelec. “It uses no solvents or additives, and there are no cure forces that might damage fragile components or coated substrates.” A parylene polymer layer can be applied in a vacuum coating operation in thicknesses ranging from 1 to 75 µm, according to customer specifications. The coating provides pinhole-free coverage. “Other coating materials such as epoxies and acrylics are already in a completely formed state when they are applied to a surface,” says Morisset. “Parylene is converted directly from a molecular monomer state to a polymer film on the surfaces being coated.” 

Sterigenics 

Sterilization and laboratory services are offered worldwide by Sterigenics (Verviers, Belgium). The company has expertise in gamma, EtO, and E-beam technologies. Clients can choose from a comprehensive selection of services before, during, and after the sterilization process.
The company is currently in the process of fitting microwave spectrometers to all its European EtO sterilizers. “Spectrometers are able to monitor accurately the EtO gas concentration and in-chamber humidity during the process,” says marketing manager Ron Peacock. “They are reliable and easy to calibrate; most importantly, they provide the measurement capability to allow us to eliminate biological indicators in routine processes,” he adds. “This speeds up the release of the product and saves our clients between three to five days on product turn times.”

This technology, already in use in the Somercotes, Lincs, UK, facility, will be installed in Verviers, Belgium, by this spring. A new EtO sterilization plant is under construction in Wiesbaden, Germany, and is expected to open in early 2005. This facility will incorporate further technology developments aimed at improving product turnaround times, potentially enabling release within 24 hours. 

Studer Hard 

Radiation services are offered in a facility located in northern Switzerland. Studer Hard (Däniken, Switzerland) operates six E-beam accelerators ranging from 1 to 10 MeV for cross-linking, materials modification, and sterilization. It also provides gamma irradiation with its 4 MCi cobalt-60 pallet irradiator.

The company conforms to ISO 9000, US FDA, and GMP requirements, serving the medical device and pharmaceutical industries. “We treat a wide range of products from simple medical devices, such as syringes, to sophisticated implants,” says sales director Conrad Günthard. “Gamma and E-beam sterilization offer high intrinsic process safety and fast throughput,” according to Günthard. “They are widely accepted and recommended methods that allow easy process documentation and validation.”

The company also provides help with materials testing, validation, and documentation for regulatory purposes. 

Sterile Health Products Inc.

Low-cost and high-quality assembly, packaging, and EtO sterilization services are offered in state-of-the-art Class 10,000 and Class 100,000 cleanrooms. Sterile Health Products Inc. (Istanbul, Turkey) is certified to ISO 9001, ISO 13485, and EN 550. “Apart from our regular manufacturing activities, we also offer contract sterilization services to third parties,” says general manager Utku Oguz. “Our sterilization system is revalidated every year by the French Mallet Group. Also, we are the only company in Turkey to have completed the software validations that are required by the new ISO 13485.”

In the Class 100,000 cleanroom, the company currently manufactures surgical sutures and carries out suture-needle attachment operations. Daily packaging capacity for IV infusion sets is 120,000. 

E-Beam Services Inc. 

A one-step E-beam process combines sterilization with performance-enhancing characteristics for the processing of medical devices. During the sterilization process, a permanent cross-linking of the plastics improves tensile and impact strength, thermal stability, and resistance to solvents, chemicals, and abrasion. Offered by E-Beam Services Inc. (Cranbury, NJ, USA), the process enables designers of moulded medical device parts, tubing, woven and nonwoven materials, and other biomedical products to use economical materials or offer small-sized products with high performance characteristics. 

Hemoteq

A dual-layer stent-coating system, Ouverture, comprises two coatings, which have been named Repulsion and Camouflage. Available from Hemoteq (Würselen, Germany), the Ouverture coating can be adapted to virtually any metallic stent material and design. Repulsion, an antirestenotic drug-eluting matrix, is designed to ensure controlled and safe release of a range of drugs. Applied over the matrix, Camouflage provides haemocompatibility and protection from thrombosis. It is a covalently bonded synthetic carbohydrate that masks the stent surface as endothelial cells.

Thanks to the coating’s elasticity and durability, the integrity of the coated surface is preserved during stent delivery and expansion. A client’s coronary stent, coated with Hemoteq’s haemocompatible basecoat, received CE marking last November. 

STS Biopolymers Inc.

A patented polymer system is designed for the localized delivery of bioactive agents from medical device surfaces. Provided by STS Biopolymers Inc. (Henrietta, NY, USA), recently acquired by Angiotech Pharmaceuticals Inc. (Vancouver, BC, Canada), MediCoat is a blend of several polymers. The drugs are entrapped in patented mixtures of hydrophilic and hydrophobic polymers. The dissolution of an entrapped drug is controlled largely by the ratio of hydrophilic to hydrophobic polymers. This ratio can be easily adjusted, ensuring controlled elution from the drug-coated surfaces. Another advantage of MediCoat is its flexibility, according to Bill Hunter, president and CEO of Angiotech. “There is usually one polymer in the combination that is suitable for delivering a given drug, and you can use more or less of that particular polymer [when making the coating].”

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