Nick DiFranco, Marketing Specialist
June 2019, European Plastic Product Manufacturer
Combination products are defined in 21 CFR 3.2(e) as therapeutic and diagnostic products comprising two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity. This broad definition includes products ranging from pre-filled syringes to drug coated implants. For medical device companies, combination products provide an attractive route to improving product performance or extending a product’s lifecycle. In this article, we will explore polymer selection and design options for implanted drug-device combination products.
Broadly speaking, drugs and implants are used together for one of two reasons: 1. the device acts as a vehicle to deliver a drug or 2. the drug is included to enhance the performance of the device. For medical device developers, the most relevant examples involve the addition of a drug to an existing medical device. Antimicrobial catheters, steroid-coated pacemaker leads, and antibiotic bone cements are examples of traditional medical devices that are enhanced by the inclusion of a drug.
Polymer selection is a critical component of medical device development, and the same guidelines apply when choosing a polymer for a combination product. Combination product developers should ensure that their chosen polymer(s), as with any key component, will be available in the grade necessary for an implant and that the manufacturer can provide the needed documentation and support.
A material showing increased use in combination products is thermoplastic polyurethane (TPU). Non-biodegradable TPU excipients, including Lubrizol Life Sciences’ Pathway™ offering, are versatile and customizable to a broad range of chemical and physical properties (Figure 1). The ability to modify TPU chemistry makes these excipients compatible with a wide range of APIs (hydrophobic and hydrophilic) and allows them to provide different drug-release kinetics (short and long-term) depending on the application. TPUs come in a range of durometers and are amenable to many processing methods, including hot melt extrusion, solvent casting, and injection molding. Lubrizol’s TPUs have a long history of in vivo safety, stability, and biocompatibility and, as a result, have been used for decades in biomedical applications such as implanted cardiac pacemakers and defibrillators. Additionally, Pathway™ TPUs have established Drug Master Files (DMFs) and are manufactured under IPEC-PQG good manufacturing practice guidelines, which is commonly required by the FDA when working with a pharmaceutical or incorporating one into a medical device. Visit go.lubrizol.com/pathway to learn more and request a sample.
The drugs incorporated with devices may be either impregnated or surface- coated. Many common medical device polymers have been combined with drugs through hot-melt extrusion (HME), a process familiar to the medical device industry. Common polymers used in HME include polyolefins, polyesters (especially those based on lactic acid, glycolic acid, and caprolactone), polyurethanes, and ethylene-co-vinyl acetate polymers. Silicone rubber can also be combined with drugs through reactive injection molding. In cases where temperature sensitivity is an issue, drug loading may be accomplished with the use of solvents.
Drug-eluting devices can take several forms, namely matrix, coating, and reservoir systems (Figure 2). In the case of matrix-type products, the drug is uniformly dispersed throughout the polymer. Drug release from matrix-type products typically follows first-order kinetics, often with an initial burst of drug and a release rate that decreases over time. In cases where a device is hollow or surface protection is critical, a drug-containing coating can be applied. These coatings can be made from biodurable or biodegradable materials and may demonstrate a wide range of release rates depending on the coating composition, thickness, and surrounding environment. The final type of combination product, reservoir-type, is less commonly utilized for modifying medical devices. An example of a medical device utilizing a reservoir is the drug-filled stent, which has laser-drilled holes that allow drug to continuously elute out of the device and prevent restenosis of a vessel. Reservoir designs are appealing because they can achieve steady drug release over time, also known as zero-order release. For medical devices, the burst release of a matrix-type product may be desirable to help fight an initial infection risk or inflammatory response. Whatever the goal of a combination product, the drug incorporation method and material selection can be optimized by experienced developers to achieve the desired drug release rate.
The addition of a drug to a medical device can greatly enhance the safety and efficacy of products, providing differentiated product performance. A wide range of combination products have been commercialized and continue to be developed as medical device companies seek ways to improve their product lines. However, combination products present unique development challenges, including the complex selection of polymers, drugs, and device designs to achieve a specific goal. Any successful combination product development requires an understanding of both the drug and device sides of the equation. Using an experienced development partner such as Lubrizol LifeSciences can mitigate much of the risk by closing knowledge gaps and shortening the time between developmental inflection points.
As a growing number of medical devices make the leap to combination products, the benefits of drug inclusion become more apparent. Drugs have allowed devices to last longer in the body, perform therapeutic actions more effectively, and mitigate unwanted effects. As long as drugs continue to improve the safety and efficacy of both existing and novel medical devices, combination products will remain an area of significant growth.