The patent's assignee is
News editors obtained the following quote from the background information supplied by the inventors: "In the area of medical devices, biomaterials research continues to search for new compositions and methods to improve and control the properties of the medical devices. This is particularly true for medical articles that are implantable within a subject, where predictable and controllable performance is essential to the successful treatment of a subject.
"An example of an implantable medical device is a stent. Stents can act as a mechanical means to physically hold open and, if desired, expand a passageway within a subject. Typically, a stent is compressed, inserted into a small vessel through a catheter, and then expanded to a larger diameter once placed in a proper location. Stents play an important role in a variety of medical procedures such as, for example, percutaneous transluminal coronary angioplasty (PTCA), a procedure used to treat heart disease by opening a coronary artery blocked by an occlusion. Stents are generally implanted in such procedures to reduce occlusion formation, inhibit thrombosis and restenosis, and maintain patency within vascular lumens. Examples of patents disclosing stents include U.S. Pat. Nos. 4,733,665; 4,800,882; and 4,886,062.
"Stents are also being developed to locally deliver active agents, e.g. drugs or other medically beneficial materials. Local delivery is often preferred over systemic delivery, particularly where high systemic doses are necessary to affect a particular site. For example, agent-coated stents have demonstrated dramatic reductions in stent restenosis rates by inhibiting tissue growth associated with restenosis.
"Proposed local delivery methods from medical devices include coating the device surface with a layer comprising a polymeric matrix and attaching an active agent to the polymer backbone or dispersing, impregnating or trapping the active agent in the polymeric matrix. For example, one method of applying an active agent to a stent involves blending the agent with a polymer dissolved in a solvent, applying the composition to the surface of the stent, and removing the solvent to leave a polymer matrix in which an active agent is impregnated, dispersed or trapped. During evaporation of the solvent, phase separation can disadvantageously occur, often resulting in hard-to-control process conditions and a drug coating morphology that is difficult to predict and control. This makes delivery of the agent unpredictable.
"Further, manufacturing inconsistencies among different stents can arise with the above coating method. For example, release-rate variability has been observed among supposedly identical stents made by the same process. Apparently, when some polymer coatings comprising active agents dry on the surface of a medical device different morphologies develop in different coatings, even if the coating process parameters are consistent. These differences in coating morphology may cause active agent release-rates from different stents to vary significantly. As a consequence of the inconsistent release-rate profiles among stents there can be clinical complications. Thus, there is a need for methods that can control the variability of active agent release-rates among medical devices and provide manufacturing consistency.
"Morphological changes that affect release-rates of active agents have been observed to be dependent on the active agent phase in the polymer matrix. When a coating composition is applied to the surface of a medical device the active agent is initially evenly dispersed in the coating composition. However, during processing the agent may migrate or phase separate to form different phase regions within the coating layer. These regions are often connected with each other and are referred to as the percolation phase. The mass transport properties of active agents are distinct through the percolation phase. Mass transport through the percolation phase is driven by the solubility of active agent in the release medium, the diffusivity of the active agent in the release medium, and the morphological feature of the percolated phase such as, for example, tortuosity and area fraction. The release-rate of the active agent is often greatly increased from these regions or phases. The formation of percolated phases is particularly pronounced at high active agent concentrations, for example above about 35% by volume fraction of active agent to polymer in the coating layer.
"Those skilled in the art will therefore appreciate that local delivery would benefit not only from improved release-rate profiles that are controlled and predictable, but also from manufacturing improvements that would provide consistency. Thus, methods for making coated medical devices with more reliable performance are highly desirable and essential to providing effective treatment of patients. In addition, control over the release-rate can assist in designing and maintaining the physical and mechanical properties of medical devices and coatings, as well."
As a supplement to the background information on this patent application, VerticalNews correspondents also obtained the inventors' summary information for this patent application: "According to one aspect of the present invention, methods are provided for controlling the morphology of coating layers for medical devices comprising a polymer matrix and one or more active agents. A further aspect of the present invention provides coated medical devices with a controlled release-rate of one or more active agents by selecting the phase distribution of the active agent phases in the layer.
"In some embodiments, the coating layer morphology is controlled by fixing the active agent morphology in a wet coating layer comprising one or more polymers, one or more active agents and one or more solvents. Methods to fix the active agent morphology or phase distribution include, but are not limited to, exposing to cold gas, dipping in cold liquid, exposing to shock freezing, exposing to flash vaporization, exposing to non-solvent exchange, and combinations thereof. In an alternative method, the active agent morphology is fixed by cross-linking the polymer matrix. After the active agent morphology is fixed, solvent is removed from the wet coating layer by a method such as, for example, evaporation, freeze-drying, non-solvent exchange, critical point drying, and combinations thereof. In one embodiment, solvent is removed by a combination of non-solvent exchange with CO.sub.2 and critical point drying. According to a further embodiment of the present invention, a portion of the solvent is removed from the wet coating layer prior to fixing the active agent morphology. This allows modulation of the active agent phase distribution in the coating layer. Further, the embodiments of the present invention may include post-formation processing steps, such as annealing, applying a top coat and/or finishing layer, or sterilization.
"According to another aspect of the present invention, selecting the phase distribution of the active agent in the polymer matrix controls the release-rate profile of active agent from a medical device coating layer. In one embodiment, the active agent phase, or phases, is fixed during coating layer formation controlling the phase distribution of the active agent. In one embodiment, the active agent phase distribution in the coating layer comprises one or more phases selected from dissolved, dispersed, and percolated phases. In one embodiment, the release-rate profile of active agent is determined by the ratio of the phases of the active agent in the coating layer.
"The coating layers of the present invention may be applied to a variety of medical devices. In one embodiment, the medical device is a stent. Active agents useful in these coating layers can vary widely. In one embodiment the active agent is selected from the group consisting of antiproliferative, antineoplastic, anti-inflammatory, steroidal anti-inflammatory, non-steroidal anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic, antioxidant, cytostatic agents, and combinations thereof.
BRIEF DESCRIPTION OF THE DRAWING
"FIG. 1 shows a ternary phase diagram for polymer, active agent and solvent coating compositions of the present invention."
For additional information on this patent application, see:
Keywords for this news article include: Surgery, Treatment, Cardiology, Restenosis, Legal Issues, Cardio Device, Heart Disease, Medical Devices, Surgical Technology,
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