Medical device with a porous surface for delivery of a therapeutic agent

Description

FIELD OF THE INVENTION

The present invention is generally directed to implantable medical devices for delivering therapeutic agents to the body tissue of a patient and methods for making such medical devices. In particular, the present invention is directed to implantable medical devices, such as intravascular stents, having a surface that includes a plurality of cavities and a plurality of pores and a composition disposed in the pores and/or cavities, as well as, implantable medical devices, such as intravascular stents, having a surface that has a coating composition disposed on the surface, wherein the coating composition includes a plurality of cavities and a plurality of pores and another coating composition disposed in the pores and/or cavities.

BACKGROUND

Medical devices have been used to deliver therapeutic agents locally to the body tissue of a patient. For example, stents having a coating containing a therapeutic agent, such as an anti-restenosis agent, can be effective in treating or preventing restenosis. Currently, such medical device coatings include a therapeutic agent alone or a combination of a therapeutic agent and a polymer. Both of these types of coatings suffer from certain limitations.

Coatings containing a therapeutic agent without a polymer are generally impractical since such coatings offer little or no control over the rate of release of the therapeutic agent. Therefore, many medical device coatings include a therapeutic agent and a polymer.

Though the use of polymers can provide control over the rate of release of the therapeutic agent, the use of such polymers in coatings may pose certain other limitations. For example, some polymer coating compositions do not actually adhere to the surface of the medical device. In order to ensure that the coating compositions remain on the surface, the area of the medical device that is coated, such as a stent strut, is encapsulated with the coating composition. However, since the polymer does not adhere to the medical device, the coating composition is susceptible to deformation and damage during loading, deployment and implantation of the medical device. Any damage to the polymer coating may alter the therapeutic agent release profile and can lead to an undesirable increase or decrease in the therapeutic agent release rate. Also, polymer in the coatings may react with the blood and cause late stage thrombosis.

For instance, balloon expandable stents must be put in an unexpanded or “crimped” state before being delivered to a body lumen. During the crimping process coated stent struts are placed in contact with each other and can possibly adhere to each other. When the stent is expanded or uncrimped, the coating on the struts that have adhered to each other can be damaged, torn-off or otherwise removed. Moreover, if the polymer coating is applied to the inner surface of the stent, it may stick or adhere to the balloon used to expand the stent when the balloon contacts the inner surface of the stent during expansion. Such adherence to the balloon may prevent a successful deployment of the medical device.

Similar to balloon-expandable stents, polymer coatings on self-expanding stents can also interfere with the delivery of the stent. Self-expanding stents are usually delivered using a pull-back sheath system. When the system is activated to deliver the stent, the sheath is pulled back, exposing the stent and allowing the stent to expand itself. As the sheath is pulled back it slides over the outer surface of the stent. Polymer coatings located on the outer or abluminal surface of the stent can adhere to the sheath as it is being pulled back and disrupt the delivery of the stent.

An alternative to coating or encapsulating the surface of a medical device is to create pores within the surface of the medical device and dispose a therapeutic agent within the pores. Though the use of a porous surface overcomes certain limitations of using a polymer coating, due to the small size of the pores the therapeutic agent may only penetrate to a certain depth of the porous coating. Such insufficient penetration can result in a limited amount of the therapeutic agent that can be loaded onto the medical device, as well as, an unwanted rate of release where the therapeutic agent is released over a short period of time. Also due to the limited surface area of the surface of the medical device, a limited number of pores and therefore, a limited amount of a therapeutic agent can be loaded onto the surface of the medical device.

Accordingly, there is a need for medical devices and coatings for medical devices that have little or no polymer and that can release an effective amount of a therapeutic agent in a controlled release manner while avoiding the disadvantages of current coatings for medical devices. Also, there is a need for coatings that can release an effective amount of a therapeutic agent in a controlled release manner that can be selectively applied to the surfaces of a medical device, such as the surfaces that contact the body tissue of a patient. Additionally, there is a need for methods of making such medical devices and coatings for medical devices.

SUMMARY

As used herein, and unless otherwise indicated, the terms “controlled release,” “sustained release”, “modulated release” and “modified release” can be used interchangeably and are used to describe the release profile of a therapeutic agent that is not an immediate release profile.

These and other objectives are accomplished by the present invention. The present invention provides a coating for a medical device, such as an intravascular stent, that is capable of releasing an effective amount of a therapeutic agent in a controlled release manner, without the limitations associated with current coatings, including polymer coatings. The coatings of the present invention can be applied to select surfaces of a medical device such as the medical device surfaces that contact the surface of a body lumen of a patient. Such selective application of the coatings of the present invention can increase the accuracy and economical use of a therapeutic agent.

In certain embodiments of the present invention, the coatings of the present invention include a first coating composition having a metal, a metal oxide, ceramic oxide, or inert carbon and a plurality of cavities and a plurality of pores within the first coating composition. At least some of the pores are formed on the surface of the cavities. The coatings also include a second coating composition having a therapeutic agent disposed in at least one of the pores.

For example, the present invention includes an implantable stent comprising a stent sidewall structure, such as a tubular stent sidewall structure, having a surface and a coating that includes a first coating composition disposed on at least a portion of the surface of the stent sidewall structure. The first coating composition has an exposed surface and includes a metal, a metal oxide, ceramic oxide, or inert carbon having a plurality of cavities therein. Some of the cavities are in fluid communication with the exposed surface and at least one of the cavities is defined by a cavity surface having a plurality of pores therein. The coating also includes a second coating composition comprising a first therapeutic agent, wherein the second coating composition is disposed within at least one of the pores.

In the above example, at least one of the pores of the first coating composition can be in fluid communication with the cavity surface. Additionally, the pores can be distributed throughout the first coating composition. In certain embodiments the pores can be homogenously distributed throughout the first coating composition.

Also, in the above described example, the second coating composition can also be disposed within at least one of the cavities. In certain embodiments, the second coating composition further includes a polymer.

The coatings of the present invention can further include a third coating composition having a second therapeutic agent, a polymer or both a therapeutic agent and a polymer. The third coating composition can also be disposed in at least one of the cavities.

Suitable stents for the embodiments described herein can have a sidewall structure having an abluminal surface having a plurality of struts and openings in the sidewall structure. In certain embodiments, the surface of the stent sidewall is the abluminal surface. The first composition, second composition or third coating composition can conform to the surface of the stent so that the openings in the stent sidewall structure are preserved. Examples of such suitable stents include, but are not limited to, intravascular stents such as intravascular balloon-expandable stents and intravascular self-expanding stents.

The first coating composition can be free of any polymer. Additionally, the first coating composition can be radiopaque. For the first coating composition, suitable metal oxides or ceramic oxides include but are not limited to, iridium oxide, titanium oxide, titanium dioxide, iron oxide, hydroxyapatite, calcium phosphates, alumina, zirconia, zirconium, silica based glasses, or a combination thereof. For the first coating composition, suitable metals include but are not limited to, gold tantalum, platinum, titanium, Nitinol or a combination thereof.

The first coating composition can have a thickness of about 1 micron to about 30 microns. The diameter or width of the pores in the first coating composition can be less than or equal to about one micron. The size of the cavities in the first coating composition can be greater than or equal to about one micron.

In other embodiments of the present invention, the present invention includes, an implantable stent having a stent sidewall structure, such as a tubular stent sidewall structure having a surface, wherein the stent sidewall structure includes a metal, a metal oxide, ceramic oxide or inert carbon having a plurality of cavities therein. At least some of the cavities can be in fluid communication with the surface and at least one cavity is defined by a cavity surface having a plurality of pores therein. The stent also includes a first composition that includes a first therapeutic agent, wherein the first composition is disposed within at least some of the pores.

In the above embodiments, at least one of the pores can be in fluid communication with the cavity surface. The pores can be distributed throughout the stent sidewall structure. For example, the pores can be homogenously distributed throughout the stent sidewall structure.

The diameter or width of the pores in the cavity surface can be less than or equal to about one micron. The size of the cavities in the stent sidewall structure can be greater than or equal to about one micron. The stent sidewall structure can be radiopaque. Suitable metal oxides or ceramic oxides for the stent sidewall structure include, but are not limited, iridium oxide, titanium oxide, titanium dioxide, iron oxide, hydroxyapatite, calcium phosphates, alumina, zirconia, zirconium, silica based glasses, or a combination thereof. For the first coating composition, suitable metals include but are not limited to

Suitable metals for the stent sidewall structure include but are not limited to, gold, tantalum, platinum, titanium, Nitinol or a combination thereof.

The first composition can also be disposed in at least one of the cavities. The first coating composition can further include a polymer. Alternatively, the stents of the present invention can further include a second composition having a second therapeutic agent, a polymer or both a therapeutic agent and a polymer, wherein the second composition is disposed in at least some of the cavities. Also, the second composition can also be disposed within at least one of the pores.

Polymers in any of the above discussed embodiments of the coatings of the present invention can include biostable and bioabsorbable polymers. Suitable polymers include, but are not limited to, styrene-isobutylene-styrene, polylactic-co-glycolic acid (PLGA), polybutyl methacrylate (PBMA), polyvinylidene fluoride (PVDF), or a combination thereof.

Suitable stents for the embodiments described herein can have a sidewall structure having an abluminal surface having a plurality of struts and openings in the sidewall structure. In certain embodiments, the first composition and/or second composition can conform to the surface of the stent so that the openings in the stent sidewall structure are preserved. Examples of such suitable stents include, but are not limited to intravascular stents such as intravascular balloon-expandable stents and intravascular self-expanding stents.

Suitable therapeutic agents that can be included in the coatings of the present invention include, but are not limited, to anti-thrombogenic agents, anti-angiogenesis agents, anti-proliferative agents, antibiotic, anti-restenosis agents, growth factors, immunosuppressants or radiochemicals. In some preferred embodiments the therapeutic agent is an anti-restenosis agent. More specifically, suitable therapeutic agents include, but are not limited to, paclitaxel, sirolimus, tacrolimus, pimecrolimus, zotarolimus or everolimus. When the embodiments of the present invention include a first and second therapeutic agent the first therapeutic agent and second therapeutic agent can be the same or different.

The present invention is also directed to methods of coating a medical device having a surface. For example the present invention includes a method of coating an implantable stent having a surface that includes the steps of (a) disposing a first coating composition on the surface, wherein the first coating composition includes a metal, a metal oxide, ceramic oxide or inert carbon; (b) creating a plurality of cavities in the first coating composition, wherein the cavities have a cavity surface; (c) creating a plurality of pores within the cavity surface; and (d) disposing a second coating composition within at least one of the pores, wherein the second coating composition comprises a first therapeutic agent.

The methods of the present invention also include a method of coating an implantable stent having a surface that includes the steps of (a) disposing a first coating composition on the surface, wherein the first coating composition includes a metal, a metal oxide, ceramic oxide or inert carbon, and wherein the first coating composition comprises a plurality of pores therein; (b) creating a plurality of cavities in the first coating composition; and (c) disposing a second coating composition within at least one of the pores, wherein the second coating composition comprises a first therapeutic agent. The plurality of pores can be formed or created or they can be naturally occurring in the metal, metal oxide, ceramic oxide or inert carbon.

The above described methods can further include disposing the second coating composition within at least some of the cavities. The second coating composition can also include a polymer. In certain embodiments the above methods can further include disposing a third coating composition within at least some of the cavities, wherein the third coating composition comprises a second therapeutic agent, a polymer or both a second therapeutic agent and a polymer. The cavities can be formed by laser ablation, drilling, chemical etching or a combination thereof.

The methods of the present invention also include, for example, a method of coating an implantable stent having a surface that includes a metal, a metal oxide, ceramic oxide or inert carbon having a plurality of pores therein, the method includes the steps of (a) creating a plurality of cavities in the surface, wherein the cavities have a cavity surface and wherein at least some of the pores are in fluid communication with a portion of the cavity surface; and (b) disposing a first composition comprising a first therapeutic agent within at least some of the pores. The plurality of pores can be formed or created or they can be naturally occurring in the metal, metal oxide, ceramic oxide or inert carbon.

The methods of the present invention also include a method of coating an implantable stent having a surface that includes a metal, a metal oxide, ceramic oxide or inert carbon, the method includes the steps of: (a) creating a plurality of cavities in the metal, metal oxide, ceramic oxide or inert carbon, wherein the cavities have a cavity surface; (b) creating a plurality of pores in the metal, metal oxide, ceramic oxide or inert carbon and wherein at least some of the pores are in fluid communication with a portion of the cavity surface; and (c) disposing a first composition having a first therapeutic agent within at least some of the pores.

The above described methods can further include disposing the first composition within at least some of the cavities. The first composition can further include a polymer. Alternatively, the methods can further include disposing a second composition within at least some of the cavities, wherein the second composition includes a second therapeutic agent, a polymer or a second therapeutic agent and a polymer. The cavities can be formed by laser ablation, drilling, chemical etching or a combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be explained with reference to the following drawings.

FIG. 1 shows an example of a medical device that is suitable for use in the present invention.

FIG. 2 shows a cross-sectional view of an embodiment of a coating composition having cavities and pores disposed on a portion of a stent.

FIG. 3 shows a cross-sectional view of another embodiment of a coating composition having cavities and pores disposed on a portion of a stent.

FIG. 4 shows a cross-sectional view of an embodiment of a first coating composition having cavities and pores disposed on a portion of a stent, wherein the pores and cavities contain a second coating composition.

FIG. 5 shows a cross-sectional view of another embodiment of a first coating composition having cavities and pores disposed on a portion of a stent, wherein the pores and cavities contain a second coating composition.

FIG. 6 shows a cross-sectional view of still another embodiment of a first coating composition having cavities and pores disposed on a portion of a stent, wherein the pores and cavities contain a second coating composition.

FIG. 7 shows a cross-sectional view of still another embodiment of a first coating composition having cavities and pores disposed on a portion of a stent, wherein the pores and cavities contain a second coating composition.

FIG. 8 shows a cross-sectional view of a portion of a stent strut having cavities and pores therein.

DETAILED DESCRIPTION

In certain embodiments, the medical devices of the present invention have a surface that has a coating disposed thereon. The coating includes a first coating composition that includes a metal, a metal oxide, ceramic oxide or inert carbon having a plurality of cavities therein. Also, when the first coating composition is disposed on the surface, the first coating composition has an exposed surface that is in fluid communication with some of the cavities. At least one of the cavities is defined by a cavity surface having a plurality of pores therein. The coatings further include a second coating composition having a first therapeutic agent disposed within at least one of the pores.

FIG. 1 shows an example of a medical device that is suitable for use in the present invention. This figure shows an implantable intravascular stent 10. As shown in FIG. 1 intravascular stent 10 is unrolled, but is generally cylindrical in shape. Stent 10 includes a sidewall 20 which comprises a plurality of struts 30 and at least one opening 40 in the sidewall 20. Generally, the opening 40 is disposed between adjacent struts 30. Also, the stent sidewall structure 20 may have a first sidewall surface 22 and an opposing second sidewall surface 54, which is not shown in FIG. 1 but can be seen in FIG. 2. The first sidewall surface 22 can be an outer or abluminal sidewall surface, which faces a body lumen wall when the stent is implanted, or an inner or luminal sidewall surface, which faces away from the body lumen surface. Likewise, the second sidewall surface can be an abluminal sidewall surface or a luminal sidewall surface.

When the coatings of the present invention are applied to a stent having openings in the stent sidewall structure, in certain embodiments, it is preferable that the coatings conform to the surface of the stent so that the openings in the sidewall stent structure are preserved, e.g. the openings are not entirely or partially occluded with coating material.

FIG. 2 shows a cross-sectional view of an embodiment of a coating of the present invention disposed on a stent strut. Stent strut 50 has a surface, such as an abluminal surface 52 and a luminal surface 54. In this embodiment, coating 60 is disposed on the abluminal surface 52 of stent strut 50. Coating 60 comprises a first coating composition 70 comprising a metal, a metal oxide, ceramic oxide or an inert carbon. In certain embodiments, the first coating composition is free of any polymer, or substantially free of any polymer, i.e. contains less than 50% polymer by weight of the first coating composition. The first coating composition 70 has an exposed surface 72. An exposed surface is an outer surface that is capable of contacting body tissue when the device is inserted or implanted and is not covered by another material. The first coating composition 70 also includes a plurality of cavities 74 therein, in which at least some of the cavities are in fluid communication with the exposed surface 72. When the cavities are in fluid communication with the exposed surface, materials or fluids placed in the cavity can come into contact with the exposed surface. The cavities 74 have a cavity surface 76, i.e. a surface that defines the cavity. Additionally, the first coating composition includes a plurality of pores 78, at least some of which are in fluid communication with cavity surface 76. When the pores are in fluid communication with the cavity surface, materials or fluids placed in the pores can come into contact with the cavity surface. As shown in this embodiment, the pores are disposed on or near the cavity surface. Disposed within some of the pores 78 is a second coating composition comprising a therapeutic agent 80. The cavities increase the surface area of the coating and allow the therapeutic agent to penetrate deeper into the coating.

FIG. 3 shows a cross-sectional view of a coating of the present invention disposed on a surface of a stent strut. As shown in FIG. 3, stent strut 50 has an abluminal surface 52 and a luminal surface 54. In this embodiment, coating 60 is disposed on the abluminal surface 52 of stent strut 50. Coating 60 comprises a first or surface coating composition 70 comprising a metal, a metal oxide, ceramic oxide or an inert carbon, wherein the first coating composition 70 has an exposed surface 72. The first coating composition 70 also has a plurality of cavities 74 at least some of which are in fluid communication with the exposed surface 72. The cavities 74 have a cavity surface 76. Additionally, the first coating composition includes a plurality of pores 78 positioned throughout the first coating composition, some of which are in fluid communication with cavity surface 76. Disposed within some of the pores 78 is a second coating composition 79 comprising a therapeutic agent 80.

The location and number of pores can vary depending on the desired amount of therapeutic agent that is to be loaded onto the coating as well as the desired therapeutic agent release profile. Pores can be in a discreet area such as on or near the cavity surface, as shown in FIG. 2 or throughout the first coating composition, as shown in FIG. 3. In certain embodiments, pores can be homogeneously, i.e. evenly, distributed throughout the first coating composition. In other embodiments, the pores may be disposed in a pattern. Patterns can be random or uniform.

FIG. 4 shows a cross-sectional view of a coating of the present invention disposed on a surface of a stent strut. The stent strut 50 has an abluminal surface 52 and a luminal surface 54. In this embodiment, coating 60 is disposed on the abluminal surface 52 of stent strut 50. Coating 60 comprises a first coating composition 70 comprising a metal, a metal oxide, ceramic oxide or an inert carbon, wherein the first coating composition 70 has an exposed surface 72. The first coating composition 70 also has a plurality of cavities 74 at least some of which are in fluid communication with the exposed surface 72. The cavities 74 have a cavity surface 76. Additionally, the first coating composition includes a plurality of pores 78, some of which are in fluid communication with a cavity surface 76. As shown in this embodiment, disposed within some of the cavities 74 and pores 78 is a second coating composition comprising a therapeutic agent 80. The benefit to disposing the therapeutic agent in both the cavities and the pores is to allow for a therapeutic agent release profile that has a quick release and a controlled release profile. The therapeutic agent in the cavities can release quickly into the body lumen, thus displaying a “burst effect.” After the therapeutic agent has released from the cavities the therapeutic agent disposed in the pores can then release more slowly displaying a more controlled release profile. Additionally, once the release of the therapeutic agent is complete, having the cavities in communication with the exposed surface can aid in vascularization and cell coverage for long-term non-inflammation.

FIG. 5 shows a cross-sectional view of a coating of the present invention disposed on a surface of a stent strut. As shown in FIG. 5, stent strut 50 has an abluminal surface 52 and a luminal surface 54. In this embodiment, coating 60 is disposed on the abluminal surface 52 of stent strut 50. Coating 60 comprises a first coating composition 70 comprising a metal, a metal oxide, ceramic oxide or an inert carbon, wherein the first coating composition 70 has an exposed surface 72. The first coating composition 70 also has a plurality of cavities 74 at least some of which are in fluid communication with the exposed surface 72. The cavities 74 have a cavity surface 76. Additionally, the first coating composition includes a plurality of pores 78, some of which are in fluid communication with a cavity surface 76. As shown in this embodiment, disposed within some of the pores 78 is a second coating composition 79 comprising a first therapeutic agent 80 and disposed within some of the cavities 76 is a third coating composition 81 comprising a second therapeutic agent 82. In other embodiments, the third coating composition can comprise at least one therapeutic agent, a polymer, or alternatively a therapeutic agent and a polymer. In FIG. 5, the third coating composition comprises a second therapeutic agent 82, wherein the first therapeutic agent and the second therapeutic agent are different.

Though, in FIGS. 2 through FIG. 5, the coating is disposed on the abluminal surface, which is the portion of the surface of the stent that faces a lumen wall, the coatings of the present invention can be applied to any surface of a medical device. In alternative embodiments, the coating can be disposed on a portion of a surface of a medical device that does not contact a lumen wall. Such embodiments can be useful when, in addition to administering a therapeutic agent to a lumen wall, it is also beneficial to introduce a therapeutic agent into the blood stream. For example, an intravascular stent having an abluminal and luminal surface can have the coating of the present invention disposed on both the abluminal and luminal surfaces. A coating on the abluminal surface can administer a therapeutic agent to a lumen wall and a coating on the luminal surface can introduce a therapeutic agent into the blood stream.

When a coating is disposed on both the abluminal and luminal surfaces of a stent, the coating disposed on the abluminal surface can be the same as or different from the coating disposed on the luminal surface of the stent. Also, the therapeutic agent disposed in the cavities of the coating on the abluminal and luminal sides can be the same or different.

Though the coatings of the present invention can provide controlled release of a therapeutic agent without the need for a polymer matrix, as shown in the coatings in FIGS. 1-5, in certain embodiments a polymer may be included in the coating compositions of the present invention. In some embodiments, the second coating composition can include a polymer. For example, a bioabsorbable polymer can be used to slow the release of the therapeutic agent disposed in the pores. A bioabsorbable polymer is capable of releasing the therapeutic agent as the polymer is being absorbed. A biostable polymer, which is not absorbed into the body, can also be used. For example, a biostable polymer can also be used to slow the release rate of the therapeutic agent by forcing the therapeutic agent to travel through the porous network to the coating surface.

In some embodiments, as shown in FIG. 6, the coatings of the present invention can further include a third coating composition, disposed in the cavities, wherein the third coating composition includes a polymer. FIG. 6 shows a cross-sectional view of a coating of the present invention disposed on a surface of a stent strut. As shown in FIG. 6, stent strut 50 has an abluminal surface 52 and a luminal surface 54. In this embodiment, coating 60 is disposed on the abluminal surface 52 of stent strut 50. Coating 60 includes a first coating composition 70 having a metal, a metal oxide, ceramic oxide or inert carbon, wherein the first coating composition 70 has an exposed surface 72. The first coating composition 70 also has a plurality of cavities 74, at least some of which are in fluid communication with the exposed surface 72. The cavities 74 have a cavity surface 76. Additionally, the first coating composition includes a plurality of pores 78, some of which are in fluid communication with a cavity surface 76. As shown in this embodiment, disposed within some of the pores 78 is a second coating composition comprising a first therapeutic agent 80 and disposed within some of the cavities 76 is a third coating composition that includes a polymer 84. In other embodiments, the third coating composition can also include a therapeutic agent, wherein the therapeutic agent can be the same or a different therapeutic agent than that included in the first coating composition.

In some embodiments, as shown in FIG. 7, the coatings of the present invention can further include a third coating composition, disposed in a portion of the cavities, wherein the third coating composition includes a polymer. FIG. 7 shows a cross-sectional view of a coating of the present invention disposed on a surface of a stent strut. As shown in FIG. 7, stent strut 50 has an abluminal surface 52 and a luminal surface 54. In this embodiment, coating 60 is disposed on the abluminal surface 52 of stent strut 50. Coating 60 includes a first coating composition 70 having a metal, a metal oxide, ceramic oxide or inert carbon, wherein the first coating composition 70 has an exposed surface 72. The first coating composition 70 also has a plurality of cavities 74, at least some of which are in fluid communication with the exposed surface 72. The cavities 74 have a cavity surface 76. Additionally, the first coating composition includes a plurality of interconnected pores 78, some of which are in fluid communication with a cavity surface 76. As shown in this embodiment, disposed within some of the pores 78 and within a portion of some of the cavities 74 is a second coating composition that includes a first therapeutic agent 80. Also disposed within a portion of some of the cavities 76 is a third coating composition that includes a polymer 84. The therapeutic agent 80 disposed in a portion of at least some of the cavities 74 can serve as a reservoir while the third coating composition that includes a polymer 84 can serve as a cap, forcing the therapeutic agent 80 to travel through the porous network to the coating surface 72.

FIG. 8 shows a cross-sectional view of another embodiment where the cavities and pores are disposed in the surface 22′ of a stent strut. As shown in FIG. 8, stent strut 50 has an abluminal surface 52 and a luminal surface 54. In this embodiment, stent strut 50 includes a metal, a metal oxide, ceramic oxide or inert carbon. The stent sidewall structure 20′ of stent strut 50 also has a plurality of cavities 94 in fluid communication with the surface 52. The cavities 94 have a cavity surface 96. Additionally, the stent strut includes a plurality of pores 98, some of which are in fluid communication with a cavity surface 96. As shown in this embodiment, disposed within some of the pores 98 is a first composition comprising or including a therapeutic agent 100.

Additionally, embodiments of the present invention wherein the cavities and pores are disposed in the surface of the stent can also include coating compositions that include a therapeutic agent, a polymer, or both a therapeutic agent and a polymer like those described in FIGS. 2-7.

In accordance with the present invention, the cavities can have any shape. For example, the cavities can be shaped like cylinders or hemispheres. Cavities can also have non-circular cross-sectional shapes. Cavities can also be shaped like conduits, channels or void pathways. In certain embodiments the cavities can have cross-sectional shapes that are narrow at the top, near the exposed surface of the coating and then become broader near the surface of the medical device. Varying the shape can be used to maximize or optimize the surface area of the cavity surface which will determine the number of pores that can be in fluid communication with the cavity wall. Cavities having a cavity surface with a greater surface area will allow for a greater number of pores to be in fluid communication with the cavity surface. A greater number of pores will allow a greater amount of therapeutic agent to be loaded onto the medical device.

The cavities can be any size that will allow a sufficient number of pores to be formed in the cavity surface. For example, the cavities can be about 0.1 microns to about 20 microns in diameter or width. Preferably, the cavities can be about 1 micron to about 10 microns in diameter or width. Additionally, the cavities can be about 0.1 microns to about 20 microns deep. Preferably, the cavities can be about 1 micron to about 10 microns deep. In certain embodiments the cavities can be in fluid communication with the exposed surface of the medical device. Alternatively, in other embodiments the cavities may not be in fluid communication with the exposed surface of the medical device. Some or all of the cavities can be interconnected to other cavities.

Additionally, the pores can have any shape. For example, the pores can be shaped like cylinders, spheres or hemispheres. Pores can also have non-circular cross-sectional shapes. Pores can also be shaped like conduits, channels or void pathways. Varying the shape of the pores can be used to maximize or optimize that amount of therapeutic agent that can be loaded onto the surface of the medical device as well as the rate of release of the therapeutic agent. For example, pores having a larger width will allow the therapeutic agent to be released more quickly than pores with a smaller width. Also, the number of pores can be adjusted to control the release rate of the therapeutic agent. For example, the presence of more pores per unit area of the cavity surface or unit volume of the first coating material can increase the release rate of the therapeutic agent.

The pores are preferably smaller in size than the cavities and can be any size so long as at least some of the pores can be disposed on the cavity surface. For example, the pores can be about 0.001 microns to about 10 microns in diameter or width. Preferably, the pores can be about 0.01 microns to about 0.05 microns in diameter or width. Additionally, the pores can be about 0.001 microns to about 10 microns deep. Preferably, the pores can be about 0.01 microns to about 0.05 microns deep. In certain embodiments, some of the pores can be in fluid communication with the surface of the medical device and the cavity surface. Alternatively, in other embodiments the pores may not be in fluid communication with the surface of the medical device. Some or all of the pores can be interconnected to other pores.

A. Medical Devices

Suitable medical devices for the present invention include, but are not limited to, stents, surgical staples, cochlear implants, catheters, such as central venous catheters and arterial catheters, guidewires, cannulas, cardiac pacemaker leads or lead tips, cardiac defibrillator leads or lead tips, implantable vascular access ports, blood storage bags, blood tubing, vascular or other grafts, intra-aortic balloon pumps, heart valves, cardiovascular sutures, total artificial hearts and ventricular assist pumps, extra-corporeal devices such as blood oxygenators, blood filters, hemodialysis units, hemoperfusion units or plasmapheresis units.

Medical devices which are particularly suitable for the present invention include any stent for medical purposes, which are known to the skilled artisan. Suitable stents include, for example, vascular stents such as self-expanding stents and balloon expandable stents. Examples of self-expanding stents are illustrated in U.S. Pat. Nos. 4,655,771 and 4,954,126 issued to Wallsten and 5,061,275 issued to Wallsten et al. Examples of appropriate balloon-expandable stents are shown in U.S. Pat. No. 5,449,373 issued to Pinchasik et al. In preferred embodiments, the stent suitable for the present invention is an Express stent. More preferably, the Express stent is an Express™ stent or an Express2™ stent (Boston Scientific, Inc. Natick, Mass.).

The framework of the suitable stents may be formed through various methods as known in the art. The framework may be welded, molded, laser cut, electro-formed, or consist of filaments or fibers which are wound or braided together in order to form a continuous structure.

Medical devices that are suitable for the present invention may be fabricated from metallic, ceramic, polymeric or composite materials or a combination thereof. Preferably, the materials are biocompatible. Metallic material is more preferable. Suitable metallic materials include metals and alloys based on titanium (such as nitinol, nickel titanium alloys, thermo-memory alloy materials); stainless steel; tantalum, nickel-chrome; or certain cobalt alloys including cobalt-chromium-nickel alloys such as Elgiloy® and Phynox®; PERSS (Platinum EnRiched Stainless Steel) and Niobium. Metallic materials also include clad composite filaments, such as those disclosed in WO 94/16646.

Suitable ceramic materials include, but are not limited to, oxides, carbides, or nitrides of the transition elements such as titanium, hafnium, iridium, chromium, aluminum, and zirconium. Silicon based materials, such as silica, may also be used.

Suitable polymers for forming the medical devices may be biostable. Also, the polymer may be biodegradable. Suitable polymers include, but are not limited to, styrene isobutylene styrene, polyetheroxides, polyvinyl alcohol, polyglycolic acid, polylactic acid, polyamides, poly-2-hydroxy-butyrate, polycaprolactone, polylactic-co-glycolic acid, and Teflon.

Polymers may be used for forming the medical device in the present invention include without limitation isobutylene-based polymers, polystyrene-based polymers, polyacrylates, and polyacrylate derivatives, vinyl acetate-based polymers and its copolymers, polyurethane and its copolymers, silicone and its copolymers, ethylene vinyl-acetate, polyethylene terephtalate, thermoplastic elastomers, polyvinyl chloride, polyolefins, cellulosics, polyamides, polyesters, polysulfones, polytetrafluorethylenes, polycarbonates, acrylonitrile butadiene styrene copolymers, acrylics, polylactic acid, polyglycolic acid, polycaprolactone, polylactic acid-polyethylene oxide copolymers, cellulose, collagens, and chitins.

Other polymers that are useful as materials for medical devices include without limitation dacron polyester, poly(ethylene terephthalate), polycarbonate, polymethylmethacrylate, polypropylene, polyalkylene oxalates, polyvinylchloride, polyurethanes, polysiloxanes, nylons, poly(dimethyl siloxane), polycyanoacrylates, polyphosphazenes, poly(amino acids), ethylene glycol I dimethacrylate, poly(methyl methacrylate), poly(2-hydroxyethyl methacrylate), polytetrafluoroethylene poly(HEMA), polyhydroxyalkanoates, polytetrafluorethylene, polycarbonate, poly(glycolide-lactide) co-polymer, polylactic acid, poly(γ-caprolactone), poly(γ-hydroxybutyrate), polydioxanone, poly(γ-ethyl glutamate), polyiminocarbonates, poly(ortho ester), polyanhydrides, alginate, dextran, chitin, cotton, polyglycolic acid, polyurethane, or derivatized versions thereof, i.e., polymers which have been modified to include, for example, attachment sites or cross-linking groups, e.g., RGD, in which the polymers retain their structural integrity while allowing for attachment of cells and molecules, such as proteins, nucleic acids, and the like.

Medical devices may also be made with non-polymers. Examples of useful non-polymers include sterols such as cholesterol, stigmasterol, β-sitosterol, and estradiol; cholesteryl esters such as cholesteryl stearate; C₁₂-C₂₄fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and lignoceric acid; C₁₈-C₃₆mono-, di- and triacylglycerides such as glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glyceryl monodocosanoate, glyceryl monomyristate, glyceryl monodicenoate, glyceryl dipalmitate, glyceryl didocosanoate, glyceryl dimyristate, glyceryl didecenoate, glyceryl tridocosanoate, glyceryl trimyristate, glyceryl tridecenoate, glycerol tristearate and mixtures thereof; sucrose fatty acid esters such as sucrose distearate and sucrose palmitate; sorbitan fatty acid esters such as sorbitan monostearate, sorbitan monopalmitate and sorbitan tristearate; C₁₆-C₁₈fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol, and cetostearyl alcohol; esters of fatty alcohols and fatty acids such as cetyl palmitate and cetearyl palmitate; anhydrides of fatty acids such as stearic anhydride; phospholipids including phosphatidylcholine (lecithin), phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, and lysoderivatives thereof; sphingosine and derivatives thereof; sphingomyelins such as stearyl, palmitoyl, and tricosanyl sphingomyelins; ceramides such as stearyl and palmitoyl ceramides; glycosphingolipids; lanolin and lanolin alcohols; and combinations and mixtures thereof. Non-polymers may also include biomaterials such as stem sells, which can be seeded into the medical device prior to implantation. Preferred non-polymers include cholesterol, glyceryl monostearate, glycerol tristearate, stearic acid, stearic anhydride, glyceryl monooleate, glyceryl monolinoleate, and acetylated monoglycerides.

B. Coating Composition Materials

Metals, Metal Oxides, Ceramic Oxides and Carbons

When the first coating composition comprises a plurality of cavities and a plurality of pores, the first coating composition can include a metal, a metal oxide, ceramic oxide or inert carbon. The first coating composition can also be radiopaque and/or have MRI compatibility. Also, the first coating composition can have the same or some of the same materials that are used to make the medical device, specifically the medical device surface, on which the first coating composition is applied to.

Suitable metals include, but are not limited to, alkali metals, alkaline earth metals, transition metals, metal alloys and metalloids. Examples of metals include, but are not limited to, titanium, scandium, stainless steel, tantalum, nickel, Nitinol, chrome, cobalt, chromium, manganese, iron, platinum, iridium, niobium, vanadium, zirconium, tungsten, rhodium, ruthenium, gold, copper, zinc, yttrium, molybdenum, technetium, palladium, cadmium, hafnium, rhenium and combinations thereof. In certain embodiments, preferred metals include without limitation, gold tantalum, platinum, titanium, Nitinol or a combination thereof.

Suitable metal oxides and ceramic oxides include but are not limited to, platinum oxides, tantalum oxides, titanium oxides, zinc oxides, iron oxides, magnesium oxides, aluminum oxides, iridium oxides, niobium oxides, zirconium oxides, tungsten oxides, rhodium oxides, ruthenium oxides, hydroxyapatite, calcium phosphates, alumina, zirconia, zirconium, silicone oxides such as silica based glasses and silicon dioxide, or combinations thereof. In certain embodiments, preferred metal oxides or ceramic oxides include without limitation, iridium oxide, titanium oxide, titanium dioxide, iron oxide, hydroxyapatite, calcium phosphates, alumina, zirconia, zirconium, silica based glasses, or a combination thereof.

In other embodiments, the first coating composition can include inert carbon. Suitable forms of inert carbon can include with out limitation, pyrolitic carbon, porous vitreous carbon, diamond-like carbon, graphite and physical vapor deposition (PVD) carbon. Use of porous carbon can help prevent thrombosis and encourage endothelial cell growth.

In some embodiments, the metal, metal oxide, ceramic oxide or inert carbon can comprise at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99% or more by weight of the coating composition. Preferably, the metal, metal oxide, ceramic oxide or inert carbon is about 10% to about 70% by weight of the coating composition.

The first coating composition may be of any thickness. In some embodiments, the first coating composition preferably has a thickness of about 1 to about 30 microns. In some instances, a relatively thicker film may be preferred to incorporate deeper cavities with more cavity surface.

Therapeutic Agents

The term “therapeutic agent” as used in the present invention encompasses therapeutic agents, genetic materials, and biological materials and can be used interchangeably with “biologically active material”. In one embodiment, the therapeutic agent is an anti-restenotic agent. In other embodiments, the therapeutic agent inhibits smooth muscle cell proliferation, contraction, migration or hyperactivity. Non-limiting examples of suitable therapeutic agent include heparin, heparin derivatives, urokinase, dextrophenylalanine proline arginine chloromethylketone (PPack), enoxaprin, angiopeptin, hirudin, acetylsalicylic acid, tacrolimus, everolimus, zotarolimus, rapamycin (sirolimus), pimecrolimus, zotarolimus, amlodipine, doxazosin, glucocorticoids, betamethasone, dexamethasone, prednisolone, corticosterone, budesonide, sulfasalazine, rosiglitazone, mycophenolic acid, mesalamine, paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones, methotrexate, azathioprine, adriamycin, mutamycin, endostatin, angiostatin, thymidine kinase inhibitors, cladribine, lidocaine, bupivacaine, ropivacaine, D-Phe-Pro-Arg chloromethyl ketone, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, aspirin, dipyridamole, protamine, hirudin, prostaglandin inhibitors, platelet inhibitors, trapidil, liprostin, tick antiplatelet peptides, 5-azacytidine, vascular endothelial growth factors, growth factor receptors, transcriptional activators, translational promoters, antiproliferative agents, growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin, cholesterol lowering agents, vasodilating agents, agents which interfere with endogenous vasoactive mechanisms, antioxidants, probucol, antibiotic agents, penicillin, cefoxitin, oxacillin, tobranycin, angiogenic substances, fibroblast growth factors, estrogen, estradiol (E2), estriol (E3), 17-beta estradiol, digoxin, beta blockers, captopril, enalopril, statins, steroids, vitamins, paclitaxel (as well as its derivatives, analogs or paclitaxel bound to proteins, e.g. Abraxane™) 2′-succinyl-taxol, 2′-succinyl-taxol triethanolamine, 2′-glutaryl-taxol, 2′-glutaryl-taxol triethanolamine salt, 2′-O-ester with N-(dimethylaminoethyl) glutamine, 2′-O-ester with N-(dimethylaminoethyl) glutamide hydrochloride salt, nitroglycerin, nitrous oxides, nitric oxides, antibiotics, aspirins, digitalis, estrogen, estradiol and glycosides. In one embodiment, the therapeutic agent is a smooth muscle cell inhibitor or antibiotic. In a preferred embodiment, the therapeutic agent is taxol (e.g., Taxol®), or its analogs or derivatives. In another preferred embodiment, the therapeutic agent is paclitaxel, (i.e. paclitaxel, its analogs or derivatives). In yet another preferred embodiment, the therapeutic agent is an antibiotic such as erythromycin, amphotericin, rapamycin, adriamycin, etc.

The term “genetic materials” means DNA or RNA, including, without limitation, of DNA/RNA encoding a useful protein stated below, intended to be inserted into a human body including viral vectors and non-viral vectors.

The term “biological materials” include cells, yeasts, bacteria, proteins, peptides, cytokines and hormones. Examples for peptides and proteins include vascular endothelial growth factor (VEGF), transforming growth factor (TGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), cartilage growth factor (CGF), nerve growth factor (NGF), keratinocyte growth factor (KGF), skeletal growth factor (SGF), osteoblast-derived growth factor (BDGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), cytokine growth factors (CGF), platelet-derived growth factor (PDGF), hypoxia inducible factor-1 (HIF-1), stem cell derived factor (SDF), stem cell factor (SCF), endothelial cell growth supplement (ECGS), granulocyte macrophage colony stimulating factor (GM-CSF), growth differentiation factor (GDF), integrin modulating factor (IMF), calmodulin (CaM), thymidine kinase (TK), tumor necrosis factor (TNF), growth hormone (GH), bone morphogenic protein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (PO-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-14, BMP-15, BMP-16, etc.), matrix metalloproteinase (MMP), tissue inhibitor of matrix metalloproteinase (TIMP), cytokines, interleukin (e.g., IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-15, etc.), lymphokines, interferon, integrin, collagen (all types), elastin, fibrillins, fibronectin, vitronectin, laminin, glycosaminoglycans, proteoglycans, transferrin, cytotactin, cell binding domains (e.g., RGD), and tenascin. Currently preferred BMP's are BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7. These dimeric proteins can be provided as homodimers, heterodimers, or combinations thereof, alone or together with other molecules. Cells can be of human origin (autologous or allogeneic) or from an animal source (xenogeneic), genetically engineered, if desired, to deliver proteins of interest at the transplant site. The delivery media can be formulated as needed to maintain cell function and viability. Cells include progenitor cells (e.g., endothelial progenitor cells), stem cells (e.g., mesenchymal, hematopoietic, neuronal), stromal cells, parenchymal cells, undifferentiated cells, fibroblasts, macrophage, and satellite cells.

Other non-genetic therapeutic agents include:

- anti-thrombogenic agents such as heparin, heparin derivatives, urokinase, and PPack (dextrophenylalanine proline arginine chloromethylketone);
- anti-proliferative agents such as enoxaprin, angiopeptin, or monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, acetylsalicylic acid, tacrolimus, everolimus, amlodipine and doxazosin;
- anti-inflammatory agents such as glucocorticoids, betamethasone, dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, rosiglitazone, mycophenolic acid and mesalamine;
- anti-neoplastic/anti-proliferative/anti-miotic agents such as paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones, methotrexate, azathioprine, adriamycin and mutamycin; endostatin, angiostatin and thymidine kinase inhibitors, cladribine, taxol and its analogs or derivatives;
- anesthetic agents such as lidocaine, bupivacaine, and ropivacaine;
- anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, aspirin (aspirin is also classified as an analgesic, antipyretic and anti-inflammatory therapeutic agent), dipyridamole, protamine, hirudin, prostaglandin inhibitors, platelet inhibitors, antiplatelet agents such as trapidil or liprostin and tick antiplatelet peptides;
- DNA demethylating therapeutic agents such as 5-azacytidine, which is also categorized as a RNA or DNA metabolite that inhibit cell growth and induce apoptosis in certain cancer cells;
- vascular cell growth promoters such as growth factors, vascular endothelial growth factors (VEGF, all types including VEGF-2), growth factor receptors, transcriptional activators, and translational promoters;
- vascular cell growth inhibitors such as anti-proliferative agents, growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin;
- cholesterol-lowering agents, vasodilating agents, and agents which interfere with endogenous vasoactive mechanisms;
- anti-oxidants, such as probucol;
- antibiotic agents, such as penicillin, cefoxitin, oxacillin, tobranycin, rapamycin (sirolimus);
- angiogenic substances, such as acidic and basic fibroblast growth factors, estrogen including estradiol (E2), estriol (E3) and 17-beta estradiol; therapeutic agents for heart failure, such as digoxin, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors including captopril and enalopril, statins and related compounds; and
- macrolides such as sirolimus, everolimus, tacrolimus, pimecrolimus or zotarolimus.

Preferred biological materials include anti-proliferative therapeutic agents such as steroids, vitamins, and restenosis-inhibiting agents. Preferred restenosis-inhibiting agents include microtubule stabilizing agents such as Taxol®, paclitaxel (i.e., paclitaxel, paclitaxel analogs, or paclitaxel derivatives, and mixtures thereof). For example, derivatives suitable for use in the present invention include 2′-succinyl-taxol, 2′-succinyl-taxol triethanolamine, 2′-glutaryl-taxol, 2′-glutaryl-taxol triethanolamine salt, 2′-O-ester with N-(dimethylaminoethyl) glutamine, and 2′-O-ester with N-(dimethylaminoethyl) glutamide hydrochloride salt.

Other suitable therapeutic agents include tacrolimus; halofuginone; inhibitors of HSP90 heat shock proteins such as geldanamycin; microtubule stabilizing agents such as epothilone D; phosphodiesterase inhibitors such as cliostazole; Barkct inhibitors; phospholamban inhibitors; and Serca 2 gene/proteins.

Other preferred therapeutic agents include nitroglycerin, nitrous oxides, nitric oxides, aspirins, digitalis, estrogen derivatives such as estradiol and glycosides.

In one embodiment, the therapeutic agent is capable of altering the cellular metabolism or inhibiting a cell activity, such as protein synthesis, DNA synthesis, spindle fiber formation, cellular proliferation, cell migration, microtubule formation, microfilament formation, extracellular matrix synthesis, extracellular matrix secretion, or increase in cell volume. In another embodiment, the therapeutic agent is capable of inhibiting cell proliferation and/or migration.

In certain embodiments, the therapeutic agents for use in the medical devices of the present invention can be synthesized by methods well known to one skilled in the art. Alternatively, the therapeutic agents can be purchased from chemical and pharmaceutical companies.

In certain embodiments, when the cavities and pores are disposed in a coating composition, the therapeutic agent comprises at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99% or more by weight of the coating composition. Preferably, the therapeutic agent is about 5% to about 35% by weight of the coating composition. More preferably, the therapeutic agent is about 8% to about 20% by weight of the second or third coating composition.

In other embodiments, when the cavities and pores are disposed in the stent, the therapeutic agent comprises at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99% or more by weight of the composition. Preferably, the therapeutic agent is about 5% to about 35% by weight of the first or second composition. More preferably, the therapeutic agent is about 8% to about 20% percent by weight of the composition.

Polymers

Polymers useful in the present invention should be ones that are biocompatible, particularly during insertion or implantation of the device into the body and avoids irritation to body tissue. Examples of such polymers include, but not limited to, polyurethanes, polyisobutylene and its copolymers, silicones, and polyesters. Other suitable polymers include polyolefins, polyisobutylene, ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinyl halide polymers and copolymers such as polyvinyl chloride, polyvinyl ethers such as polyvinyl methyl ether, polyvinylidene halides such as polyvinylidene fluoride and polyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics such as polystyrene, polyvinyl esters such as polyvinyl acetate; copolymers of vinyl monomers, copolymers of vinyl monomers and olefins such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, ethylene-vinyl acetate copolymers, polyamides such as Nylon 66 and polycaprolactone, alkyd resins, polycarbonates, polyoxyethylenes, polyimides, polyethers, epoxy resins, polyurethanes, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, carboxymethyl cellulose, collagens, chitins, polylactic acid, polyglycolic acid, and polylactic acid-polyethylene oxide copolymers.

In certain embodiment hydrophobic polymers can be used. Examples of suitable hydrophobic polymers or monomers include, but not limited to, polyolefins, such as polyethylene, polypropylene, poly(1-butene), poly(2-butene), poly(1-pentene), poly(2-pentene), poly(3-methyl-1-pentene), poly(4-methyl-1-pentene), poly(isoprene), poly(4-methyl-1-pentene), ethylene-propylene copolymers, ethylene-propylene-hexadiene copolymers, ethylene-vinyl acetate copolymers, blends of two or more polyolefins and random and block copolymers prepared from two or more different unsaturated monomers; styrene polymers, such as poly(styrene), poly(2-methylstyrene), styrene-acrylonitrile copolymers having less than about 20 mole-percent acrylonitrile, and styrene-2,2,3,3-tetrafluoropropyl methacrylate copolymers; halogenated hydrocarbon polymers, such as poly(chlorotrifluoroethylene), chlorotrifluoroethylene-tetrafluoroethylene copolymers, poly(hexafluoropropylene), poly(tetrafluoroethylene), tetrafluoroethylene, tetrafluoroethylene-ethylene copolymers, poly(trifluoroethylene), poly(vinyl fluoride), and poly(vinylidene fluoride); vinyl polymers, such as poly(vinyl butyrate), poly(vinyl decanoate), poly(vinyl dodecanoate), poly(vinyl hexadecanoate), poly(vinyl hexanoate), poly(vinyl propionate), poly(vinyl octanoate), poly(heptafluoroisopropoxyethylene), poly(heptafluoroisopropoxypropylene), and poly(methacrylonitrile); acrylic polymers, such as poly(n-butyl acetate), poly(ethyl acrylate), poly(1-chlorodifluoromethyl)tetrafluoroethyl acrylate, poly di(chlorofluoromethyl)fluoromethyl acrylate, poly(1,1-dihydroheptafluorobutyl acrylate), poly(1,1-dihydropentafluoroisopropyl acrylate), poly(1,1-dihydropentadecafluorooctyl acrylate), poly(heptafluoroisopropyl acrylate), poly 5-(heptafluoroisopropoxy)pentyl acrylate, poly 11-(heptafluoroisopropoxy)undecyl acrylate, poly 2-(heptafluoropropoxy)ethyl acrylate, and poly(nonafluoroisobutyl acrylate); methacrylic polymers, such as poly(benzyl methacrylate), poly(n-butyl methacrylate), poly(isobutyl methacrylate), poly(t-butyl methacrylate), poly(t-butylaminoethyl methacrylate), poly(dodecyl methacrylate), poly(ethyl methacrylate), poly(2-ethylhexyl methacrylate), poly(n-hexyl methacrylate), poly(phenyl methacrylate), poly(n-propyl methacrylate), poly(octadecyl methacrylate), poly(1,1-dihydropentadecafluorooctyl methacrylate), poly(heptafluoroisopropyl methacrylate), poly(heptadecafluorooctyl methacrylate), poly(1-hydrotetrafluoroethyl methacrylate), poly(1,1-dihydrotetrafluoropropyl methacrylate), poly(1-hydrohexafluoroisopropyl methacrylate), and poly(t-nonafluorobutyl methacrylate); polyesters, such a poly(ethylene terephthalate) and poly(butylene terephthalate); condensation type polymers such as and polyurethanes and siloxane-urethane copolymers; polyorganosiloxanes, i.e., polymers characterized by repeating siloxane groups, represented by Ra SiO 4-a/2, where R is a monovalent substituted or unsubstituted hydrocarbon radical and the value of a is 1 or 2; and naturally occurring hydrophobic polymers such as rubber.

In alternative embodiments, hydrophilic polymers can be used. Examples of suitable hydrophilic polymers or monomers include, but not limited to; (meth)acrylic acid, or alkaline metal or ammonium salts thereof; (meth)acrylamide; (meth)acrylonitrile; those polymers to which unsaturated dibasic, such as maleic acid and fumaric acid or half esters of these unsaturated dibasic acids, or alkaline metal or ammonium salts of these dibasic adds or half esters, is added; those polymers to which unsaturated sulfonic, such as 2-acrylamido-2-methylpropanesulfonic, 2-(meth)acryloylethanesulfonic acid, or alkaline metal or ammonium salts thereof, is added; and 2-hydroxyethyl (meth)acrylate and 2-hydroxypropyl (meth)acrylate.

Polyvinyl alcohol is also an example of hydrophilic polymer. Polyvinyl alcohol may contain a plurality of hydrophilic groups such as hydroxyl, amido, carboxyl, amino, ammonium or sulfonyl (—SO₃). Hydrophilic polymers also include, but are not limited to, starch, polysaccharides and related cellulosic polymers; polyalkylene glycols and oxides such as the polyethylene oxides; polymerized ethylenically unsaturated carboxylic acids such as acrylic, mathacrylic and maleic acids and partial esters derived from these acids and polyhydric alcohols such as the alkylene glycols; homopolymers and copolymers derived from acrylamide; and homopolymers and copolymers of vinylpyrrolidone.

Additional suitable polymers include, but are not limited to, thermoplastic elastomers in general, polyolefins, polyisobutylene, ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinyl halide polymers and copolymers such as polyvinyl chloride, polyvinyl ethers such as polyvinyl methyl ether, polyvinylidene halides such as polyvinylidene fluoride and polyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics such as polystyrene, polyvinyl esters such as polyvinyl acetate, copolymers of vinyl monomers, copolymers of vinyl monomers and olefins such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS (acrylonitrile-butadiene-styrene) resins, ethylene-vinyl acetate copolymers, polyamides such as Nylon 66 and polycaprolactone, alkyd resins, polycarbonates, polyoxymethylenes, polyimides, polyethers, polyether block amides, epoxy resins, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, carboxymethyl cellulose, collagens, chitins, polylactic acid, polyglycolic acid, polylactic acid-polyethylene oxide copolymers, EPDM (ethylene-propylene-diene) rubbers, fluoropolymers, fluorosilicones, polyethylene glycol, polysaccharides, phospholipids, and combinations of the foregoing.

Other polymers which can be used include ones that can be easily dissolved in water or organic solvents, cured or polymerized in the cavities of the first coating composition, have relatively low melting points and/or can be blended with therapeutic agents. Also bioabsorbable polymers may be used wherein the therapeutic agent is release as the polymer is absorbed into the body. An additional advantage of using a bioabsorbable material is that once the polymer is absorbed, the empty cavities can help prevent thromboses and encourage endothelial cell growth.

In certain embodiments preferred polymers include, but are not limited to, styrene-isobutylene-styrene, polylactic-co-glycolic acid (PLGA), polybutyl methacrylate (PBMA), polyvinylidene fluoride (PVDF), or a combination thereof.

C. Methods of Making the Coatings

In certain embodiments, the medical devices of the present invention are made by a method that includes the steps of disposing a first coating composition on at least a portion of a surface of a medical device wherein the first coating composition includes a metal, metal oxide, ceramic oxide or inert carbon; forming a plurality of cavities in the first coating composition, wherein the cavities have a cavity surface; forming a plurality of pores within the cavity surface; and disposing a second coating composition in the pores wherein the second coating composition includes a therapeutic agent.

In other embodiments, the medical device coatings of the present invention can be made by a method including the steps of disposing a first coating composition on at least a portion of a surface of a medical device wherein the first coating composition includes a metal, metal oxide, ceramic oxide or inert carbon; forming a plurality of pores within the first coating composition; thereafter forming a plurality of cavities in the first coating composition, wherein the cavities have a cavity surface and wherein at least some of the pores are in fluid communication with at least a cavity surface; and disposing a second coating composition in the pores wherein the second coating composition includes a therapeutic agent.

In the above methods, the first coating composition can be disposed on at least a portion of the surface of the medical device by any suitable method such as, but not limited to, dipping, spraying, painting, electroplating, evaporation, plasma vapor deposition, physical vapor deposition, cathodic-arc deposition, sputtering, ion implantation, electrostatically, electrochemically or a combination thereof.

The cavities and/or the pores in the first coating composition can be formed by any method known in the art as well. These methods include, but are not limited to, laser ablation, drilling, or chemical etching, microcontact printing, inkjet printing, screen printing, replica molding, microtransfer molding, micromolding in capillaries, solvent-assisted micromolding, proximal probe lithography, photolithography, scanning probe lithography, and embossing techniques.

Additionally, cavities and/or the pores in the first coating composition can be formed by removing a secondary material from the first coating composition. Techniques for removing a secondary material include, but are not limited to, dealloying or anodization processes. For example, a first coating composition containing a secondary material is disposed on a portion of a surface of a medical device. The first coating composition comprises a metal, metal oxide, ceramic oxide or inert carbon. The secondary material can be any material so long as it can be removed from the first coating composition. For example, the secondary material can be more electrochemically active than other metals in the coating composition. Preferably, the secondary material is a metal. Suitable metals include, but are not limited to, silver, gold, tantalum, platinum, bismuth, iridium, zirconium, iodine, titanium, and barium. After the first coating composition with the secondary material is disposed on the surface of the medical device, a plurality of cavities and/or pores are formed in the first coating composition by removing the secondary material.

The secondary material can be removed from the first coating composition by a dealloying process such as selective dissolution of the secondary material. In this method, the first coating composition and the secondary material are exposed to an acid which removes the secondary metal. Thus, the first coating composition is preferably one that will not dissolve when exposed to the acid, while the secondary metal is one that will dissolve. Any suitable acid can be used to remove the second metal. One of ordinary skill in the art would recognize the appropriate concentration and reaction conditions to use to remove the second metal. For example, if the secondary material is silver, nitric acid may be used at a concentration of up to 35% and a temperature up to 120° F. Also, a nitric acid and sulfuric acid mixture (95%/5%) immersion process at 80° F. may be used. The reaction conditions may be varied to vary the geometry, distribution, and depth of the coating layer.

Alternatively, the secondary material can be removed anodically. For example, silver may be removed anodically using a dilute nitric acid bath comprising up to 15% nitric acid, wherein the anode is the plated stent, and the cathode is platinum. Voltages up to 10V DC can be applied across the electrodes. The bath chemistry, temperature, applied voltage, and process time may be varied to vary the geometry, distribution, and depth of the coating layer. In another example, a Technic Envirostrip Ag 10-20 amps per square foot may be used with a stainless steel cathode.

In another embodiment, the present invention includes a method of coating a medical device that includes the steps of masking a portion of a surface of a medical device, such as a stent, with a masking material; disposing a first coating composition on the surface of the medical device, wherein the first coating composition includes a metal, metal oxide, ceramic oxide or inert carbon; forming a plurality of pores in the first coating composition; removing the masking material, creating a plurality of cavities; and disposing a second coating composition in the pores wherein, the second coating composition comprises a therapeutic agent.

For example, before the first coating composition is disposed on a portion of the surface of the medical device, polymer droplets can be applied to a portion of a surface of a medical device to mask the portion of the surface which that will comprise the cavities. The polymer droplets can be applied by methods such as inkjet printing and lithography. Once the first coating composition is disposed on the surface of the medical device, the polymer is removed, forming a plurality of cavities.

In the embodiments where the first coating composition includes cavities and pores, a second coating composition can be disposed in the pores. The second coating composition can include a therapeutic agent. Alternatively, the second coating composition can further include a polymer. The second coating composition can be disposed in the pores or cavities of the first coating composition in any suitable way known in the art. Such methods include, but are not limited to, inkjet printing or vacuum impregnation. Additional methods include coating the medical device with the second coating composition and removing the excess. For example, the second coating composition can be applied to a portion of a surface of a medical device by such methods as dipping, spraying, painting, roll coating, or a combination thereof and then removing the excess.

To facilitate disposing the second coating composition within the pores, a solution or suspension can be formed by dissolving or suspending the therapeutic agent in an organic or aqueous solvent, which is then disposed in at least some of the pores and the solvent is removed.

The above methods can further include disposing the second coating composition within at least some of the cavities. Alternatively, in other embodiments of the methods of the present invention, the methods can further include disposing a third coating composition within the cavities. The third coating composition can include a second therapeutic agent, wherein the second therapeutic agent is the same or different therapeutic agent than the first therapeutic agent. Alternatively, the third therapeutic agent can include a polymer or a polymer and a second therapeutic agent.

In general, when the coating compositions of the present invention includes polymer or a therapeutic agent and a polymer, a monomer can be mixed together and disposed in the pores and/or cavities with an initiator. Once in the pores and/or cavities the monomer can be polymerized by such methods as exposure to UV radiation or heat. The degree of polymerization, monomer and initiator used will be determined by the desired rate of release of the therapeutic agent.

Also encompassed in the present invention are methods of making an implantable stent having a surface including a metal, a metal oxide, ceramic oxide or inert carbon, wherein the method includes the steps of forming a plurality of pores in the metal oxide, ceramic oxide or inert carbon surface; forming a plurality of cavities in the metal, metal oxide, ceramic oxide or inert carbon surface, wherein the cavities have a cavity surface and wherein at least some of the pores are in fluid communication with the cavity surface; and disposing a first composition having a first therapeutic agent within at least some of the pores.

Alternatively, in certain embodiments of the methods of the present invention include methods of making an implantable stent having a surface having a metal, a metal oxide, ceramic oxide or inert carbon, the method comprising forming a plurality of cavities in the metal, metal oxide, ceramic oxide or inert carbon surface, wherein the cavities have a cavity surface thereafter; forming a plurality of pores in the metal, metal oxide, ceramic oxide or inert carbon surface, wherein at least some of the pores are in fluid communication with the cavity surface; and disposing a first composition having a first therapeutic agent within at least some of the pores.

Cavities and pores can be formed in the metal, metal oxide, ceramic oxide or inert carbon surface of a stent by any methods known in the art. For example, the cavities and the pores can be formed by the methods used to form the cavities and pores in the first coating composition discussed above.

Once cavities and pores are formed in the metal, metal oxide, ceramic oxide or inert carbon surface of the stent, a first composition can be disposed in the pores. The first composition can include a therapeutic agent. Alternatively, the first composition can further include a polymer. The first composition can be disposed in the pores of the surface of the stent in any suitable way known in the art. Such methods include, but are not limited to, inkjet printing or vacuum impregnation. Additional methods include coating the medical device with the first composition and removing the excess. For example, the first composition can be applied to a portion of a surface of a medical device by such methods as dipping, spraying, painting, roll coating, or a combination thereof and then removing the excess.

To facilitate disposing the first composition within the pores in the metal, metal oxide, ceramic oxide or inert carbon surface of the sent, a solution or suspension can be formed by dissolving or suspending a therapeutic agent in an organic or aqueous solvent which is then deposited in at least some of the pores and then the solvent is removed. The first composition can also be disposed within at least some of the cavities.

The medical devices and stents of the present invention may be used for any appropriate medical procedure. Delivery of the medical device can be accomplished using methods well known to those skilled in the art.

The following examples are for purposes of illustration and not for purposes of limitation.

EXAMPLE 1

A stainless steel stent is coated with a porous carbon coating having pores of nanometer size. The coating is applied using a PVD process. Cavities are ablated in the carbon coating using a UV laser, excimer or DPSS laser focused to a small size (<10 microns). The stent is then sprayed with a solution of paclitaxel in a toluene/TFH solvent system.

The description contained herein is for purposes of illustration and not for purposes of limitation. Changes and modifications may be made to the embodiments of the description and still be within the scope of the invention. Furthermore, obvious changes, modifications or variations will occur to those skilled in the art. Also, all references cited above are incorporated herein, in their entirety, for all purposes related to this disclosure.

Claims

1. An implantable stent comprising: a stent sidewall structure comprising(a) a stent strut body having a surface defined by the stent strut body or by a surface coating on the stent strut body, the surface comprising a metal, a metal oxide, a ceramic oxide, or inert carbon;(b) the surface defining a plurality of cavities therein, at least some of the cavities being in fluid communication with the surface and at least one cavity being defined by a cavity surface having a plurality of pores therein;(c) a second coating composition comprising a first therapeutic agent, wherein the second coating composition is disposed within a portion of at least one of the cavities; and(d) a cap disposed in the at least one of the cavities and covering the second coating composition, wherein the cap is within the at least one of the cavities and wherein at least some of the pores in the cavity surface being not covered by the cap and being in fluid communication with the surface,thereby causing the first therapeutic agent to release through the pores to the surface and to not substantially release from the cavity directly to the surface.
2. The implantable stent of claim 1, wherein: the stent sidewall structure comprises the stent strut body and the surface coating on the stent strut, the surface is a surface of the surface coating, and the cavities are defined by the surface coating.
3. The stent of claim 1, wherein the sidewall structure comprises a plurality of struts and openings in the sidewall structure.
4. The stent of claim 2, wherein the surface is on an abluminal side of the stent strut body.
5. The stent of claim 3, wherein the surface coating conforms to a surface of the stent strut body so that the openings of the stent sidewall structure are preserved, and wherein the surface of the sidewall structure comprises an abluminal surface.
6. The stent of claim 1, wherein the stent is an intravascular balloon-expandable stent.
7. The stent of claim 1, wherein the stent is an intravascular self-expanding stent.
8. The stent of claim 2, wherein the surface coating composition is radiopaque.
9. The stent of claim 2, wherein the surface coating composition is free of any polymer.
10. The stent of claim 2, wherein the pores are distributed throughout the surface coating.
11. The stent of claim 10, wherein the pores are homogenously distributed throughout the surface coating.
12. The stent of claim 1, wherein the second coating composition is also disposed within at least one of the pores.
13. The stent of claim 1, wherein the second coating composition further comprises a polymer.
14. The stent of claim 13, wherein the polymer is biostable.
15. The stent of claim 13, wherein the polymer is bioabsorbable.
16. The stent of claim 13, wherein the polymer comprises styrene-isobutylene-styrene, polylactic-co-glycolic acid (PLGA), polybutyl methacrylate (PBMA), polyvinylidene fluoride (PVDF), or a combination thereof.
17. The stent of claim 1, wherein the metal oxide or ceramic oxide comprises iridium oxide, titanium oxide, titanium dioxide, iron oxide, hydroxyapatite, calcium phosphates, alumina, zirconia, zirconium, silica based glasses, or a combination thereof.
18. The stent of claim 1, wherein the metal comprises gold, tantalum, platinum, titanium, Nitinol or a combination thereof.
19. The stent of claim 1, wherein the surface coating is about 1 micron to about 30 microns thick.
20. The stent of claim 1, wherein the diameter of the pores is less than or equal to one micron.
21. The stent of claim 1, wherein the width of the cavities is greater than or equal to one micron.
22. The stent of claim 1, wherein the stent sidewall structure further comprises a third coating composition comprising a second therapeutic agent and, wherein the third coating composition is disposed within the pores.
23. The stent of claim 22, wherein the first therapeutic agent and second therapeutic agent are different.
24. The stent of claim 1, wherein the first therapeutic agent comprises an anti-thrombogenic agent, anti-angiogenesis agent, anti-proliferative agent, antibiotic, anti-restenosis agent, growth factor, immunosuppressant, or radiochemical.
25. The stent of claim 1, wherein the first therapeutic agent comprises an anti-restenosis agent.
26. The stent of claim 1, wherein the first therapeutic agent comprises paclitaxel.
27. The stent of claim 1, wherein the first therapeutic agent comprises sirolimus, tacrolimus, pimecrolimus, zotarolimus, or everolimus.
28. The stent of claim 1, wherein the cap comprises a polymer.
29. The stent of claim 1, wherein the stent sidewall structure further comprises a third coating composition comprising a second therapeutic agent, wherein the third coating composition is disposed in at least some of the pores.
30. The stent of claim 29, wherein the first therapeutic agent and second therapeutic agent are different.
31. The stent of claim 29, wherein the third coating composition further comprises a polymer.
32. The implantable stent of claim 1, wherein the stent sidewall structure comprises the stent strut body and the surface is a surface of the stent strut body.
33. The stent of claim 32, wherein the surface of the stent strut body is an abluminal surface.
34. The stent of claim 32, wherein the pores are distributed throughout the stent strut body.
35. The stent of claim 32, wherein the pores are homogenously distributed throughout the stent strut body.
36. A method of coating an implantable stent having a stent sidewall structure, the stent sidewall structure comprising a stent strut body having a surface defined by the stent strut body or by a surface coating on the stent strut body, the surface coating comprising a surface coating composition comprising a metal, a metal oxide or a ceramic oxide, or inert carbon, the stent sidewall structure defining a plurality of pores therein and, the method comprising: (a) creating a plurality of cavities in the surface, wherein the cavities have a cavity surface and wherein at least some of the pores are in fluid communication with a portion of the cavity surface;(b) disposing a second composition comprising a first therapeutic agent within a portion of at least one of the cavities; and(c) forming a cap in the at least one of the cavities to cover the second coating composition, wherein the cap is within the at least one of the cavities and wherein at least some of the pores in the cavity surface being not covered by the cap and being in fluid communication with the surface,thereby causing the first therapeutic agent to release through the pores to the surface and to not substantially release from the cavity directly to the surface.
37. The method of claim 36, wherein the stent sidewall structure comprises the stent strut body with the surface coating and the cavities are created in the surface coating composition.
38. The method of claim 36, further comprising disposing the second coating composition within at least some of the pores.
39. The method of claim 37, further comprising disposing a third coating composition within at least some of the pores, wherein the third coating composition comprises a second therapeutic agent.
40. The method of claim 36, wherein the cap comprises a polymer.
41. The method of claim 36, wherein the second coating composition further comprises a polymer.
42. The method of claim 36, wherein the cavities are created by laser ablation, drilling, chemical etching or a combination thereof.
43. The method of claim 36, further comprising disposing a third coating composition within at least some of the pores, wherein the third coating composition comprises a second therapeutic agent.
44. The method of claim 36, wherein the surface of the stent sidewall structure is a surface of the stent strut body, the pores are defined in the stent strut body, and the cavities are created in the stent strut body.
45. A method of coating an implantable stent having a stent sidewall structure, the stent sidewall structure comprising a strut and a surface coating comprising a surface coating composition comprising a metal, a metal oxide or a ceramic oxide, or inert carbon, the method comprising: (a) creating a plurality of cavities in the metal or ceramic oxide or inert carbon, wherein the cavities have a cavity surface;(b) creating a plurality of pores in the metal or ceramic oxide or inert carbon and wherein at least some of the pores are in fluid communication with a portion of the cavity surface; and(c) disposing a second composition comprising a first therapeutic agent within a portion of at least one of the cavities; and(d) forming a cap in the at least one of the cavities to cover the second coating composition, wherein the cap is within the at least one of the cavities and wherein at least some of the pores in the cavity surface being not covered by the cap and being in fluid communication with the surface,thereby causing the first therapeutic agent to release through the pores to the surface and to not substantially release from the cavity directly to the surface.
46. The method of claim 45, further comprising disposing the second composition within at least some of the pores.
47. The method of claim 45, further comprising disposing a third coating composition within at least some of the pores, wherein the third coating composition comprises a second therapeutic agent.
48. The method of claim 45, wherein the cap comprises a polymer.
49. The method of claim 45, wherein the cavities are formed by laser ablation, drilling, chemical etching or a combination thereof.
50. The implantable stent of claim 1, wherein the cap is within the at least one of the cavities and at least some of the pores in the cavity surface being not covered by the cap and being in fluid communication with the surface.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 60/904,674, filed Mar. 1, 2007.

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Related Publications (1)

	Number	Date	Country
	20080243231 A1	Oct 2008	US

Provisional Applications (1)

	Number	Date	Country
	60904674	Mar 2007	US

Medical device with a porous surface for delivery of a therapeutic agent

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