Patent Grant
7819914
1. Field of the Invention
The present invention relates to tissue-supporting medical devices, and more particularly to expandable, non-removable devices that are implanted within a bodily lumen of a living animal or human to support the organ and maintain patency, and that have openings for delivery of a plurality of beneficial agents to the intervention site as well as a surface coating of an antithrombotic agent. The present invention also relates to primer coatings for use between the antithrombotic agent coating and other therapeutic agent/polymer matrices.
2. Discussion of the Related Art
In the past, permanent or biodegradable devices have been developed for implantation within a body passageway to maintain patency of the passageway. These devices are typically introduced percutaneously, and transported transluminally until positioned at a desired location. These devices are then expanded either mechanically, such as by the expansion of a mandrel or balloon positioned inside the device, or expand themselves by releasing stored energy upon actuation within the body. Once expanded within the lumen, these devices, called stents, become encapsulated within the body tissue and remain a permanent implant.
Known stent designs include monofilament wire coil stents (U.S. Pat. No. 4,969,458); welded metal cages (U.S. Pat. Nos. 4,733,665 and 4,776,337); and, most prominently, thin-walled metal cylinders with axial slots formed around the circumference (U.S. Pat. Nos. 4,733,665; 4,739,762; and 4,776,337). Known construction materials for use in stents include polymers, organic fabrics and biocompatible metals, such as, stainless steel, gold, silver, tantalum, titanium, and shape memory alloys, such as nickel-titanium.
U.S. Pat. No. 6,241,762, which is incorporated herein by reference in its entirety, discloses a non-prismatic stent design which remedies several performance deficiencies of previous stents. In addition, preferred embodiments disclosed in this patent provide a stent with large, non-deforming strut and link elements, which may contain holes without compromising the mechanical properties of the strut or link elements, or the device as a whole. Further, these holes may serve as large, protected reservoirs for delivering various beneficial agents to the device implantation site without the need for a surface coating on the stent.
Of the many problems that may be addressed through stent-based local delivery of beneficial agents, one of the most important is restenosis. Restenosis is a major complication that may arise following vascular interventions such as angioplasty and the implantation of stents. Simply defined, restenosis is a wound healing process that reduces the vessel lumen diameter by extracellular matrix deposition and vascular smooth muscle cell proliferation and which may ultimately result in renarrowing or even reocclusion of the lumen. Despite the introduction of improved surgical techniques, devices and pharmaceutical agents, the overall restenosis rate for bare metal stents is still reported in the range of about twenty-five percent to about fifty percent within six to twelve months after an angioplasty procedure. To treat this condition, additional revascularization procedures are frequently required, thereby increasing trauma and risk to the patient.
Conventional stents with surface coatings of various beneficial agents have shown promising results in reducing restenosis. U.S. Pat. No. 5,716,981, for example, discloses a stent that is surface-coated with a composition comprising a polymer carrier and paclitaxel. The patent offers detailed descriptions of methods for coating stent surfaces, such as spraying and dipping, as well as the desired character of the coating itself: it should “coat the stent smoothly and evenly” and “provide a uniform, predictable, prolonged release of the anti-angiogenic factor.” Surface coatings, however, may provide little actual control over the release kinetics of beneficial agents. These coatings are necessarily very thin, typically five to eight microns deep. The surface area of the stent, by comparison is very large, so that the entire volume of the beneficial agent has a very short diffusion path to discharge into the surrounding tissue. The resulting cumulative drug release profile is characterized by a large initial burst, followed by a rapid approach to an asymptote, rather than the desired “uniform, prolonged release,” or linear release.
Increasing the thickness of the surface coating has the beneficial effects of improving drug release kinetics including the ability to better control drug release and to allow increased drug loading. However, the increased coating thickness results in an increased overall thickness of the stent wall. This is undesirable for a number of reasons, including potential increased trauma to the vessel lumen during implantation, reduced flow cross-section of the lumen after implantation, and increased vulnerability of the coating to mechanical failure or damage during expansion and implantation. Coating thickness is one of several factors that affect the release kinetics of the beneficial agent, and limitations on thickness thereby limit the range of release rates, durations, and the like that may be achieved.
Surface coatings may also limit the delivery of multiple drugs from a stent. For example, if multiple drugs were to be released from a surface coating, the release rates, delivery periods and other release characteristics may not be independently controlled in a facile way. However, restenosis involves multiple biological processes and may be treated most effectively by a combination of drugs selected to act on these different biological processes.
A paper entitled “Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery” by Chao-Wei Hwang et al. has revealed an important interrelationship between the spatial and temporal drug distribution properties of drug eluting stents, and cellular drug transport mechanisms. In pursuit of enhanced mechanical performance and structural properties, stent designs have evolved to more complex geometries with inherent inhomogeneity in the circumferential and longitudinal distribution of stent struts. Examples of this trend are the typical commercially available stents which expand to a roughly diamond or polygonal shape when deployed in a bodily lumen. Both have been used to deliver a beneficial agent in the form of a surface coating. Studies have shown that lumen tissue portions immediately adjacent to the struts acquire much higher concentrations of drug than more remote tissue portions, such as those located in the middle of the “diamond” shaped strut cells. Significantly, this concentration gradient of drug within the lumen wall remains higher over time for hydrophobic beneficial agents, such as paclitaxel or a rapamycin, which have proven to be the most effective anti-restinotics to date. Because local drug concentrations and gradients are inextricably linked to biological effects, the initial spatial distribution of the beneficial agent sources (the stent struts) is key to efficacy.
In addition to the sub-optimal spatial distribution of beneficial agents, there are further potential disadvantages with surface coated stents. Certain fixed matrix polymer carriers frequently used in the device coatings typically retain a significant percent of the beneficial agent in the coating indefinitely. Since these beneficial agents may be cytotoxic, for example, paclitaxel, sub-acute and chronic problems such as chronic inflammation, late thrombosis, and late or incomplete healing of the vessel wall may occur. Additionally, the carrier polymers themselves are often inflammatory to the tissue of the vessel wall. On the other hand, the use of bio-degradable polymer carriers on stent surfaces may result in “mal-apposition” or voids between the stent and tissue of the vessel wall after the polymer carrier has degraded. The voids permit differential motion between the stent and adjacent tissue. Resulting problems include micro-abrasion and inflammation, stent drift, and failure to re-endothelialize the vessel wall.
Early human clinical trials suggest that there may be certain disadvantages associated with first generation drug delivery devices. Follow-up examination of clinical trial patients at six to eighteen months after drug coated stent implantation indicates that mal-apposition of stent struts to arterial walls and edge effect restenosis may occur in significant numbers of patients. Edge effect restenosis occurs just beyond the proximal and distal edges of the stent and progresses around the stent edges and into the interior (luminal) space, frequently requiring repeat revascularization of the patient.
Another potential disadvantage is that expansion of the stent may stress an overlying polymeric coating causing the coating to peel, crack, or rupture which may effect drug release kinetics or have other untoward effects. These effects have been observed in first generation drug coated stents when these stents are expanded to larger diameters, preventing their use thus far in larger diameter arteries. Further, expansion of such a coated stent in an atherosclerotic blood vessel will place circumferential shear forces on the polymeric coating, which may cause the coating to separate from the underlying stent surface. Such separation may again have untoward effects including embolization of coating fragments causing vascular obstruction.
Another problem that may be addressed through stent-based local delivery of beneficial agents is thrombosis. A stent may be coated with an anti-thrombotic agent in addition to one or more therapeutic agents for treating restenosis. However, depending on the coatings on the surface of the stent, for example, an antithrombotic drug coating, additional layer(s) or primer layer(s) may be preferable to enhance the adhesion of other therapeutic agents to the coated surfaces of the stent.
The adhesion promoting primer for heparin coated surfaces of the present invention overcomes the difficulties briefly described above.
In accordance with one aspect, the present invention is directed to an implantable medical device. The implantable medical device comprising an intraluminal scaffold having a plurality of openings therein, a first coating comprising a material having a first electric charge affixed to at least a portion of a surface of the intraluminal scaffold and a surface of the plurality of openings, a second coating comprising a material having a second electric charge affixed to at least a portion of the first coating, the second electric charge being opposite of the first electric charge, and at least one therapeutic agent deposited in at least one of the plurality of openings, wherein the second coating is configured as an intermediate layer between the first coating and the at least one therapeutic agent.
In accordance with another aspect, the present invention is directed to an implantable medical device. The implantable medical device comprising a substantially cylindrical intraluminal scaffold which is expandable from a first diameter for delivery into a vessel, to a second diameter for expanding the vessel, the intraluminal scaffold having a luminal surface and an abluminal surface, the distance between the luminal surface and the abluminal surface defining the wall thickness of the intraluminal scaffold, the intraluminal scaffold also including a plurality of openings extending from the luminal to abluminal surface, a first coating comprising a material having a first electric charge affixed to at least a portion of the abluminal surface, the luminal surface and a surface of the plurality of openings, a second coating comprising a material having a second electric charge affixed to at least a portion of the first coating, the second electric charge being opposite of the first electric charge, and at least one therapeutic agent deposited in at least one of the plurality of openings, wherein the second coating is configured as an intermediate bonding layer between the first coating and the at least one therapeutic agent.
In accordance with another aspect, the present invention is directed to a method for coating an intraluminal scaffold having a plurality of openings therein. The method comprising applying a first coating comprising a material having a first electric charge to at least a portion of a surface of the intraluminal scaffold and a surface of the plurality of openings, applying a second coating comprising a material having a second electric charge to at least a portion of the first coating, the second electric charge being opposite of the first electric charge, and applying at least one therapeutic agent into at least one of the plurality of openings.
In view of the drawbacks of the prior art, it would be advantageous to provide a stent capable of delivering a relatively large volume of a beneficial agent to a traumatized site in a vessel lumen while avoiding the numerous potential problems associated with surface coatings containing beneficial agents, without increasing the effective wall thickness of the stent, and without adversely impacting the mechanical expansion properties of the stent.
It would further be advantageous to provide a tissue supporting device with different beneficial agents provided in different holes to achieve a desired spatial distribution of two or more beneficial agents.
It would further be advantageous to provide a tissue supporting device with different beneficial agents provided in different holes to achieve a desired different release kinetic for two different beneficial agents from the same device.
It would further be advantageous to provide a tissue supporting device having all surfaces coated with an anti-thrombotic agent and then utilize a primer in the holes or openings therein to increase the adhesion of the one or more beneficial agents that fill the holes.
The present invention is directed to primer compositions and configurations for improving the adhesion of a drug delivery matrix, e.g. therapeutic agent and polymer combination, to openings of a medical device, for example, a stent, that have a heparin coating. The present invention is particularly advantageous where the heparin coating is covalently bonded to a metallic or polymer surface of the medical device. In the present invention, the primer preferably comprises a high molecular weight component or a low molecular weight component, and the drug delivery matrix comprises a drug and/or other beneficial agent and an excipient, preferably a polymeric excipient. In addition, the primer may also preferably comprise a material having an opposite charge with similar density to that of the underlying layer, for example, heparin.
The foregoing and other features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention as illustrated in the accompanying drawings.
As illustrated in
The exemplary embodiments of the present invention may be further refined by using Finite Element Analysis and other techniques to optimize the deployment of the beneficial agents within the openings 30. Basically, the shape and location of the openings 30, may be modified to maximize the volume of the voids while preserving the relatively high strength and rigidity of the struts with respect to the ductile hinges 20. According to one preferred exemplary embodiment of the present invention, the openings have an area of at least 5×10−6 square inches, and preferably at least 7×10−6 square inches. Typically, the openings are filled, from about fifty percent to about ninety-five percent full of beneficial agent.
The terms “agent,” “therapeutic agent” or “beneficial agent” as used herein are intended to have the broadest possible interpretation and are used to include any therapeutic agent or drug, as well as inactive agents such as barrier layers, carrier layers, therapeutic layers, or protective layers.
The terms “drug” and “therapeutic agent” are used interchangeably to refer to any therapeutically active substance that is delivered to a bodily lumen of a living being to produce a desired, usually beneficial, effect. Beneficial agents may include one or more drug or therapeutic agent.
The present invention is particularly well suited for the delivery of antineoplastics, antiangiogenics, angiogenic factors, anti-inflammatories, immuno-suppressants such as a rapamycin, antirestenotics, antiplatelet agents, vasodilators, anti-thrombotics, antiproliferatives, such as paclitaxel, for example, and antithrombins, such as heparin, for example.
The term “erosion” means the process by which components of a medium or matrix are bioresorbed and/or degraded and/or broken down by chemical or physical or enzymatic processes. For example in reference to biodegradable polymer matrices, erosion may occur by cleavage or hydrolysis of the polymer chains, thereby increasing the solubility of the matrix and suspended beneficial agents.
The term “erosion rate” is a measure of the amount of time it takes for the erosion process to occur, usually reported in unit-area per unit-time.
The terms “matrix” or “bioresorbable matrix” are used interchangeably to refer to a medium or material that, upon implantation in a subject, does not elicit a detrimental response sufficient to result in the rejection of the matrix. The matrix typically does not provide any therapeutic responses itself, though the matrix may contain or surround a beneficial agent, as defined herein. A matrix is also a medium that may simply provide support, structural integrity or structural barriers. The matrix may be polymeric, non-polymeric, hydrophobic, hydrophilic, lipophilic, amphiphilic, and the like. In addition, bioresorbable matrix shall also be understood to mean complete absorption of the matrix by the body over time.
The term “openings” includes both through openings and recesses.
The term “pharmaceutically acceptable” refers to the characteristic of being non-toxic to a host or patient and suitable for maintaining the stability of a beneficial agent and allowing the delivery of the beneficial agent to target cells or tissue.
The term “polymer” refers to molecules formed from the chemical union of two or more repeating units, called monomers. Accordingly, included within the term “polymer” may be, for example, dimers, trimers and oligomers. The polymer may be synthetic, naturally-occurring or semisynthetic. In preferred form, the term “polymer” refers to molecules which typically have a MW greater than about 3000 and preferably greater than about 10,000 and a MW that is less than about 10 million, preferably less than about a million and more preferably less than about 200,000. Examples of polymers include but are not limited to, poly-.alpha.-hydroxy acid esters such as, polylactic acid (PLLA or DLPLA), polyglycolic acid, polylactic-co-glycolic acid (PLGA), polylactic acid-co-caprolactone; poly(block-ethylene oxide-block-lactide-co-glycolide)polymers (PEO-block-PLGA and PEO-block-PLGA-block-PEO); polyethylene glycol and polyethylene oxide, poly(block-ethylene oxide-block-propylene oxide-block-ethylene oxide); polyvinyl pyrrolidone; polyorthoesters; polysaccharides and polysaccharide derivatives such as polyhyaluronic acid, poly(glucose), polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose, methyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, cyclodextrins and substituted cyclodextrins, such as beta-cyclodextrin sulfobutyl ethers; polypeptides and proteins, such as polylysine, polyglutamic acid, albumin; polyanhydrides; polyhydroxy alkonoates such as polyhydroxy valerate, polyhydroxy butyrate, and the like.
The term “primarily” with respect to directional delivery, refers to an amount greater than about fifty percent of the total amount of therapeutic agent provided to a blood vessel is provided in the primary direction.
The various exemplary embodiments of the present invention described herein provide different beneficial agents in different openings in the expandable device or beneficial agent in some openings and not in others. The particular structure of the expandable medical device may be varied without departing from the spirit of the invention. Since each opening is filled independently, individual chemical compositions and pharmacokinetic properties may be imparted to the beneficial agent in each opening.
One example of the use of different beneficial agents in different openings in an expandable medical device or beneficial agents in some openings and not in others, is in addressing edge effect restenosis. As discussed above, current generation coated stents may have a difficulty with edge effect restenosis or restenosis occurring just beyond the edges of the stent and progressing around the stent and into the interior luminal space.
The causes of edge effect restenosis in first generation drug delivery stents are currently not well understood. It may be that the region of tissue injury due to angioplasty and/or stent implantation extends beyond the diffusion range of current generation beneficial agents such as paclitaxel, which tends to partition strongly in tissue. A similar phenomenon has been observed in radiation therapies in which low doses of radiation at the edges of stent have proven stimulatory in the presence of an injury. In this case, radiating over a longer length until uninjured tissue is irradiated solved the problem. In the case of drug delivery stents, placing higher doses or higher concentrations of beneficial agents along the stent edges, placing different agents at the stent edges which diffuse more readily through the tissue, or placing different beneficial agents or combinations of beneficial agents at the edges of the device may help to remedy the edge effect restenosis problem.
Other mechanisms of edge effect restenosis may involve the cytotoxicity of particular drugs or combinations of drugs. Such mechanisms could include a physical or mechanical contraction of tissue similar to that seen in epidermal scar tissue formation, and the stent might prevent the contractile response within its own boundaries, but not beyond its edges. Further, the mechanism of this latter form of restenosis may be related to sequelae of sustained or local drug delivery to the arterial wall that is manifest even after the drug itself is no longer present in the wall. That is, the restenosis may be a response to a form of noxious injury related to the drug and/or the drug carrier. In this situation, it might be beneficial to exclude certain agents from the edges of the device.
In addition to use in reducing edge effect restenosis, the expandable medical device 200 of
Preferably, each end portion of the device 300 which includes the holes 330a comprising the first beneficial agent extends at least one hole and up to about fifteen holes from the edge. This distance corresponds to about 0.005 to about 0.1 inches from the edge of an unexpanded device. The distance from the edge of the device 300 which includes the first beneficial agent is preferably about one section, where a section is defined between the bridging elements.
Different beneficial agents comprising different drugs may be disposed in different openings in the stent. This allows the delivery of two or more beneficial agents from a single stent in any desired delivery pattern. Alternately, different beneficial agents comprising the same drug in different concentrations may be disposed in different openings. This allows the drug to be uniformly distributed to the tissue with a non-uniform device structure.
The two or more different beneficial agents provided in the devices described herein may comprise (1) different drugs; (2) different concentrations of the same drug; (3) the same drug with different release kinetics, i.e., different matrix erosion rates; or (4) different forms of the same drug. Examples of different beneficial agents comprising the same drug with different release kinetics may use different carriers to achieve the elution profiles of different shapes. Some examples of different forms of the same drug include forms of a drug having varying hydrophilicity or lipophilicity.
In one example of the device 300 of
The device 300 may have an abrupt transition line at which the beneficial agent changes from a first agent to a second agent. For example, all openings within 0.05 inches of the end of the device may comprise the first agent while the remaining openings comprise the second agent. Alternately, the device may have a gradual transition between the first agent and the second agent. For example, a concentration of the drug in the openings may progressively increase (or decrease) toward the ends of the device. In another example, an amount of a first drug in the openings increases while an amount of a second drug in the openings decreases moving toward the ends of the device.
In addition to the use of different beneficial agents in different openings to achieve different drug concentrations at different defined areas of tissue, the loading of different beneficial agents in different openings may be used to provide a more even spatial distribution of the beneficial agent delivered in instances where the expandable medical device has a non-uniform distribution of openings in the expanded configuration.
The use of different drugs in different openings in an interspersed or alternating manner allows the delivery of two different drugs which may not be deliverable if combined within the same polymer/drug matrix composition. For example, the drugs themselves may interact in an undesirable way. Alternately, the two drugs may not be compatible with the same polymers for formation of the matrix or with the same solvents for delivery of the polymer/drug matrix into the openings.
Further, the exemplary embodiment of
The system of
Restenosis or the recurrence of occlusion post-intervention, involves a combination or series of biological processes. These processes include the activation of platelets and macrophages. Cytokines and growth factors contribute to smooth muscle cell proliferation and upregulation of genes and metalloproteinases lead to cell growth, remodeling of extracellular matrix, and smooth muscle cell migration. A drug therapy which addresses a plurality of these processes by a combination of drugs may be the most successfully antirestenotic therapy. The present invention provides a means to achieve such a successful combination drug therapy.
The examples discussed below illustrate some of the combined drug systems which benefit from the ability to release different drugs in different holes or openings. One example of a beneficial system for delivering two drugs from interspersed or alternating holes is the delivery of an anti-inflammatory agent or an immunosuppressant agent in combination with an antiproliferative agent or an anti-migratory agent. Other combinations of these agents may also be used to target multiple biological processes involved in restenosis. The anti-inflammatory agent mitigates the initial inflammatory response of the vessel to the angioplasty and stenting and is delivered at a high rate initially followed by a slower delivery over a time period of about two weeks to match the peak in the development of macrophages which stimulate the inflammatory response. The antiproliferative agent is delivered at a relatively even rate over a longer time period to reduce smooth muscle cell migration and proliferation.
In addition to the examples that are be given below, the following chart illustrates some of the useful two drug combination therapies which may be achieved by placing the drugs into different openings in the medical device.
The placement of the drugs in different openings allows the release kinetics to be tailored to the particular agent regardless of the hydrophobilicity or lipophobicity of the drug. Examples of some arrangements for delivery of a lipophilic drug at a substantially constant or linear release rate are described in WO 04/110302 published on Dec. 23, 2004, which is incorporated herein by reference in its entirety. Examples of some of the arrangements for delivery of hydrophilic drug are described in WO 04/043510, published on May 27, 2004 which is incorporated herein by reference in its entirety. The hydrophilic drugs listed above include CdA, Gleevec, VIP, insulin, and ApoA-1 milano. The lipophilic drugs listed above include paclitaxel, Epothilone D, rapamycin, pimecrolimus, PKC-412 and Dexamethazone. Farglitazar is partly liphophillic and partly hydrophilic.
In addition to the delivery of multiple of drugs to address different biological processes involved in restenosis, the present invention may deliver two different drugs for treatment of different diseases from the same stent. For example, a stent may deliver an anti-proliferative, such as paclitaxel or a limus drug from one set of openings for treatment of restenosis while delivering a myocardial preservative drug, such as insulin, from other openings for the treatment of acute myocardial infarction.
In many of the known expandable devices and for the device illustrated in
Another example of an application for the use of different beneficial agents in different openings is in an expandable medical device 600, as illustrated in
In addition to the delivery of different beneficial agents to the mural or abluminal side of the expandable medical device for treatment of the vessel wall, beneficial agents may be delivered to the luminal side of the expandable medical device to prevent or reduce thrombosis. Drugs which are delivered into the blood stream from the luminal side of the device may be located at a proximal end of the device or a distal end of the device.
The methods for loading different beneficial agents into different openings in an expandable medical device may include known techniques such as dipping and coating and also known piezoelectric micro-jetting techniques. Micro-injection devices may be computer controlled to deliver precise amounts of two or more liquid beneficial agents to precise locations on the expandable medical device in a known manner. For example, a dual agent jetting device may deliver two agents simultaneously or sequentially into the openings. When the beneficial agents are loaded into through openings in the expandable medical device, a luminal side of the through openings may be blocked during loading by a resilient mandrel allowing the beneficial agents to be delivered in liquid form, such as with a solvent. The beneficial agents may also be loaded by manual injection devices.
As illustrated in
The paclitaxel is loaded within the openings 720 in a manner which creates a release kinetic having a substantially linear release after the first approximately twenty-four hours, as illustrated in
The amount of the drugs delivered varies depending on the size of the stent. For a three mm by six mm stent the amount of pimecrolimus is about fifty to about three hundred micrograms preferably about one hundred to about two hundred fifty micrograms. The amount of paclitaxel delivered from this stent is about five to about fifty micrograms preferably about ten to about thirty micrograms. In one example, about two hundred micrograms of pimecrolimus and about twenty micrograms of paclitaxel are delivered. The drugs may be located in alternating holes in the stent. However, in view of the large difference in the doses to be delivered between the two drugs, it may be desirable to place the paclitaxel in every third of fourth hole in the stent. Alternatively, the holes for delivery of the low dose drug (paclitaxel) may be made smaller than the holes for the high dose.
The polymer/drug inlays are formed by computer controlled piezoelectric injection techniques as described in WO 04/026182 published on Apr. 1, 2004, which is incorporated herein by reference in its entirety. The inlays of the first agent may be formed first followed by the inlays of the second agent using the piezoelectric injector. Alternately, the system of WO 04/02182 may be equipped with dual piezoelectric dispensers for dispensing the two agents at the same time.
According to this example, the dual drug stent includes the Gleevec in the first set of openings 710 in combination with the antiproliferative agent paclitaxel in the second set of openings 720. Each agent is provided in a matrix material within the holes of the stent in a specific inlay arrangement designed to achieve the release kinetics illustrated in
The Gleevec is delivered with a two phase release including a high initial release in the first day and then a slow release for one to two weeks. The first phase of the Gleevec release delivers about fifty percent of the loaded drug in about the first twenty-four hours. The second phase of the release delivers the remaining fifty percent over about one-two weeks. The paclitaxel is loaded within the openings 720 in a manner which creates a release kinetics having a substantially linear release after the first approximately twenty-four hours, as illustrated in
The amount of the drugs delivered varies depending on the size of the stent. For a three mm by six mm stent the amount of Gleevec is about two hundred to about five hundred micrograms, preferably about three hundred to about four hundred micrograms. The amount of paclitaxel delivered from this stent is about five to about fifty micrograms, preferably about ten to about thirty micrograms. As in Example 1, the drugs may be located in alternating holes in the stent or interspersed in a non-alternating manner. The polymer/drug inlays are formed in the manner described in Example 1.
According to this example, the dual drug stent includes the PKC-412 (a cell growth regulator) in the first set of openings in combination with the antiproliferative agent paclitaxel in the second set of openings. Each agent is provided in a matrix material within the holes of the stent in a specific inlay arrangement designed to achieve the release kinetics discussed below.
The PKC-412 is delivered at a substantially constant release rate after the first approximately twenty-four hours, with the release over a period of about four to sixteen weeks, preferably about six to twelve weeks. The paclitaxel is loaded within the openings in a manner which creates a release kinetic having a substantially linear release after the first approximately twenty-four hours, with the release over a period of about four to sixteen weeks, preferably about six to twelve weeks.
The amount of the drugs delivered varies depending on the size of the stent. For a three mm by six mm stent the amount of PKC-412 is about one hundred to about four hundred micrograms, preferably about one hundred fifty to about two hundred fifty micrograms. The amount of paclitaxel delivered from this stent is about five to about fifty micrograms, preferably about ten to about thirty micrograms. As in Example 1, the drugs may be located in alternating holes in the stent or interspersed in a non-alternating manner. The polymer/drug inlays are formed in the manner described in Example 1.
Therapeutic Agents
The present invention relates to the delivery of anti-restenotic agents including paclitaxel, rapamycin, cladribine (CdA), and their derivatives, as well as other cytotoxic or cytostatic agents and microtubule stabilizing agents. Although anti-restenotic agents have been primarily described herein, the present invention may also be used to deliver other agents alone or in combination with anti-restenotic agents. Some of the therapeutic agents for use with the present invention which may be transmitted primarily luminally, primarily murally, or both and may be delivered alone or in combination include, but are not limited to, antiproliferatives, antithrombins, immunosuppressants including sirolimus, antilipid agents, anti-inflammatory agents, antineoplastics, antiplatelets, angiogenic agents, anti-angiogenic agents, vitamins, antimitotics, metalloproteinase inhibitors, NO donors, estradiols, anti-sclerosing agents, and vasoactive agents, endothelial growth factors, estrogen, beta blockers, AZ blockers, hormones, statins, insulin growth factors, antioxidants, membrane stabilizing agents, calcium antagonists, retenoid, bivalirudin, phenoxodiol, etoposide, ticlopidine, dipyridamole, and trapidil alone or in combinations with any therapeutic agent mentioned herein. Therapeutic agents also include peptides, lipoproteins, polypeptides, polynucleotides encoding polypeptides, lipids, protein-drugs, protein conjugate drugs, enzymes, oligonucleotides and their derivatives, ribozymes, other genetic material, cells, antisense, oligonucleotides, monoclonal antibodies, platelets, prions, viruses, bacteria, and eukaryotic cells such as endothelial cells, stem cells, ACE inhibitors, monocyte/macrophages or vascular smooth muscle cells to name but a few examples. The therapeutic agent may also be a pro-drug, which metabolizes into the desired drug when administered to a host. In addition, therapeutic agents may be pre-formulated as microcapsules, microspheres, microbubbles, liposomes, niosomes, emulsions, dispersions or the like before they are incorporated into the therapeutic layer. Therapeutic agents may also be radioactive isotopes or agents activated by some other form of energy such as light or ultrasonic energy, or by other circulating molecules that can be systemically administered. Therapeutic agents may perform multiple functions including modulating angiogenesis, restenosis, cell proliferation, thrombosis, platelet aggregation, clotting, and vasodilation.
Anti-inflammatories include but are not limited to non-steroidal anti-inflammatories (NSAID), such as aryl acetic acid derivatives, e.g., Diclofenac; aryl propionic acid derivatives, e.g., Naproxen; and salicylic acid derivatives, e.g., Diflunisal. Anti-inflammatories also include glucocoriticoids (steroids) such as dexamethasone, aspirin, prednisolone, and triamcinolone, pirfenidone, meclofenamic acid, tranilast, and nonsteroidal anti-inflammatories. Anti-inflammatories may be used in combination with antiproliferatives to mitigate the reaction of the tissue to the antiproliferative.
The agents may also include anti-lymphocytes; anti-macrophage substances; immunomodulatory agents; cyclooxygenase inhibitors; anti-oxidants; cholesterol-lowering drugs; statins and angiotens in converting enzyme (ACE); fibrinolytics; inhibitors of the intrinsic coagulation cascade; antihyperlipoproteinemics; and anti-platelet agents; anti-metabolites, such as 2-chlorodeoxy adenosine (2-CdA or cladribine); immuno-suppressants including sirolimus, everolimus, tacrolimus, etoposide, and mitoxantrone; anti-leukocytes such as 2-CdA, IL-1 inhibitors, anti-CD116/CD18 monoclonal antibodies, monoclonal antibodies to VCAM or ICAM, zinc protoporphyrin; anti-macrophage substances such as drugs that elevate NO; cell sensitizers to insulin including glitazones; high density lipoproteins (HDL) and derivatives; and synthetic facsimile of HDL, such as lipator, lovestatin, pranastatin, atorvastatin, simvastatin, and statin derivatives; vasodilators, such as adenosine, and dipyridamole; nitric oxide donors; prostaglandins and their derivatives; anti-TNF compounds; hypertension drugs including Beta blockers, ACE inhibitors, and calcium channel blockers; vasoactive substances including vasoactive intestinal polypeptides (VIP); insulin; cell sensitizers to insulin including glitazones, P par agonists, and metformin; protein kinases; antisense oligonucleotides including resten-NG; antiplatelet agents including tirofiban, eptifibatide, and abciximab; cardio protectants including, VIP, pituitary adenylate cyclase-activating peptide (PACAP), apoA-I milano, amlodipine, nicorandil, cilostaxone, and thienopyridine; cyclooxygenase inhibitors including COX-1 and COX-2 inhibitors; and petidose inhibitors which increase glycolitic metabolism including omnipatrilat. Other drugs which may be used to treat inflammation include lipid lowering agents, estrogen and progestin, endothelin receptor agonists and interleukin-6 antagonists, and Adiponectin. Therapeutic agents may also include phosphodiesterase inhibitors (PDEi), such as cilastazol and adenosine receptor agonists, preferably A2A receptor, agonists such as regadenoson.
Agents may also be delivered using a gene therapy-based approach in combination with an expandable medical device. Gene therapy refers to the delivery of exogenous genes to a cell or tissue, thereby causing target cells to express the exogenous gene product. Genes are typically delivered by either mechanical or vector-mediated methods.
Some of the agents described herein may be combined with additives which preserve their activity. For example additives including surfactants, antacids, antioxidants, and detergents may be used to minimize denaturation and aggregation of a protein drug. Anionic, cationic, or nonionic surfactants may be used. Examples of nonionic excipients include but are not limited to sugars including sorbitol, sucrose, trehalose; dextrans including dextran, carboxy methyl (CM) dextran, diethylamino ethyl (DEAE) dextran; sugar derivatives including D-glucosaminic acid, and D-glucose diethyl mercaptal; synthetic polyethers including polyethylene glycol (PEO) and polyvinyl pyrrolidone (PVP); carboxylic acids including D-lactic acid, glycolic acid, and propionic acid; surfactants with affinity for hydrophobic interfaces including n-dodecyl-.beta.-D-maltoside, n-octyl-.beta.-D-glucoside, PEO-fatty acid esters (e.g. stearate (myrj 59) or oleate), PEO-sorbitan-fatty acid esters (e.g. Tween 80, PEO-20 sorbitan monooleate), sorbitan-fatty acid esters (e.g. SPAN 60, sorbitan monostearate), PEO-glyceryl-fatty acid esters; glyceryl fatty acid esters (e.g. glyceryl monostearate), PEO-hydrocarbon-ethers (e.g. PEO-10 oleyl ether; triton X-100; and Lubrol. Examples of ionic detergents include but are not limited to fatty acid salts including calcium stearate, magnesium stearate, and zinc stearate; phospholipids including lecithin and phosphatidyl choline; (PC) CM-PEG; cholic acid; sodium dodecyl sulfate (SDS); docusate (AOT); and taumocholic acid.
In accordance with another exemplary embodiment, a stent or intraluminal scaffold as described herein, may be coated with an anti-thrombotic agent in addition to one or more therapeutic agents deposited in the holes or openings. In one exemplary embodiment, the stent may be fabricated with the openings therein and prior to the addition or deposition of other therapeutic agents into the openings, an anti-thrombotic agent, with or without a carrier vehicle (polymer or polymeric matrix) may be affixed to the stent or a portion thereof. In this exemplary embodiment, the luminal and abluminal surfaces of the stent may be coated with the anti-thrombotic agent or coating, as well as the surfaces of the walls of the openings. In an alternative exemplary embodiment, a stent may first be coated with an anti-thrombotic agent or coating and then the openings may be fabricated. In this exemplary embodiment, only the luminal and abluminal surfaces would have the anti-thrombotic agent or coating and not the walls of the openings. In each of these embodiments any number of anti-thrombotic agents may be affixed to all or portions of the stents. In addition, any number of known techniques may be utilized to affix the anti-thrombotic agent to the stent such as that utilized with the HEPACOAT™ on the Bx Velocity® Coronary Stent from Cordis Corporation. Alternatively, the stents may be manufactured with a rough surface texture or have a micro-texture to enhance cell attachment and endothelialization, independently of or in addition to the anti-thrombotic coating. In addition, any number of therapeutic agents may be deposited into the openings and different agents may be utilized in different regions of the stent.
As described above, it is important to note that any number of drugs and or agents may be utilized in accordance with the present invention including: antiproliferative/antimitotic agents including natural products such as vinca alkaloids (i.e. vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (i.e. etoposide, teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents such as G(GP)IIbIIIa inhibitors and vitronectin receptor antagonists; antiproliferative/antimitotic alkylating agents such as nitrogen mustards (mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU) and analogs, streptozocin), trazenes—dacarbazinine (DTIC); antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate), pyrimidine analogs (fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine {cladribine}); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones (i.e. estrogen); anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory; antisecretory (breveldin); antiinflammatory: such as adrenocortical steroids (cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone, triamcinolone, betamethasone, and dexamethasone), non-steroidal agents (salicylic acid derivatives i.e. aspirin; para-aminophenol derivatives i.e. acetominophen; indole and indene acetic acids (indomethacin, sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac, and ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, gold sodium thiomalate); immunosuppressives: (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil); angiogenic agents: vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) platelet derived growth factor (PDGF), erythropoetin; angiotensin receptor blocker; nitric oxide donors; anti-sense oligionucleotides and combinations thereof; cell cycle inhibitors, mTOR inhibitors, and growth factor signal transduction kinase inhibitors.
Referring now to
As illustrated in
In
In accordance with this exemplary embodiment, the hole or openings may be configured not only for the most efficacious drug therapy, but also for creating a physical separation between different drugs. This physical separation may aid in preventing the agents from interacting.
As used herein, rapamycin includes rapamycin and all analogs, derivatives and conjugates that bind to FKBP12, and other immunophilins and possesses the same pharmacologic properties as rapamycin including inhibition of TOR. In addition, all drugs and agents described herein in their analogs, derivatives and conjugates.
As described herein, a stent having through-holes, holes, reservoirs or openings therein may be coated with an anti-thrombotic agent and/or drug or combination of drugs such as those described herein, and the openings filled with one or more therapeutic agents alone or in combination with one or more polymers. Essentially, the stent may be fabricated with the openings therein and prior to the addition or deposition of therapeutic agents alone or in combination with one or more polymers into the openings, an anti-thrombotic agent, with or without a carrier vehicle, may be affixed to the stent or a portion thereof. In the exemplary embodiment as described herein, the luminal and abluminal surfaces of the stent as well as the surfaces of the walls of the openings may be coated with the anti-thromobotic agent. In this exemplary embodiment, the anti-thrombotic agent comprises heparin or its various derivatives such as low molecular-weight heparin (LMWH), although any number of suitable anti-thrombotic agents may be utilized. Heparin and/or LMWH have very high negative charges.
The entire surface of the stent described herein, including the interior surfaces of the through-holes or openings that become reservoirs for the therapeutic agent and/or combination polymers and therapeutic agent, is first given a covalently bonded heparin coating. The heparin coating itself is bonded to the metal surface of the stent by its own primer comprising alternating layers of poly(ethyleneimine), a strongly cationic polymer known by the abbreviation PEI, and dextran sulfate, a polymeric anion. The application of this type of primer is known in the art and is set forth in a number of patents, including U.S. Pat. Nos. 5,213,898, 5,049,403, 6,461,665 and 6,767,405. More specifically, the heparin is covalently bonded to the primer, including the PEI-dextran sulfate layers, which is in turn bonded to the metal surface. Once all surfaces are coated with the heparin mixture, each of the holes or reservoirs are filled utilizing one of the processes described herein.
In accordance with another exemplary embodiment, the present invention is directed to primer compositions and configurations for improving the adhesion of a drug delivery matrix, e.g. therapeutic agent and polymer combination, to a heparin coated surface of a medical device, for example, a stent. The present invention is particularly advantageous where the heparin coating is covalently bonded to a metallic or polymer surface of the medical device. In the present invention, the primer preferably comprises a high molecular weight component or a low molecular weight component, and the drug delivery matrix comprises a drug and/or other beneficial agent and an excipient, preferably a polymeric excipient. In addition, the primer may also preferably comprise a material having an opposite electrical charge and similar charge density to that of the underlying layer, for example, heparin.
The concept of a primer on top of a heparin layer or coating to increase the bonding of a heparin coated surface to any other matrix or coating is unique given that typically the heparin surface is utilized to confer anti-thromobotic properties and hence will not be covered in practical uses. In the present invention, it is only the interior wall surfaces of the holes or openings in the stent that hold the drug-polymer reservoirs that will be covered with the primer of the present invention, thus increasing the adhesion between the two layers and limiting the potential loss of the drug-polymer matrix without substantially affecting the heparin surface outside the reservoirs. It is important to note that the heparin blocking primers in accordance with the present invention are biocompatible in their original intended uses.
The primer of the present invention may be utilized with any type of stent. In the exemplary embodiment described herein, the primer is utilized with the stent or stents illustrated in
In accordance with one exemplary embodiment, the primer comprises polymer-poly(ethyleneimine) conjugates, for example polylactic-co-glycolic acid (PLGA) and poly(ethyleneimine) PEI and/or PLGA-protamine. Poly(ethyleneimine) is a strongly cationic polymer that binds to certain negatively charged proteins or polysaccharides. In addition to PEI, the other material useful in this conjugate is protamine. Protamine is an approved low molecular weight protein drug that is utilized as an antidote to heparin. It is sparsely solution in water. In this manner, the primer may simultaneously interact strongly with both the heparin coating and the drug containing matrix, thus improving the adhesion between the two substances. Since heparin is a poly(anionic) species, it is anticipated that a poly(cationic) species such as protamine would bond well to the heparin, but would be sufficiently hydrophobic in the other sections of its structure to allow good bonding of the PLGA component of the drug polymer matrix in the reservoir.
The bonding reactions between PLGA and PEI and PEI and heparin may be ionic-bonding or covalent-bonding reactions.
The Table below illustrates the effectiveness of PEI as a primer for increasing the adhesion of the drug/polymer complex to the heparin coated surfaces. The test stents are immersed in a testing medium comprising a phosphate buffer saline and bovine serum albumin which simulates physiological fluid conditions. The drug/polymer complex comprises a rapamycin and PLGA.
In an alternate exemplary embodiment, the primer may comprise low molecular weight complexing cations to heparin, including benzalkonium chloride and/or oligomeric arginine peptides, or high molecular weight complexing cations, including polylysine, poly(arginine), protamine, poly(dimethylaminoethyl)methacrylate or poly(dimethylaminoethyl)acrylate.
In accordance with the present invention, the process for increasing adhesion of the drug complex to the heparin may include the application of the adhesion promoting primer followed by polymer/drug fill solution or the application of the adhesion promoting primer followed by carboxyl-ended PLGA or a blend of carboxyl-ended and regular PLGA and PLGA/drug fill solution.
The primer of the present invention will be applied to the interior, heparin coated walls of the holes or openings in the stent prior to the openings being filled with a local drug delivery matrix. In other words, in the finished drug eluting stent, the primer will occupy a space between the surface of the heparin coating and the body of the drug delivery matrix and will increase the adhesion between the heparin coating and the drug delivery matrix. The enhancement of adhesion is achieved through multiple factors, including the reduction of osmolarity/water infiltration of the heparin coating in use after the charge neutralization by a cationic primer, reduced aqueous solubility of heparin/cationic primer complex as compared to the heparin surface alone, ionic bonding, covalent bonding and better physical adhesion between the primer and the polymer/drug matrix due to surface tension and the like.
In another exemplary embodiment of the present invention, the primer of the present invention will preferably have a portion of its molecular structure that is positively charged for bonding to the negatively charged heparin coating, and a portion that is hydrophobic, hydrophilic, or balanced for bonding to the polymer component of the drug delivery matrix. This portion of the primer will vary depending on the nature of the drug delivery matrix. More specifically, the primer is designed to improve the adhesion of the drug delivery matrix to the heparin coated openings of the stent so that none or substantially none of the openings or reservoirs lose their contents when the stent comes into contact with water based fluids, such as saline, blood and/or intercellular fluid.
Although the primer of the present invention has been described specifically to increasing the adhesion between the heparin coated interior walls of a stent reservoir and the drug/polymer mixture filling the reservoir, it may be useful for the attachment or bonding of any substrate to a portion of a heparin coated surface. For example, blood contacting plastic medical devices are often coated with heparin to minimize thrombosis on the device, but it may be desired to bond later to that surface. A mixture of the primers of the present invention in a solvent could be applied to a selected area of the device, the solvent evaporated to provide a primer coated area on the heparin surface, then subsequently a new subsystem could be bonded to the primer covered area.
The primer material will be advantageously applied as a solution of the polymeric primer in a solvent such as dimethyl sulfoxide (DMSO), N-methylpyrrolidone, or water mixtures thereof and may be introduced into the reservoirs using any of the filling techniques described in the instant application. Such a primer solution could then be dried to provide the coating of the primer layer over the heparin coated surface. Preferably, the application of the primer layer will require only a single deposition step in the stent filling process. The selection of a suitable solvent for the deposition of a cationic primer is determined primarily by its ability to dissolve a primer and its compatibility with the filling apparatus and process described herein.
The present invention may be simply characterized as an implantable medical device. The medical device comprises an intraluminal scaffold having a plurality of openings therein, a first coating comprising a material having a first electric charge affixed to at least a portion of a surface of the intraluminal scaffold and a surface of the plurality of openings, a second coating comprising a material having a second electric charge affixed to at least a portion of the first coating, the second electric charge being opposite of the first electric charge, and at least one therapeutic agent deposited in at least one of the plurality of openings, wherein the second coating is configured as an intermediate layer between the first coating and the at least one therapeutic agent.
The first coating may comprise any suitable anti-thrombotic as described herein. For example, a polysaccharide such as heparin may be utilized. The second coating may comprise a polymeric cation or a polymeric conjugate having cationic segments as described herein. Examples of polymeric cations include oligomeric arginine peptides, polylysine, poly(arginine), protamine, poly(dimethylaminoethyl)poly(ethyleneimine). Examples of polymeric cationic conjugates include a first component such as polylactic-co-glycolic acid and the second component comprises any of the cations set forth above. The therapeutic agent may comprise an anti-restenotic, an anti-inflammatory, an anti-thrombotic, an anti-proliferative, an agent for minimizing damage to infarcted tissue or any combination thereof.
In a more general sense, the concept of the present invention may be expanded to include primers that increase the bonding strength between hydrophilic and hydrophobic surfaces. For example, other hydrophilic surfaces of interest are the so called “lubricious” coatings, such as those utilized in conjunction with catheters. These hydrophilic surfaces are often also covalently bonded, but may be just conformal coatings. Examples of chemical structures that occur in lubricious coatings are those based on polyvinylpyrrolidone, hydroxyethyl methacrylate, poly(ethylene oxide) or poly(ethylene glycol) and the like.
Although shown and described is what is believed to be the most practical and preferred embodiments, it is apparent that departures from specific designs and methods described and shown will suggest themselves to those skilled in the art and may be used without departing from the spirit and scope of the invention. The present invention is not restricted to the particular constructions described and illustrated, but should be constructed to cohere with all modifications that may fall within the scope of the appended claims.
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