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United States Patent

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United States Patent 7,056,338
Shanley ,   et al. June 6, 2006
Therapeutic agent delivery device with controlled therapeutic agent release rates


Abstract

The present invention relates to implantable medical devices for the localized delivery of therapeutic agents, such as drugs, to a patient. More particularly, the invention relates to a device having a gradient of water soluble therapeutic agents within a therapeutic agent layer and a mixing layer that allows for controlled release of the therapeutic agents.

Inventors: Shanley; John F. (Redwood City, CA), Parker; Theodore L. (Danville, CA)
Assignee: Conor Medsystems, Inc. (Menlo Park, CA)
Appl. No.: 10/402,893
Filed: March 28, 2003

Current U.S. Class: 623/1.42 ; 427/2.13; 623/920
Current International Class: A61F 2/06 (20060101)
Field of Search: 623/1.15-1.48,920 427/2.13

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Primary Examiner: Gherbi; Suzette J-J
Attorney, Agent or Firm: Lynch; Cindy A.
Claims


What is claimed is:

1. A method for preparing an implantable medical device, which method comprises: a) providing an implantable medical device with a plurality of holes; b) loading into the plurality of holes an amount of a liquefied therapeutic agent, which amount is sufficient to form a therapeutic agent layer; c) allowing said liquefied therapeutic agent layer to at least partially solidify; d) loading into the plurality of holes an amount of a liquefied bioresorbable polymer which amount is sufficient to liquefy a portion of the therapeutic agent layer, thereby allowing a portion of the therapeutic agent layer to be disposed within a mixing layer; e) allowing said liquefied bioresorbable polymer and said portion of the therapeutic agent layer to solidify; wherein a concentration of therapeutic agent contained within the mixing layer upon solidification is smaller than a concentration of therapeutic agent contained in the therapeutic agent layer; wherein the loading of the liquefied therapeutic agent and the liquefied bioresorbable polymer are performed in a dropwise matter; and further wherein steps d and e may optionally be repeated to form multiple mixing layers.

2. The method for preparing an implantable medical device of claim 1, wherein the liquefied therapeutic agent is formed by dissolving the therapeutic agent in a solvent.

3. The method for preparing an implantable medical device of claim 1, wherein the liquefied bioresorbable polymer is formed by dissolving the bioresorbable polymer in a solvent.

4. The method for preparing an implantable medical device of claim 1, further comprising the step of forming a barrier layer by loading into the plurality of holes an amount of a liquefied biocompatible polymer, which amount is sufficient to form a barrier layer, wherein the barrier layer is located adjacent the therapeutic agent layer.

5. The method for preparing an implantable medical device of claim 4, wherein the liquefied biocompatible polymer is liquefied by maintaining the biocompatible polymer at a temperature that is higher than its melting point, or glass transition temperature.

6. The method for preparing an implantable medical device of claim 4, wherein the liquefied biocompatible polymer is formed by dissolving the biocompatible polymer in a solvent.

7. The method for preparing an implantable medical device of claim 1, wherein the liquefied bioresorbable polymer loaded into the holes does not contain the therapeutic agent.

8. The method for preparing an implantable medical device of claim 1, wherein the liquefied therapeutic agent layer comprises the therapeutic agent and a pharmaceutically acceptable polymer.

9. The method for preparing an implantable medical device of claim 8, wherein the liquefied therapeutic agent layer comprises from about 50% to about 95% therapeutic agent and from about 5% to about 50% pharmaceutically acceptable polymer.

10. The method for preparing an implantable medical device of claim 1, wherein the loading of the liquefied therapeutic agent and the liquefied bioresorbable polymer are performed by a piezoelectric micro-jetting device.

11. A method for preparing an implantable medical device, which method comprises: a) providing an implantable medical device with a plurality of holes; b) loading into the plurality of holes an amount of a liquefied therapeutic agent, which amount is sufficient to form a therapeutic agent layer; c) allowing said liquefied therapeutic agent layer to at least partially solidify; d) loading into the plurality of holes an amount of a liquefied bioresorbable polymer which amount is sufficient to liquefy a portion of the therapeutic agent layer, thereby allowing a portion of the therapeutic agent layer to be disposed within a mixing layer; e) allowing said liquefied bioresorbable polymer and said portion of the therapeutic agent layer to solidify; wherein a concentration of therapeutic agent contained within the mixing layer upon solidification is smaller than a concentration of therapeutic agent contained in the therapeutic agent layer; further wherein steps d and e may optionally be repeated to form multiple mixing layers; and wherein the liquefied therapeutic agent is liquefied by maintaining the therapeutic agent at a temperature that is higher than its melting point, or glass transition temperature.

12. A method for preparing an implantable medical device, which method comprises: a) providing an implantable medical device with a plurality of holes; b) loading into the plurality of holes an amount of a liquefied therapeutic agent, which amount is sufficient to form a therapeutic agent layer; c) allowing said liquefied therapeutic agent layer to at least partially solidify; d) loading into the plurality of holes an amount of a liquefied bioresorbable polymer which amount is sufficient to liquefy a portion of the therapeutic agent layer, thereby allowing a portion of the therapeutic agent layer to be disposed within a mixing layer; e) allowing said liquefied bioresorbable polymer and said portion of the therapeutic agent layer to solidify; wherein a concentration of therapeutic agent contained within the mixing layer upon solidification is smaller than a concentration of therapeutic agent contained in the therapeutic agent layer; further wherein steps d and e may optionally be repeated to form multiple mixing layers; and wherein the liquefied bioresorbable polymer is liquefied by maintaining the bioresorbable polymer at a temperature that is higher than its melting point, or glass transition temperature.
Description


FIELD OF THE INVENTION

The invention relates to a therapeutic agent delivery device which comprises a gradient of therapeutic agent within mixing layers which provides for the controlled release of water soluble therapeutic agents.

DESCRIPTION OF THE RELATED ART

Implantable medical devices are often used for delivery of a beneficial agent, such as a drug, to an organ or tissue in the body at a controlled delivery rate over an extended period of time. These devices may deliver agents to a wide variety of bodily systems to provide a wide variety of treatments.

One of the many implantable medical devices which have been used for local delivery of beneficial agents is the coronary stent. Coronary stents 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 Nitinol.

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 can 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, neointimal hyperplasia, 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 is still reported in the range of 25% to 50% 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.

One of the techniques under development to address the problem of restenosis is the use of surface coatings of various beneficial agents on stents. 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 (a well-known compound that is commonly used in the treatment of cancerous tumors). 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, can provide little actual control over the release kinetics of beneficial agents. These coatings are necessarily very thin, typically 5 to 8 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.

Increasing the thickness of the surface coating has the beneficial effects of improving drug release kinetics including the ability to control drug release and to allow increased drug loading. However, the increased coating thickness results in increased overall thickness of the stent wall. This is undesirable for a number of reasons, including increased trauma to the vessel wall 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, duration of drug delivery, and the like that can be achieved.

In addition to sub-optimal release profiles, there are further problems with surface coated stents. The fixed matrix polymer carriers frequently used in the device coatings typically retain approximately 30% of the beneficial agent in the coating indefinitely. Since these beneficial agents are frequently highly cytotoxic, 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 highly inflammatory to the tissue of the vessel wall. On the other hand, use of biodegradable polymer carriers on stent surfaces can result in the creation of "virtual spaces" or voids between the stent and tissue of the vessel wall after the polymer carrier has degraded, which permits 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.

Another significant problem is that expansion of the stent may stress the overlying polymeric coating causing the coating to plastically deform or even to rupture, which may therefore effect drug release kinetics or have other untoward effects. 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.

In addition, it is not currently possible to deliver some drugs with a surface coating for a variety of reasons. In some cases, the drugs are sensitive to water, other compounds, or conditions in the body which degrade the drugs. For example, some drugs lose substantially all their activity when exposed to water for a period of time. When the desired treatment time is substantially longer than the half life of the drug in water the drug cannot be delivered by know coatings. Other drugs, such as protein or peptide based therapeutic agents, lose activity when exposed to enzymes, pH changes, or other environmental conditions. And finally drugs that are highly-soluble in water tend to be released from the coatings at an undesirably high rate and do not remain localized for a therapeutically useful amount of time. These types of drugs which are sensitive to compounds or conditions in the body often cannot be delivered using surface coatings.

Accordingly, it would be desirable to provide a beneficial agent delivery device for delivery of agents, such as drugs, to a patient while protecting the agent from compounds or conditions in the body which would degrade the agent.

SUMMARY OF THE INVENTION

The present invention relates to medical device for the controlled delivery of therapeutic agents where the release of the therapeutic agent is mediated by a mixing layer.

In one of its device aspects the present invention provides for an implantable medical device comprising an implantable device body having a plurality of holes; a therapeutic agent provided in a first therapeutic agent layer and contained within the plurality of holes in the device body; and at least one mixing layer provided adjacent the first therapeutic agent layer in the plurality of holes; wherein the therapeutic agent layer and the at least one mixing layer together contain a concentration gradient of said therapeutic agent and allow for the controlled release of the therapeutic agent contained within the therapeutic agent layer and the at least one mixing layer.

In another of its device aspects the present invention provides for an implantable medical device comprising an implantable device body having a plurality of holes; a therapeutic agent within the plurality of holes in the device body provided in a therapeutic agent layer; and a mixing layer provided in the plurality of holes; wherein the therapeutic agent layer and the mixing layer contain a concentration gradient of said therapeutic agent created by delivering a mixing layer material without the therapeutic agent and liquefying a portion of the therapeutic agent layer with the mixing layer material, whereby the mixing layer has a lesser amount of therapeutic agent contained therein than the therapeutic agent layer.

The mixing layers are preferably a pharmaceutically acceptable bioresorbable matrix, more preferably pharmaceutically acceptable polymers. Even more preferably the mixing layers are selected from the group consisting of polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polylactic acid-co-caprolactone, polyethylene glycol, polyethylene oxide, poly lactic acid-btock-poly ethylene glycol, poly glycolic acid-block-poly ethylene glycol, poly lactide-co-glycolide-block-poly ethylene glycol, poly ethylene glycol-block-lipid, polyvinyl pyrrolidone, poly vinyl alcohol, a glycosaminoglycan, polyorthoesters, polysaccharides, polysaccharide derivatives, polyhyaluronic acid, polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polypeptides, polylysine, polyglutamic acid, albumin, polyanhydrides, polyhydroxy alkonoates, polyhydroxy valerate, polyhydroxy butyrate, proteins, polyphosphate esters, lipids, and mixtures thereof.

The therapeutic agent layer preferably comprises the therapeutic agent and a water soluble binding agent. The water soluble binding agent is preferably selected from poly ethylene glycol, poly ethylene oxide, poly vinylpyrrolidone, poly vinyl alcohol, a glycosaminoglycan, polysaccharides, polysaccharide derivatives, poly hyaluronic acid, poly alginic acid, chitin, chitosan, chitosan derivatives, cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, poly peptides, poly lysine, poly glutamic acid, and proteins, such as albumin.

The liquefied therapeutic agent layer comprises from about 20% to about 95% therapeutic agent and from about 5% to about 70% pharmaceutically acceptable polymer preferably from about 50% to about 95% therapeutic agent and from about 5% to about 50% pharmaceutically acceptable polymer, more preferably from about 50% to about 60% therapeutic agent and from about 40% to about 50% pharmaceutically acceptable polymer.

The therapeutic agent is preferably antithrombotic agents, a antineoplastic agent, a neoplastic agent, an antiproliferative agent, an antisense compound, an immunosuppresant, an angiogenic agent, an angiogenic factor, an antiangiogenic agent, or an anti-inflammatory agent, or combinations thereof. More preferably the therapeutic agent is of 2-chlorodeoxyadenosine, bivalirudin, Resten NG, or an oliogonucleotide, or mixtures thereof.

The therapeutic agent maybe homogeneously or heterogeneously dispersed in the therapeutic agent layer and/or the mixing layer(s). The therapeutic agent may be homogeneously or heterogeneously disposed in a layer as a solid particle dispersion, encapsulated agent dispersion, an emulsion, a suspension, a liposome, niosome, or a microparticle, wherein said niosome, liposome or microparticle comprise a homogeneous or heterogeneous mixture of the therapeutic agent. When a therapeutic agent is homogeneously disposed in a therapeutic agent layer, it may be a solid-solution or a multi-phase mixture.

Optionally the liquefied bioresorbable polymer loaded into the holes does not contain the therapeutic agent.

The implantable medical device is useful in the treatment of restenosis and inflammation and is preferably a stent.

The bioresorbable polymers, binding agents of the individual layers may be the same or different. In one embodiment, the polymers used in the therapeutic agent layer is different than the polymer used in the mixing layer. The polymers and binging agents of the individual layers maybe liquified by dissolution of the materials in a solvent or by maintaining the materials at a temperature that is higher than their melting points, or glass transition temperatures.

The implantable medical device may optionally further comprise a barrier layer, wherein the barrier layer is located adjacent the therapeutic agent layer. The barrier layer is formed by loading into the plurality of holes an amount of a liquified biocompatible polymer, which amount is sufficient to form a barrier layer, wherein the barrier layer is located adjacent the therapeutic agent layer.

In one of its method aspects the present invention provides for an method for preparing an implantable medical device as described herein above, which method comprises:

a) providing an implantable medical device with a plurality of holes;

b) loading into the plurality of holes an amount of a liquified therapeutic agent, which amount is sufficient to form a therapeutic agent layer;

c) allowing said liquified therapeutic agent layer to at least partially solidify;

d) loading into the plurality of holes an amount of a liquified bioresorbable polymer which amount is sufficient to liquify a portion of the therapeutic agent layer, thereby allowing a portion of the therapeutic agent layer to be disposed within a mixing layer;

e) allowing said liquified bioresorbable polymer and said portion of the therapeutic agent layer to solidify;

wherein an amount of therapeutic agent contained within the mixing layer upon solidification is smaller than an amount of therapeutic agent contained in the therapeutic agent layer and further wherein steps d and e may optionally be repeated to form multiple mixing layers.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

The invention will now be described in greater detail with reference to the preferred embodiments illustrated in the accompanying drawings, in which like elements bear like reference numerals, and wherein:

FIG. 1 is a perspective view of a therapeutic agent delivery device in the form of an expandable stent.

FIG. 2 is a cross sectional view of a portion of a therapeutic agent delivery device having a beneficial agent contained in an opening in layers.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a delivery device for delivery of water soluble therapeutic agents to a patient. More particularly, the invention relates to a medical device having therapeutic agents protected from premature release into a patient by one or more mixing layers. Details for the device design, therapeutic agents, therapeutic agent layers, and mixing layers may also be found in U.S. patent application Ser. No. 10/253,020, filed on Sep. 23, 2002, incorporated herein by reference in its entirety. First, the following terms, as used herein, shall have the following meanings:

The term "beneficial agent" as used herein is intended to have its broadest possible interpretation and is used to include any therapeutic agent or drug, as well as inactive agents such as barrier layers, carrier layers, therapeutic layers or mixing layers.

The terms "drug" and "therapeutic agent" are used interchangeably to refer to any therapeutically active substance that is delivered to a bodily conduit of a living being to produce a desired, usually beneficial, effect. The present invention is particularly well suited for the delivery of antineoplastic, angiogenic factors, immuno-suppressants, and antiproliferatives (anti-restenosis agents) such as paclitaxel, Rapamycin or 2-chlorodeoxyadenosine, for example, and antithrombins such as heparin, for example.

The therapeutic agents used in the present invention include classical low molecular weight therapeutic agents commonly referred to as drugs including all classes of action as exemplified by, but not limited to: antineoplastic, immuno-suppressants, antiproliferatives, antithrombins, antiplatelet, antilipid, anti-inflammatory, angiogenic, anti-angiogenic, vitamins, ACE inhibitors, vasoactive substances, antimitotics, metello-proteinase inhibitors, NO donors, estradiols, anti-sclerosing agents, alone or in combination. Therapeutic agent also includes higher molecular weight substances with drug like effects on target tissue sometimes called biologic agents including but not limited to: peptides, lipids, protein drugs, protein conjugates drugs, enzymes, oligonucleotides, ribozymes, genetic material, prions, virus, bacteria, and eucaryotic cells such as endothelial cells, 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, the therapeutic agents may be pre-formulated as a microcapsules, microspheres, microbubbles, liposomes, niosomes, emulsions, dispersions or the like before it is incorporated into the therapeutic layer. The therapeutic agent 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.

A water soluble drug is one that has a solubility of greater than 1.0 mg/mL in water at body temperature.

The term "matrix" or "biocompatible 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 therapeutic agent, and/or modulate the release of the therapeutic agent into the body. 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.

The term "bioresorbable" refers to a matrix, as defined herein, that can be broken down by either chemical or physical process, upon interaction with a physiological environment. The matrix can erode or dissolve. A bioresorbable matrix serves a temporary function in the body, such as drug delivery, and is then degraded or broken into components that are metabolizable or excretable, over a period of time from minutes to years, preferably less than one year, while maintaining any requisite structural integrity in that same time period.

The term "pharmaceutically acceptable" refers to a matrix or an additive, as defined herein, that is not toxic to the host or patient. When in reference to a matrix, it provides the appropriate storage and/or delivery of therapeutic, activating or deactivating agents, as defined herein, and does not interfere with the effectiveness or the biological activity of the agent.

The term "mixing layer" refers to a matrix layer which is adjacent a therapeutic agent layer. Before the mixing layer is introduced to the device, the mixing layer preferably contains no therapeutic agent, or it contains a therapeutic agent which is different from the therapeutic agent of the therapeutic agent layer. The mixing layer is introduced in a liquified state and may mix with the therapeutic agent layer causing the mixing layer to incorporate a portion of the adjacent therapeutic agent layer once the layer has at least partially solidified. The mixing layer may also serve to control the rate at which a drug is released into the reaction environment. The release rate can be controlled by the rate of erosion or dissolution of the mixing layer or by the rate of diffusion of the therapeutic agent from within the mixing and therapeutic agent layers. The mixing layer is preferably bioresorbable.

The term "erosion" refers to the process by which the components of a medium or matrix are bioresorbed and/or degraded and/or broken down by either chemical or physical processes. For example in reference to polymers, erosion can occur by cleavage or hydrolysis of the polymer chains, such that the molecular weight of the polymer is lowered. The polymer of lower molecular weight will have greater solubility in water and is therefore dissolved away. In another example, erosion occurs by physically breaking apart upon interaction with a physiological environment.

The term "erosion rate" is a measure of the amount of time it takes for the erosion process to occur and is usually report in unit area per unit time.

The term "degrade" or "deactivate" refers to any process that causes an active component, such as a therapeutic agent, to become unable, or less able, to perform the action which it was intended to perform when incorporated in the device.

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 M.sub.w greater than about 3000 and preferably greater than about 10,000 and a M.sub.w 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, polyglycolic acid, polylactic-co-glycolic acid, polylactic acid-co-caprolactone; polyethylene glycol and polyethylene oxide, polyvinyl pyrrolidone, polyorthoesters; polysaccharides and polysaccharide derivatives such as polyhyaluronic acid, polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose; polypeptides, and proteins such as polylysine, polyglutamic acid, albumin; polyanhydrides; polyhydroxy alkonoates such as polyhydroxy valerate, polyhydroxy butyrate, and the like.

The term "lipid", as used herein, refers to a matrix that comprises preferably non-polymeric small organic, synthetic or naturally-occurring, compounds which are generally amphipathic and biocompatible. The lipids typically comprise a hydrophilic component and a hydrophobic component. Exemplary lipids include, for example, fatty acids, fatty acid esters, neutral fats, phospholipids, glycolipids, aliphatic alcohols, waxes, terpenes, steroids and surfactants. Term lipid is also meant to include derivatives of lipids. More specifically the term lipids includes but is not limited to phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin as well as synthetic phospholipids such as dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, distearoyl phosphatidylglycerol, dipalmitoyl phosphatidyl-glycerol, dimyristoyl phosphatidylserine, distearoyl phosphatidylserine and dipalmitoyl phosphatidylserine.

The term "additives" refers to pharmaceutically acceptable compounds, materials, and compositions that may be included in a matrix along with a therapeutic agent. An additive may be encapsulated in or on or around a matrix. It may be homogeneously or heterogeneously disposed, as defined herein, in the matrix. Some examples of additives are pharmaceutically acceptable excipients, adjuvants, carriers, antioxidants, preservatives, buffers, antacids, and the like, such as those disclosed in Remington: The Science and Practice of Pharmacy, Gennaro, ed., Mack Publishing Co., Easton, Pa., 19th ed., 1995.

The term "holes" refers to holes of any shape and includes both through-openings and recesses.

The term "reaction environment" or "environment" refers to the area between a tissue surface abutting the device and the first intact layer of beneficial agent within a hole in the medical device.

The term "liquified" is used herein to define a component which is put in a liquid state either by heating the component to a temperature higher than its melting point, or glass transition temperature, or by dissolving the component in a solvent. The typical liquified materials of the present invention will have a viscosity of less than about 13,000 centipoise, and preferably less about 10,000 centipoise.

The term "homogeneously disposed" or "homogeneously dispersed" refers to a mixture in which each of the components are uniformly dispersed within the matrix.

The term "heterogeneously disposed" or "heterogeneously dispersed" refers to a mixture in which the components are not mixed uniformly into a matrix.

The term "solid solution" refers to a homogeneously dispersed mixture of two or more substances. A component that is mixed uniformly in a matrix in such a manner that the component is macroscopically indistinguishable from the matrix itself. An example of a solid solution is a metal alloy, such as brass.

The term "multi-phase mixture" refers to a mixture of two or more substances in which at least one component is macroscopically distinguishable from the matrix itself. An example of a multi-phase mixture is a macro emulsion.

Implantable Medical Devices with Holes

FIG. 1 illustrates a medical device 10 according to the present invention in the form of a stent design with large, non-deforming struts 12 and links 14, which can contain holes 20 without compromising the mechanical properties of the struts or links, or the device as a whole. The non-deforming struts 12 and links 14 may be achieved by the use of ductile hinges 16 which are described in detail in U.S. Pat. No. 6,241,762 which is incorporated hereby by reference in its entirety. The holes 20 serve as large, protected reservoirs for delivering various beneficial agents to the device implantation site.

The relatively large, protected openings 20, as described above, make the expandable medical device of the present invention particularly suitable for delivering larger molecules or genetic or cellular agents, such as, for example, protein drugs, enzymes, antibodies, antisense oligonucleotides, ribozymes, gene/vector constructs, and cells (including but not limited to cultures of a patient's own endothelial cells). Many of these types of agents are biodegradable or fragile, have a very short or no shelf life, must be prepared at the time of use, or cannot be pre-loaded into delivery devices such as stents during the manufacture thereof for some other reason. The large holes 20 in the expandable device of the present invention form protected areas or receptors to facilitate the loading of such an agent either at the time of use or prior to use, and to protect the agent from abrasion and extrusion during delivery and implantation.

The volume of beneficial agent that can be delivered using holes 20 is about 3 to 10 times greater than the volume of a 5 micron coating covering a stent with the same stent/vessel wall coverage ratio. This much larger beneficial agent capacity provides several advantages. The larger capacity can be used to deliver multi-drug combinations, each with independent release profiles, for improved efficacy. Also, larger capacity can be used to provide larger quantities of less aggressive drugs and to achieve clinical efficacy without the undesirable side-effects of more potent drugs, such as retarded healing of the endothelial layer.

Holes also decrease the surface area of the beneficial agent bearing compounds to which the vessel wall surface is exposed. For typical devices with beneficial agent openings, this exposure decreases by a factors ranging from about 6:1 to 8:1, by comparison with surface coated stents. This dramatically reduces the exposure of vessel wall tissue to polymer carriers and other agents that can cause inflammation, while simultaneously increasing the quantity of beneficial agent delivered, and improving control of release kinetics.

FIG. 2 shows a cross section of a medical device 10 in which one or more beneficial agents have been loaded into the opening 20 in discrete layers 30. Examples of some methods of creating such layers and arrangements of layers are described in U.S. patent application Ser. No. 09/948,989, filed on Sep. 7, 2001, which is incorporated herein by reference in its entirety.

According to one example, the total depth of the opening 20 is about 125 to about 140 microns, and the typical layer thickness would be about 2 to about 50 microns, preferably about 12 microns. Each typical layer is thus individually about twice as thick as the typical coating applied to surface-coated stents. There would be at least two and preferably about ten to twelve such layers in a typical opening, with a total beneficial agent thickness about 4 to 28 times greater than a typical surface coating. According to one preferred embodiment of the present invention, the openings have an area of at least 5.times.10.sup.-6 square inches, and preferably at least 7.times.10.sup.-6 square inches.

Since each layer is created independently, individual chemical compositions and pharmacokinetic properties can be imparted to each layer. Numerous useful arrangements of such layers can be formed, some of which will be described below. Each of the layers may include one or more agents in the same or different proportions from layer to layer. The layers may be solid, porous, or filled with other drugs or excipients.

FIG. 2 shows an arrangement of layers provided in a through opening 20 which include a barrier layer 30, one or more therapeutic agent layers 40, and a plurality of mixing layers 50. The barrier layer 30 substantially prevents delivery of the therapeutic agent in the therapeutic agent layers and the mixing layers from being delivered to a side of the device 10 adjacent the barrier layer. The therapeutic agent layer 40 and the mixing layers 50 are loaded sequentially into the medical device opening 20, such that a concentration gradient of therapeutic agent is present with a highest concentration of therapeutic agent at the interior layers closer to the barrier layer and a lowest concentration of therapeutic agent at the exterior mixing layers. The combination of therapeutic agent layer and mixing agent layers allows a water soluble therapeutic agent to be delivered over an extended time period of time. The time period for delivery can be modulated from minutes, to hours, to days. Preferably the time period for delivery is greater than 1 day, more preferably greater than 3 days.

In one embodiment the layers are loaded into the medical device by first loading the therapeutic agent layer, 40, into the holes of the medical device in a liquefied state. The therapeutic agent layer is then allowed to solidify. A first mixing layer, 50, is then loaded into the holes within the medical device in a liquefied state. When the liquid mixing layer, 50, comes into contact with the therapeutic agent layer, 40, a portion of the therapeutic agent layer is liquefied allowing a co-mingling of some of the components of each of the two layers. When the mixing layer solidifies, there is therapeutic agent within the mixing layer.

Optionally, a second mixing layer is then loaded into the holes within the medical device in a liquefied state. When the second liquid mixing layer comes into contact with the first mixing layer, a portion of the first mixing layer is liquefied allowing a co-mingling of some of the components of each of the two layers. When the mixing layer solidifies, there is an amount of therapeutic agent within the second mixing layer that is less than the amount of therapeutic agent in the first mixing layer. Subsequent additions of mixing layers results in the formation of multiple mixing layers with decreasing amounts of therapeutic agent. The gradient of therapeutic agent incorporated in a mixing layers adjacent the therapeutic agent layer is especially advantageous for the delivery of water soluble drugs such as a 2-chlorodeoxyadenosine.

An example of a binding agent is Poly vinylpyrrolidone. The polymers of the therapeutic agent layer may be the same as or different from the polymer of the mixing layers. The polymer can be liquefied by maintaining the material at a temperature that is greater than its melting point, or glass transition temperature, or by dissolution in a solvent.

Some examples of hydrophobic, bioresorbable matrix materials for the mixing layer are lipids, fatty acid esters, such as glycerides. The erosion rate is controlled by varying the hydrophilic-lipophilic balance (HLB). The polymers of the individual mixing layers may be the same or different. These polymers can be liquefied by maintaining the material at a temperature that is greater than its melting point, or glass transition temperature, or by dissolution in a solvent.

Bioerosion of the mixing layers may induce the release of the therapeutic agent from either the mixing layer or the therapeutic agent layer. However, in some embodiments, the mixing layer remains essentially intact, and the therapeutic agent is released into the reaction environment by diffusing from the therapeutic agent layer and through the mixing layers.

Therapeutic Layer Formulations

The therapeutic agent layers of the present invention may consist of the therapeutic agent alone or a therapeutic agent in combination with a bioresorbable matrix. The matrix of the therapeutic agent layers can be made from pharmaceutically acceptable polymers, such as those typically used in medical devices. This polymer may also be referred to as a binding agent. Typically, when a lesser amount of matrix material is used relative to the amount of drug, for example 5 50% polymer to 95 50% drug, the material is called a binding agent.

Polymers useful in the therapeutic agent layer as either a matrix material or a binding agent are well known and include but are not limited to poly-.alpha.-hydroxy acid esters such as, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polylactic acid-co-caprolactone; polyethylene glycol and polyethylen