WO2008024626A2

WO2008024626A2 - Bioresorbable stent with extended in vivo release of anti-restenotic agent

Info

Publication number: WO2008024626A2
Application number: PCT/US2007/075504
Authority: WO
Inventors: Stephen H. Diaz; John F. Shanley; Theodore L. Parker; Frank Litvack
Original assignee: Innovational Holdings Llc
Priority date: 2006-08-21
Filing date: 2007-08-08
Publication date: 2008-02-28
Also published as: WO2008024626A3

Abstract

A method for decreasing the level of restenosis following a stent placement medical intervention involves the continuous administration of a dose of an anti- restenotic agent, such as paclitaxel, from the stent to vascular tissue in need of treatment in a controlled and extended drug release profile for a period of at least 60 days in vivo. The in vivo release profile is determined by in vivo animal experiments involving implanting a series of stents in animals, explanting the stents from the animals at selected time points, and extracting remaining drug from the explanted stents.

Description

BIORESORBABLE STENT WITH EXTENDED IN VIVO RELEASE OF ANTI-RESTENOTIC AGENT

Background

Most coronary artery-related deaths are caused by atherosclerotic lesions which limit or obstruct coronary blood flow to heart tissue. To address coronary artery disease, doctors often resort to percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG). PTCA is a procedure in which a small balloon catheter is passed down a narrowed coronary artery and then expanded to re-open the artery. The major advantage of angioplasty is that patients in which the procedure is successful need not undergo the more invasive surgical procedure of coronary artery bypass graft. A major difficulty with PTCA is the problem of post- angioplasty closure of the vessel, both immediately after PTCA (acute reocclusion) and in the long term (restenosis).

Coronary stents are typically used in combination with PTCA to reduce reocclusion of the artery. Stents are introduced percutaneously, and transported transluminal Iy until positioned at a desired location. The stents are then expanded either mechanically, such as by the expansion of a balloon positioned inside the stent, or expand themselves by releasing stored energy upon actuation within the body. Once expanded within the lumen stents become encapsulated within the body tissue and remain a permanent implant.

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. To treat restenosis, additional revascularization procedures are frequently required, thereby increasing trauma and risk to the patient.

While the exact mechanisms of restenosis are still being determined, certain agents have been demonstrated to reduce restenosis in humans. Drug eluting stents represent the most advanced and sophisticated treatment currently available to address restenosis. Two examples of agents which have been demonstrated to reduce restenosis when delivered from a stent are paclitaxel, a well-known compound that is commonly used in the treatment of cancerous tumors, and Rapamycin, an immunosuppressive compound used to prevent rejection of organ or tissue transplants.

There are two types of stents that are presently utilized; permanent stents and bioresorbable stents. A permanent stent is designed to be maintained in a body lumen for an indeterminate amount of time. Permanent stents are typically designed to provide long-term support for damaged or traumatized wall tissues of the lumen. There are numerous conventional applications for permanent stents including cardiovascular, peripheral, urological, gastrointestinal, and gynecological applications.

Bioresorbable stents may advantageously be eliminated from body lumens after a predetermined, clinically appropriate period of time, for example, after the traumatized tissues of the lumen have healed and a stent is no longer needed to maintain the patency of the lumen. Bioresorbable stents can be used in many of the same applications as permanent stents as well as some additional applications.

It is known that the permanent stents may become encrusted, encapsulated, endothelialized or ingrown with body tissue. Permanent stents could possibly cause irritation to the surrounding tissues in a lumen due to the fact that metal, or other material of the stent, is typically much harder and stiffer than the surrounding tissues in a lumen, which may result in an anatomical or physiological mismatch, thereby damaging tissue or eliciting unwanted biologic responses.

It is known to use bioabsorbable and bioresorbable materials for manufacturing stents. The conventional bioabsorbable or bioresorbable materials from which such stents are made are selected to resorb or degrade over time, thereby eliminating the need for subsequent surgical procedures to remove the stent from the body lumen if problems arise. However, formation of a bioresorbable stent with a drug within the stent is difficult because the thermoforming processes necessary for formation of the bioresorbable stents are often not tolerated by the drug. Further, surface coatings on bioabsorbable stents, like the coatings on permanent metal stents have difficulty in controlling the release of the drug due to the limitations of a surface coating. In addition, coatings can adversely affect the resorbtion of a bioresorbable stent. Summary of the Invention

The present invention relates to bioresorbable stents for reducing restenosis which deliver drug in vivo over an extended administration period of at least 60 days.

In accordance with one aspect of the present invention, a method of reducing restenosis comprises the steps of providing a bioresorbable stent having a dosage of anti-restenotic agent for delivery to an artery, the dosage arranged such that substantially all the agent is releasable from the stent upon implantation of the stent in the artery, implanting the stent within an artery of a patient, and delivering the agent from the stent in vivo over an administration period beginning on a date of implantation and ending between about 60 days and about 8 months after implantation, wherein the bioresorbable stent is substantially resorbed by the body between about 3 and about 12 months after the date of implantation.

In accordance with another aspect of the invention a bioresorbable stent for reducing restenosis is comprised of a bioresorbable stent having initial unexpanded diameter for insertion of the stent into a coronary artery and an expanded diameter for implantation within a coronary artery, the stent having a dosage of anti-restenotic agent for delivery to an artery, the dosage arranged such that substantially all the agent is releasable from the stent upon implantation of the stent in the artery, wherein the dosage of the agent is arranged to be released over an in vivo administration period beginning on the date of implantation and ending between 60 days and 8 months after implantation, and wherein after the administration period no drug remains on the stent.

BRIEF DESCRIPTION OF THE DRAWINGS

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 one example of a stent according to the present invention.

FIG. 2 is a side view of a portion of the stent of FIG. 1.

FIG. 3 is a side cross sectional view of an example of an opening in a stent showing a matrix with a therapeutic agent and polymer. FIG. 4 is a graph of the in vivo cumulative release and release rate of paclitaxel from a paclitaxel loaded stent system.

FlG. 5 is a graph of the in vivo release by percentage released of paclitaxel and polymer from a paclitaxel loaded stent system.

FIG. 6 is a graph of the in vivo cumulative percent of Pimecrolimus released from a stent over time.

DETAILED DESCRIPTION

A biodegradable or bioresorbable drug delivery stent as illustrated in FIGS. 1- 3 of the present invention includes a substantially cylindrical expandable stent formed of a bioresorbable material and a plurality of reservoirs formed in the stent containing a beneficial agent matrix. The bioresorbable stent material can be a bioresorbable metal alloy, a bioresorbable polymer, a bioresorbable composite or the like which has sufficient structural integrity to support a lumen, such as a blood vessel lumen for a predetermined period of time. The reservoirs containing the beneficial agent matrix allow delivery of the beneficial agent, such as an antirestenotic drug, for an administration period which is generally equal to or less than a time that the bioresorbable stent is retained in the lumen. The beneficial agent matrix may include one or more bioresorbable polymers or other matrix materials in combination with one or more therapeutic agents or drugs for treatment of restenosis or other coronary or peripheral diseases.

A method for decreasing the level of restenosis following a stent placement medical intervention involves the continuous administration of a dose of an antirestenotic agent or drug from the bioresorbable stent to vascular tissue in need of treatment in a controlled and extended in vivo drug release profile. It is envisioned that the vascular tissue in need of treatment is arterial tissue, specifically coronary arterial tissue. The method of extended in vivo release increases the therapeutic effectiveness of administration of a given dose of anti-restenotic agent and reduces side effects. hi one example described in detail herein the agent or drug will be contained in reservoirs in the stent body prior to release, hi the reservoir example, the drug will be held within the reservoirs in the stent in a drug delivery matrix comprised of the drug and a polymeric material and optionally additives to regulate the drug release. Preferably the polymeric material is a bioresorbable polymer. Although a reservoir example is described, the drug delivery bioresorbable stent of the present invention can include matrices fixed to a stent in a variety of manners including reservoirs, coatings, microspheres, affixed with adhesion materials or combinations thereof.

The following terms, as used herein, shall have the following meanings:

The terms "drug" and "therapeutic agent" are used interchangeably to refer to any therapeutically active substance that is delivered to a living being to produce a desired, usually beneficial, effect.

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 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 matrix may be bioresorbable or non-bioresorbable.

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, usually less than one year, while maintaining any requisite structural integrity in that same time period.

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 therapeutic agent and allowing the delivery of the therapeutic 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, oligomers, and copolymers prepared from two or more different monomers. 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-α-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 50% of the total amount of therapeutic agent provided to a blood vessel.

The term "restenosis" refers to the renarrowing of an artery following an angioplasty procedure which may include stenosis following stent implantation. 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.

The term "anti-restenotic" refers to a drug which interferes with any one or more of the processes of restenosis to reduce the renarrowing of the lumen.

The term "substantially linear release profile" refers to a release profile defined by a plot of the cumulative drug released versus the time during which the release takes place in which the linear least squares fit of such a release profile plot has a correlation coefficient, r² (the square of the correlation coefficient of the least squares regression line), of greater than 0.92 for data time points after the first day of delivery. A substantially linear release profile is clinically significant in that it allows release of a prescribed dosage of drug at a uniform rate over an administration period. This controlled release allows a release system to stay within the toxic / therapeutic window for a particular drug over an extended administration period. FIG. 1 illustrates one example of an implantable medical device in the form of a bioresorbable stent 10. FlG. 2 is an enlarged flattened view of a portion of the stent of FIG. 1 illustrating one example of a stent structure including struts 12 interconnected by ductile hinges 20. The struts 12 include openings 14 which can be non-deforming through openings containing a therapeutic agent. One example of a stent structure having non-deforming openings is shown in U.S. Patent No. 6,562,065, which is incorporated herein by reference in its entirety.

The bioresorbable stent 10 can be formed of a bioresorbable metal alloy or a bioresorbable polymer. Bioresorbable metal alloys useful for stents include zinc- titanium alloys, and magnesium alloys, such as lithium-magnesium, sodium- magnesium, and magnesium alloys containing rare earth metals. Some examples of bioresorbable metal alloys are described in U.S. Patent No. 6,287,332, which is incorporated herein by reference in its entirety. Bioresorbable metal alloy stents can be formed in the configuration illustrated in FIGS. 1 and 2 by laser cutting. When cutting stents from these alloys, an inert atmosphere may be desired to minimize oxidation of the alloy during cutting in which case, a helium gas stream, or other inert atmosphere can be applied during cutting. Magnesium alloys are used in the aeronautic industry and the processing systems used for the aeronautic industry can also be used for forming the stents. Bioresorbable metal alloys provide the necessary structural strength needed for the stent, however, it is difficult to incorporate a drug within the bioresorbable metal alloy and is difficult to release the drug if it could be incorporated.

The use of coatings on the bioresorbable metal alloy surface containing a drug may interfere with the biodegradation of the stent. Therefore, the openings in the bioresorbable stent and the filling of the openings with a bioresorbable matrix containing drug provides a solution because there is no requirement for a coating on the stent.

When the bioresorbable stent 10 is formed of a bioresorbable polymer material, similar problems can occur when attempting to add a drug to the stent by incorporating drug into the polymer or coating drug onto the stent. For example, bioresorbable polymers which have sufficient strength to be used as a stent may not be capable of incorporating a drug and releasing the drug in a desired manner. Further, drug coatings require that they adhere well without cracking or flaking during delivery and also release the drug in a desired manner. Additionally, polymer stents tend to have high recoil.

Another difficulty in incorporating drugs in polymer stents is that methods for forming bioresorbable polymer stents tend to be high temperature processes which are not suitable for many drugs. With polymer stents, as with bioresorbable metal alloys, a coating may also interfere with bioresorbtion of the stent.

The bioresorbable stent of the present application provides a solution to these problems by selecting a first bioresorbable polymer for the struts of the stent and providing openings in the stent containing a beneficial agent matrix. The polymer or other matrix material in the openings require none of the structural properties of the stent, and also require very little flexibility or adhesion which is required by a coating. Thus, the matrix material selection may be made based on the ability of the material to release the drug with a desired release profile. Directional delivery of one or more drugs can also be achieved with reservoirs which cannot be easily achieved with coatings, impregnation, or other methods.

Examples of bioresorbable polymers which can be used for the structural struts of the stent 10 include, without limitation, polylactic acid (PLA), polyglycolic acid (PGA), copolymers of PLA and PGA, poly-L-lactide (PLLA), poly-D,L-lactide (PDLA), poly-ε-capralactone (PCL), and combinations thereof. U.S. Patent No. 4,889,119, which is incorporated herein by reference in its entirety, describes some of the bioresorbable polymers which are useful in the present invention.

As some bioresorbable polymer and bioresorbable metal stents degrade within the body the pH may increase or decrease to a level which can affect stability of the drug. In these cases an additive can be used to counteract this pH change. For example, the acidic environment resulting from degradation of the polymer PLGA can be counteracted by an antacid. Conversly, the degradation of a bioresorbable metal alloy can result in a basic environment which can be counteracted by an acid. Where interactions between he drug and the stent material may be problematic, the interiors of the openings can be covered with a polymer.

Bioresorbable polymer or metal stents are resorbed by the body after structural support of the body lumen is no longer needed. For example, the bioresorbable stent can be resorbed by the body in about 3-12 months after implantation. Preferably, the stent maintains structural support, i.e., resists collapse, for a period of at least two months after the date of implantation.

The implantable medical devices of the present invention are configured to release at least one therapeutic agent from a matrix affixed to the implantable body. The matrix is formed such that the distribution of the agent in the polymer matrix controls the rate of elution of the agent from the matrix. The release kinetic is also controlled by the selection of the matrix, the concentration of the agent in the matrix, any additives, and any cap or rate controlling deposits.

In one embodiment, the matrix is a polymeric material which acts as a binder or carrier to hold the agent in or on the stent and/or modulate the release of the agent from the stent. The polymeric material can be a bioresorbable or a non-bioresorbable material.

The therapeutic agent containing matrix can be disposed in the stent or on surfaces of the stent in various configurations, including within volumes defined by the stent, such as openings, holes, or concave surfaces, as a reservoir of agent, or arranged in or on all or a portion of surfaces of the stent structure. When the therapeutic agent matrix is disposed within openings in the strut structure of the stent to form a reservoir, the openings may be partially or completely filled with matrix containing the therapeutic agent.

FIG, 3 is a cross section of one strut of the stent 10 and blood vessel 100 illustrating one example of an opening 14 arranged adjacent the vessel wall with a mural surface 26 abutting the vessel wall and a luminal surface 24 opposite the mural surface. The opening 14 of FIG. 3 contains a matrix 60 with a therapeutic agent illustrated by O's in the matrix. The luminal side 24 of the stent opening 14 is provided with a base 50. The base 50 causes the therapeutic agent to be delivered primarily to the mural side 26 of the stent so that it is delivered directly to the artery wall. The base 50 may be formed of a material which also forms the matrix 60 or of a different material. The base 50 can be formed to erode more slowly than the matrix 60 containing the therapeutic agent. This can be achieved by selecting a different molecular weight of the matrix in the base 50, by different processing (i.e., annealing) of the same matrix, or by other means. A thickness of the base 50 can vary from about 5% to about 75%, preferably about 10% to 50%, of the depth of the opening 14. The matrix 60 and therapeutic agent are arranged in a programmable manner to achieve a desired in vivo release rate and administration period which will be described in further detail below. As can be seen in the example of FIG. 3, the concentration of the therapeutic agent (O 's) is highest adjacent the base 50 and transitions to a lower concentration at the mural side 26 of the stent. This configuration and other configurations of concentration gradients within the matrix allow the in vivo release profile to be programmed to match a particular application. In contrast, a uniform agent distribution in the matrix would result in a first order release profile with a large burst followed by a slower release.

The methods by which the drug can be precisely arranged within the matrix in the openings is a stepwise deposition process are further described in U.S. Patent Publications 2005-0010170 and 2004-0073294, both of which are incorporated herein by reference in their entirety.

Numerous other useful arrangements of the matrix and therapeutic agent can be formed to achieve the substantially linear release, increasing release rate, extended release, and substantially complete release described herein. Each of the areas of the matrix may include one or more agents in the same or different proportions from one area to the next. The matrix may be solid, porous, or filled with other drugs or excipients. The agents may be homogeneously disposed or heterogeneously disposed in different areas of the matrix.

In the example of FIGS. 4 and 5, a stent is cut from a bioresorbable metal alloy according to the pattern shown in FIGS. 1 and 2 and paclitaxel is loaded in a PLGA matrix within reservoirs in the stent. The drug and matrix are arranged for directional delivery of the drug to the mural side of the stent. The in vivo drug release rate is programmed by providing different concentrations of drug in different areas of the matrix similar to the concentration gradient shown in FIG. 3. The in vivo drug releases described herein are normalized for a 3.0 mm diameter X 16 mm long expanded stent which has almost 500 reservoirs and a total drug volume of about 0.54 mm³.

When the anti-restenotic agent delivered by the method of the invention is paclitaxel, the total amount delivered (and loaded) is preferably between 5 micrograms and 30 micrograms for a 3.0 mm x 16 mm stent and other amounts depending on the size of the stent. The methods of the invention will result in sustained release of substantially all the drug loaded onto the stent as well as the polymer matrix over an administration period which lasts at least 60 days and preferably no longer than 8 months.

FIG. 4 illustrates one example of an in vivo extended paclitaxel release profile from a bioresorbable matrix in openings in a stent. The release profile is characterized by a small initial release of drug in the first day, followed by an extended increasing release from day 1 until about 60 to 120 days, followed by a decreasing release until all the drug loaded on the stent is released between about 90 and 180 days. The increasing release rate shown between day 1 and about 90-180 days is different from the releases shown during this time period from coated stents which reach a maximum release rate at a burst in generally the first day and then show a continuously decreasing release rate thereafter.

The increasing in vivo release rate after the first day shown in FIG. 4 more closely matches the delivery of drug to the biological process of restenosis.

The total drug load on the stents of FIGS. 4 and 5 is between about 10 μg and about 14 μg normalized for a 3 mm X 16 mm stent. The initial release in the first day is about 5-25% of the total amount of paclitaxel loaded on the stent or about 1.5 μg in the first day. The release rate drops to under 0.1 μg per day after day one and continues at this reduced rate for up to about 90 days. A release of between 0.01 μg and 0.2 μg per day continues after day one for at least 60 days and preferably for at least 90 days. A dosage of about 10-14 μg on a 3 mm X 16 mm size stent corresponds to about 0.078 μg/mm² of vessel surface area and about 0.732 μg/mm of vessel length. Equivalent dosages are used on stents of other sizes.

The relatively low initial release and slow extended release result in the in vivo release of not more than 40% of the paclitaxel on the stent in the first 30 days after implantation. This is followed by the complete release of the entire dose of paclitaxel loaded on the stent within about 8 months and preferably within about 6 months. A similar in vivo release is also used for other anti-restenotic agents including pimecrolimus and rapamycin which include an initial day one release of up to 25% of the total drug load, a 30 day release of not more than 70% of the total drug load and complete release between 60 days and 8 months.

FIG. 5 illustrates the in vivo release of the paclitaxel from the stent described above compared to the rate that the polymer is resorbed in vivo. The polymer is resorbed at a rate slower than the release of the drug. Therefore, substantially all of the paclitaxel is delivered before the polymer matrix is completely resorbed. hi one embodiment the drug is completely delivered about 1-3 months, preferably about 1-2 months, before the polymer is completely resorbed. Preferably, the polymer is completely resorbed between 60 days and 8 months from the date of implantation.

The polymer is resorbed at a rate that is somewhat slower than the release rate of the drug. Pn the example of FIG. 5, about 10-30% of the polymer is resorbed by about 60 days, about 50-80% of the polymer is resorbed by about 120 days and all the polymer is resorbed between 4 and 7 months. The use of the resorbable polymer which completely disappears from the stent within a period of months allows an administration of antiplatelet drugs to the patient according to current procedures for drug eluting stents to be discontinued after the polymer is completely resorbed and the drug has been released. There is no non-releasable drug or polymer remaining once the stent has been in physiologic conditions for 8 months.

It has been shown in clinical trials that longer in vivo release (greater than 60 days) of the anti-restenotic paclitaxel, such as in the release profiles shown in FIGS. 4 and 5 result in lower in stent neointimal proliferation than the more rapid release of the same dosage. The method of extended in vivo release of anti-restenotic agents increases the therapeutic effectiveness of administration of a given dose of agent and reduces side effects. hi the example of FIG.6, a stent is cut from a bioresorbable metal alloy according to the pattern shown in FIGS. 1 and 2 and Pimecrolimus is loaded in a PLGA matrix within reservoirs in the stent. The drug and matrix are arranged for directional delivery of the drug primarily to the mural side of the stent. The in vivo drug release rate is programmed by providing different concentrations of drug in different regions of the matrix similar to the regions shown in FIG. 3, with a luminal region 50 of primarily PLGA, a middle region of about 75% Pimecrolimus and about 25% PLGA, and a mural region of about 95% Pimecrolimus and about 5% PLGA. The reservoirs are filled, by volume, with about 20-25% base or luminal region, 40- 45% middle region, and 25-30% mural region. The in vivo drug releases described herein are normalized for a 3.0 mm diameter X 16 mm long expanded stent which has almost 500 reservoirs and a total drug volume of about 0.54 mm³. When the anti-restenotic agent delivered by the method of the invention is Pimecrolimus, the total amount delivered (and loaded) is preferably between about 50μg and about 600μg depending on the size of the stent.

The methods of the invention will result in sustained release of substantially all the drug loaded onto the stent as well as the polymer matrix over an administration period which lasts at least 30 days and preferably no longer than 1 year.

FIG. 6 illustrates one example of an in vivo extended Pimecrolimus release profile from a bioresorbable matrix. The release profile is characterized by a moderate initial release or bolus of drug in the first 12-48 hours, followed by an extended, substantially linear release from day 2 until about 45 to 150 days, followed by a decreasing release until all the drug loaded on the stent is released between about 90 and 300 days.

The total drug load on the stents of FIG. 6 is between about 150μg and about 400μg normalized for a 3 mm X 16 mm stent. The initial release in the first day is about 5-50%, preferably about 20-45%, of the total amount of Pimecrolimus loaded on the stent, and the initial release in the first two days is about 20-60%, preferably about 25-50%. After day two, the release rate drops to under about 15μg per day and, preferably about 1 μg to about 10 μg per day and continues at this reduced rate for up to about 180 days. The extended phase of release after the first two days results in less than 80% of the Pimecrolimus being delivered in the first 30 days. More specifically, the 4 hour release is about 10%, the 24 hour release is about 25%, and the 2 day release is about 40%, the 8 day release is about 50%, and the 30 and 50 day releases are about 70%.

As shown in FIG. 6, the release after day two is substantially linear until less than 10% of the total drug is remaining on the stent. A dosage of about 300-350μg on a 3 mm X 16 mm size stent corresponds to about 2.0 - 2.4 μg/mm² of vessel surface area and about 18-22 μg/mm of vessel length. Equivalent dosages are used on stents of other sizes. When the Pimecrolimus is used in combination with another anti- restenotic drug, the dosage can be Vz of this dosage.

The initial bolus and slow extended release result in the in vivo release of not more than 90%, preferably not more than 80% of the Pimecrolimus on the stent in the first 45 days after implantation. This is followed by the complete release of the entire dose of Pimecrolimus loaded on the stent within about 1 year and preferably within about 6 months. A similar in vivo release is also used for other anti-inflammatory agents.

According to one example, the polymer is resorbed in vivo at a rate slower than the release of the drug. Therefore, substantially all of the Pimecrolimus is delivered before the polymer matrix is completely resorbed. Tn one embodiment the drug is completely delivered at about 1-3 months, preferably about 1-2 months, before the polymer is completely resorbed. Preferably, the polymer is completely resorbed between 45 days and 1 year from the date of implantation. The use of the resorbable polymer which completely disappears from the stent within a period of months allows an administration of antiplatelet drugs to the patient according to current procedures for drug eluting stents to be discontinued after the polymer is completely resorbed and the drug has been released. There is no non-releasable drug or polymer remaining once the stent has been in physiologic conditions for 1 year. The drug can be considered completely released or the administration can be considered complete once 95% or more of the drug which is releasable from the stent has been released.

The method of extended in vivo release of anti-inflammatory agents increases the therapeutic effectiveness of administration of a given dose of agent and reduces side effects.

While the invention has been described with respect to treatment of restenosis, other therapeutic agents may be delivered at the in vivo release profiles described for treatment of acute myocardial infarction, thrombosis, or for passivation of vulnerable plaque.

THERAPEUTIC AGENTS

The present invention relates to the in vivo release kinetics involved in delivering anti-restenotic agents including taxol, rapamycin, everolimus, ABT- 578, Pimecrolimus, cladribine, colchicines, vinca alkaloids, heparin, hinrudin and their derivatives, as well as other cytotoxic or cytostatic, and microtubule stabilizing and microtubule inhibiting agents from a bioresorbable stent. These anti-restenotic agents can be delivered alone or in combination.

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. Other therapeutic agents for use with the present invention may, for example, take the form of small molecules, 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, eukaryotic cells such as endothelial cells, stem cells, ACE inhibitors, monocyte/macrophages and vascular smooth muscle cells. Such agents can be used alone or in various combinations with one another. For instance, anti-inflammatories may be used in combination with antiproliferatives to mitigate the reaction of tissue to the antiproliferative. 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 matrix. 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.

Exemplary classes of therapeutic agents include antiproliferatives, antithrombins (i.e., thrombolytics), immunosuppressants, antilipid agents, antiinflammatory agents, antineoplastics including antimetabolites, antiplatelets, angiogenic agents, anti-angiogenic agents, vitamins, antimitotics, metalloproteinase inhibitors, NO donors, nitric oxide release stimulators, anti-sclerosing agents, vasoactive agents, endothelial growth factors, beta blockers, AZ blockers, hormones, statins, insulin growth factors, antioxidants, membrane stabilizing agents, calcium antagonists (i.e., calcium channel antagonists), retinoids, anti -macrophage substances, antilymphocytes, cyclooxygenase inhibitors, immunomodulatory agents, angiotensin converting enzyme (ACE) inhibitors, anti- leukocytes, high-density lipoproteins (HDL) and derivatives, cell sensitizers to insulin, prostaglandins and derivatives, anti-TNF compounds, hypertension drugs, protein kinases, antisense oligonucleotides, cardio protectants, petidose inhibitors (increase blycolitic metabolism), endothelin receptor agonists, interleukin-6 antagonists, anti-restenotics, vasodilators, and other miscellaneous compounds.

Antiproliferatives include, without limitation, paclitaxel, actinomycin D, rapamycin, everolimus, ABT-578, tacrolimus, cyclosporin, and pimecrolimus. Antithrombins include, without limitation, heparin, aspirin, sulfinpyrazone, ticlopidine, ABCIXIMAB, eptifibatide, tirofiban HCL, coumarines, plasminogen, α₂- antiplasmin, streptokinase, urokinase, bivalirudin, tissue plasminogen activator (t- PA), hirudins, hirulogs, argatroban, hydroxychloroquin, BL-3459, pyridinolcarbamate, Angiomax, and dipyridamole.

Immunosuppressants include, without limitation, cyclosporine, rapamycin and tacrolimus (FK-506), ABT-578, everolimus, etoposide, and mitoxantrone,

Antilipid agents include, without limitation, HMG CoA reductase inhibitors, nicotinic acid, probucol, and fibric acid derivatives (e.g., clofibrate, gemfibrozil, gemfibrozil, fenofibrate, ciprofibrate, and bezafibrate).

Anti-inflammatory agents include, without limitation, pimecrolimus, salicylic acid derivatives (e.g., aspirin, insulin, sodium salicylate, choline magnesium trisalicylate, salsalate, dflunisal, salicylsalicylic acid, sulfasalazine, and olsalazine), para-amino phenol derivatives (e.g., acetaminophen), indole and indene acetic acids (e.g., indomethacin, sulindac, and etodolac), heteroaryl acetic acids (e.g., tolmetin, diclofenac, and ketorolac), arylpropionic acids (e.g., ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, and oxaprozin), anthranilic acids (e.g., mefenamic acid and meclofenamic acid), enolic acids (e.g., piroxicam, tenoxicam, phenylbutazone and oxyphenthatrazone), alkanones (e.g., nabumetone), glucocorticoids (e.g., dexamethaxone, prednisolone, and triamcinolone), pirfenidone, and tranilast.

Antineoplastics include, without limitation, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan, and chlorambucil), methylnitrosoureas (e.g., streptozocin), 2-chloroethylnitrosoureas (e.g., carmustine, lomustine, semustine, and chlorozotocin), alkanesulfonic acids (e.g., busulfan), ethylenimines and methylmelamines (e.g., triethylenemelamine, thiotepa and altretamine), triazines (e.g., dacarbazine), folic acid analogs (e.g., methotrexate), pyrimidine analogs (5-fluorouracil, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, cytosine arabinoside, 5-azacytidine, and 2',2'- difluorodeoxycytidine), purine analogs (e.g., mercaptopurine, thioguanine, azathioprine, adenosine, pentostatin, cladribine, and erythrohydroxynonyladenine), antimitotic drugs (e.g., vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, epipodophyllotoxins, dactinomycin, daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycins, plicamycin and mitomycin), phenoxodiol, etoposide, and platinum coordination complexes (e.g., cisplatin and carboplatin).

Antiplatelets include, without limitation, insulin, dipyridamole, tirofiban, eptifibatide, abciximab, and ticlopidine,

Angiogenic agents include, without limitation, phospholipids, ceramides, cerebrosides, neutral lipids, triglycerides, diglycerides, monoglycerides lecithin, sphingosides, angiotensin fragments, nicotine, pyruvate thiolesters, glycerol-pyruvate esters, dihydoxyacetone-pyruvate esters and monobutyrin.

Anti-angiogenic agents include, without limitation, endostatin, angiostatin, fumagillin and ovalicin.

Vitamins include, without limitation, water-soluble vitamins (e.g., thiamin, nicotinic acid, pyridoxine, and ascorbic acid) and fat-soluble vitamins (e.g., retinal, retinoic acid, retinaldehyde, phytonadione, menaqinone, menadione, and alpha tocopherol).

Antimitotics include, without limitation, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, epipodophyllotoxins, dactinomycin, daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycins, plicamycin and mitomycin.

Metal loproteinase inhibitors include, without limitation, TlMP-I, TIMP-2, TIMP-3, and SmaPI.

NO donors include, without limitation, L-arginine, amyl nitrite, glyceryl trinitrate, sodium nitroprusside, molsidomine, diazenϊumdiolates, S-nitrosothiols, and mesoionic oxatriazole derivatives.

NO release stimulators include, without limitation, adenosine.

Anti-sclerosing agents include, without limitation, collagenases and halofuginone.

Vasoactive agents include, without limitation, nitric oxide, adenosine, nitroglycerine, sodium nitroprusside, hydralazine, phentolamine, methoxamine, metaraminol, ephedrine, trapadil, dipyridamole, vasoactive intestinal polypeptides (VIP), arginine, and vasopressin.

Endothelial growth factors include, without limitation, VEGF (Vascular Endothelial Growth Factor) including VEGF-121 and VEG-165, FGF (Fibroblast Growth Factor) including FGF-I and FGF -2, HGF (Hepatocyte Growth Factor), and Angl (Angiopoietin 1).

Beta blockers include, without limitation, propranolol, nadolol, timolol, pindolol, labetalol, metoprolol, atenolol, esmolol, and acebutolol.

Hormones include, without limitation, progestin, insulin, the estrogens and estradiols (e.g., estradiol, estradiol valerate, estradiol cypionate, ethinyl estradiol, mestranol, quinestrol, estrond, estrone sulfate, and equilin).

Statins include, without limitation, mevastatin, lovastatin, simvastatin, pravastatin, atorvastatin, and fluvastatin.

Insulin growth factors include, without limitation, IGF-I and IGF-2.

Antioxidants include, without limitation, vitamin A, carotenoids and vitamin E.

Membrane stabilizing agents include, without limitation, certain beta blockers such as propranolol, acebutolol, labetalol, oxprenolol, pindolol and alprenolol.

Calcium antagonists include, without limitation, amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine and verapamil.

Retinoids include, without limitation, all-trans-retinol, all-trans-14- hydroxyretroretinol, all-trans-retinaldehyde, all-trans-retinoic acid, all-trans-3,4- didehydroretinoic acid, 9-cis-retinoic acid, 11-cis-retinal, 13-cis-retinal, and 13-cis- retinoic acid.

Anti-macrophage substances include, without limitation, NO donors.

Anti-leukocytes include, without limitation, 2-CdA, IL-I inhibitors, anti- CD 116/CD 18 monoclonal antibodies, monoclonal antibodies to VCAM, monoclonal antibodies to ICAM, and zinc protoporphyrin.

Cyclooxygenase inhibitors include, without limitation, Cox-1 inhibitors and Cox-2 inhibitors (e.g., CELEBREX® and VIOXX®).

Immunomodulatory agents include, without limitation, immunosuppressants (see above) and immunostimulants (e.g., levamisole, isoprinosine, Interferon alpha, and Interleukin-2).

ACE inhibitors include, without limitation, benazepril, captopril, enalapril, fosinopril sodium, lisinopril, quinapril, ramipril, spirapril, and 2B3 ACE inhibitors.

Cell sensitizers to insulin include, without limitation, glitazones, P PAR agonists and metformin. Antisense oligonucleotides include, without limitation, resten-NG.

Cardio protectants include, without limitation, VIP, pituitary adenylate cyclase-activating peptide (PACAP), apoA-I milano, amlodipine, nicorandil, cilostaxone, and thienopyridine.

Petidose inhibitors include, without limitation, omnipatrilat.

Anti-restenotics include, without limitation, include vincristine, vinblastine, actinomycin, epothilone, paclitaxel, paclitaxel derivatives (e.g., docetaxel), rapamycin, rapamycin derivatives, everolimus, tacrolimus, ABT-578, and pimecrolimus.

PPAR gamma agonists include, without limitation, farglitizar, rosiglitazone, muraglitazar, pioglitazone, troglitazone, and balaglitazone.

Miscellaneous compounds include, without limitation, Adiponectin.

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 detergents may be used. Examples of nonionic additives 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 (PEF and PEO) and polyvinyl pyrrolidone (PVP); carboxylic acids including D-lactic acid, glycolic acid, and propionic acid; detergents with affinity for hydrophobic interfaces including n-dodecyl-β-D-maltoside, n-octyl-β-D-glucoside, PEOfatty 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 mono stearate), PEO-glyceryl-fatty acid esters; glyceryl fatty acid esters (e.g. glyceryl mono stearate), PEO-hydrocarbon-ethers (e.g. PEO-IO oleyl ether; triton X-IOO; 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; CM-PEG; cholic acid; sodium dodecyl sulfate (SDS); docusate (AOT); and taumocholic acid.

These therapeutic agents for use with the present invention may be transmitted primarily luminally, primarily murally, or both and may be delivered alone or in combination.

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 detergents may be used. Examples of nonionic additives 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 (PEF and PEO) and polyvinyl pyrrol idone (PVP); carboxy Hc acids including D-lactic acid, glycolic acid, and propionic acid; detergents with affinity for hydrophobic interfaces including n-dodecyl-β-D-maltoside, n-octyl-β-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-IO oleyl ether; triton X-IOO; 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; CM-PEG; cholic acid; sodium dodecyl sulfate (SDS); docusate (AOT); and taumocholic acid.

Example 1

The measurement of in vivo paclitaxel release from a stent can be performed according to the following Example. The in vivo release from other implantable medical devices can be performed in a similar manner by removal of tissue and measurement of total drug load and release kinetics by high pressure liquid chromatography (FIPLC). Stents are implanted in a porcine model and explanted at selected time points by removing the entire artery section. The expanded stents are labeled and frozen. The tissue is removed from the stent by slicing the tissue on the outside of the stent lengthwise, inverting the tissue, and removing the tissue by cutting and turning the tissue inside out. The stent may still be covered by a tough elastic membrane which is then removed by splitting the membrane and peeling it off the stent. For longer time points, there will also be a tub of tissue inside the stent. This tube is separated from the stent with tweezers, turned inside out and pulled out of the stent.

The following is the test procedure for generating the in vivo release curves for paclitaxel in FIGS. 4 and 5, The elution rates of drug from the examples are determined in a standard sink condition experiment.

The total drug load (TDL) of paclitaxel from a stent is determined by extracting all the polymer and drug from the stent in a solvent such as dimethyl sulfoxide (DMSO) or acetonitrile. The amount of paclitaxel in a solution sample is determined by High Pressure Liquid Chromatography (HPLC). The following conditions are used:

Analysis Column: Discovery BIO Wide Pore C5 HPLC Column (150 mm X 4.6 mm 5 micron particle)

Mobile phase: Water / Acetonitrile :: 56% vol. / 44% vol.

Flow Rate: 1.0 mL / minute

Temperature: 25 ⁰C ambient

Detection wavelength: 227 nm

Injection volume: 75 μL

Retention time: 14 minutes

The in vivo release kinetic (RK) for paclitaxel from a stent is determined by running the TDL for multiple explanted time points. The TDL for the explanted samples is subtracted from the TDL of an unimplanted stent to determine the amount of paclitaxel released at each of the explanted time points.

The following is the test procedure for generating the in vivo release curve for polymer in FIG. 5. The explanted stents are cleaned of any tissue as described above. The amount of polymer on the stent is determined by thermal analysis therm ogravemetric analysis (TGA). The explanted stent is placed on a sensitive balance in a controlled atmosphere furnace where the furnace temperature is slowly increased from 25 to 440°C at a rate of 5⁰C per minute. Different constituents in the sample vaporize at different temperatures beginning with residual solvent followed by polymer plus drug. The temperatures of vaporization of polymer and drug are sufficiently close that the weight of polymer and drug together is determined. The amount of polymer is calculated as the difference between the weight loss measured by thermogravimetric analysis minus the weight of drug measured according to the paclitaxel TDL procedure. This procedure is then repeated for the multiple explanted time points to determine the in vivo release curve for polymer.

Example 2

The measurement of in vivo Pimecrolimus release from a stent can be performed according to the following Example. The in vivo release from other implantable medical devices can be performed in a similar manner by removal of tissue and measurement of total drug load and release kinetics by high pressure liquid chromatography (HPLC).

Stents are implanted in a porcine model and explanted at selected time points by removing the entire artery section. The expanded stents are labeled and frozen. The tissue is removed from the stent by slicing the tissue on the outside of the stent lengthwise, inverting the tissue, and removing the tissue by cutting and turning the tissue inside out. The stent may still be covered by a tough elastic membrane which is then removed by splitting the membrane and peeling it off the stent. For longer time points, there will also be a tube of tissue inside the stent. This tube is separated from the stent with tweezers, turned inside out and pulled out of the stent.

The following is the test procedure for generating the in vivo release curves for Pimecrolimus in FIG. 6.

The total drug load (TDL) of Pimecrolimus from a stent is determined by extracting all the polymer and drug from the stent in the solvent acetonitrile. The amount of Pimecrolimus in a solution sample is determined by High Pressure Liquid Chromatography (HPLC). The following conditions are used:

Analysis Column: Chromolith (100 mm X 4.6 mm 3 micron RP-E)

Mobile phase: Water / Acetonitrile :: 68% vol. / 32% vol.

Flow Rate: 1.5 mL / minute

Temperature: 50 ⁰C Detection wavelength: 194 nm

Injection volume: 30 μL

Retention time: 15 minutes

The TDL for the example of FIG. 4 is about 325μg normalized to a 3 mm X 16mm stent.

The in vivo release kinetic (RK) for Pimecrolimus from a stent is determined by running the TDL for multiple explanted time points. The TDL for the explanted samples is subtracted from the TDL of an unimplanted stent to determine the amount of Pimecrolimus released at each of the explanted time points.

FIG. 6 shows that after day 2, the release profile is substantially linear with a least squares correlation coefficient (r²) of about 0.973.

While the invention has been described in detail with reference to the preferred embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made and equivalents employed, without departing from the present invention.

Claims

WHAT IS CLAIMED IS:

1. A method of reducing restenosis comprising: providing a bioresorbable stent having a dosage of anti-restenotic agent for delivery to an artery, the dosage arranged such that substantially all the agent is releasable from the stent upon implantation of the stent in the artery; implanting the stent within an artery of a patient; and delivering the agent from the stent in vivo over an administration period beginning on a date of implantation and ending between about 60 days and about 8 months after implantation, wherein the bioresorbable stent is substantially resorbed by the body between about 3 and about 12 months after the date of implantation.

2. The method of Claim 1, wherein the administration period ends between about 90 and 180 days from the date of implantation.

3. The method of Claim 1, wherein the in vivo release profile of the anti- rest enotic agent after day one is substantially linear.

4. The method of Claim 1, wherein the anti-restenotic agent is paclitaxel.

5. The method of Claim 4, wherein the amount of paclitaxel released per day after day one is about 0.01 to about 0.2μg per day delivered from a 3 mm by 16 mm expanded stent, and equivalent dosages are delivered from stents of other sizes,

6. The method of Claim 4, wherein the paclitaxel is deposited in openings in the stent.

7. The method of Claim 4, wherein the paclitaxel is contained in a polymer matrix.

8. The method of Claim I₅ wherein the anti-restenotic agent is delivered primarily murally from the stent.

9. The method of Claim 1, wherein the step of delivering paclitaxel delivers not more than 40% of the anti-restenotic agent in the first 30 days,

10. The method of Claim 1, wherein the step of delivering drug further comprises delivering 5-25% of the total amount of the agent loaded into the stent in the First day.

11. The method of Claim 6, wherein the paclitaxel is contained in a polymer matrix.

12. The method of Claim 6, wherein the paclitaxel is delivered primarily murally from the stent,

13. A bioresorbable stent for reducing restenosis comprising: a bioresorbable stent having initial unexpanded diameter for insertion of the stent into a coronary artery and an expanded diameter for implantation within a coronary artery, the stent having a dosage of anti-restenotic agent for delivery to an artery, the dosage arranged such that substantially all the agent is releasable from the stent upon implantation of the stent in the artery, wherein the dosage of the agent is arranged to be released over an in vivo administration period beginning on the date of implantation and ending between 60 days and 8 months after implantation, and wherein after the administration period no drug remains on the stent.

14. The stent of Claim 13, wherein the administration period ends between about 90 and 180 days from the date of implantation.

15. The stent of Claim 13, wherein the anti-restenotic agent is paclitaxel.

16. The stent of Claim 15, wherein the amount of paclitaxel released per day after day one is about 0.01 to about 0,2 μg per day delivered from a 3 mm by 16 mm expanded stent, and equivalent dosages are delivered from stents of other sizes.

17. The stent of Claim 13, wherein the agent is deposited in openings in the stent.

18. The stent of Claim 17, wherein the agent is contained in a bioresorbable matrix.

19. The stent of Claim 13, wherein the agent is contained in a polymer matrix,

20. The stent of Claim 19, wherein the polymer matrix is selected to delivery substantially all the agent from the stent before the polymer matrix is completely resorbed.

21. The stent of Claim 13, wherein the agent is arranged to be delivered primarily murally from the stent.

22. The stent of Claim 13, wherein the agent is affixed to the stent such that 5-25% of the total amount of agent loaded into the stent is delivered in the first day.

23. The stent of Claim 13, wherein the agent is loaded for delivery at an increasing release rate between days 1 and 60 after implantation.

24. The stent of Claim 13, wherein the agent is Pimecrolimus.

25. The stent of Claim 24, wherein the release of Pimecrolimus after day two is between 1 μg and about ΪO μg per day delivered from a 3 mm by 16 mm expanded stent, and equivalent dosages are delivered from stents of other sizes.

26. The method of Claim 24, wherein the Pimecrolimus is contained in a bioresorbable matrix.

27. The method of Claim 24, wherein the Pimecrolimus is contained in a polymer matrix.

28. The method of Claim 24, wherein the Pimecrolimus is delivered primarily murally from the stent.

29. The method of Claim 13, wherein the bioresorbable stent is resorbed by the body between about 3 and about 12 months after the date of implantation.

30. The method of Claim 13, wherein the bioresorbable stent maintains structural support of a body lumen for at least two months after the date of implantation.