Drug delivery system and method of manufacturing it

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DRUG DELIVERY SYSTEM AND METHOD OF MANUFACTURING THEREOF

Applicant: EXOGENESIS CORPORATION WO 2007/092894 PC17US2007/061787

DRUG DELIVERY SYSTEM AND METHOD OF MANUFACTURING THEREOF

Field of the Invention 5 This invention relates generally to drug delivery systems such as, for example, medical devices implantable in a mammal (e.g., coronary stents, prostheses, etc.), and more specifically to a method and system for applying and adhering drugs to the surface of medical devices and for controlling the surface characteristics of such drug delivery systems such as. for example, the drug release rate and bio-reactivity, using gas cluster ion 10 beam technology in a manner that permits efficacious release of the drugs from the surface over time.

Background of the Invention Λ coronary stent is an implantable medical device that is used in combination with 15 balloon angioplasty. Balloon angioplasty is a procedure used to treat coronary atherosclerosis. Balloon angioplasty compresses built-up plaque against the walls of the blocked artery by the inflation of a balloon at the tip of a catheter inserted into the artery during the a ng ioplasty procedure, Unfortunately, the body's response to this procedure often includes thrombosis or blood clotting and the formation of scar tissue or other 20 trauma-induced tissue reactions at the treatment site. Statistics show that restenosis or re-narrowing of the artery by scar tissue after balloon angioplasty occurs in up to 35 percent of die treated patients within only six months after these procedures, leading to severe complications in many patients.

To reduce restenosis, cardiologists are now often placing small tubular devices of 25 various forms, such as wire mesh; expandable metal; and non-degradable and biodegradable polymers called a coronary stent at the site of blockage during balloon angioplasty. The goal is to have the stent act as a scaffold to keep the coronary artery open after the removal of the balloon.

However, there are also serious complications associated with the use of coronary 30 stents, Coronary restenolic complications associated with stents occur in 16 to 22 percent WO 2007/092894 PCT/US2007/06I787 of all eases within six months after insertion of the stent and are believed to be caused by many factors acting alone or in combination. These complications could be reduced by several types of drugs introduced locally at the site of stent implantation. Because of the substantial financial costs associated with treating the complications of restenosis, such as 5 catheterization, restenting, intensive care, etc., u reduction in restenosis rates would save money and reduce patient suffering.

Numerous studies suggest that the current popular designs of coronary stents are functionally equivalent. Although the use of coronary stents is growing, the benefits of their use remain controversial in certain clinical situations or indications due to their 10 potential complications. It is widely held that during the process of expanding the stent, damage occurs to the endothelial lining of the blood vessel triggering a healing response that rc-occhides the artery. To help combat that phenomenon, drug-coaled stents are being introduced to the market to help control the abnormal cell growth associated with this healing response. These drugs are typically mixed with a liquid polymer and applied to the 15 stent surface. When implanted, the drug elutes out of the polymer in time, releasing the medicine into the surrounding tissue. There remain a number of problems associated with this technology. Because the stent is expanded at the diseased site, the polymeric material has a tendency to cruck and sometimes delaminate from the stent surface. These polymer (lakes can travel throughout the cardlo-vascular system and cause significant damage. 20 There is some evidence to suggest that the polymers themselves cause a toxic reaction in the body. Additionally, because of the thickness ol’lhc coating necessary to carry the required amount of medicine, the stents can become somewhat rigid making expansion difficult. In other prior art stents, the wire mesh of the stent itself is impregnated with one or more drugs through processes such as high pressure loading, spraying, and dipping. 25 However, loading, spraying and dipping do not satisfactorily adhere the drug to the stent surface and therefore, in many instances, do not yield the optimal, time-release dosage of the drugs delivered to the surrounding (issue. The polymer coating can include several layers such as the above drug containing layer as well as a drug free encapsulating layer, which can help to reduce the initial drug release amount caused by initial exposure to 30 liquids when the device is first implanted. A further base coating of polymer located beneath the drug bearing layer is also known. One example of this arrangement used on stain less steel stents includes a base layer of Paralene C. and a drug/polyiner mixture r WO 201)7/092894 PCT/US2007/061787 3 including polyethylcnc-co-vinyl acetate (PEVA) and poly n-bulyl methacrylate (PUMA) in a two to one ratio, along with an non-drug impregnated top layer of the same mixture of PEVA and PBMA. The drug used is Sirolimus, a relatively new immunosuppressant drug also known us kapamyctn. Several other drug/polymer combinations exist from several 5 manufactures.

In view of this new approach to in situ drug delivery, it is desirable to have greater control over the drug release rate from the implantable device as well as control over oilier surface characteristics of the drug delivery medium.

It is therefore an object of this invention to provide a means of applying and 10 adhering drugs to medical devices using gas cluster ion beam technology.

It is a further object of this invention to apply drugs to medical stents by gas cluster ion beams to decrease the complication of restenosis and thrombosis.

It is a further object of this invention to provide a means for controlling surface characteristics of a drug eluting material using gas cluster ion beam technology. 15 It is a further object of this invention to transform the surfaces of medical devices into drug delivery systems by applying and adhering drugs to the surfaces with gas cluster ion beams so as to facilitate a timed release of the drug(s) from the surfaces.

It is a further object of this invention to improve the functional characteristics of known in said to drug release mechanisms using gas cluster ion beam technology. 20

Summary of the Invention

The objects set forth above as well as further and other objects and advantages of the present invention are achieved by the invention described herein below'. 'flic present invention is directed to the use of gas cluster ion-beam (GCIB) surface 25 modification to implant, apply, or adhere various drug molecules directly into or onto the surface of a stent or other medical device, thereby eliminating the need for a polymer or any other binding agent and transforming the medical device surface into a drug delivery system. Th is will prevent the problem of toxicity and the damage caused by transportation of delaminated polymeric material throughout the body. Unlike the prior art stents 30 described above that load the stent material itself, the present invention provides the WO 2007/092894 PC'l7US2007/0fil787 ability to adhere for time-re lease an optimal dosage of the drug or drugs.

The application of the drug(s) is achieved through the useofGClB technology.

The application ofthedrug(s) is accomplished by several methods:

The surface of the medical device, which may be composed, for example, of a 5 polymer, metal or any other material, is optionally first processed using a GCIB which will remove any contaminants and oxide layers from the surface rendering the surface electrically active and creating dangling bonds. The desired drug wilt then be deposited upon the active surface and will bond with the dangling bonds, Λ second method for producing a drug delivery system involves depositing a layer 10 of one or more drug substances onto at least one surface region of a medical device (which may or may not have been pre-processed with a GCIB) in liquid, powder or other form, perhaps through sublimating the drug, and then impacting the deposited drug layer with an energetic GCIB so us to form an adhered drug layer. The GCIB dose crcutes a carbonized drug matrix including a plurality of interstices through which non-carbonized 15 drug will diffuse or elute over time. If the deposited drug layer is suitably thin, some

GCIB clusters may penetrate through the deposited drug layer and reach the surface of the medical device, such that the adhered drug layer may include some portion of the deposited drug molecules implanted sub-surface in the form of a mechanical bond. I fill e deposited drug layer has a thickness above a threshold thickness (for a particular GCIB 20 dose), however, the carbonized drug matrix will not he "stitched" to the surface of the medical device. Rather, the carbonized matrix will be formed over the remaining non-carbonized, mobile volume of the deposited drug. In one stent embodiment, for example, a ring-like, carbonized drug matrix is formed concentrically about a layer of non-carbonized, deposited drug which, in turn, is disposed about the stent on the stent surface, 25 with little to no portion of the carbonized matrix directly stitched to the stent surface.

In multi-layered embodiments of the invention, subsequent drug layers may be comprised of identical, similar or distinct drug substances. Additionally, identical, simitar or different drug deposition techniques than those used to deposit preceding layers may be employed. Controlled variations in the GCIB characteristics and dosing delivered to 30 different layers (and between spatially distinct regions of a single layer) may also be employed. Substantially similar GCIB doses delivered to substantially similar drug substances wilt result in similar drug elution profiles, while different doses can achieve WO 2007/092894 PCT/US2007/061787 distinct inter-layer elution profiles. Judicious selection of drug substanec(s), and control over the deposition technique and GC1B dosing permits formation of a drug delivery system comprised of multiple, adhered drug layers each having similar or differing drug elution profiles which, in preferred embodiments of the invention, cooperate to achieve at least one overall drug elution profile, For example, the elution profiles of individual layers may be designed such that, as drug is diffused from the outermost adhered drug layer, it is replenished by drug(s) eluting from lower adhered layers. Λ number of techniques may be employed to deposit the drug subslanee(s) onto the medical device surface, or one or more spatially distinct regions thereof. If the drug is to be deposited in liquid form, techniques such as dipping, spraying, vapor phase deposition, und ultrasonic atomization may be utilized. Alternatively, if the drug is in powder form, it may be electrostatically deposited onto the medical device surface or deposited by sublimation, and then GC1B irradiated in the same manner described above.

Any of the methods described may optionally include an irradiation step prior to drug deposition to obtain a smoother surface, which wili help reduce non-uniform thickness in the adhered drug laycr(s). ‘ The application of drugs via GCIB surface modification such as described above will reduce complications, lead to genuine cost savings and an improvement in patient quality of life, und overcome prior problems of thrombosis and restenosis. Preferred therapeutic agents for delivery in the drug delivery systems of the present invention include anti-coagulants, antibiotics, immunosuppressant agents, vasodilators, anti-protifics, anti-thrombotic substances, anti-platelet substances, cholesterol reducing agents, anti-tumor medications and combinations thereof.

In one embodiment, a drug delivery system, comprises a member including a combination of a drug substance and a polymer or other material, and an encapsulating layer formed in an outer surface of the member by gas cluster ion beam irradiation of the outer surface of the member, which encapsulating layer is adapted to determine a release rale for the drug from the member.

The encapsu tilting layer may include a plurality of openings located at an outer surface of the encapsulating layer and adapted to permit amounts of the drug substance to be released from the member at a rate determined by the encapsulating layer. The WO 2007/092894 PCT/US2007/061787 encapsulating layer may include a carbonized or densified matrix. The encapsulating layer may be adapted to improve a measure of biocompatibilily of the member.

The member may be located on a surface ofa medical device. The drug substance may be selected from the group consisting of anti-coagulants, antibiotics, anti-tumor 5 substances, immune-suppressing agents, vasodilators, anti-prolitics, anti-thrombotic substances, anti-platelet substances, cholesterol reducing agents and combinations thereof. Λ medical device may include the drug delivery system described above.

In another embodiment, a drug delivery system comprises a cohesive mixture including a combination of a drug substance and a polymer or other material, and a i 0 carbonized or densified matrix formed on an outer surface of the cohesive mixture, which carbonized or densified matrix is adapted to determine a release rate for the drug substance from die cohesive mixture.

In yet another embodiment, a method lor producing a drug delivery system, comprises the steps of providing a member including a combination ofa drug substance 15 and a polymer or other material, and irradiating on outer surface of the member with a gas cluster ion beam to determine a release rate for the drug substance from the member. 'fhe step of providing a member may include forming a cohesive mixture of the drug substance and the polymer or other material on a surface ofa medical device. The step of irradiating may include forming an encapsulating layer on at least an external 20 surface of the member, which encapsulating layer is adapted to control release of the drug substance from the member. The encapsulating layer may include a plurality of openings at an outer surface of the encapsulating layer so as to permit portions of the drug substance to be released from the member at a rule determined by the encapsulating layer. The encapsulating layer may include a carbonized or densified matrix. 25 The step of providing a member may include the steps of providing a polymer element and adhering a drug substance to an outer surface of the polymer element. The step of providing a polymer element may include the step of irradiating the outer surface of the polymer element with a gas cluster ion beam prior to the step of adhering. The step of irradiating may be adapted to lower in situ chemical reactivity of the external surfucc of 30 the cohesive mixture. The drug substance may be selected from the group consisting of anti-coagulants, antibiotics, anti-tumor substances, immune-suppressing agents, WO 2007/092894 PC17US2007/061787 vasodilators, anti-prolifics, unli-thrambotic substances, anti-plalelel substances, cholesterol reducing agents and combinations thereof.

Brief Description of the Drawings 5 For a better understanding of the present invention, together with other and further objects thereof, reference is made to the accompanying drawings, wherein: FIG. ! is a schematic view of a gas cluster ion beam processing system used for practicing the method of the present invention; FIG. 2 is an exploded view of a portion of the gas cluster ion beam processing 10 system of FIG. 1 showing the workpiece holder; FIG. 3 is an atomic force microscope image showing the surface of a coronary stent before GC1B processing; FIG, 4 is an atomic force microscope image showing the surface of a coronary stent alter GC1B processing; 15 FIGS. 5A-5F1 are illustrations of a surface region of a medical device at various stages of drug delivery system formation in accordance with an embodiment of the present invention; FIGS. 6A-6B arc illustrations of alternative drug delivery structure embodiments in accordance with (he present invention; 20 FIG. 7A is a graph showing the release rate of fluorescence over time; FIG. 73 is a graph showing the cumulative release rate of fluorescence over time; FIG. 8 Is a graph showing comparative drug elution rate test results for a conventional drug-coated stent and a stent processed in accordance with the present invention. 25 FIG. 9 is a cross section of a drug delivery system prior to processing in accordance with another embodiment of the present invention; and FIG. 10 is a cross section of the drug delivery system of FIG. 9 shown during gas cluster ion beam processing performed in accordance with the present invention; WO 2007/092894 PCT/US2007/061787

Detailed Description of the Drawings

Beams of energetic ions, electrically charged atoms or molecules accelerated through high voltages under vacuum, are widely utilized to form semiconductor device junctions, to smooth surfaces by sputtering, and to enhance the properties of 5 semiconductor thin films. In the present invention, these same beams of energetic ions are utilized for the applying and adhering drugs to a surface and for affecting surface characteristics of drug ctuting medical devices, such as, for example, coronary stents, thereby converting the surface into a drug delivery system with enhanced drug delivery properties and bio-compatibility.

10 In the preferred embodiment of the present invention, gas cluster ion beam GCIB processing is utilized, Gas cluster ions are formed from large numbers of weakly bound atoms or molecules sharing common electrical charges and accelerated together through high voltages to huve high total energies. Cluster ions disintegrate upon impact and the total energy of the cluster is shared among the constituent atoms. Because of this energy 15 sharing, the atoms arc individually much less energetic than the ease of conventional ions or ions not clustered together and, as a result, the atoms penetrate to much shorter depths. Surface sputtering effects are orders of magnitude stronger than corresponding effects produced by conventional ions, thereby making important microscale surface effects possible that are not possible in any other way. 20 The concept of GCIB processing has only emerged over the past decade. Using a GCIB for dry etching, cleaning, and smoothing of materials is known in the art and hus been described, for example, by Deguchi, et al. in U.S. Pat, No. 5,814,194, "Substrate Surface Treatment Method", 1998. Because ionized clusters containing on the order of thousands of gas atoms or molecules may be formed and accelerated to modest energies 25 on the order of a lew thousands of electron volts, individual atoms or molecules in the clusters may each only have an average energy on the order of a few electron volts. It is known from the teachings of Yamada in, for example, U.S. Pat. No. 5,459,326, that such individual atoms are not energetic enough to significantly penetrate a surface to cause the residual sub-surface damage typically associated with plasma polishing. Nevertheless, the 30 clusters themselves arc sufficiently energetic (some thousands of electron volts) to effectively etch, smooth, or clean hard surfaces. WO 2007/092894 PCT/US2007/06I7S7

Because the energies'of individual atoms within a gas cluster ion are very small, typically a few eV, the atoms penetrate through only a few atomic layers, at most, of a target surface during impact, 'fins shallow penetration of'the impacting atoms means all of the energy carried by the entire cluster ion is consequently dissipated in an extremely 5 small volume in the top surface layer during a period on the order of 10*12 seconds (i.e. one picosecond). This is different from the case of ion implantation which is normally done with conventional monomer ions and where the intent is to penetrate into the material, sometimes penetrating several thousand angstroms, to produce changes in the surface properties of the material. Because of the high total energy of the cluster ion and 10 extremely smalt interaction volume, the deposited energy density at the impact site is far greater than in the case of bombardment by conventional monomer ions.

Reference is now made to PIG. I of the drawings which shows the GCIB processor 100 of this invention utilized for applying or adhering drugs to the surface of a medical device such as, for example, coronary stent 10. Although not limited to the specific 15 components described herein, the processor 100 is mude up ofa vacuum vessel 102 which is divided into three communicating chambers, a source chamber 104, an ionization/acceleration chamber 106, and a processing chamber 108 which includes therein a uniquely designed workpiece holder 150 capable of positioning the medical device for uniform GCIB bombardment and drug application by a gas cluster ion beam, 20 During the processing method of this invention, the three chambers arc evacuated to suitable operating pressures by vacuum pumping systems i 46a, 146b, and 146c. respectively. Λ condensable source gas 112 (for example argon or Na) stored in a cylinder ! 11 is admitted under pressure through gas metering valve 112 and gas feed tube 114 into stagnation chamber 116 and is ejected into the substantially lower pressure vacuum 25 through a properly shaped nozzle 110, resulting in a supersonic gas jet 118. Cooling, which results from the expansion in the jet, causes a portion of the gas jet 118 to condense into clusters, each consisting of from several to several thousand weakly bound atoms or molecules. A gas skimmer aperture 120 partially separates the gas molecules that have not condensed into a cluster jet from the cluster jet so as to minimize pressure in the 30 downstream regions where such higher pressures would be detrimental (e.g., ionizer 122, high voltage electrodes 126, and process chamber 108). Suitable condensable source gases 112 include, but are not necessarily limited to argon, nitrogen, carbon dioxide, oxygen. WO 2007/092894 PCT/US20U7/06J787 10 Λ iter the supersonic gas jet 118 containing gas clusters hus been loaned, the clusters are ionized in an ionizer 122. The ionizer 122 is typically an electron impact ionizer that produces thermo-electrons from one or more incandescent filaments 124 and accelerates and directs the electrons causing them to collide with the gas clusters in the gas 5 jet 118. where the jet passes through the ionizer 122. The electron impact ejects electrons from the clusters., causing a portion the clusters to become positively ionized. A set of suitably biased high voltage electrodes 120 extracts the cluster ions from the ionizer 122, forming a beam, then accelerates the cluster ions to a desired energy (typically from I keV to several tens of keV) and focuses them to form a GCIB 128 having an initial trajectory 10 154. filament powersupply 136 provides voltage Vrto heat the ionizer filament 124.

Anode power supply 134 provides voltage VA to accelerate thermoelectrons emitted from filament 124 to cause them to bombard the cluster containing gas jet i 18 to produce ions. Extraction power supply 138 provides voltage Vr to bias a high voltage electrode to extract ions from the ionizing region of ionizer 122 and to form a GOB 128. Accelerator 15 power supply 140 provides voltage Vacc to bias a high voltage electrode with respect to the ionizer 122 so as to result in u total GC113 acceleration energy equal to VAce electron volts (cV). One or more lens power supplies (142 and 144, for example) may be provided to bias high voltage electrodes with potentials (Vu and VL2 for example) io focus the GCIB 128.

20 A medical device, such as coronal·/ stent 10, to be processed by the GCIB processor 100 is held on a workpiece holder 150, and disposed in the path of the GCIB 128 for irradiation. The present invention may be utilized with medical devices composed of a variety of materials, such as melul, ceramic, polymer, or combinations thereof. In order for the stent to be uniformly processed using GCIB, the workpiece holder 150 is 25 designed in a manner set forth below to manipulate the stent 10 in a specific way.

Referring now to FIG. 2 of the drawings, medical device surfaces that are non-planar, such as those of stenls, must remain oriented within a specific angle tolerance with respect to the normal beam incidence to obtain paramount effect to the stent surfaces utilizing GCIB. This requires a fixture or workpiece holder 150 with the ubililv to be fully 30 articulated to orient all non-planar surfaces of stent 10 to be modi lied within that specific angle tolerance at a constant exposure level for process optimization and uniformity. Any stent 10 containing surfaces that would be exposed to the process beam at angles of greater WO 2007/092894 PCT/lfS2007/061787 11 than +/-15 degrees from normal incidence may require manipulation. More specifically, when applying GCIB lu u coronary stent 10, the workpiece holder 150 is rotated and articulated by a mechanism 152 located at the end of the GCIB processor 100, The articulation/rotation mechanism 152 preferably permits 360 degrees of device rotation 5 about longitudinal axis 154 and sufficient device articulation about an axis 156 perpendicular to axis 154 to maintain the stent's surface to within +/-15 degrees from normal beam incidence.

Referring back to PIG. 1, under certain conditions, depending upon the size oflhe coronary stent 10, a scanning system may be desirable to produce uniform smoothness. 10 Although not necessary for GCIB processing, two pairs of orthogonally oriented electrostatic scan plates 130 and 132 may be utilized to produce a raster or other scanning pattern over an extended processing area. When such beam scanning is performed, a scan generator 156 provides X-axis and Y-axis scanning signal voltages to the pairs of scan plates 130 and 132 through lead pairs 158 and 160 respectively. The scanning signal 15 voltages are commonly triangular waves of different frequencies that cause the GCIB 128 to be converted into a scanned GCIB 148, which scans the entire surface of the stent 10. Additional means for orienting, articulating and/or rotating devices such as stents and orthopedic products arc disclosed hi U.S. Patent Nos. 6,491,800 to Kirkpatrick, e( al.t 6,676,989 to Kirkpatrick, ei αί„ and 6,863,786 to Blinn, e/ «/., the contents of each which 20 arc hereby incorporated by reference.

When beam scanning over an extended region is not desired, processing is generally con lined to a region that is defined by the diameter of the beam. The diameter of the beam at the stem's surface can be set by selecting the voltages (VL] and/or VL2) of one or more lens power supplies (142 and 144 shown for example) to provide the desired beam 25 diameter at the workpiece.

In one processing step related to the present invention, the surface of a medical device is irradiated with a GCIB prior to the deposition of any substance on the surface thereof. This will remove any contaminants and oxide layers from the stent surface rendering the surface electrically active and capable of attracting and bonding drug and 30 polymer molecules that are then introduced to the surface. One or more types of drugs are deposited upon surface through vapor phase deposition or by introducing a liquid form of the drug onto the surface. In some instances, the liquid form of the drug is in solution with WO 20117/(192894 PCT/US2007/061787 12 a volatile solvent thereby requiring the solvent to be evaporated. As the formed mechanical bonds are broken over time, the drug is slowly released to the site of device implantation.

Studies have suggested that a wide variety of drugs may be useful at the site of 5 contact between the medical device and the in vivo environment, for example, drugs such as anti-coagulants, anti-prolifics, antibiotics, imtnune-supressing agents, vasodilators, antithrombotic substances, anti-platelet substances, and cholesterol reducing agents may reduce instances of restenosis when diffused Into the blood vessel wall after insertion of the stent, 10 In another processing step, GOB processing is utilized to impact a deposited drug layer (and the surface of the medical device if the deposited drug layer is thin enough to permit gas clusters penetration to the surface) with energetic clusters thus implanting and forming a mechanical bond between the surface and the deposited drug molecules; or to implant the drug molecules of the electrostatically coated or sublimated medicine in 15 powder form to the stent surface in the same manner described above. The impact energy of the gas clusters causes a portion of the deposited drug molecules to form a carbonized drug matrix. As the carbon matrix is formed, the remaining (non-carbon ized) drug molecules become embedded within the interstices of the matrix, and/or are encapsulated between the carbon matrix and the medical device surface. Over time, these drug 20 molecules diffuse through the matrix and are released at the contact site between the stent and the blood vessel wall thereby continuously providing medication to the site.

As the utomic force microscope (AFM) images shown in FIGS. 3 and 4 demonstrate, It is possible to dramatically affect the medical device surface utilizing gas cluster ion beam processing. FIG. 3 shows a stent surface before GCIB treatment with 25 gross surface micro-roughness on a strut edge. The surface roughness measured un R„ of 113 angstroms and an R(lMs θΓ 148 angstroms. These irregularities highlight the surface condition at the cellular level where thrombosis begins. FIG, 4 shows the stent surface after GCIB processing where the surface micro-roughness has been eliminated without any measurable physical or structural change to the integrity of the stent itself. 'I’he post- 30 GCIB surface roughness measured an Raof 19 angstroms and un I<kms of'25 angstroms. In this manner, GCIB processing also provides the added benefit of smoothing the surface of the medical device. Non-smuoth surfaces may snare fibrinogen, platelets, and other matter WO 2007/092894 PCT/US2IW7/061787 13 further promoting stenosis.

With reference to PIGS. 5Λ-5Ρ, a method of producing a drug delivery system will now be described. PIG. 5Λ illustrates a surface region 12 of a medical device such as, for example, stent 10, that has been positioned in a vacuum chamber such that it cun be 5 irradiated with gas clusters 15 of a GCIB, as would occur in an optional smoothing process step. PIG, 6A illustrates an exemplary drug delivery structure in accordance with an embodiment'of the present invention. Note that the drug delivery structure may cover all or less than the entirety of the exterior surface of stent 10. In the latter case, surface region 12 represents but one of a plurality of spatially distinct, surface regions Ι2Ί4 of 10 stent 10 upon which the drug delivery system is formed. Each of the distinct surface regions 12-14 may elute the same or similar type of drug, or completely distinct types of drugs, for ease in understanding, the description that follows focuses on the formation of the drug delivery structure at surface region 12 only. PIG. 5B illustrates surface region 12 as being relatively smooth, following an 15 optional surface preparation step through GCIB irradiation. As described above, such processing removes contaminants and electrically activates the surface region 12. PIG. 5C shows a drug layer 16, which may be deposited by any of (lie techniques described above, and which preferably has been deposited to have a substantially uniform thickness in the vicinity of region 12. A "deposited drug layer" is used herein to refer to a contiguous drug 20 layer deposited over the entirety of the surface of the medical device, such as deposited drug layer 16, or alternatively may be used in a collective sense to refer to numerous spatially distinct deposits of the same or different therapeutic agents on the surface 12. In either ease, the deposited drug layer is GCIB irradiated to form an adhered drug layer on the device surface from which a portion of the deposited agent will be released over time 25 to a patient’s tissue adjacent the medical device.

As the term is used herein, an "adhered drug'layer" refers collectively to the post- GCIB irradiated layer comprised of at least one portion of non-earbonized deposited drug subslunce(s) and at least one carbonized matrix through which the deposited drug substance(s) is released at an expected rate. In embodiments described below, a drug 30 delivery system comprised of multiple, adhered drug layers may subsequently be formed by repeatedly depositing additional layers of a selected drug substance onto a preceding adhered layer and irradiating the additional deposited drug layer with GCIB's. The 193283/2 with the subsequent layer and the surface of the medical device. Rather, such layers will be adhered to preceding drug matrix layers. And in certain embodiments, the carbonized drug matrix of even the first layer will not be bonded, or stitched, to the stent surface, FIG. 5D illustrates the step of irradiating the first deposited drug layer 16 with 5 GC1B gas clusters 18a. This results in the formation of a first adhered drug layer 18, which is comprised of two primary components, such as shown in FIG. 5E. First adhered drug layer 18, and subsequently formed adhered drug layers, each include a carbonized drug matrix 20 having a plurality of intersLices 22 in which will be disposed the remainder of the deposited drug that was not carbonized by the GCIB. Drug layer 18 is adhered to the 10 surface region 12, and a portion of the non-carbonized drug will be released at an expected rate (characterized as an elution profile) from the adhered drug layer 18 by diffusion through the interstices 22 of the carbonized drug matrix 20. A number of the interstices 22 are interconnected, and a portion of the interstices are open at each surface of the drug matrix 20 so as to permit non-carbonized drug to eventually elute from a substantial 15 number of the interstices 22 of the drug matrix 20. FIGS. 5F-5H illustrate how the drug deposition and GCIB irradiation process steps may be repeated, generally, to achieve multi-layered drug delivery structures having variable and extremely accurate drug loading. More particularly, FIG. 5F illustrates a second drug layer 24 deposited upon the first adhered drug layer 18 using the same or an 20 alternative deposition process. The second drug layer 24 is then irradiated (FIG. 5G) with GCIB gas clusters 26 delivering substantially similar dosing or different, depending upon desired elution profile. Similar GCIB irradiation doses delivered to substantially similar or identical therapeutic agents will result in substantially similar elution profiles between or among adhered layers, FIG. 5 ft illustrates a drug delivery system comprised of an adhered 25 drug layer 28 that is further comprised of the first adhered drug layer 18 and a second adhered drug layer 30. As many repetitions of the drug deposition and GCIB irradiation steps as needed to attain an overall elution prof 3e, or profiles (if multiple therapeutic agents are utilized), may be performed. In one preferred embodiment, the first adhered drug layer 18 and second adhered drug layer 30 are similarly formed to have similar 30 elution profiles, such that, as drug is released from the interstices 32 of layer 30, drug eluting from layer 18 into layer 30 replenishes the released drug, lire adhered drug layers 18, 30 are not necessarily, however, comprised of the same drug substance(s).

Several alternative drug delivery systems in accordance with the present invention 14 WO 2007/1)92894 FCT/US2007/061787 J5 agents arc utilized). may be performed. In one preferred embodiment, the first adhered drug layer 18 and second adhered drug layer 30 arc similarly formed to have similar elution profiles, such that, as drug is released from the interstices 32 of layer 30, drug eluting from layer 18 into layer 30 replenishes the released drug. The adhered drug layers 5 18, 30 are not necessarily, however, comprised of the same drug suhstance(s).

Several alternative drug delivery systems in accordance with the present invention will now be described, with reference to FIGS. 6A-6B.

As noted above, multiple factors, including the thickness of the deposited drug layer, will determine whether GCIB gas clusters will penetrate a deposited drug layer so as 10 to reach the surface onto which a new drug layer is to be adhered. PIG. 6A (and PIG. 5E) illustrates a drug delivery system 38 that is further comprised of spatially distinct adhered drug structures 34-36 formed when GCIB gas clusters penetrate a thinly deposited drug layer (e.g., on the order of several to tens of Angstroms, or greater.) Note that some portion of the adhered drug structures 34-36 are bonded (or stitched) to associated, 15 spatially distinct surface regions 12-14. Formation of each of the adhered drug structures 34-36 may be accomplished nearly simultaneously or in separate processing routines. The therapeutic agent to be released from each of the adhered drug structures 34-36 is deposited at the associated spatially distinct surface region 12-14 and then GC1B irradiated. Again, the drug deposited at each surface region 12-14 is not necessarily the 21) same. Forming adhered drug structures on Jess tbun the entire surface of the medical device has the benefit of cost savings when an expensive drug is to be used. Also, certain drugs may only need to be delivered at particular locations, such as at a site of significant tissue interaction with an implanted medical device. PIG. 6B illustrates an alternative embodiment of a drug delivery system, such as 25 may be formed when the GCIB does not penetrate the thickness of a drug layer deposited on the surface region 12 of the medical device 10. In such embodiments, a carbonized drug matrix 22 is still formed having interstices within which some portion oftion-carbonized drug is disposed, and from which non-carbonized drug is released, however the drug matrix 22 docs not extend to the surface 12 of the medical device 10. Rather, the 30 carbonized matrix 22 encapsulates the remainder of deposited drug 24 that was not carbonized by the GCIB (and not captured in the interstices), between the drug matrix 22 and the surface 12 of the device 10, As noted above, the expression "adhered drug layer" WO 2007/092894 PCT/US2007Z061787 16 as used herein refers collectively to the carbonized matrix 22, and the non-carbon! zed portions of the deposited drug, whether disposed in the interstices or encapsulated by the drug matrix 22 and the device surface.

Now turning to PICS. 7 A and 7B, elution rates for a substance adhered to a surface 5 of a coronary stent using GCIB processing in accordance with one embodiment of the present invention is shown. To demonstrate the release rale of a molecule adhered to the surface in accordance with the present invention, the surface was irradiated and a flourescent organic dye was vapor deposited onto the freshly irradiated surface while the surface remained in the vacuum chamber. The dye elution rate was measured by observing 10 the ilourescence of the elute us a function of lime. In FIG. 7Λ, the release rate is shown over time. In FIG. 713, the cumulative release rate is shown over time. FIG. 8 illustrates results of comparative elution rale testing performed on a conventional drug-coated stent and a stent upon which an exemplary drug delivery system has been firmed utilizing GCIB irradiation in accordance with the present invention. 15 Paelitaxol was selected as the test drug, which in the case of the non-GCIB processed stent was deposited, and for the GCIB processed stent was deposited by ultrasonic atomization prior to being irradiated with an Argon GCIB while rotating the stent between 3-5 RPM. The Paelitaxol was allowed to elute from the respective stents over time into a 4% Bovine Serum Albumin/Phosphate Buffered Saline solution, and the drug remaining on the stents 20 was measured. As shown, significantly more drug remained loaded on the drug-adhered stent lor a longer period of time that the conventional drug coated stent

With reference to FIG, 9, a drug delivery system I 10. which includes a drug containing medium 112 and an optional substrate or medical device 114, is shown prior to processing by the method of the present invention. Medical device 114 is only 25 representational and may lake any suitable form. Device 114 may include an implantable medical device such as a stent or any other medical device which may benefit from an in situ drug delivery mechanism. Optionally, the use of substrate or device I 14 may be limited to the fabrication of drug containing medium 112, wherein substrate or device I 14 is removed from medium 112 prior to implantation. Substrate or device 114 maybe he 30 constructed of any suitable material such as, for example, metal, ceramic or a polymer. Portions of substrate or device 114 may also be surface treated using GCIB in accordance with the method mentioned above, prior to the application ofdrug/polymer medium 112. WO 2007/092894 PCT/US2007/061787 17

Drug containing medium 112 may take any suitable form such as the various polymer arrangements discussed above. Medium 112 may include just a single layer of drug containing material, or it may include multiple layers 116, 118, 120, us described above. Although the existing art identifies the use of an outer layer to control initial drug 5 release, the process of the present invention may be used with this known arrangement to further control surface characteristics of the medium, including the drug release rate alter initial in situ liquid exposure. Drug medium 112 may be applied to device I 14 in any suitable arrangement from just a portion to complete or til most complete enclosure of device 114. 10 One method of application ofmedium 112 to device 114 uses a drug polymer mixture with a volatile solvent, which is deposited upon a surface of device 114. The solvent is evaporated to leave a cohesive drug/polymer mixture in the form of medium 112, attached to the substrate. Once the solvent is evaporated, drug medium 112 may form a cohesive mixture or mass and thereby provide a suitable drug delivery system, even in 15 the absence of device 114.

With reference to FIG. 10, the drug.delivery system 110 is shown undergoing irradiation with a gas cluster ion beam. A stream 130 of gas cluster molecules is being scanned across the cross .sect iun of drug delivery device 110. The clusters 132 break up upon impact with the surface 134 resulting in the shallow implantation of individual or

20 small groups of molecules 136. Most ofthe individual molecules 136 stop within the first couple of molecular levels ofmedium 112 with the result that most of a thin layer 138 at surface 134 is densiiicd or carbonized by the impinging molecules, The scaling of surface 134 is not complete, as various openings 139 remain in surface 134 which openings allow for the elution of drugs from medium 112. Thus, It is through the amount of GCIB 25 irradiation that the characteristics of surface 134 are determined. The greater the amount of irradiation, the fewer and smaller are the openings in surface 134, thereby slowing the release of drugs from medium 112. Also, this densifieation or carbonization ofsurlace 134 causes pacification or sealing of surface 134. which can decrease the bio-reactivity of surface 134 in contact with living tissue. In the case of some polymer materials which 30 may be used for medium 112, the densifieation or carbonization can limit the release of volatile organic compounds by the medium 112 into surrounding living tissue. Thus, the process ofthe present invention enhances the choices of materials which may be used to WO 2007/092894 PCT/US2007/M1787 18 construct medium 12 and cun reduce risk factors associated with those material choices.

Studies have suggested that a wide variety of drugs may be useful at the site of contact between the medical device and the in situ environment. For example, drugs such as anti-coagulants, anti-prob lies, antibiotics, immunc-supressing agents, vasodilators, anti- 5 thrombotic substances, ami-platelet substances, and cholesterol reducing ugenls may reduce instances of restenosis when diffused into the blood vessel wall alter insertion of the stent. Although the present invention is described in reference to stents, its applications and the claims hereof are not limited to stents and may include any contact with a living body where drug delivery may be helpful. 0 Although the invention has been described with respect to various embodiments, it should be realized this invention is also capable of a wide variety of further and other embodiments within the spirit and scope of the appended claims. cra&’an , crnxan rwzn ατα inia^n pnow pnszn irn πτ “|»oa ,ρνιη ηχΰπ naoana ma™ na^maa np’ioa .zruwan rwaa mpnan pmi1? oxnm οιηπη Pi?

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