Bioactive agent release coating

A coating composition for use in coating implantable medical devices to improve their ability to release bioactive agents in vivo. The coating composition is particularly adapted for use with devices that undergo significant flexion and/or expansion in the course of their delivery and/or use, such as stents and catheters. The composition includes the bioactive agent in combination with a mixture of a first polymer component such as poly(butyl methacrylate) and a second polymer component such as poly(ethylene-co-vinyl acetate).

TECHNICAL FIELD
 In one aspect, the present invention relates to a process of treating
 implantable medical devices with coating compositions to provide the
 release of pharmaceutical agents from the surface of the devices under
 physiological conditions. In another aspect, the invention relates to the
 coating compositions, per se, and to devices coated with such
 compositions.
 BACKGROUND OF THE INVENTION
 Many surgical interventions require the placement of a medical device into
 the body. While necessary and beneficial for treating a variety of medical
 conditions, the placement of metal or polymeric devices in the body gives
 rise to numerous complications. Some of these complications include:
 increased risk of infection; initiation of a foreign body response
 resulting in inflammation and fibrous encapsulation; and initiation of a
 wound healing response resulting in hyperplasia and restenosis. These, and
 other complications must be dealt with when introducing a metal or
 polymeric device into the body.
 One approach to reducing the potential harmful effects of such an
 introduction is to attempt to provide a more biocompatible implantable
 device. While there are several methods available to improve the
 biocompatibility of implantable devices, one method which has met with
 limited success is to provide the device with the ability to deliver
 bioactive compounds to the vicinity of the implant. By so doing, some of
 the harmful effects associated with the implantation of medical devices
 can be diminished. Thus, for example, antibiotics can be released from the
 surface of the device to minimize the possibility of infection, and
 anti-proliferative drugs can be released to inhibit hyperplasia. Another
 benefit to the local release of bioactive agents is the avoidance of toxic
 concentrations of drugs which are sometimes necessary, when given
 systemically, to achieve therapeutic concentrations at the site where they
 are needed.
 Although the potential benefits expected from the use of medical devices
 capable of releasing pharmaceutical agents from their surfaces is great,
 the development of such medical devices has been slow. This development
 has been hampered by the many challenges that need to be successfully
 overcome when undertaking said development. Some of these challenges are:
 1) the requirement, in some instances, for long term release of bioactive
 agents; 2) the need for a biocompatible, non-inflammatory device surface;
 3) the need for significant durability, particularly with devices that
 undergo flexion and/or expansion when being implanted or used in the body;
 4) concerns regarding processability, to enable the device to be
 manufactured in an economically viable and reproducible manner; and 5) the
 requirement that the finished device be sterilizable using conventional
 methods.
 Several implantable medical devices capable of delivering medicinal agents
 have been described. Several patents are directed to devices utilizing
 biodegradable or bioresorbable polymers as drug containing and releasing
 coatings, including Tang et al, U.S. Pat. No. 4,916,193 and MacGregor,
 U.S. Pat. No. 4,994,071. Other patents are directed to the formation of a
 drug containing hydrogel on the surface of an implantable medical device,
 these include Amiden et al, U.S. Pat. No. 5,221,698 and Sahatjian, U.S.
 Pat. No. 5,304,121. Still other patents describe methods for preparing
 coated intravascular stents via application of polymer solutions
 containing dispersed therapeutic material to the stent surface followed by
 evaporation of the solvent. This method is described in Berg et al, U.S.
 Pat. No. 5,464,650.
 However, there remain significant problems to be overcome in order to
 provide a therapeutically significant amount of a bioactive compound on
 the surface of the implantable medical device. This is particularly true
 when the coating composition must be kept on the device in the course of
 flexion and/or expansion of the device during implantation or use. It is
 also desirable to have a facile and easily processable method of
 controlling the rate of bioactive release from the surface of the device.
 Although a variety of hydrophobic polymers have previously been described
 for use as drug release coatings, Applicant has found that only a small
 number possess the physical characteristics that would render them useful
 for implantable medical devices which undergo flexion and/or expansion
 upon implantation. Many polymers which demonstrate good drug release
 characteristics, when used alone as drug delivery vehicles, provide
 coatings that are too brittle to be used on devices which undergo flexion
 and/or expansion. Other polymers can provoke an inflammatory response when
 implanted. These or other polymers demonstrate good drug release
 characteristics for one drug but very poor characteristics for another.
 Some polymers show good durability and flexibility characteristics when
 applied to devices without drug, but lose these favorable characteristics
 when drug is added. Furthermore, often times the higher the concentration
 of drugs or the thicker the application of polymer to the device surface,
 the poorer the physical characteristics of the polymer become. It has been
 very difficult to identify a polymer which provides the proper physical
 characteristics in the presence of drugs and one in which the drug
 delivery rate can be controlled by altering the concentration of the drug
 in the polymer or the thickness of the polymer layer.
 There remains a need, therefore, for an implantable medical device that can
 undergo flexion and/or expansion upon implantation, and that is also
 capable of delivering a therapeutically significant amount of a
 pharmaceutical agent or agents from the surface of the device.

SUMMARY OF THE INVENTION
 The present invention provides a coating composition and related method for
 using the composition to coat an implantable medical device with a
 bioactive agent in a manner that permits the surface to release the
 bioactive agent over time when implanted in vivo. In a particularly
 preferred embodiment, the device is one that undergoes flexion and/or
 expansion in the course of implantation or use in vivo.
 The composition comprises a bioactive agent in combination with a plurality
 of polymers, including a first polymer component and a second polymer
 component. The polymer components are adapted to be mixed to provide a
 mixture that exhibits an optimal combination of physical characteristics
 (e.g., adherence, durability, flexibility) and bioactive release
 characteristics as compared to the polymers when used alone or in
 admixture with other polymers previously known. In a preferred embodiment
 the composition comprises at least one poly(alkyl)(meth)acrylate, as a
 first polymeric component and poly(ethylene-co-vinyl acetate) ("pEVA") as
 a second polymeric component.
 The composition and method can be used to control the amount and rate of
 bioactive agent (e.g., drug) release from one or more surfaces of
 implantable medical devices. In a preferred embodiment, the method employs
 a mixture of hydrophobic polymers in combination with one or more
 bioactive agents, such as a pharmaceutical agent, such that the amount and
 rate of release of agent(s) from the medical device can be controlled,
 e.g., by adjusting the relative types and/or concentrations of hydrophobic
 polymers in the mixture. For a given combination of polymers, for
 instance, this approach permits the release rate to be adjusted and
 controlled by simply adjusting the relative concentrations of the polymers
 in the coating mixture. This obviates the need to control the bioactive
 release rate by polymer selection, multiple coats, or layering of coats,
 and thus greatly simplifies the manufacture of bioactive-releasing
 implantable medical devices.
 A preferred coating of this invention includes a mixture of two or more
 polymers having complementary physical characteristics, and a
 pharmaceutical agent or agents applied to the surface of an implantable
 medical device which undergoes flexion and/or expansion upon implantation
 or use. The applied coating is cured (e.g., solvent evaporated) to provide
 a tenacious and flexible bioactive-releasing coating on the surface of the
 medical device. The complementary polymers are selected such that a broad
 range of relative polymer concentrations can be used without detrimentally
 affecting the desirable physical characteristics of the polymers. By use
 of the polymer mixtures of the invention the bioactive release rate from a
 coated medical device can be manipulated by adjusting the relative
 concentrations of the polymers. Similarly, a spectrum of pharmaceutical
 agents can be delivered from the coating without the need to find a new
 polymer or layering the coating on the device.
 DETAILED DESCRIPTION OF THE INVENTION
 The present invention relates to a coating composition and related method
 for coating an implantable medical device which undergoes flexion and/or
 expansion upon implantation. The structure and composition of the
 underlying device can be of any suitable, and medically acceptable, design
 and can be made of any suitable material that is compatible with the
 coating itself. The surface of the medical device is provided with a
 coating containing one or more bioactive agents.
 In order to provide a preferred coating, a composition is prepared to
 include a solvent, a combination of complementary polymers dissolved in
 the solvent, and the bioactive agent or agents dispersed in the
 polymer/solvent mixture. The solvent is preferably one in which the
 polymers form a true solution. The pharmaceutical agent itself may either
 be soluble in the solvent or form a dispersion throughout the solvent.
 The resultant composition can be applied to the device in any suitable
 fashion, e.g., it can be applied directly to the surface of the medical
 device, or alternatively, to the surface of a surface-modified medical
 device, by dipping, spraying, or any conventional technique. The method of
 applying the coating composition to the device is typically governed by
 the geometry of the device and other process considerations. The coating
 is subsequently cured by evaporation of the solvent. The curing process
 can be performed at room temperature, elevated temperature, or with the
 assistance of vacuum.
 The polymer mixture for use in this invention is preferably biocompatible,
 e.g., such that it results in no induction of inflammation or irritation
 when implanted. In addition, the polymer combination must be useful under
 a broad spectrum of both absolute concentrations and relative
 concentrations of the polymers. This means that the physical
 characteristics of the coating, such as tenacity, durability, flexibility
 and expandability, will typically be adequate over a broad range of
 polymer concentrations. Furthermore, the ability of the coating to control
 the release rates of a variety of pharmaceutical agents can preferably be
 manipulated by varying the absolute and relative concentrations of the
 polymers.
 A first polymer component of this invention provides an optimal combination
 of various structural/functional properties, including hydrophobicity,
 durability, bioactive agent release characteristics, biocompatability,
 molecular weight, and availability (and cost).
 Examples of suitable first polymers include poly(alkyl)(meth)acrylates, and
 in particular, those with alkyl chain lengths from 2 to 8 carbons, and
 with molecular weights from 50 kilodaltons to 900 kilodaltons. An example
 of a particularly preferred first polymer is poly n-butylmethacrylate.
 Such polymers are available commercially, e.g., from Aldrich, with
 molecular weights ranging from about 200,000 daltons to about 320,000
 daltons, and with varying inherent viscosity, solubility, and form (e.g.,
 as crystals or powder).
 A second polymer component of this invention provides an optimal
 combination of similar properties, and particularly when used in admixture
 with the first polymer component. Examples of suitable second polymers are
 available commercially and include poly(ethylene-co-vinyl acetate) having
 vinyl acetate concentrations of between about 10% and about 50%, in the
 form of beads, pellets, granules, etc. (commercially available are 12%,
 14%, 18%, 25%, 33%). pEVA co-polymers with lower percent vinyl acetate
 become increasingly insoluble in typical solvents, whereas those with
 higher percent vinyl acetate become decreasingly durable.
 A particularly preferred polymer mixture for use in this invention includes
 mixtures of poly(butylmethacrylate) (pBMA) and poly(ethylene-co-vinyl
 acetate) co-polymers (pEVA). This mixture of polymers has proven useful
 with absolute polymer concentrations (i.e., the total combined
 concentrations of both polymers in the coating composition), of between
 about 0.25 and about 70 percent (by weight). It has furthermore proven
 effective with individual polymer concentrations in the coating solution
 of between about 0.05 and about 70 weight percent. In one preferred
 embodiment the polymer mixture includes poly(n-butylmethacrylate) (pBMA)
 with a molecular weight of from 100 kilodaltons to 900 kilodaltons and a
 pEVA copolymer with a vinyl acetate content of from 24 to 36 weight
 percent. In a particularly preferred embodiment the polymer mixture
 includes poly(n-butylmethacrylate) with a molecular weight of from 200
 kilodaltons to 400 kilodaltons and a pEVA copolymer with a vinyl acetate
 content of from 30 to 34 weight percent. The concentration of the
 bioactive agent or agents dissolved or suspended in the coating mixture
 can range from 0.01 to 90 percent, by weight, based on the weight of the
 final coating composition.
 The bioactive (e.g., pharmaceutical) agents useful in the present invention
 include virtually any therapeutic substance which possesses desirable
 therapeutic characteristics for application to the implant site. These
 agents include: thrombin inhibitors, antithrombogenic agents, thrombolytic
 agents, fibrinolytic agents, vasospasm inhibitors, calcium channel
 blockers, vasodilators, antihypertensive agents, antimicrobial agents,
 antibiotics, inhibitors of surface glycoprotein receptors, antiplatelet
 agents, antimitotics, microtubule inhibitors, anti secretory agents, actin
 inhibitors, remodeling inhibitors, antisense nucleotides, anti
 metabolites, antiproliferatives, anticancer chemotherapeutic agents,
 anti-inflammatory steroid or non-steroidal anti-inflammatory agents,
 immunosuppressive agents, growth hormone antagonists, growth factors,
 dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes,
 extracellular matrix components, ACE inhibitors, free radical scavengers,
 chelators, antioxidants, anti polymerases, antiviral agents, photodynamic
 therapy agents, and gene therapy agents.
 A coating composition of this invention is preferably used to coat an
 implantable medical device that undergoes flexion or expansion in the
 course of its implantation or use in vivo. The words "flexion" and
 "expansion" as used herein with regard to implantable devices will refer
 to a device, or portion thereof, that is bent (e.g., by at least 45
 degrees or more) and/or expanded (e.g., to more than twice its initial
 dimension), either in the course of its placement, or thereafter in the
 course of its use in vivo.
 Examples of suitable catheters include urinary catheters, which would
 benefit from the incorporation of antimicrobial agents (e.g., antibiotics
 such as vancomycin or norfloxacin) into a surface coating, and intravenous
 catheters which would benefit from antimicrobial agents and or from
 antithrombotic agents (e.g., heparin, hirudin, coumadin). Such catheters
 are typically fabricated from such materials as silicone rubber,
 polyurethane, latex and polyvinylchloride.
 The coating composition can also be used to coat stents, e.g., either
 self-expanding stents (such as the Wallstent variety), or
 balloon-expandable stents (as are available in a variety of styles, for
 instance, Gianturco-Roubin, Palnaz-Shatz, Wiktor, Strecker, ACS
 Multi-Link, Cordis, AVE Micro Stent), which are typically prepared from
 materials such as stainless steel or tantalum.
 A coating composition of the present invention can be used to coat an
 implant surface using any suitable means, e.g., by dipping, spraying and
 the like. The suitability of the coating composition for use on a
 particular material, and in turn, the suitability of the coated
 composition can be evaluated by those skilled in the art, given the
 present description.
 The overall weight of the coating upon the surface is typically not
 important. The weight of the coating attributable to the bioactive agent
 is preferably in the range of about 0.05 mg to about 10 mg of bioactive
 agent per cm.sup.2 of the gross surface area of the device. More
 preferably, the weight of the coating attributable to the bioactive is
 between about 1 mg and about 5 mg of bioactive agent per cm.sup.2 of the
 gross surface area of the device. This quantity of drug is generally
 required to provide adequate activity under physiological conditions.
 In turn, the coating thickness of a presently preferred composition will
 typically be in the range of about 5 micrometers to about 100 micrometers.
 This level of coating thickness is generally required to provide an
 adequate density of drug to provide adequate activity under physiological
 conditions.
 The invention will be further described with reference to the following
 non-limiting Examples. It will be apparent to those skilled in the art
 that many changes can be made in the embodiments described without
 departing from the scope of the present invention. Thus the scope of the
 present invention should not be limited to the embodiments described in
 this application, but only by the embodiments described by the language of
 the claims and the equivalents of those embodiments. Unless otherwise
 indicated, all percentages are by weight.
 EXAMPLES
 Test Methods
 The potential suitability of particular coated compositions for in vivo use
 can be determined by a variety of methods, including the Durability,
 Flexibility and Release Tests, examples of each of which are described
 herein.
 Sample Preparation
 One millimeter diameter stainless steel wires (e.g. 304 grade) are cut into
 5 centimeter lengths. The wire segments can be Parylene treated or
 evaluated with no treatment. The wire segments are weighed on a
 micro-balance.
 Bioactive agent/polymer mixtures are prepared at a range of concentrations
 in an appropriate solvent, in the manner described herein. The coating
 mixtures are applied to respective wires, or portions thereof, by dipping
 or spraying, and the coated wires are allowed to cure by solvent
 evaporation. The coated wires are re-weighed. From this weight, the mass
 of the coating is calculated, which in turn permits the mass of the coated
 polymer(s) and bioactive agent to be determined. The coating thickness can
 be measured using any suitable means, e.g., by the use of a microprocessor
 coating thickness gauge (Minitest 4100).
 The Durability and Flexibility of the coated composition can be determined
 in the following manner.
 Durability Test
 A suitable Durability Test, involves a method in which a coated specimen
 (e.g., wire) is subjected to repeated frictional forces intended to
 simulate the type of wear the sample would be exposed to in actual use,
 such as an implantable device undergoing flexion and/or expansion in the
 course of its implantation or use.
 The Test described below employs a repetitive 60 cycle treatment, and is
 used to determine whether there is any change in force measurements
 between the first 5 cycles and the last 5 cycles, or whether there is any
 observable flaking or scarring detectable by scanning electron microscopy
 ("SEM") analysis. Regenerated cellulose membrane is hydrated and wrapped
 around a 200 gram stainless steel sled. The cellulose membrane is clipped
 tightly on the opposite side of the sled. The sled with rotatable arm is
 then attached to a 250 gram digital force gauge with computer interface.
 The testing surface is mounted on a rail table with micro-stepper motor
 control. The wires are clamped onto the test surface. The cellulose
 covered sled is placed on top of the wires. Initial force measurements are
 taken as the sled moves at 0.5 cm/sec over a 5 cm section for 5 push/pull
 cycles. The sled then continues cycling over the coated samples for 50
 push/pull cycles at 5 cm/sec to simulate abrasion. The velocity is then
 reduced to 0.5 cm/sec and the final force measurements are taken over
 another 5 push/pull cycles.
 SEM micrographs are taken of abraded and nonabraded coated wires to
 evaluate the effects of the abrasion on the coating.
 Flexibility Test
 A suitable Flexibility Test, in turn, can be used to detect imperfections
 (when examined by scanning electron microscopy) that develop in the course
 of flexing of a coated specimen, an in particular, signs of cracking at or
 near the area of a bend.
 A wire specimen is obtained and coated in the manner described above. One
 end of the coated wire (1.0 cm) is clamped in a bench vice. The free end
 of the wire (1.0 cm) is held with a pliers. The wire is bent until the
 angle it forms with itself is less than 90 degrees. The wire is removed
 from the vice and examined by SEM to determine the effect of the bending
 on the coating.
 Bioactive Agent Release Assay
 A suitable Bioactive Agent Release Assay, as described herein, can be used
 to determine the extent and rate of drug release under physiological
 conditions. In general it is desirable that less than 50% of the total
 quantity of the drug released, be released in the first 24 hours. It is
 frequently desirable for quantities of drug to be released for a duration
 of at least 30 days. After all the drug has been released, SEM evaluation
 should reveal a coherent and defect free coating.
 Each coated wire is placed in a test tube with 5 mls of PBS. The tubes are
 placed on a rack in an environmental orbital shaker and agitated at
 37.degree. C. At timed intervals, the PBS is removed from the tube and
 replaced with fresh PBS. The drug concentration in each PBS sample is
 determined using the appropriate method.
 After all measurable drug has been released from the coated wire, the wire
 is washed with water, dried, re-weighed, the coating thickness
 re-measured, and the coating quality examined by SEM analysis.
 Example 1
 Release of Hexachlorophene from Coated Stainless Steel Wires
 A one millimeter diameter stainless steel wire (304 grade) was cut into two
 centimeter segments. The segments were treated with Parylene C coating
 composition (Parylene is a trademark of the Union Carbide Corporation).
 This treatment deposits a thin, conformal, polymeric coating on the wires.
 Four solutions were prepared for use in coating the wires. The solutions
 included mixtures of: pEVA (33 weight percent vinyl acetate, from Aldrich
 Chemical Company, Inc.); poly(butyl methacrylate "pBMA") (337,000 average
 molecular weight, from Aldrich Chemical Company, Inc.); and
 hexachlorophene ("HCP") from Sigma Chemical Co., dissolved in
 tetrahydrofuran. The solutions were preared as follows:
 1) 10 mg/ml pEVA//60 mg/ml pBMA//100 mg/ml HCP
 2) 35 mg/ml pEVA//35 mg/ml pBMA//100 mg/ml HCP
 3) 60 mg/ml pEVA//10 mg/ml pBMA//100 mg/ml HCP
 4) 0 mg/ml pEVA//0 mg/ml pBMA//100 mg/ml HCP
 Nine wire segments were coated with each coating solution. The following
 protocol was followed for coating the wire segments. The Parylene-treated
 wire segments were wiped with an isopropyl alcohol dampened tissue prior
 to coating. The wire segments were dipped into the coating solution using
 a 2 cm/second dip speed. The wire segments were immediately withdrawn from
 the coating solution at a rate of 1 cm/second, after which the coated
 segments were air-dried at room temperature.
 Individual wire segments were placed in tubes containing 2 ml of phosphate
 buffered saline ("PBS", pH 7.4). The tubes were incubated at 37 degrees
 centigrade on an environmental, orbital shaker at 100 rotations/minute.
 The PBS was changed at 1 hour, 3 hours, and 5 hours on the first day, and
 daily thereafter. The PBS samples were analyzed for HCP concentration by
 measuring the absorbance of the samples at 298 nms on a UV/visible light
 spectrophotometer and comparing to an HCP standard curve.
 Results are provided in FIG. 1, which demonstrates the ability to control
 the elution rate of a pharmaceutical agent from a coated surface by
 varying the relative concentrations of a polymer mixture described by this
 invention.
 Example 2
 The polymers described in this disclosure have been evaluated using an
 Assay protocol as outlined above. The polymer mixtures evaluated have
 ranged from 100% pBMA to 100% pEVA. Representative results of those
 evaluations are summarized below.
 Control coatings that are made up entirely of pBMA are very durable showing
 no signs of wear in the Durability Test. When subjected to the Flexibility
 Test, however, these coatings develop cracks, particularly in the presence
 of significant concentrations of drug. These coatings also release drug
 very slowly.
 Control coatings that are made up entirely of pEVA, in contrast, are less
 durable and show no signs of cracking in the Flexibility Test, but develop
 significant scarring in the Durability Test. These coatings release drugs
 relatively rapidly, usually releasing more than 50% of the total within 24
 hours.
 Coatings of the present invention, which contain a mixture of both
 polymers, are very durable, with no signs of wear in the Durability Test
 and no cracking in the Flexibility Test. Drug release from these coatings
 can be manipulated by varying the relative concentrations of the polymers.
 For instance, the rate of drug release can be controllably increased by
 increasing the relative concentration of pEVA.
 Bioactive agent containing coatings which show no signs of scarring in the
 Durability Test and no cracking in the Flexibility Test possess the
 characteristics necessary for application to implantable medical devices
 that undergo flexion and/or expansion in the course of implantation and/or
 use.