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DRUG DELIVERY SYSTEM MAKING USE OF A
HYDROGEL POLYMER COATING
This application is a continuation-in-part of applica- 5 tion U.S. Ser. No. 07/635,732, titled Balloon Drug Delivery System, filed Dec. 28, 1990 now abandoned. The entire contents of this application are hereby incorporated by reference.
This application is also a continuation-in-part of co- 10 pending U.S. patent application Ser. No. 451,507 filed Dec. 15,1989, now U.S. Pat. No. 5,135,516, issued Aug. 4, 1992.
FIELD OF THE INVENTION 15
The invention relates to delivery of drugs to the walls of body lumens.
BACKGROUND OF THE INVENTION
Systemic administration of drugs treats the organism 20 as a whole, even though the disease may be localized, such as occlusion of a duct or vessel. Localization of a drug poses special problems in cases involving the walls of ducts and vessels, since, by nature, these organs serve as transport systems. 25
Arthrosclerotic disease, for example, causes localized occlusion of the blood vessels resulting from the buildup of plaque. As the deposits increase in size, they reduce the diameter of the arteries and impede blood circulation. Angioplasty, which involves the insertion 30 of catheters, such as balloon catheters, through the occluded region of the blood vessel in order to expand it, has been used to treat arthrosclerosis.
The aftermath of angioplasty in many cases is problematic, due to restenosis, or closing of the vessel, that 35 can occur from causes including mechanical abrasion and the proliferation of smooth muscle cells stimulated by the angioplasty treatment. Restenosis may also occur as a result of clot formation following angioplasty, due to injury to the vessel wall which triggers the natural 40 clot-forming reactions of the blood.
SUMMARY OF THE INVENTION
In one aspect, the invention features a catheter and method for delivering drug to tissue at a desired loca- 45 tion of the wall of a body lumen. The catheter is constructed for insertion in a body lumen and has a catheter shaft and an expandable portion mounted on the catheter shaft. The expandable portion is expandable to a controlled pressure to fill the cross-section of the body 50 lumen and press against the wall of the body lumen. At least a portion of the exterior surface of the expandable portion is defined by a coating of a tenaciously adhered swellable hydrogel polymer. Incorporated in the hydrogel polymer is an aqueous solution of a preselected drug 55 to be delivered to the tissue. The hydrogel polymer and drug are selected to allow rapid release of a desired dosage of the drug from the hydrogel polymer coating during compression of the hydrogel polymer coating against the wall of the lumen when the expandable 60 portion is expanded.
Various embodiments may include one or more of the following features. The catheter is adapted for insertion in a blood vessel, and the expandable portion is an inflatable dilatation balloon adapted for inflation at pressures 65 in the range for effecting widening of a stenosed blood vessel. The pressure is in the range of about 1 to 20 atmospheres. The hydrogel polymer and drug are effec
tive to release about 20% or more of the drug during inflation in the pressure range. The compression is effective to deliver the drug over a duration of about 10 minutes or less. The hydrogel polymer coating is about 10 to 50 microns thick in the swelled, uncompressed state. The hydrogel polymer is selected from the group consisting of polycarboxylic acids, cellulosic polymers, gelatin, polyvinylpyrrolidone, maleic anhydride polymers, polyamides, polyvinyl alcohols, and polyethylene oxides. The hydrogel polymer is polyacrylic acid. The drug is an anti-thrombogenic drug selected from the group consisting of heparin, PPack, enoxaprin, aspirin and hirudin. The drug is an anti-proliferative drug selected from the group consisting of monoclonal antibodies, capable of blocking smooth muscle cell proliferation, heparin, angiopeptin and enoxaprin. The expandable portion is adapted for application of heat to the polymer material to control the rate of administration. The catheter further comprises a sheath member, extendable over the balloon to inhibit release of the drug into body fluids during placement of the catheter. The balloon catheter is a perfusion catheter having an expandable balloon. The expandable portion includes a stent, mountable in the blood vessel by expansion thereof. The drug is bound in the hydrogel polymer for slow time release of the drug after the compression of the hydrogel polymer by the expansion. The hydrogel polymer is a polyacrylic acid including an ammonium anion and the drug is heparin. The stent is expandable by a balloon. The catheter where the stent and balloon both include the swellable hydrogel coating incorporating the drug. The expandable portion is prepared by introducing an aqueous solution of the drug to the hydrogel polymer coating, the catheter is introduced to the body lumen to position the expandable portion at the point of desired drug application, and the expandable portion is expanded to enable delivery of the drug by compression of the hydrogel polymer coating against the wall at the body lumen. The expandable portion is positioned at a point of occlusion in the blood vessel and expanding the expandable portion at pressures sufficient to simultaneously dilate the vessel and deliver the drug by compression of the hydrogel polymer coating.
In a particular aspect, the invention includes a balloon catheter for delivering drug to tissue at a desired location of the wall of a blood vessel. The catheter is constructed for insertion in a blood vessel and has a catheter shaft and an expandable dilatation balloon mounted on the catheter shaft. The expandable balloon is expandable by an expansion controller to engage the tissue at a controlled pressure in the range of about 1 to 20 atmospheres to fill the cross-section of the blood vessel and press against the wall of the blood vessel. At least a portion of the exterior surface of the expandable balloon is defined by a coating of a tenaciously adhered swellable hydrogel polymer with a thickness in the range of about 10 to 50 microns in the swelled state, and incorporated within the hydrogel polymer coating, an aqueous solution of a preselected drug to be delivered to the tissue. The hydrogel polymer and drug are selected to allow rapid release of a desired dosage of about 20% or more of the drug solution from the hydrogel polymer coating during compression of the hydrogel polymer coating against the wall of the vessel when the expandable portion is expanded in the pressure range.
In various embodiments, the hydrogel polymer is selected from the group consisting of polycarboxylic acids, cellulosic polymers, gelatin, polyvinylpyrrolidone, maleic anhydride polymers, polyamides, polyvinyl alcohols, and polyethylene oxides. The hydrogel 5 polymer is polyacrylic acid. The drug is an anti-thrombogenic drug selected from the group consisting of heparin, PPack enoxaprin, aspirin and hirudin. The drug is an anti-proliferative drug selected from the group consisting of monoclonal antibodies, capable of 10 blocking smooth muscle cell proliferation, heparin, angiopeptin and enoxaprin. The catheter further comprises a sheath member, extendable over the balloon to inhibit release of the drug into body fluids during placement of the catheter.
In another aspect, the invention features a catheter for delivering drug to tissue at a desired location of the wall of a body lumen, comprising. The catheter is constructed for insertion in a body lumen having a catheter shaft and an expandable portion mounted on the catheter shaft, the expandable portion is expandable to a controlled pressure to fill the cross-section of the body lumen and press against the wall of the body lumen. At least a portion of the exterior surface of the expandable 2J portion is defined by a coating of a body-fluid soluble polymer, and incorporated within the soluble polymer, a preselected drug to be delivered to the tissue. The soluble polymer and drug are selected to allow release of the polymer from the surface of the balloon during J0 compression of the polymer coating against the wall of the body lumen when the expandable portion is expanded to coat the wall of the body lumen.
Various embodiments include the following. The polymer is selected from the group consisting of polyca- 35 prolactone, polyorthoesters, polylactic acids, polyglycolic acids, and albumin. The catheter where the drug is selected from anti-thrombogenic drugs and antiproliferative drugs. The catheter where the expandable portion is adapted for application of heat to the polymer 40 material to control the rate of administration. The catheter where the polymer is a meltable polymer, and the release of the polymer is aided by the application of heat.
In general, an advantage of the invention is the appli- 45 cation of drugs by active diffusion directly into the tissue within the body requiring treatment. The drug is preferably applied in a rapid but low-stress, low energy manner that does not further injure the tissue to be treated, and administration is selectively and evenly 50 distributed over the treated area such that the drug can be taken up by tissue and plaque, without, e.g., being washed away by body fluids.
FIG. Id is a further enlarged, schematic cross-sectional view of the portion of FIG. lc indicated in the circle le, but taken prior to full inflation.
FIG. le, which corresponds to the portion of FIG. lc indicated in the circle le, is an enlarged, schematic cross-sectional view, as in FIG. Id, but with the balloon under full inflation to release the drug coated on the balloon.
FIG. 2 is an enlarged cross-sectional view of another embodiment of the drug delivery balloon catheter of the invention including a sheath for covering the catheter as it is being moved through a vessel toward the occlusion to be treated.
FIG. 2a is an enlarged cross-sectional view of the catheter of FIG. 2 with the sheath retracted and balloon inflated at the site of occlusion.
FIG. 3 is an enlarged, schematic cross-sectional view of another embodiment of the drug delivery balloon catheter in which the drug, originally held within a polymer applied to a thermal balloon of the invention, is now entering the surrounding tissue.
FIG. 3a is a further enlarged, schematic illustration of the embodiment of FIG. 3 and illustrates the entry of the drug, shown as circles, into the surrounding tissue.
FIG. 4 shows a balloon catheter with the hydrogel and drug coated endoprosthesis mounted on the balloon section, in the region of the thrombus, before radial expansion of the balloon section and endoprosthesis.
FIG. 4a is an enlargement of FIG. 4 showing the hydrogel polymer and drug coated endoprosthesis and FIG. 4i> is a cross-section along the line b—b in FIG. 4a.
FIG. 5 shows the endoprosthesis compressed against the vessel wall by radial expansion of the balloon section with the drug diffused into the compressed thrombus before removal of the balloon catheter.
FIG. 6 shows the endoprosthesis positioned against the drug inside the compressed thrombus, after removal of the balloon catheter.
Referring to FIGS. 1-le, in one embodiment, the invention includes a drug delivery balloon catheter device 1 comprising a catheter body 3 having a balloon 4 attached at its distal end. The balloon 4 on the catheter 3 includes a swellable hydrogel polymer coating 6. As shown in FIGS. 1-la, a drug 8 in an aqueous solution is absorbed into the hydrogel with the balloon in the deflated state prior to insertion into the patient by the physician, e.g., the hydrogel-coated balloon may be immersed in a small tube or vial containing the drug. The drug may also be applied in the form of droplets, such as from an eyedropper, or the drug may be precipitated into the hydrogel prior to sterilization and sold as a finished device. Exposure of the hydrogel to the solution causes the hydrogel to swell.
As shown in FIG. lb, typically the device 1 is inserted into the duct or vessel 2 having a region to be treated, such as an occlusion due to a deposition of plaque 5 on the vessel wall tissue 9. The device I is moved along the vessel to position the balloon 4 at the occlusion site, as shown in FIG. lc. The vessel may be, for example, a narrow, tortuous opening through which the catheter is passed by torquing from the distal end. As the balloon is inflated the pressure created by the balloon against the tissue compresses the hydrogel and the drug is quickly and freely released for transfer by active diffusion into the plaque and tissue. The pressure applied to the plaque and tissue by the expansion of the
balloon during application of the drug enhances transfer of the drug into the tissue and plaque. This process is referred to here as active diffusion. The balloon and catheter may be exposed to the body fluids of the lumen for a considerable time, e.g., up to about 15 minutes in 5 some angioplasty procedures. An advantage of this invention is that large amounts of the drug, e.g., greater than 20%, even 30-50% or more, of the drug solution contained in the hydrogel, is diffused into the effected area in the short time duration which the hydrogel is 10 compressed, e.g., 2-10 minutes after the balloon is inflated at the treatment site. The inflation pressure needed to dilate the vessel which also approximates the compression of the coating, is in the range of 1 to 20, typically about 2 to 10 atmospheres. The balloon is 15 preferably a compliant material such as polyethylene which conforms to the shape of the lumen wall. The balloon may also be formed of other materials used in angioplasty, e.g., a nondistending material, such as polyethylene terephthalate (PET). Transporting the drug in 20 the hydrogel prevents substantial release of the drug to body fluids prior to reaching the treatment area and during the drug application phase and allows large dosages to be delivered at a desired location.
In the embodiment of FIG. lc, the balloon coating 6 25 is a swellable, compressible coating formed of the hydrogel and drug in solution. In FIG. Id, the balloon 4 is shown inflated such that the coating 6, which has an initial thickness, is in contact with the occlusion 5 but not under substantial pressure. Further inflation of the 30 balloon 4, as shown in FIG. le, compresses the hydrogel coating 6 against the occluded areas 5 causing quick release of the drug (represented by circles) contained in the coating 6 directly into the plaque and nearby healthy tissue, as indicated by the directional arrows, 35 much in the nature of squeezing liquid from a sponge. The introduction of the drug into the plaque and tissue occurs simultaneously with widening of the occlusion by the dilatation balloon. Thus, as cracking of the plaque and stimulation of smooth muscle cells beneath 40 the plaque and along healthy tissue of the vessel wall are caused by dilatation, a therapeutic drug is simultaneously applied to the effected area, e.g., to counteract the effects of the trauma. The thickness of the balloon 4 remains substantially the same, while the thickness of 45 the coating 6 decreases due to the compression of the coating and the release of the drug 8. (FIGS, ld-le are schematic drawings and are not to scale with respect to the thickness of the balloon relative to the thickness of the hydrogel coating.) The drug carried by the balloon 50 is evenly applied to plaque and tissue and isolated by the pressure of the balloon from the flow of body fluids in the lumen such that the drug, e.g., an anti-proliferative, may actively diffuse through the cracks formed in the plaque and reach the smooth muscle tissue. (It will also 55 be understood that, as an alternative procedure, after dilation with a conventional angioplasty balloon catheter, a catheter carrying a drug-delivery, inflatable balloon, such as has been described, may be used to treat the vessel.) 60
The hydrogel coating is characterized by the ability to incorporate a substantial amount of the drug, typically in aqueous solution form, and is swellable such that the aqueous drug solution can be effectively squeezed out of the coating when pressure is applied by 65 inflation of the balloon. Administration of the drug in this way enables the drug to be site specific, such that release of high concentrations and/or highly potent
drugs may be limited to direct application to the diseased tissue. Furthermore, the drug is applied to the diseased tissue by the sponge-like coating in an even, gentle manner without disrupting or injuring the healthy tissue, while diffusion of the drug into the tissue is facilitated by the application of the pressure of the inflated balloon. The pressure also effectively forms a seal that prevents the flow of body fluids from washing the drug downstream of the treatment area. The dosage applied to the tissue may be controlled by regulating the time of presoaking the drug into the hydrogel coating to determine the amount of absorption of the drug solution by the hydrogel coating. Other factors affecting the dosage are the concentration of the drug in the solution applied to the coating and the releasability of the hydrogel coating, determined by, for example, the thickness of the hydrogel coating, its resiliency, porosity and the ability of the hydrogel coating to retain the drug, e.g., electrostatic binding or pore size, or the ionic strength of the coating, e.g., changed by changing the pH.
The drug may be an anti-thrombogenic drug, such as heparin or a heparin derivative, PPack (dextrophenylalanine proline arginine chloromethylketone) or an anti-proliferative, such as heparin (also known to have anti-proliferative properties), enoxaprin, angiopeptin, or monoclonal antibodies capable of blocking smooth muscle cell proliferation, or it may be hirudin or acetylsalicylic acid (i.e., aspirin). Dosages applied to the tissue, for example, of heparin are typically in the range of 10-30 mg of heparin solution containing 200-1,000 units of sodium heparin. For use with hydrogels, the drug is preferably water soluble, so that the drug may be easily absorbed into the coating matrix.
The sponge-like characteristics of the hydrogel allows the aqueous drug solution to be effectively squeezed out of the coating when pressure is applied by inflation of the balloon. The hydrogel and drug combination are preferably noncomplexed, i.e., held together through the ability of the hydrogel to swell and absorb the drug solution, thereby allowing the preferable freerelease of the drug at the treatment site.
In particular embodiments it may be advantageous to select a hydrogel coating for a particular drug such that the drug is not substantially released into body fluids prior to application of pressure by expansion of the balloon. Binding of the drug may also be accomplished by electrostatic attraction of the drug to the coating or a coating additive or by mechanical binding, e.g., employing a coating having a pore size that inhibits inward flow of body fluids or outward flow of the drug itself, that might tend to release the drug. Hydrogels are particularly advantageous in that the drug is held within the hydrogen-bond matrix formed by the gel.
The hydrogel is a cross-linked polymer material formed from the combination of a colloid and water. Cross-linking reduces solubility and produces a jellylike polymer that is characterized by the ability to swell and absorb a substantial amount of the drug, typically in aqueous solution form. The hydrogel coating is also particularly hydrophilic, water swellable, and lubricous (i.e., having a low coefficient of friction). Preferred hydrogels are polyacrylic acid polymers available as HYDROPLUS® (Boston Scientific, Watertown, Mass.) and as described in U.S. Pat. No. 5,091,205, the portion disclosed in the parent application to this patent being incorporated by reference). The drug, e.g., heparin in aqueous solution, is absorbed into the coating without complexing and is freely released therefrom.