CA2264564A1 - Inhibition of blood platelet aggregation in blood exposed to a foreign body by a polymer coating on the surface thereof containing a nitric oxide-releasing nitrosyl-containing organometallic compound and foreign bodies thus coated - Google Patents
Inhibition of blood platelet aggregation in blood exposed to a foreign body by a polymer coating on the surface thereof containing a nitric oxide-releasing nitrosyl-containing organometallic compound and foreign bodies thus coated Download PDFInfo
- Publication number
- CA2264564A1 CA2264564A1 CA002264564A CA2264564A CA2264564A1 CA 2264564 A1 CA2264564 A1 CA 2264564A1 CA 002264564 A CA002264564 A CA 002264564A CA 2264564 A CA2264564 A CA 2264564A CA 2264564 A1 CA2264564 A1 CA 2264564A1
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- Canada
- Prior art keywords
- blood
- coating
- nitric oxide
- living
- polymer coating
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/02—Use of inorganic materials
- A61L33/027—Other specific inorganic materials not covered by A61L33/022 or A61L33/025
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/08—Materials for coatings
- A61L29/085—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
- A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
- A61F2250/0068—Means for introducing or releasing pharmaceutical products into the body the pharmaceutical product being in a reservoir
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
- Y10S623/924—Material characteristic
- Y10S623/926—Synthetic
Abstract
The aggregation of platelets on the surface of a foreign body exposed to the flowing blood of a living being (such as plastic tubing, a balloon or the end of a catheter surgically inserted in a blood vessel, a stent implanted therein or synthetic grafts, which surface normally promotes such platelet aggregation to form a coating firmly affixed to that surface which would restrict the flow of blood past that surface or to form a blood clot detachable from that surface), is inhibited by a gas permeable coating on the surface of a physiologically acceptable polymer as which contains dissolved or dispersed therein a nitrosyl-containing organometallic compound, such as sodium nitroprusside, which is protected from diffusion from the coating and from direct contact with the blood and which slowly decomposes at the body temperature within the coating and in so doing releases a platelet aggregation-inhibiting amount of nitric oxide which diffuses from the coating during the period when platelet aggregation by the surface of the foreign body would be promoted in the absence of the polymer coating.
Description
CA 02264564 1999-03-01
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INHIBITION OF BLOOD PLATELET AGGREGATION IN BLOOD EXPOSED TO A
FOREIGN BODY BY A POLYMER COATING ON THE SURFACE THEREOF
CONTAINING A NITRIC OXIDE-RELEASING NITROSYL-CONTAINING
ORGAN OMETALLIC COMPOUND AND FOREIGN BODIES THUS COATED
BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates generally to novel drug delivery systems containing a nitric
oxide-releasing metal compound entrapped therein and methods for using them, more
particularly for the inhibition of restenosis after percutaneous transluminal coronary
angioplasty and for the inhibition of acute or subacute thrombotic occlusion related to the
use or deployment of a synthetic device within the vascular tree or extracorporeally.
Description of the Prior Art
Sodium nitroprusside (SNP) and similar nitrosy1âcontaining organometallic com-
pounds, whether ionic salts or chelates, which can release nitric oxide (NO), have been
SUBSTITUTE SHEET (RULE 26)
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known since the midâ1950's to exhibit shortâterm hypotensive effects. The mechanism byâââ
which this drug elicited its pharmacological activity was not known until the discovery that
endothelial cells secreted a factor, which regulated vascular tone, termed Endothelia1â
Derived Relaxation Factor (EDRF) (Furchgott and Zawadzki, Nature, 288: 373-376, 1980).
In 1987, Palmer and coworkers (Nature, 327: 524-526, 1987) determined that the free
radical nitric oxide mimicked many of the physiologic properties reported for EDRF.
Besides regulating vascular tone, nitric oxide has been found to control a wide variety of
physiologic functions, including (a) inhibition of neutrophil adhesion (Kubes, et al., Proc.
Natl. Acad. Sci. USA, 88:465lâ4655, 1991), (b) enhancement of macrophageâmediated
microbial killing (De Groote and Fang, Clirz. Infect. Dis. 12 (Suppl 2): S162-S165, 1995) (c)
amelioration of impotence (Burnett, et al., Science, 257: 401-403, 1992) and (d) regulation
of various CNS functions (Dawson, et al., Ann. Neurol. 32: 297-311, 1992). Of relevance to
this invention are those studies demonstrating that nitric oxide inhibits platelet aggregation
(Furlong, et aI., Brit. J. Pharmacol. 90: 687-692, 1987; Radomski, et aI., Lancet, ii, 1057-
1058, 1987) and prevents restenosis (McNamara, et al., Biochem. Biophys. Res. Commun.
193: 291-296, 1993).
Since nitric oxide regulates many physiologic functions, this free radical is an
essential ingredient for maintaining normal life processes. However, pharmacological
applications of nitric oxide are limited, since systemic use can result in severe toxicity. For
instance, administration of gaseous nitric oxide systemically to treat localized abnormalities
or diseases is
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impractical except in a hospital intensive care setting, because control of its dosage in the
therapeutic range cannot easily be achieved. Even if it were possible to carefully titrate the
gaseous dose of nitric oxide to minimize systemic toxicity, it would be very diï¬icult to locally
administer this drug to sites of interest. Therefore, the development of therapeutic agents, which
would mimic the pharmacological action of nitric oxide, has received considerable attention.
Several classes of nitric oxide-releasing compounds have been developed, including
syndnoeimine (Noack and Feelisch, J Cardiovasc. Pharmacol. 14S: 51-55, 1989),
nitroglycerin (Noack and Feelisch, J. Cardiovasc. Pharmacol. 14S: 51-55, 1989), S-nitroso
derivatives (Ignarro, Lippton, Edwards, Baribos, Hyman, Kadowitz and Gretter, J Pharmacol.
Exp. Yher. 218: 729-739, 1981; Kowalulc and Fung, .1 Pharmacol. Em. Iher. 255: 1254-
1256, 1990; Starnler, Loscalzo, Slivka, Simon, Brown and Drazen, U.S. patent 5,380,758,
1995) and N-nitroso compounds (Maragos, Morley, Wink, Dunams, Saavedra, Hoï¬inan,
Bove, Issac, Hrabie and Keefer, J. Med Chem. 34: 3242-3247, 1991; Keefer, Dunams and
Saavedra, U.S. patent 5,366,997, 1994; Keefer and Hrabie, U.S. Patent 5,405,919, 1995;
Keefer, Hrabie and Saavedra, U.S. patent 5,525,357, 1996). These compounds require either
hydrolysis or metabolic activation, through either oxidation or reduction, to generate nitric
oxide. Alternatively, several studies have reported on the development of photolyzed "caged-
nitric oxide" compounds. For example, the organometallic compound sodium nitroprusside has
been found to release nitric oxide upon light activation (Bates, Baker, Guerra and Harrison,
Biochem. Pharmacol. 42S: S157-S165, 1991). Contrary to this, nitric oxide generation from
light activation of ruthenium nitrosyl trichloride failed to inhibit platelet aggregation, thereby
questioning the utility of this approach (Makings and Tsien, J. Biol. Chem. 269: 6282-6285,
1994).
; Clinically, sodium nitroprusside is used therapeutically to treat hypertension acutely. Its
use is limited to acute hospitalâbased treatment because this nitric oxide releasing compound has
a short lifetime of several minutes in blood (Palmer and Lasseter, New Engl. J Med 292: 294-
297, 1975; Packer, Meller, Medine, Gorlin and Hennan, New Engl. J. Med. 301: 1193-1197,
1979). The degradation of sodium nitroprusside is thought to arise through reductive processes
taking. place in the bloodstream. Even though it has been suggested that sulfhydryl groups
attached to endothelial cells lining the vascular walls might initiate this reaction, other
reductants such as glutathione or ascorbic acid may likewise contribute to its unusually short
physiologic lifetime (I-Iâoâbel, Kreye and Raithelhuber, Herz. 1: 130-136, 1976; Ivankovitch,
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Miletich and Tinker, Int. Anesthesia]. Clin. 16: 1-29, 1978; Kreye and Reske, Arch.
Pharmacol. 320: 260-265, 1982). Based on this pharmacological behavior, the current clinical
use of this drug requires that it is given continuously as an intravenous solution or it rapidly
looses its efficacy concomitant with an increase in blood pressure to a hypertensive level.
Apparatuses and methods have been developed for delivering nitric oxide-releasing
compounds and other drugs selectively and locally to a speciï¬c intemal body site, e.g., for
preventing restenosis after percutaneous translurninal coronary angioplasty. For instance,
Cooke, Dzau and Gibbons (US. Patent 5,428,070, 1995) described the use of orally adrninâ
istered L-arginine as a dietary supplement to enhance nitric oxide production by providing the
substrate to nitric oxide synthase, the enzyme which metabolizes L-arginine to L-citrulline and
nitric oxide. This would not be applicable to restenosis, since in this pathology, the endothelial
cell levels of L-arginine are not diminished, but rather the speciï¬c isoforrn of nitric oxide
synthase localized in endothelial cells is dysfunctional. Furthermore, even if levels of L-arginine
were low, replacement therapy through supplementation of dietary L-arginine is an
inappropriate treatment as cellular sources of L-arginine arise primarily from the reverse
metabolism of L-citrulline to L~arginine (Sessa, Hecker, Mitchell and Vane, Proc. Natl. Acad
Sci. USA, 87: 8607-8611, 1990).
U.S. patent 5,282,785 employs a drug delivery apparatus comprising a ï¬exible catheter
for insertion into an internal target area of the body and a dmg delivery means connected to the
catheter. In this version, the latter delivers the drug in a radially restricted manner and comprises
(a) a drug delivery chamber at the distal end of the drug delivery apparatus, which has a
selectively permeable outer membrane portion and circumferential lips adjacent to both the
proximal and distal ends of the drug delivery system to minimize movement of a drug beyond a
segment of internal tissue and a ï¬uid delivery passageway extending from the chamber to the
proximal end of the catheter; and (b) a non-perrneable balloon aï¬ixed to and surrounding a
portion of the chamber, which, when inï¬ated, secures the chamber at the target area and radially
restricts local delivery of the drug by providing intimate contact between balloon and a portion
of the internal body tissue. The use of such an indwelling catheter device is limited to short term
applications (usually no longer than 10-20 minutes), because it obstructs arterial blood ï¬ow.
The apparatus also includes means of assisting the transport of the drug across the selectively
permeable outer membrane with or without application of pressure.
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Similarly, U.S. patent 5,286,254, also employs an apparatus, comprising a ï¬exible cath-
eter having a distal end and a proximal end and which is adapted for insertion into an internal
area of a body; a drug delivery means having a ï¬uid delivery passageway for delivering a drug
to the distal end of the apparatus, an outer wall and a selectively permeable microporous outer
membrane portion proximate to the distal end and an impermeable end to enhance delivery of
the dmg to the target area; and phoresis means for assisting the transport of the drug across the
selectively pemieable membrane.
These types of apparatuses described in U.S. patents 5,282,785 and 5,286,254 have
several disadvantages. These catheter-based devices obstruct blood ï¬ow and therefore cannot
stay in the circulation system very long. Therefore, long-tenn drug delivery is not possible using
these systems. The presence of these items in the circulatory system promotes platelet
deposition on the device.
U.S. Patent 5,370,614 describes the employment of a sheath coated with a matrix con-
taining a drug and placed over the balloon of a balloon catheter. When placed at the point of
treatment, the balloon is expanded and the sheath bursts from the pressure applied, releasing the
drug as a bolus at the site of interest. Because restenosis occurs over a period of weeks and
treatment would likely require the slow presentation of nitric oxide over an extended period of
time, the approach of U.S. patent 5,370,614 carmot be applied to this disease condition.
U.S. Patent 5,470,307 describes the use of a coating to an apparatus to which a drug is
covalently bonded to a substrate on the exterior surface of a catheter using a linker, which
photolytically releases the agent upon exposure to a light source at an appropriate wavelength.
The necessity to photolytically break a chemical bond in order to release nitric oxide has a clear
disadvantage as there is no continued light source in the blood stream to cleave the linker
molecule.
U.S. patent 5,278,192 describes the continual use of organic nitrites as vasodilator
therapy on a chronic basis for 24 hours without developing tolerance. The necessity of organic
nitrites to be metabolized by endothelial cells that have been made dysï¬inctional as the result of
a disease state would not provide a continued local ï¬ux of nitric oxide to prevent restenosis
and/or platelet aggregation at the atfected site (Munson, "Principles of Pharmacology â Basic
Concepts & Clinical Applications", pp. 482-483, 1995). Furthermore, regulating vascular tone
is not the primary purpose of our invention and the local control of platelet aggregation and
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inhibition of intirnal proliferation, leading to restenosis, altering systemic vascular tone through
administration of either nitric oxide or a nitric oxide-releasing proâdrug is contraindicated.
U.S. patent 5,536,241 discloses a device for relaxing a smooth muscle of a hollow
organ, the organ being a non-respiratory tract organ containing a nonâblood biologic ï¬uid and a
source of nitric oxide, including nitric oxide gas and an NO-releasing compound such as sodium
nitroprusside. This patent pertains to a device that does not come in contact with blood whereas
our invention deals exclusively with the reactions of nitric oxide in blood, including inhibition of
platelet aggregation and prevention of restenosis. In fact, the introduction of nitric oxide as a
gas into the blood is contraindicated, since relaxation of the underlying smooth muscle could
result in severe hypotension and death (see, Furchgott and Zawadzki, 1980, cited in the
application).
U.S. patent 5,605,696 teaches that to prevent complications associated with insertion of
a stent, such as restenosis, a polymer into which a therapeutic dmg is incorporated therein, is
coated onto this device. The pores of the coating have to be suï¬iciently large to allow the drug
to diffuse ï¬'om the coated stent into the blood stream of a human being. Ifthe porosity of a
coating produced by the selected polymer is not suï¬iciently to allow the diffusion of the drug
into the vasculature, a porosigen, such as lactose, is added to the polymer, thereby increasing
the porosity suï¬icient to achieve release of the drug into the blood stream. This drug delivery
system allows the eï¬icient efflux of the therapeutic drug from the polymer into the vasculature.
In contrast to the above cited patents, our invention relates to a different concept, viz.,
coating the surface of a foreign body, such as a stent, a catheter, a synthetic vascular graï¬, an
implantable pump, a synthetic heart valve or other intravascular device or an extracorporeal
device, such as the lumen (interior wall) of plastic tubing or the interior surfaces of pumps used
for renal dialysis or cardiopulmonary bypass, with which the flowing blood of a living being
comes in contact, with a polymeric coating containing a nitrosyl-containing organometallic
compound, such as sodium nitroprusside (which is the pro-drug for nitric oxide), the drug
employed in this invention, which is prevented by the coating from leaching into the blood
stream but which permits the nitric oxide produced by the decomposition thereof to diï¬iise
therefrom (for applications like renal dialysis or cardiopulmonary bypass) - with which blood or
body tissue would come in contact.
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Summary of the Invention
I In an article of manufacture aspect, this invention relates to an improvement in a device
adapted for exposure to blood ï¬owing in a living being and having a surface which is exposed
to the blood and which is coated with a coating of a physiologically acceptable polymer which
contains dissolved or dispersed therein a therapeutic drug, wherein the polymer coating is
insoluble in the blood, inhibits diï¬iision of blood-bome reductants from entering the polymer
coating and is gas permeable and the therapeutic drug dissolved or dispersed therein is an
amount of nitrosylâcontaining organometallic compound which at the body temperature of the
living being slowly decomposes within the polymer coating when the device is exposed to the
blood of the bloodstream of the living being and in so doing releases from the coating into the
bloodstream of the living being nitric oxide at a rate effective to inhibit the platelet aggregation
which could otherwise occur after the device is exposed to the blood.
In a process aspect, this invention relates to a method for the production of a device
adapted for exposure to blood ï¬owing in a living being and having a surface which is exposed
to the blood which comprises the step of coating the surface with a coating of a physiologically
acceptable polymer which contains dissolved or dispersed therein a therapeutic drug, wherein
the polymer applied to the surface to fonn the coating is insoluble in the blood, inhibits diï¬iision
of blood-bome reductants from entering the polymer coating and is gas permeable and the
therapeutic drug dissolved or dispersed therein is an amount of nitrosylâcontaining organe-
metallic compound which at the body temperature of the living being slowly decomposes within
the polymer coating when the device is exposed to the blood of the bloodstream of the living
beingand in so doing releases from the coating into the bloodstream of the living being nitric
oxide at a rate effective to inhibit the platelet aggregation which could otherwise occur aiter the
device is exposed to the blood.
In a method of use aspect, this invention relates to a method for inhibiting the
aggregation of platelets from blood ï¬owing in a living being from exposure of the blood to a
foreign body by coating the surface of the foreign surface of a device adapted for exposure to
blood ï¬owing in a living being and having a surface which is exposed to the blood and which is
coated with a coating of a physiologically acceptable polymer which contains dissolved or
dispersed therein a therapeutic drug, wherein the polymer which is applied to the surface to
form the coating is insoluble in the blood, inhibits diï¬iision of blood-bome reductants from
entering the polymer coating and is gas permeable and the therapeutic drug dissolved or
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dispersed therein is an amount of nitrosyl-containing organometallic compound which at the
body temperature of the living being slowly decomposes within the polymer coating when the
device is exposed to the blood of the bloodstream of the living being and in so doing releases
ï¬'om the coating into the bloodstream of the living being nitric oxide at a rate eï¬âective to inhibit
the platelet aggregation which could otherwise occur after the device is exposed to the blood.
In a composition of matter aspect, this invention relates to a coating composition
comprising (a) either an aqueous or an organic vehicle; (b) an injectable physiologically
acceptable polymer dissolved or dispersed in the vehicle; and (c) a nitrosyl-containing
organometallic compound, whether an ionic salt or a chelate, as deï¬ned herein which is
precipitable from vehicle, e.g., by evaporation thereof to form a continuous coating containing
the organometallic compound dissolved or dispersed therein.
Detailed Description
This invention is based on the discovery that the aggregation of platelets in blood as a
result of exposure of the blood to a foreign body or to the injured endothelium can be inhibited
by a polymer coating on at least the surface(s) of the foreign body to which the circulating
blood is exposed which contains an amount of a nitrosylâcontaining organometallic compound,
whether an ionic salt or a chelate, which is stable at room temperature but at body temperature
and/or in the presence of ambient light while the foreign body is exposed to the blood releases
from the coating a platelet-aggregation-inhibiting amount of nitric oxide, which amount
produces a nitric oxide concentration locally at the surface of the foreign body which carmot
safely be achieved by the systemic administration of a nitrosyl-containing organometallic
compound, whether by intravenous or intra-arterial inï¬rsion.
Thus, this invention is useï¬rl for the inhibition of restenosis, a gradual re-occlusion of
the blood vessel which usually occurs over a prolonged period of time, usually up to 6 weeks
following trauma to the blood vessel, by providing a therapeutic concentration of NO proximate
to the site of the trauma during that period of time.
In one article of manufacture aspect, this invention relates to intravascular medical
devices such as synthetic (prosthetic) grafts, implantable pumps, heart valves and stents adapted
for long tenn or permanent insertion into the lumen of a blood vessel, e.g., in conjunction with
percutaneous translurninal angioplasty. In another aspect, the intravascular device is adapted for
temporary insertion in a blood vessel, e.g., a balloon or catheter tip.
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In yet another article of manufacture aspect, this invention relates to extravascular
medical devices, such as plastic tubing or a membrane insert in the extravascular path of the
blood stream of a living being undergoing a medical procedure requiring the cycling of the
blood stream or a portion thereof outside the body of the living being, e.g., coronary artery
bypass surgery or renal dialysis. In each of these aspects of this invention, a surface of the
device which is in contact with the blood stream is coated with a polymer coating as described
herein which contains an organometallic compound as described herein.
The method of this invention provides a method of inhibiting platelet aggregation, either
in the form of a layer that builds up on a medical device that is permanently implanted in a blood
vessel or that comes in contact with the circulating blood of a living being on a temporary basis
or in the form of a detachable clot which, if it travels to the organs such as brain, lung, heart,
kidney and liver, can be debilitating or have lifeâthreatening sequelae. This method also applies
to stents, indwelling catheters, other intravascular devices, either temporary or permanent, or to
extracorporeal synthetic circuits for applications such as cardiopulmonary bypass or kidney
dialysis.
This invention provides a novel method for the inhibition of restenosis, i.e., a gradual re-
occlusion of the blood vessel over a prolonged time period frequently occurring 4 to 6 weeks
after surgery - by coating the surface of the foreign body, typically a stent, that contacts the
blood with a polymer coating of this invention which contains dissolved or dispersed therein an
amount of a nitrosyl-containing organometallic compound or a chelate which slowly
decomposes within the polymer coating while the stent is in position in a vascularity of a living
being and in so doing releases locally an amount of nitric oxide from the coating for a time
period of up to 4 to 6 weeks or longer, which is effective to inhibit restenosis.
The polymeric coating employed in this invention contains a nitrosyl-containing or-
ganometallic compound, such as sodium nitroprusside, which is a pro-drug for the nitric oxide
employed as the platelet aggregation inhibiting drug in this invention. Its porosity is sufficiently
low to inhibit the diï¬iision of the nitrosylâcontaining organometallic compound from the coating
into the blood stream and also to inhibit blood-bome reductants from entering the polymer. The
coating is, however, gas permeable and thus does not prevent the diffusion of nitric oxide from
within the polymer coating into the blood stream.
Nitrosylâcontaining organometallic compounds, whether ionic salts or chelates,
employed in the composition of this invention are:
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a. non-toxic, that is, substantially free from any signiï¬cant toxic eï¬ects at their effective
applied concentration;
b. substantially ï¬'ee of symptomology, that is, they do not produce signiï¬cant
symptoms detectable to the person treated at their effective applied concentration;
c. relatively stable at room temperature, away from light, i.e., once a nitrosylâmetal
chelate is impregnated into a polymer and coated onto a stem or tubing or other device, nitric
oxide is not released therefrom at a signiï¬cant rate, e.g., during the preparation of the coating or
its application to the stent, tubing or other device or thereafter, during self storage in a
packaged container, is released at a rate, for example, less than 1% per month;
(1. long lasting, that is, once a stent, tubing or other intra- or extravascular device
bearing on the surface thereof a coating of the polymer impregnated with the nitrosyl-containing
organometallic compound, whether an ionic salt or a chelate, comes in contact with blood or is
inserted into a blood vessel, the duration of the delivery of nitric oxide can be adjusted by
varying the concentration of the nitrosyl-containing organometallic compound in the polymer to
conform to the clinical situation to be a matter of minutes, (e.g., 5-90 minutes in the case of a
angioplasty balloon or catheter), hours (e.g., 1-4 hours in the case of hypothermic surgery blood
circulation or cardiopulmonary bypass), hours to days (e.g., 3 hours to 3 days in the case of
dialysis of blood passing though plastic tubing), or days to weeks (e.g., 4 to 6 weeks or longer
in the case of a stent).
The Examples of a nitrosyl-containing organometallic compound employed in this
invention, involve a compound of the formula [l\/lXsNO]'2 Yâ or ZYH where M is a transition
metal such as Fe, Co, Mn, Cu, Ni, Pt; X is a negatively a charged ion such as CN, Cl, Br, I, or
chelates such as EDTA, DTPA, carbamates and dithiolates that at physiologic pH have
negatively charged carboxylic and thiocarboxylic acid groups and Y is a positively charged salt.
A readily available example of the nitrosylâcontaining organometallic chelates that can
be employed in our invention is sodium nitroprusside, a compound in which an iron ion is
complexed to ï¬ve cyano groups and the sixth ligand position is occupied by a nitrosyl group.
Exposure of the polymer coating on the surface of a device of this invention containing
such an organometallic compound encapsulated or dissolved therein to the blood steam of a
living being releases nitric oxide from the coating in a controlled manner while retaining the
other nonâvolatile decomposition products within the polymer coating. The enhanced stability
of sodium nitroprusside in such a polymer coating, compared to its extremely short lifetime in
10
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such a blood stream, is the result of the inability of blood-containing reductants such as thiols
and ascorbic acid to diï¬iise through the polymer coating and inactivate the sodium
nitroprusside or rapidly decompose all of it, with concurrent rapid release of nitric oxide ï¬'om
the polymer coating, which thereby reduces or eliminates the long temi beneï¬ts of prolonged
release of nitric oxide achieved by protecting the sodium nitroprusside from direct contact with
the blood stream.
Other suitable complexing agents for the iron ion are ethylenediaminetetraacetic acid,
EDTA; diethylenetriaminepentaacetic acid, DTPA and others of this class of chelates; l,4,7,10-
tetraazacyclododecane-N,Nâ,N",Nâ'âtetraacetic acid, DOTA and trans-l,2-
cyclohexylenediamine-N,N,N',N'-tetraacetic acid and others of this class of chelates;
diethylthiocarbamate and similarly related carbarnates; l,2-dicyanoethylene-1,2-dithiolate and
similarly related dithiolates. 9
This invention relates to methods, composition and articles of manufacture useful in the
inhibition of platelet deposition either on a foreign body introduced surgically into a blood
vessel or at vascular sites which have received treatment. Examples of such medical procedures
include cardiopulmonary bypass during coronary artery bypass grafting ("CABG"), percu-
taneous transluminal angioplasty ("PTA") of peripheral arteries, arterial bypass surgery (either
peripheral or coronary) using synthetic (prosthetic) vascular graï¬s, percutaneous transluminal
coronary angioplasty ("PTCA") with stent implantation, and renal dialysis.
The reduction of platelet deposition has important implications for reducing the
incidence of restenosis occurring following balloon angioplasty. By employing a polymer coat-
ing as deï¬ned herein to coat an implantable intravascular device such as a metal stent containing
dissolved or dispersed therein a nitrosylâcontaining organometallic compound in ionic salt or
chelate form, nitric oxide can be locally delivered at any desired dose proï¬le, which can be
controlled by varying the concentration of the nitrosyl-containing organometallic compound,
the speciï¬c polymer used to form or the nature and thickness of the coating, e. g., by employing
multiple polymer coats containing varying concentrations of the organometallic compound.
Thus, systemic nitric oxide toxicity, e. g., hypotension, can be prevented from occurring while at
the same time achieving nitric oxide level locally at the site of the foreign body effective to
inhibit platelet aggregation thereon or the fonnation of a detached or potentially detachable
thrombus.
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CA 02264564 1999-03-01
W0 98,084â PCT/US97/15022
The nitrosyl-containing organometallic compound must be incorporated into a polymer
coating whose porosity is suï¬iciently low to inhibit the diï¬irsion of bloodâbome reductants from
entering the polymer and thereby inactivating the nitric oxide releasing compound of this
invention yet is gasâpermeable, i.e., has pores large enough to allow the passive difï¬rsion of
nitric oxide from inside the polymer coating into the bloodstream.
The coating on the foreign body preferably is from 0.1-1.0 mm thick and contains 1
rnicromole to 100 micromoles of the nitrosyl-containing organometallic compound per m2.
Higher concentrations are desirable when the diffusion rate of the nitric oxide ï¬-om the polymer
is very slow or when it is desired that the release of the nitric oxide occurs over a prolonged
period of time, e. g., more than 48 hours.
A wide variety of polymers can be used to encapsulate sodium nitroprusside and other
nitrosyl-containing organometallic compounds, whether ionic salts or chelates, including both
physiologically inert and biodegradable polymers and those which are only slowly soluble and
those which are insoluble in blood for at least the period of time when any portion of the
organometallic compound remains present therein. Insoluble polymers which are suitable are
those which form a gas-permeable membrane coating around the foreign body so that the nitric
oxide can migrate therefrom as it is produced. When the foreign body is inserted into the living
being, it preferably is physiologically inert and, when permanently implanted, also
biodegradable. Examples of biodegradable polymers which can be used as drug delivery
systems include the natural polymers: collagen, albumin, casein, ï¬brin and gelatin (S.
Bogdansky, in: Biodegradable Polymers as Drug Delivery Systems, ed. by M. Chasin and R.
Langer, Marcel Dekker,. Inc. New York, pp. 231-259, 1990). Synthetic polymer systems
include polylactide and polyglycodide (D.H. Lewis, in: Biodegradable Polymers as Drug
Delivery Systems, ed. by M. Chasin and R. Langer, Marcel Dekker,. Inc. New York, pp. 1-42,
1990); polyvinyl alcohols (P.R. Byron and R.N. Dalby, J. Pharm. Sci. 76: 65-67, 1987);
polyalkylene oxides and polyvinyl chlorides. Other suitable polymers include polyesters,
polylactic anhydrides, celluloses, vinyl copolymers, homopolymers, acrylate, polycyanoacrylate,
polyurethanes, silicone polymers and other types of polymers, such the dendrimers.
Characteristics of an "ideal" coating for a stent is one which can be applied to lurninal or
subluminal surfaces, does not cause a signiï¬cant increase in stent wall thickness; is stable over
time without desquamation; has a surface tension below 30 dyne/cm; has a smooth surface
texture (<1 micron irregularities) has a negative or neutral surface charge; allows rapid
12
CA 02264564 1999-03-01
W0 93m3432 PCT/U S97] 15022
endothelialization; permits timed elution of the nitric oxide; and delivers an effective
concentration of nitric oxide locally to the site (S.R. Bailey, "Coating of Endovascular Stents"
in: Textbook of Interventional Cardiology, ed. by E.J. Topol, Vol. 2, 2nd edition, W.B.
Saunders, Philadelphia, pp. 754-765, 1994).
The desired coating can be formed by immersing the foreign body in a solution or
colloidal dispersion of the selected polymer in either an aqueous or an organic vehicle
containing dispersed therein the nitrosyl-containing organometallic compound, and then making
the polymer insoluble, e.g., by changing the pH or the ionic strength, by or through evaporation
of the solvent or by denaturing a proteinaceous polymer, so that a coating of the polymer with
the nitrosyl-containing organometallic compound occluded therein deposits on the exposed
surfaces of the foreign body. For example, a stent is placed in a tetrahydroï¬iran (THF) solution
of polyvinyl chloride (PVC) in which the nitrosylâcontaining organometallic compound is
included therein, frequently a solid dispersed in the TI-IF/PVC solution. The surface of the stem
is thereby coated with a nitrosylâcontaining organometallic compound dissolved in a solution of
THF/PVC. Upon evaporation of the solution, the polymer encasing the nitric oxide releasing
compound forms a ï¬lm onto the surface of the stent.
The foreign body can be any medical device or product which has a surface that is
exposed to the blood stream of a living being, which preferably is a human being, and is
susceptible to or which promotes platelet aggregation. Intravascular devices and angioplasty
surgery in general frequently promote platelet adhesion and aggregation. Placement of a stent
into a living human being can also promote platelet aggregation and subsequent restenosis.
Local delivery of nitric oxide can ameliorate these lifeâthreatening conditions. Similarly, patients
undergoing blood ï¬ow diversion outside the body, e.g., in conjunction with hypothermic
surgery and dialysis of organs such as the kidney, have increased susceptibility to platelet
aggregation due to a foreign body response resulting trom the exposure of the blood to the
plastic tubing used to transport the blood. A similar risk of foreign body response occurs in
patients undergoing angiograms as a result of the insertion of plastic tubing into an artery.
Therefore, anticoagulants are conventionally administered (with unavoidable associated risks)
to suppress this response. When the interior of the tubing is coated with coating according to
this invention, anticoagulants can be reduced or even eliminated entirely. Synthetic or
reconstituted natural, e.g., from powdered bone and binder, bony structures can also trigger a
13
CA 02264564 1999- 03 - 01
WO 98/08482 PCT/US97/15022
foreign body response and therefore can beneï¬t ï¬'om a coating thereon according to this
invention.
A preferred embodiment of the intravascular device aspect of this invention is a metal,
e.g., stainless steel, or a polymeric intravascular stent which typically is implanted temporarily or
permanently in a blood vessel after percutaneous transluminal coronary angioplasty.
The intravascular or extracorporeal devices of this invention can be constructed with
pockets, grooves or other depressions in the surface of the device which can be ï¬lled with the
polymer containing the organometallic compound. Alternatively, the nitrosylâcontaining
organometallic compound can ï¬rst be deposited in the pockets, grooves or other depressions
and the surface containing them and then coated with a polymer which does not contain the
organometallic compound. Or a polymer coating containing the organometallic compound can
ï¬rst be formed on all of the surface(s) of the device which is exposed to the blood stream, or
only a portion of that surface, and that polymer coating then covered with a protective polymer
coating lacking the organometallic compound fonned from the same polymer or a different
polymer. Alternatively, the nitrosyl-containing organometallic compound can be incorporated
into the structure of the device itself and the device then covered with a protective polymer
coating which allows the diï¬irsion of nitric oxide therethrough into the blood stream.
Preferred embodiments of the devices of this invention comprise one or more of the
following:
a. The device is an intravascular device adapted for insertion into the bloodstream of
the living being.
b. The intravascular device is in the fomr of a balloon, a catheter or a stent adapted to
be inserted surgically into a blood vessel of a living being in conjunction with transluminal
coronary angioplasty.
c. The intravascular device is a stent and the nitrosyl-containing organometallic com-
pound is sodium nitroprusside.
d. The intravascular device has the nitrosyl-containing organometallic compound pos-
itioned within pockets, grooves or other depressions in the surface of the device and is covered
with a coating of the physiologically acceptable polymer.
e. The coating containing the nitrosyl-containing organometallic compound is coated
with a second coating of the same or different polymer that does not contain the organometallic
compound.
14
CA 02264564 1999-03-01
WO 98/08482 PCT/U S97/ 15022
f. The device is an extravascular device adapted to transport the blood of a patient
undergoing coronary artery bypass surgery or renal dialysis.
g. The device is an extravascular device which comprises plastic tubing that is adapted
to transport the blood and whose inner surface is coated with the polymer coating.
h. The extravascular device has the polymer coating on the surface of a membrane
insert or on the inner surface of a section of the plastic tubing coated with the polymer coating,
which is otherwise uncoated, which contacts the blood stream.
i. The extravascular device has sodium nitroprusside as the nitrosyl-containing
organometallic compound.
The preferred methods for the production of a device of this invention and the preferred
methods of using such a device also involve one or more of the above described preferred
embodiments of this invention.
Brief Description of the Drawings
In the drawings:
Figure 1 shows the exterior, interior and cross sectional views of a platelet-inhibition
element of this invention comprising a container adapted to be inserted in the blood ï¬ow loop
of a; patient undergoing renal dialysis or surgery involving extravascular transport of the blood
stream of the patient and an accordion folded biologically inert synthetic polymer mesh insert
for the container through which the blood of the patient must ï¬ow; and
Figure 2 shows the side view and cross sectional top view of a stent of this invention
which contains grooves in the inner walls thereof for deposition of the organometallic
compound and an end view of the cross sectional section of the stent with the organometallic
compound deposited in the grooves and covered with the polymer coating of this invention.
From the foregoing description, one skilled in the art can easily ascertain the essential
characteristics of this invention, and without departing from the spirit and scope thereof; can
make various changes and modiï¬cations of the invention to adapt it to various usages and
conditions. The entire disclosures of all applications, patents and publications, cited above and
below are incorporated by reference. The following preferred speciï¬c embodiments are,
therefore, to be construed as merely illustrative and not limiting to the disclosure in anyway
whatsoever.
15
CA 02264564 1999-03-01
W0 98/03432 PCT/US97/15022
EXAMPLE 1
Preparation of Nitric Oxide Delivery Systems. A 5% (w/w) of polyvinyl chloride
(PVC, inherent viscosity 1.02, M.W. 40,000â85,000) solution was prepared by dissolving PVC
(5 gm) in tetrahydroï¬rran (100 mL) at room temperature for 1 hour. Aï¬er this PVC solution
was prepared, sodium nitroprusside (1 gm SNP) was mixed with the PVC/TI-IF solution to give
a SNP/PVC/TI-IF suspension. Polyvinyl chloride tubing was coated with either PVC containing
SNP or with PVC alone by allowing the solution of PVC containing the SNP or the
corresponding solution containing only the PVC to flow through the tubing. After air drying the
tubing, the coating process is repeated a number of times to obtain a coating containing the
amount of SNP required to produce the desired ï¬ux of nitric oxide. Once the desired release
rate of nitric oxide is achieved, a TI-IF/PVC solution can be placed over the dried PVC-
containing SNP. In this manner, SNP is protected by an additional coating of PVC alone from
blood elements, which rapidly inactivate SNP. Other surfaces, such as plastic Falcon tubes or
glass coverslips, were coated in a similar manner.
EXAMPLE 2
Kinetics of Nitric Oxide Release from Plastic Surfaces. A plastic tube was coated with
a solution of polyvinyl chloride (PVC, inherent viscosity 1.02, M.W. 40,000-85,000, solution
was prepared by dissolving 5 gm of PVC in 100 mL tetrahydroï¬iran at room temperature for 1
hour) containing particulate sodium nitroprusside (< 38 microns; 0.5% w/v). The solvent was
removed by air drying to leave a polymer coating 0.1 to 1 mm thick. Nitrite accumulation using
the Griess reagent in a sodium phosphate buffer was used as a measure of nitric oxide. Samples
of the buffer was removed and analyzed daily, thereby ensuring that the determination of nitrite
(a measure of nitric oxide) gave an accurate account of the daily release of nitric oxide. Samples
(0.6 mL) were taken and added to freshly prepared Griess's reagent (0.4 mL of 0.1% N-(1-
naphthyl)-ethylenediamine in water and 1% sulfanilamide in 5% phosphoric acid mixed 1:1).
This reaction incubates for 15 minutes at room temperature and absorbance is recorded at 550
nm. Concentrations of nitrite were estimated by comparing absorbances at 550 nm against
standard solutions of sodium nitrite prepared in the same buffer (Green, Wagner, Giogowski,
Skipper, Wishnok and Tannebaum, Anal. Biochem. 126: 131-138, 1982). The ï¬rst few days of
nitric oxide release from the polymer into the phosphate buffer at 37°C was high, achieving a
maximal concentration of approximately 35 micromolar of nitric oxide by day 3. At this point,
16
CA 02264564 1999-03-01
WO 98/08432 PCT/US97/15022
the concentration of nitric oxide decreased slowly, achieving, by day 35, an equilibrium ï¬ux of 8
micromolar of nitric oxide. This rate of nitric oxide release remained constant for 52 days, when
the experiment was terminated. These results demonstrate that sodium nitroprusside
incorporated into a PVC coating can release nitric oxide into a phosphate buffer at 37°C in the
absence ofblood-containing reductants.
EXAIVIPLE 3
An in vivo experiment was employed to evaluate the ability of a polymer coating,
produced by casting a solution of polyvinyl chloride (PVC, inherent viscosity 1.02, M.W.
40,000-85,000, solution was prepared by dissolving 5 gm of PVC in 100 mL tetrahydrofuran at
room temperature for 1 hour) containing particulate (< 38 microns; 0.5% w/v) sodium
nitroprusside dispersed therein onto the lumen of PVC tubing and air drying to remove the
solvent, to inhibit platelet aggregation. An artiï¬cial A-V ï¬stula was created between the femoral
artery and vein of a pig with PVC - and PVC/SNP-coated tubing connected in parallel. The
ï¬ow rate in the A-V ï¬stula tubing was adjusted to 80 mL/min. Blood samples were taken for
ADP-induced platelet aggregation and measurement of serum nitrite concentrations at locations
close to the femoral artery and at the distal end of the PVC-coated and PVC/SNP-coated
tubing. Samples were collected every hour after establishing the artiï¬cial A-V ï¬stula and 20
minutes after the disconnection of the ï¬stula. After the blood pressure was stabilized at about
75 mm Hg, the ï¬ow through the tubing was begun. One hour after establishing the A-V ï¬stula,
blood sampled from the PVC/SNP-coated tubing showed 69% inhibition of platelet aggregation
as compared to 24% inhibition for blood sampled from the uncoated control tubing. Of interest
is the ï¬nding that even aï¬er 4 hours of flow through the PVC/SNP-coated tubing during which
platelet aggregation remained markedly inhibited (platelet inhibition of the PVC/SNP-coated
tubing at over 200% of control), blood pressure was unchanged, remaining at about 75 mm Hg.
It is clear from these data that a slow release of nitric oxide through the PVC polymer inhibits
platelet aggregation as compared to the control, PVC alone.
Biologic Assay for Nitric Oxide - Platelet Aggregation. Aggregation of human platelets
was measured optically with a four-channel platelet aggregometer (Model 560-Ca, Chromo-
log, Havertown, PA). Venous blood was collected in a citrated tube, centriï¬iged at 250 x g to
isolate platelet rich plasma (PRP, platelet count with approximately 300,000/mL). Platelet
aggregation was induced by ADP (10 micromolar, ï¬nal concentration).
17
CA 02264564 1999' 03 ' 01
WO 98/08482 PCT/US97/15022
EXAMPLE 4
The fact that selective diifusion is achievable by our invention was verified by the
following experiments, which were designed to test the relative diï¬iisiveness of sodium
nitroprusside (a readily available example of the general class of nitrosyl~conta.ining
organometallic compounds employed in our invention) and nitric oxide through a polyvinyl
chloride coating.
A solution of sodium nitroprusside (10 mM in sodium phosphate buffer, pH 7.4) was
placed within a PVC tube (the inner tube) and sealed. A second larger PVC tube (the outer
tube) ï¬lled with only sodium phosphate buï¬âer at pH 7.4 was ï¬tted around the inner tube
containing the solution of SNP and it also was sealed. This device was placed on a laboratory
bench and maintained at ambient conditions for 3 days. At this point, the contents of each of the
sealed tubes were analyzed.
We analyzed for SNP in each tube. The analysis showed that the inner tube contained
residual SNP and the non-volatile components of the portion of the SNP which had decom-
posed, as shown by the UV-visible spectrum analysis for SNP in the phosphate bulfer. In
contrast, the contents of the outer tube did not exhibit any UV-visible spectrum absorption.
These findings demonstrate that the sodium nitroprusside did not diï¬iise through the wall of the
inner tube into the outer tube. We also analyzed for nitric oxide to determine whether the nitric
oxide produced by the decomposition of the sodium nitroprusside in the solution in the inner
tube had diffused into the outer tube. We did so by measuring the amount of nitrite present,
which provides an estimate of nitric oxide content, using the method of Green, et al., (Anal.
Biochem. 126: 131-138, 1982). This analysis demonstrated that 80 micromolar nitrite had
accumulated in the outer tube, thus conï¬rming that nitric oxide had diï¬iised from the inner
tubing into the outer tubing, whereas the SNP had not.
Taken together, these experiments proved that the sodium nitropmsside in the inner
tube had decomposed and produced nitric oxide and the porosity of the coating was sufï¬ciently
small to prevent sodium nitropnisside ï¬âom migrating therefrom and collecting in the outer tube
but was gas permeable and therefore did not prevent the nitric oxide generated in the inner tube
from diï¬iising through the wall thereof into the buffer solution in the outer tube.
18
CA 02264564 1999-03-01
wo 93/03482 PCT/US97/15022
EXAl\/IPLE 5
I Construction of a platelet-inhibition element. A platelet-inhibition element (Figure 1)
may be constructed by placing a large surface area ï¬lter into a cylindrical device which then can
be inserted into an extracorporeal blood pathway during procedures such as cardiopulmonary
bypass surgery and renal dialysis. The membrane and/or the internal surfaces of the cylinder can
be coated with a polymer into which the nitrosyl-containing organometallic compound is
incorporated therein. A preparation of this nitric oxide delivery system is as follows: A 5%
(w/w) of polyvinyl chloride (PVC, inherent viscosity 1.02, M.W. 40,000-85,000) solution is
prepared by dissolving PVC (5 gm) in tetrahydrofuran (100 mL) at room temperature for 1
hour. After this PVC solution is prepared, sodium nitroprusside (1 gm SNP) is mixed with the
PVC/THF solution to give a SNP/PVC/THF suspension. The membrane and/or the internal
surfaces of the platelet-inhibition element are coated with PVC containing SNP by allowing the
corresponding solution to ï¬ow through the device. After air drying the device, the coating
process can be repeated at number of times to obtain the desired ï¬ux of nitric oxide.
EXAMPLE 6
Construction of a drug-delivery stent. The stent (Figure 2) is constructed of metal in
which grooves are created along its length into which a nitrosylâcontaining organometallic
compound can be placed. This surface in which the nitrosyl-containing organometallic
compound is placed is then covered with a physiologically acceptable polymer. A preparation of
this nitric oxide delivery system is as follows: First sodium nitroprusside (1 gm SNP) is ground,
and the resulting powder placed in the grooves of the stent. Then a 5% (w/w) of polyvinyl
chloride (PVC, inherent viscosity 1.02, M.W. 40,000-85,000) solution is prepared by dissolving
PVC (5 gm) in tetrahydroï¬iran (100 mL) at room temperature for 1 hour. This solution is then
coated over the grooves on the stent containing the sodium nitroprusside. Aï¬er air drying the
drug delivery stent, the coating process can be repeated a number of times to obtain the desired
ï¬ux of nitric oxide. In this manner, SNP is protected ï¬'om blood elements, which rapidly
inactivate SNP, by the coating of PVC alone.
19
Claims (16)
1. In a method for producing a medical device of inhibiting the aggregation of platelets from blood flowing in a living being resulting from exposure of the blood to the medical device by coating the surface of the medical device prior to contact therewith, with a physiologically acceptable polymer coating which contains dissolved or dispersed therein a therapeutic drug the improvement wherein the polymer coating is insoluble in the blood and has a porosity sufficiently small to inhibit diffusion of blood-borne reductants from entering the coating and sufficiently large to allow passive diffusion of nitric oxide within the polymer coating into the blood stream of the living being and contains dissolved or dispersed therein as the therapeutic drug and the source of the nitric oxide an amount of a nitrosyl-containing organometallic compound, which slowly decomposes at body temperature within the polymer coating when the device is exposed to the blood stream of the living being and in so doing releases from the coating from the coating into the blood stream an amount of nitric oxide effective to inhibit platelet aggregation which would otherwise be promoted by contact of the blood with the foreign body.
2. A method according to claim 1, wherein the living being is a human.
3. A method according to claim 2, wherein the organometallic compound is nitroprusside.
4. A method according to claim 2, wherein the medical device is an intravascular device adapted to be inserted surgically into a blood vessel of a human in conjunction with percutaneous transluminal coronary angioplasty.
5. A method according to claim 4, wherein the device is a stent.
6. A method according to claim 5, wherein the coating is applied to all of the exposed surfaces of the stent.
7. A method according to claim 5, wherein the nitrosyl-containing organometalliccompound is nitroprusside and the amount of nitric oxide released from the polymer coating is effective to prevent restenosis.
8. A method according to claim 2, wherein the device is the inner surface of plastic tubing adapted to transport blood of a patient undergoing hypothermic surgery or dialysis.
9. A method according to claim 2, wherein the device is a balloon, a catheter or a stent adapted to be inserted surgically into a blood vessel of a human in conjunction with transluminal coronary angioplasty, and the nitric oxide releasing compound is nitroprusside.
10. A method according to claim 2, wherein the foreign body is plastic tubing adapted to transport a stream of blood, the nitrosyl-containing organometllic compound is nitroprusside and the amount of nitric oxide released from the polymer coating is effective to prevent thrombotic occlusion.
11. In a device adapted for exposure to blood flowing in a living being, said device having an exterior surface coated with a coating of a physiologically acceptable polymer which contains dissolved or dispersed therein a therapeutic drug, the improvement wherein the polymer coating is insoluble in the blood and has a porosity sufficiently small to inhibit diffusion of blood-borne reductants from entering the coating and sufficiently large to allow passive diffusion of nitric oxide from within the polymer coating into the blood stream of the living being and contains dissolved or dispersed therein as the therapeutic drug and the source of the nitric oxide an amount of a nitrosyl-containing organometallic compound which slowly at the body temperature of the living being decomposes within the polymer coating when the device is exposed to the blood of the blood stream of the living being and in so doing releases from the coating into the blood stream an amount of nitric oxide at a rate effective to mediate the platelet aggregation which could otherwise occur after the device is exposed to the blood.
12. A device according to claim 11, which is an intravascular device adapted for insertion into the blood stream of the living being and whose exterior surfaces which are exposed to the blood are coated with the polymer coating.
13. An intravascular device according to claim 12, which is a stent.
14. A stent according to claim 13, wherein the nitrosyl-containing organometallic compound is nitroprusside.
15. A device according to claim 11, which is an extravascular device comprising plastic tubing adapted for transporting the blood of a living being and whose inner surface is coated with the polymer coating.
16. An extravascular device according to claim 15, wherein the organometallic compound is nitroprusside.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US08/703,646 | 1996-08-27 | ||
US08/703,646 US5797887A (en) | 1996-08-27 | 1996-08-27 | Medical device with a surface adapted for exposure to a blood stream which is coated with a polymer containing a nitrosyl-containing organo-metallic compound which releases nitric oxide from the coating to mediate platelet aggregation |
PCT/US1997/015022 WO1998008482A2 (en) | 1996-08-27 | 1997-08-27 | Polymeric coating for a surface exposed to blood |
Publications (1)
Publication Number | Publication Date |
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CA2264564A1 true CA2264564A1 (en) | 1998-03-05 |
Family
ID=24826237
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002264564A Abandoned CA2264564A1 (en) | 1996-08-27 | 1997-08-27 | Inhibition of blood platelet aggregation in blood exposed to a foreign body by a polymer coating on the surface thereof containing a nitric oxide-releasing nitrosyl-containing organometallic compound and foreign bodies thus coated |
Country Status (8)
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US (2) | US5797887A (en) |
EP (1) | EP0975274A4 (en) |
JP (1) | JP2001501104A (en) |
AU (1) | AU733616B2 (en) |
CA (1) | CA2264564A1 (en) |
IL (1) | IL128739A (en) |
NZ (1) | NZ334392A (en) |
WO (1) | WO1998008482A2 (en) |
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