WO2000071182A1

WO2000071182A1 - Radiopaque compositions

Info

Publication number: WO2000071182A1
Application number: PCT/US2000/013401
Authority: WO
Inventors: Antonio Moroni
Original assignee: Scimed Life Systems, Inc.
Priority date: 1999-05-20
Filing date: 2000-05-16
Publication date: 2000-11-30
Also published as: US6426145B1; AU5271300A

Abstract

A radiopaque polymeric composition useful as a polymer coating on a substrate. The compositions are designed to be bioabsorbable and are particularly useful on implantable medical devices, such as vascular prostheses and the like.

Description

RADIOPAQUE COMPOSITIONS

FIELD OF THE INVENTION

The present invention relates to polymeric radiopaque materials. More particularly, the

present invention relates to biocompatible and biostable radiopaque coatings useful in conjunction with implantable medical devices.

BACKGROUND OF THE INVENTION

Medical radiography is a well known and important method used for early detection and

diagnosis of various disease states of the human body. However, most implantable and non-

implantable surgical devices exhibit little absorption of x-ray radiation so that radiographs of

both the devices and their environs are difficult to obtain. The ability to see the radiographic

image of a medical device being used in or implanted within the body is very important. For

example, an implanted medical device, such as an endovascular prosthesis, may need adjustment

and monitoring both during and after implantation in the body. Radiographic imaging provides

the surgeon with the ability to properly perform such adjustments. Additionally, minimally invasive procedures, which are now very commonplace, require monitoring via radiographic

imaging to guide the physician. Devices such as catheters which are not intended to be left for

any length of time in the body may employ conventional radiopaque metal markers which are

usually disposed at the distal end to indicate the catheter whereabouts in the vessel. Such radiopaque markers are not useful, however, in implantable devices which are required to be

porous and flexible, such as vascular prosthesis. Vascular grafts, including those which are

surgically implanted and those which are introduced intraluminally, are designed to mimic the

natural vessels and hence require a unique combination of features to be present. The graft must

be sufficiently porous to allow cellular ingrowth and encapsulation by the body, yet be fluid-tight to prevent leakage of blood. Additionally, flexibility and compliance are also key features of a

successful graft product. Thus, use of metal bands or conventional radiopaque markers are

unacceptable in such devices. Moreover, if a radiopaque composition is to be applied as a

coating over the graft, it must permit the natural process of cellular ingrowth to occur within the first few weeks of being implanted.

To overcome this problem a variety of conventional approaches have been developed,

and numerous patents disclose radiopaque compounds or polymers used in the body.

Radiographic techniques have included the injection of micro-encapsulated particles into

the patient which release a radiopaque agent into the body to aid X-ray analysis of tissue and

organs which are not otherwise visible by X-rays. For example, U.S. Patent No. 5,342,605

discloses an X-ray contrast composition for oral or retrograde examination of the gastrointestinal

tract comprising a divalent cation capable of forming a coating on the tract, and an iodinated

radiopaque agent. Gref, et al., U.S. Patent No. 5,565,215 discloses an injectable microparticle

for the controlled release of substances for diagnostic imaging that can optionally be targeted to

specific organs or cells. While these techniques may be useful for radioscopy of the gastrointestinal tract and target organs, they do not provide adequate means to detect and monitor medical devices inserted into the body which are otherwise transparent to X-ray imaging.

Moreover, these radiopaque agents are not useful as biostable materials which can be used as

polymeric coatings on implantable medical devices such as vascular grafts.

Furthermore, a number of patents disclose polymeric tubing which includes radiopaque

polymer. U.S. Patent No. 3,361,700 discloses a family of alkoxyalkyl esters of diiodobenzoic

acid that are radiopaque and suitable to plasticize vinyl resins into a form useful for the

manufacture of tubings for catheters and similar products. U.S. Patent No. 3,645,955 discloses

that di- and tetraiodoesters are superior for this purpose because they show less tendency to

exude from the polymer tubing and can be used in lower concentrations, thereby providing a better balance between flexibility and stiffness of the polymer article. While these compositions

are quite suitable for the production of tubing of simple types, they are not completely

satisfactory for production of more complicated shaped devices, as they have problems retaining

more complex shapes. U.S. Patent Nos. 4,250,072, and 4,283,447 disclose that if the vinyl resin

is replaced partially or completely by thermoplastic polyurethane, the iodoester radiopacified

compositions are amenable to the induction of complex shapes, i.e., they retain their shape. U.S.

Patent No. 4,579,879 discloses employing a controlled amount of platinum-cured silicon network

polymers in such tubing to provide a surface which is more hydrophobic and gives a longer

service life.

Neuenschwander, et al., U.S. Patent No. 5,319,059 disclose a biocompatible X-ray contrasting composition wherein the X-ray contrast material is covalently attached to a polyurethane matrix. However, the polyurethane matrix is unstable, and may be reabsorbed into

the body, rendering the article invisible by radiographic imaging. This may be problematic for

applications to implantable articles, whose presence would become undetectable to x-rays after decomposition of the x-ray contrast material.

Larsen, European Patent Publication No. 0 203 833, discloses a composition comprising a

x-ray contrasting thermoset polymer comprised of a crosslinkable polyester resin which is

dissolved in a vinyl monomer. This composition may be used to manufacture surgical articles.

However, due to the solid polymer's inflexibility it may not be used to create flexible devices

and would certainly be inappropriate to use as any time of prosthetic implant which required

flexibility.

Thus, while the prior art has suggested various radiopaque compounds and additives to

compositions which are useful in the body, there has yet to be developed a safe, biostable

polymeric coating which is easy to apply to the surface of flexible, porous medical devices, such

as a vascular graft, and which forms a stable coating. Thus, there is a definite need for a

radiopaque polymeric composition which can be particularly useful as a coating for medical

devices, and particularly implantable medical devices, and is biocompatible and biostable.

Therefore, it is an object of the present invention to provide such a polymeric radiopaque

composition. In particular, the inventive composition is capable of adhering to or becoming part of a substrate, and capable of forming a flexible film. Furthermore, the inventive composition also possesses an appropriate amount of tackiness, crystallinity and lubricity for use as a medical

device coating. Such properties can be obtained in the inventive compositions by tailoring the molecular structure in the polymer groups attached to the radiopaque components.

The present invention may be applied as a coating to a medical device or may become

part of the polymer matrix used to form the device, in either case serving to provide radiopaque

character to the device, and thus making the device visible by X-ray imaging techniques.

Furthermore, the present invention utilizes a polymeric composition which displays

improved physical properties over prior radiopaque compositions and forms a coating which has

a wide adaptable range of physical properties including tackiness, lubricity, hemocompatibility,

cell compatibility, and flexibility. The physical characteristics of the polymer are especially

important when it is employed on vascular grafts which require natural tissue ingrowth for

assimilation into the body. The polymeric radiopaque composition may be tailored to provide a

substrate surface which allows the necessary neointimal ingrowth and renders the graft

radiopaque, while also maintaining the graft's flexibility.

SUMMARY OF THE INVENTION

The present invention includes a radiopaque polymeric composition having the formula:

R⁴ R⁶ I I

-[-[-R⁸-[-R'-]-R²-[R³-]-R⁷-]-R⁹-]-

| x I n p q

A R⁵

wherein A is a substituted or unsubstituted aromatic or aliphatic group containing a radiopaque

component and at least one functional group, said functional group being capable of forming a

linkage with R¹ and is selected from the group consisting of carboxyl, amino, hydroxyl,

isocyanato, and halo. R¹ and R³ are substituted or unsubstituted aliphatic or aromatic groups

having from 1 to 20 carbons, and having at least two reactive ends being the same or different,

said reactive ends being selected from the group consisting of carboxyl, amino, hydroxyl,

isocyanato, and halo. X is an integer from 1 to 1,000. N is an integer from 0 to 1,000, provided

that when n is zero R⁷ is absent. R², R⁷ and R⁸ may be optionally present, and may be the same

or different, substituted or unsubstituted groups selected from the difunctional groups consisting

of diols, diamines, hydroxy acids and amino acids. R⁴, R⁵, and R⁶ may be the same or different

substituents selected from the group consisting of hydrogen, halogen or a hydrocarbon chain

having from 1 to 100 carbons. R⁹ is an optional chain extender containing at least two end

groups being the same or different and selected from the group consisting of amino, hydroxyl,

icocyanate, carbonate, anhydride, acyl chloride, and carboxyl. P is an integer from 1 to 100, and

q is an integer from 1 to 100. DETAILED DESCRIPTION OF THE INVENTION:

The following is a detailed description of the present invention. The description is meant

to describe the preferred embodiments, and is not meant to limit the invention in any way.

In a preferred embodiment of the present invention the carbon groups of R¹ and R³ may

be polyester, polyether, polycarbonate, polyamide, or a polyester polyamide copolymer.

Polyester is an especially desirous group to attach to the aromatic component because of several

advantageous physical properties it imparts.

The radiopaque polymeric compositions of the present invention need not be cross-linked to perform effectively. The physical properties of the inventive compositions make them very

suitable for use as coatings on medical devices. Furthermore, certain portions of the polymeric

compositions, i.e., groups R⁴, R⁵, and R⁶ may be varied, and depending on the choice of

substituents, the composition's properties of adhesion, crystallinity, tackiness, lubricity,

hemocompatibility, cell compatibility and flexibility can be controlled.

In another preferred embodiment of the present invention the radiopaque component of

the invention includes an iodinated aromatic ring. In another preferred embodiment of the

invention, R² of the radiopaque polymeric composition forms an ester group connected to said

aromatic or aliphatic group of R³. The polyester is optimally attached through the functional

groups to a radiopaque component which includes an iodinated aromatic ring. The compositions of the present invention may be applied as a coating to an implantable

or a non-implantable medical device. The compositions of the present invention are suitable to coat substrates of implantable devices because they possess desirous properties of

biocompatibility and biostability. Such devices may include, without limitation, catheters, stents,

or grafts. A method of imparting the radiopaque polymeric composition to a surface of such a device is also disclosed.

Many of the physical properties of the radiopaque compositions of the present invention

can be altered with different compositions some of the components. Specifically, R⁴, R⁵, and R⁶

may be chosen from a variety of different formulations in order to impart characteristics which

alter one or more of the composition^'s properties, said properties being selected from the group

consisting of adhesion, crystallinity, tackiness, lubricity, hemocompatibility, cell compatibility,

and flexibility.

The present invention also comprises a medical device having at least one radiopaque

surface, the radiopaque surface comprising a polymeric composition having the formula:

R⁴ R⁶

I I -[-[-R⁸-[-R'-]-R²-ΓR³-]-R⁷-]-R⁹-]-

I x I n p q

A R⁵

wherein A is a substituted or unsubstituted aromatic or aliphatic group containing a radiopaque component and a functional group, said functional group being capable of forming a linkage with R¹ and is selected from the group consisting of carboxyl, amino, hydroxyl, isocyanato, and a

halo; R¹ and R³ are substituted or unsubstituted aliphatic or aromatic groups having from 1 to 20

carbons, and having at least two reactive ends being the same or different, said reactive ends being selected from the group consisting of carboxyl, amino, hydroxyl, isocyanato, and halo; x is

an integer from 1 to 1,000 and preferably from 10 to 100; and n is an integer from 0 to 1,000, and

preferably from 10 to 100; provided that when n is zero R⁷ is absent. R², R⁷, and R⁸ may be optionally present, and may be the same or different, substituted or unsubstituted groups selected

from the difunctional groups consisting of diols, diamines, hydroxy acids, and amino acids. R⁴,

R^s, and R⁶ may be the same or different substituents selected from the group consisting of

hydrogen, halogen, or a hydrocarbon chain having from 1 to 100 carbons. R⁹ is an optional chain

extender containing at least two end groups being the same or different and selected from the

group consisting of amino, hydroxyl, isocyanato, carbonate, anhydride, acyl chloride, and

carboxyl. P is an integer from 1 to 100, and q is an integer from 1 to 100.

The medical device may be a wide variety of devices, and may be implantable or non-

implantable. A list of such medical devices includes, but is not limited to catheters, balloons,

grafts, surgical felts, stents, nets, PTFE, or any other medical fabrics. Non-medical device uses

for the present compositions include engineering, automotive and aerospace applications where

diagnostic testing is used.

The present invention also describes a method of imparting a radiopaque polymeric coating of the above formula to a surface of an article by contacting said surface with the radiopaque polymeric composition listed above.

The radiopaque polymeric composition may be applied to a medical device or other

article in a variety of ways, including dipping, steeping, or spraying the coating on to the article.

A number of layers may be imparted onto the device or article, ranging from 1 to 10 number of

layers. In order to apply the polymer to a substrate, the polymeric composition should have a

viscosity in a suitable range where it is low enough that it can be sprayed or applied, and high

enough to ensure proper application with no problems with adhering the polymeric composition

to the substrate.

The radiopaque polymeric coatings of the present invention may be prepared by a variety

of chemical reaction routes. The compositions of the present invention may be formed by

condensation reactions but is not limited by this type of reaction.

Claims

WHAT IS CLAIMED IS:

1. A radiopaque polymeric composition having the formula

R⁴ R⁶

-[-[-R⁸-[-R'-]-R²-[R³-]-R⁷-]-R⁹-]-

| x I n p q

A R⁵

component and a functional group, said functional group being capable of forming a linkage with

R^l and is selected from the group consisting of carboxyl, amino, hydroxyl, isocyanato, and a

carbons, and having at least two reactive ends being the same or different, said reactive ends

being selected from the group consisting of carboxyl, amino, hydroxyl, isocyanato, and halo; x is

an integer from 1 to 1,000; n is an integer from 0 to 1,000 provided that when n is zero R⁷ is

absent; R², R⁷, and R⁸ may be optionally present, and may be the same or different, substituted or

unsubstituted groups selected from the difunctional groups consisting of diols, diamines,

hydroxy acids, and amino acids; R⁴, R⁵, and R⁶ may be the same or different substituents selected

from the group consisting of hydrogen, halogen, or a hydrocarbon chain having from 1 to 100

carbons; R⁹ is an optional chain extender containing at least two end groups being the same or

different and selected from the group consisting of amino, hydroxyl, carbonate, anhydride, acyl

chloride, and carboxyl; p is an integer from 1 to 100; q is an integer from 1 to 100.

2. A radiopaque polymeric composition according to claim 1 wherein the substituted or unsubstituted aromatic or aliphatic carbon groups of R¹ and R³ are a polymeric group, said group being selected from the group consisting of polyester, polyether, polycarbonate, polyamide, or

polyester polyamide copolymer.

3. A radiopaque polymeric composition according to claim 1 wherein R² forms an ester group connected to an said aromatic or aliphatic group of R³.

4. A radiopaque polymeric composition according to claim 1 wherein the radiopaque

component includes an iodinated aromatic ring.

5. A radiopaque polymeric composition according to claim 1 which is both biocompatible

and biodegradable.

6. A radiopaque polymeric composition according to claim 1 wherein the polymeric

composition is not cross linked.

7. A radiopaque polymeric composition according to claim 1 applied to the substrate of a

medical device.

8. A medical device according to claim 6 wherein the medical device is implantable.

9. A radiopaque polymeric composition according to claim 1 wherein R⁴, R⁵ and R⁶ are

chosen to impart characteristics which alter one or more of the composition's properties, said

properties being selected from the group consisting of adhesion, crystallinity, tackiness, lubricity, hemocompatibility, cell compatibility, and flexibility.

10. A medical device having at least one radiopaque surface, said radiopaque surface comprising: a polymeric composition having the formula

R⁴ R⁶

-[-[-R⁸-[-R'-]-R²-[R³-]-R⁷-]-R⁹-]-

| x I n p q

A R⁵

wherein A is a substituted or unsubstituted aromatic or aliphatic or aliphatic group containing a

radiopaque component and a functional group, said functional group being capable of forming a

isocyanato and halo; R¹ and R³ are substituted or unsubstituted aliphatic or aromatic groups

having from 1 to 20 carbons, and having at least two reactive ends being same or different, said reactive ends being selected from the group consisting of carboxyl, amino, hydroxyl, isocyanato,

and halo; x is an integer from 1 to 1 ,000; n is an integer from 0 to 1 ,000 provided that when n is

zero R⁷ is absent; R², R⁷, and R⁸ may be optionally present, and may be the same or different,

substituted or unsubstituted groups selected from the difunctional groups consisting of diols,

diamines, hydroxy acids, and amino acids; R⁴, R⁵, and R⁶ may be the same or different substituents selected from the group consisting of hydrogen, halogen, or a hydrocarbon chain

having from 1 to 100 carbons; R⁹ is an optional chain extender containing at least two end groups being the same or different and selected from the group consisting of amino, hydroxyl, carbonate, anhydride, acyl chloride, and carboxyl; p is an integer from 1 to 100; q is an integer

from 1 to 100.

11. A medical device according to claim 9 wherein R¹ and R³ of the polymeric composition

which comprises the radiopaque surface are a polymeric group, said group being selected from

the group consisting of polyester, polyether, polycarbonate, polyamide, or polyester polyamide

copolymer.

12. A medical device according to claim 9 wherein the polymeric composition which

comprises the radiopaque surface includes an iodinated ring.

13. A medical device according to claim 9 wherein the polymeric composition which

comprises the radiopaque surface is both biocompatible and biodegradable.

14. A medical device according to claim 9 wherein the polymeric composition which comprises the radiopaque surface is not cross linked.

15. A medical device according to claim 9 wherein such device is a graft.

16. A medical device according to claim 9 wherein such device is a stent.

17. A medical device according to claim 9 wherein such device is a catheter.

18. A method of imparting a radiopaque polymeric coating to a surface of an article which

comprises: a) contacting said surface with a radiopaque polymeric composition, said composition

having the following formula:

R⁴ R⁶

-[-[-R⁸-[-R'-]-R²-[R³-]-R⁷-]-R⁹-]-

| x I n p q

A R⁵

R¹ and is selected from the group consisting of carboxyl, amino, hydroxyl, isocyanato, and halo;

R¹ and R³ are substituted or unsubstituted aliphatic or aromatic groups having form 1 to 20

an integer from 1 to 1 ,000; n is an integer fro 0 to 1 ,000 provided that when n is zero R⁷ is absent; R², R⁷, and R⁸ may be optionally present, and may be the same or different, substituted or

hydroxy acids, and amino acids; R⁴, R⁵, and R⁶ may be the same or different substituents selected from the group consisting of hydrogen, halogen, or a hydrocarbon chain having from 1 to 100 carbons; R⁹ is an optional chain extender containing at least two end groups being the same or

19. The method of claim 17 wherein said article is a medical device.

20. The method of claim 17 wherein said article is a graft.

21. The method of claim 17 wherein said article is a stent.

22. The method of claim 17 wherein said article is a catheter.

23. The method of claim 17 wherein said contacting is by dipping, brushing or spraying.

24. The method of claim 17 wherein said contacting further comprises applying from about 0

to 100 layers of the radiopaque polymeric composition to the surface of said article.