WO1996030060A1

WO1996030060A1 - Medical device treated with a hydrophilic polymer composition

Info

Publication number: WO1996030060A1
Application number: PCT/GB1996/000725
Authority: WO
Inventors: Edward Mcdaid; James Gordon Wright
Original assignee: Aortech Europe Ltd.
Priority date: 1995-03-28
Filing date: 1996-03-27
Publication date: 1996-10-03
Also published as: BR9607909A; AU712268B2; AU5154496A; CA2216639A1; EP0817652A1; GB9506769D0; JPH11502734A

Abstract

There is provided medical devices for use as cardiac, coronary or vascular prostheses, for example heart valves, coronary artery bypass grafts and arterial grafts. The devices described are at least partially coated or impregnated with a hydrophilic polymer composition which desirably contains of from 1 to 99 % by weight of water, preferably 50 to 95 % by weight of water. The hydrophilic polymer composition may be biodegradable and preferably contains a polyurethane. Optionally the hydrophilic polymer composition may contain a pharmaceutically active agent, for example an anti-coagulant, a thrombolytic agent or an antibiotic. The device may be treated with two or more hydrophilic polymer compositions in separate coatings; a triple-layered coating may be especially beneficial. The presence of the hydrophilic polymer coating is beneficial in reducing the thrombogenesis which may occur following implantation of the device

Description

"Medical Device Treated with a Hydrophilic Polymer Composition"

The present invention relates to medical implants and equipment having a hydrophilic polymer composition coating. In particular, the present invention is concerned with cardiac implants and vascular prostheses.

In mammals the heart is a vital organ responsible for maintaining an adequate flow of blood (and hence oxygen and nutrients) to all parts of the body. Essentially the heart acts as a mechanical pump, forcing the blood delivered to it via veins out along arteries at higher pressure. The blood is prevented from flowing backwards through the heart by the presence of valves located therein.

Dysfunction of one or more of the valves in the heart can have serious medical consequences. Dysfunction of heart valves may be the result of a congenital defect, or of disease-induced damage or degeneration. Dysfunction frequently results from stenosis or narrowing of the valve aperture, preventing sufficient blood through-flow. Further, dysfunction also frequently results from valve insufficiency. In addition to cardiac valve replacement operations, operations for coronary bypass are also frequently required.

To date, the only solution to treat severe heart valve dysfunction is to replace the malfunctioning valve. Such a valve replacement operation, in addition to being extremely costly, requires complex open-heart surgery. There is a also a finite number of times that a heart valve can be replaced successfully for any particular patient, making the design and operational lifetime of any replacement valve extremely important.

Mechanical valves have been developed and used for heart valve replacement operations. Whilst such valves exhibit excellent operational lifetimes, they suffer from a higher incidence of thrombosis (blood clotting) due to the trigger of clotting in the blood as the material of the valve is recognised by the immune system as being "foreign" to the body. Suitable heart valves are manufactured, for example, by Aortech Europe Limited, Strathclyde, UK under the name ULTRACOR (Trade Mark) . Heat valves manufactured by St Jude Medical, CarboMedics, Medtronic or ATS Medical, USA are all suitable as are valves manufactured by Sorin, Italy

Currently mechanical valve implants are estimated at 110,000 implants worldwide with an average price of between US$2,000 and $3,000 retail to the hospital. The one major clinical problem facing mechanical valves is anti-coagulation. It is currently believed that the majority of emboli and clots initially grow from the junction of the sewing ring with the metal or pyrolite housing. Also suture material and large knots put in place when the surgeon implants the valve may be the cause of some of these phenomena. Currently no manufacturer has an anti-thrombogenic coating on their valves and the ability to do this with the consequent lowering of the frequency of embolic episodes or the more catastrophic thrombosis which can lead to death of the patient would be highly desirable.

In an effort to reduce the risk of thrombosis to a patient, it has been proposed (see for example EP-A- 0,402,036 of ProMedica International Inc) to use porcine pulmonary valves in human patients. Surprisingly such xenografts show less tendency to be destroyed by the recipient, especially where the donor organ has been pre-treated with glutaraldehyde to reduce the risk of calcification. However, such valves have a finite lifetime and must generally be replaced within 10 years of implantation.

With increasing life expectancy for humans, there is a corresponding rise in patients requiring cardiac valve replacement and/or coronary bypass operations. There is thus an increasing need for cardiac and vascular prostheses having both an extended useful lifetime and also a low risk of inducing thrombosis in a recipient.

It has now been found that coating or impregnating at least part of a cardiac prosthesis (such as a heart valve) with a hydrophilic polymer composition significantly reduces thrombogenesis.

The present invention thus provides a cardiac, coronary or vascular prosthesis having a coating of hydrophilic polymer composition on at least a part thereof and/or being at least partially impregnated with a hydrophilic polymer composition. Viewed from a further aspect the present invention provides a heart valve wherein at least part of the valve (for example the sewing ring and/or the junction of the sewing ring with the heart valve housing) is coated or impregnated with a hydrophilic polymer composition.

Viewed from a yet further aspect the present invention provides a prosthesis (for example coronary artery bypass grafts and arterial grafts) suitable for coronary bypass operations and vascular surgery wherein at least part of the surface to be contacted by bodily fluids (preferably substantially all of such surfaces) is coated or impregnated with a hydrophilic polymer composition.

In coronary bypass operations surgeons currently harvest the saphenous vein from the patient's leg, which often causes the patient post-operatively more pain problems than the thoracoto y. It is estimated that after ten years a significant number of all coronary artery bypass grafts are either grossly inefficient at providing extra blood flow to the ischemic part of the heart or have completely clotted and closed down. An artificial coronary artery bypass graft, which would be coated or impregnated completely with an anti-thro bogenic material would be desirable despite the fact that vein grafts are harvested free.

Where the prosthesis is a mechanical heart valve, the hydrophilic polymer composition may be present on the sewing ring thereof and/or on the junction of the sewing ring with the metallic part of the valve housing, Suitable sewing ring material which may be coated according to the present invention includes Teflon. Optionally, the hydrophilic polymer composition may coat or be used to impregnate substantially all of the surfaces of the coronary prostheses or vascular grafts.

The hydrophilic polymer composition may contain of from 1% to 99% water (by weight) , for example said composition may contain 20% to 99% water, especially 40 to 95% water. The composition will normally be liquid at ambient temperature and may be sprayed or painted onto the device of the present invention. Alternatively the device may be dipped into the composition and allowed to dry thereon.

Desirably, the hydrophilic polymer has low surface adhesion properties, thus reducing the incidence or risk of thrombogenesis.

Suitable hydrophilic polymers are described in US-A- 4,256,066; US-A-4 ,156,067; US-A- ,255,550; ; US-A- 4,359,588; US-A-4,408, 023 ; US-A-4,424,305; US-A- 4,490,432; US-A-4,496, 535; US-A-4 ,729 ,914; US-A-4,743, 673; US-A-4,780, 512; US-A-4,789,720; US-A-4,798,876; US-A-4,810,582; US-A-5,000,955 and US-A-4,789,720 all of Tyndale Plains Hunter Ltd, Princeton, New Jersey.

In particular, the hydrophilic polymers may be polyurethanes, as described in US-A-5, 120,816 and in US-A-4 ,789,720. The polymers exemplified in US-A- 4,789,720 and in US-A-5 , 120,816 are especially suitable.

The advantageous biomedical properties of certain hydrophilic polymers suitable for use in the present invention (for example as disclosed in US-A-4,789,720 and in US-A-5,120,816) derive from the structure of the polymers which are prepared by reacting an aliphatic diisocyanate with different polyoxyalkylene glycols, usually with a majority of polyoxyethylene glycol. The polymers contain terminal hydroxyl groups and can be made to different molecular weights and degrees of hydrophilicity by adjusting the ratio of hydrophilic to hydrophobic glycol. The hydrophilicity of these polymers can be varied over a wide range, from extremely hydrophilic to hydrophobic polymers as required. Preferably, the polymer composition contains of from 50 to 95% water. The polymer will normally have an average molecular weight range of about 10,000 to 200,000.

In one embodiment, the hydrophilic polymers are biodegradable. Mention may be made of the polyurethane polymers of US-A-4 ,789,720 and of US-A-5, 120,816 which are degraded over time to produce urea, which is then excreted from the body in urine. The time taken for the polymer to be degraded and thus the operational lifetime of the polymer composition may be varied by adjusting or modifying the chemical nature of the polymer structure. Such modification can be carried out during manufacture of the polymer, or may be a post-production modification to the polymer.

Alternatively, a polymer which is viewed as non- biodegradable within the art may be used and this may be preferred in certain aspects.

In a further embodiment, the hydrophilic polymer composition may be used as a carrier for pharmaceutically active agents. Suitable agents include immuno-suppressant drugs (to reduce the risk of prosthesis rejection or to combat such rejection reaction) ; anti-bacterial agents, such as antibiotics (to reduce the risk of infection or to combat infection introduced during the operation to implant the prosthesis) , growth factor regulators and anti- coagulant, anti-thrombogenic or thrombolytic drugs (to reduce the risk or to combat thrombosis and emboli formation) . Mention may be made of heparin, heparin fragments tissue-type plasminogen activator (tPA) , urokinase (uPA) , anti-thrombosis agents (such as Hirudan) and albumin, as examples of suitable anti- coagulant agents to combat thrombosis. Also suitable are anti-coagulant agents which are antibodies (for example antibodies directed against platelet receptor GPIb and/or GPIb, against platelet receptor GPIIb/IIIa, and/or against von Willebrand Factor (vWF) ) and also such agents with vasoactive properties (such as Prostacyclin and Nitric Oxide) . With regard to pharmaceutically active agents which act as growth factor regulators particular mention may be made of antibodies, such as antibodies directed against Platelet-derived Growth Factor (PDGF) , Fibroblastic Growth Factor (FGF) , Transforming Growth Factor beta (TGF) , Insulin-like Growth Factor (IGF) , Interleukins (IL1-8) , Endothelin, Thrombin, and/or Endothelial adhesion molecules eg ICAM-1. Also suitable are angiotensin converting enzyme (ACE) inhibitors (for example Captopril) , and endothelial cell growth factor (ECGF) . In certain aspects use of anti-sense oligonucleotides or antibodies to particular mRNAs may be advantageous, for example anti-sense oligonucleotides to a -myc, PCNA and the like or antibodies to the RNA molecules encoding for growth factors.

Suitable antibiotics which may advantageously be present in the polymer of the invention include Penicillins, Cephaolsporins, Aminoglycosides, Tetracyclines, Macrolides, Glycopeptides eg Vancomycin, Teicoplanin, Sulphonamides and/or Anti-fungals eg Fluconazole. More than one pharmaceutically active agent may be present.

The pharmaceutically active agent may be chemically bound (for example via a covalent or ionic bond) to the hydrophilic polymer. Alternatively, the pharmaceutically active agent may be physically entrapped within the polymer and released as the polymer degrades in the body.

In certain instances it may be desirable to have more than one coating on said prostheses. Thus, for example the hydrophilic polymer (optionally comprising a pharmaceutically active agent) may itself be coated, for example with a delay release coating or more preferably may itself be coated with a further coating of hydrophilic polymer.

In an analogous manner, there may be three or more different layers of hydrophilic polymer coatings. Each layer may be of the same or different chemical composition (ie chemical structure of the hydrophilic polymer and/or water content thereof) and may contain the same or different amounts of identical or distinct pharmaceutically active agent(s) . By careful selection of the layers used to coat a prosthesis, the lifetime of the polymer coatings and/or release of any pharmaceutically active agent comprised therein may be controlled.

For example a triple-layer coating may be desirable. The first coating immediate to the prosthesis may optionally comprise an agent which is released only slowly, the first coating layer being degradable very slowly over time. Instead of a first coating layer, the prosthesis may be impregnated with such a hydrophilic polymer composition. An intermediate coating may then be coated over said first layer, the intermediate layer having a lifetime of approximately 6 weeks and an appropriate amount of pharmaceutically active agent. The top layer covering said intermediate layer may be designed to release an amount of anti- thrombogenic agent over the danger period (extending for approximately 10 days) for producing blood clots and emboli; this being the lifetime of the top layer once in the body.

Viewed from a further aspect, the present invention provides a method of treating prostheses to reduce the risk (and incidence) of thrombogenesis after implantation in a patient, said method comprising treating at least a part of said prostheses with a hydrophilic polymer composition. Generally, said prostheses may be impregnated and/or coated with said polymer by any suitable conventional means. Mention may be made of producing a polymer film which is then adhered to the prostheses or, more usually, forming said polymer on said prostheses in situ.

Viewed from a yet further aspect the present invention provides a method of treating cardiac and vascular dysfunction in a patient, said method comprising implanting coronary prostheses coated and/or impregnated with a hydrophilic polymer composition as hereinbefore described.

In a yet further aspect the present invention provides the use of prostheses coated and/or impregnated with a hydrophilic polymer composition (especially a mechanical heart valve, coronary artery bypass grafts and arterial grafts) for implantation in a patient to relieve cardiac and vascular dysfunction.

In a still yet further aspect the present invention provides the use of a hydrophilic polymer composition as hereinbefore described to coat and/or impregnate cardiac, coronary or vascular prostheses.

Viewed from another aspect the present invention provides the use of a hydrophilic polymer composition as hereinbefore described in the manufacture of cardiac, coronary or vascular prostheses for implantation in a patient to relieve coronary or vascular dysfunction.

Figure 1 is a schematic view in partial cross-section of a conventional heart valve prosthesis.

Figure 2 is a detailed cross-section of the junction between the sewing ring and heart valve housing of the heart valve prosthesis shown in Figure 1 following implantation into a patient.

Figures 3 and 4 are schematic partial cross-sections of the conventional heart valve prosthesis of Figure 1 at different stages after implantation in the patient.

Figure 5 is a cross-section giving details of the attachment of a conventional heart valve to patient tissue.

Figures 6 and 7 are cross-sections of the heart valve illustrated in Figure 5 following different periods of implantation in the patient.

Figure 8 is a cross-section of a portion of the sewing ring of the heart valve following treatment with a hydrophilic polymer composition.

In more detail. Figures 1 to 7 illustrate conventional heart valves as currently used in heart valve replacement surgery. The heart valves illustrated are mechanical prostheses, likely to initiate blood clot formation as shown in Figures 2, 3 , 4 , 6 and 7. Conventional mechanical heart valve 10 comprise sewing ring 1 which completely surrounds the outer ring of the valve housing 2. There is a junction 3 between the sewing ring 1 and valve housing 2.

As is illustrated in Figure 5 sewing ring 1 is used to attach the mechanical heart valve 10 into the patient by means of sutures, staples or the like. As illustrated, a suture 6 has been used to extend through sewing ring 1 and a flap of patient tissue 5. The suture 6 is securely fastened with knot 7. Alternative means of attachment of the heart valve 10 into the patient may also be used.

Following implantation of mechanical heart valve 10 into a patient, the heart valve 10 is exposed to the patient's immune system and its near presence within the patient may initiate blood clotting as a form of immune reaction. Blood clotting may be initiated in two locations, in particular the junction 3 between sewing ring 1 and valve housing 2 and also surrounding the suture knot 7. Figure 2 illustrates an initial blood clot 4 which has become established at junction 3 between sewing ring 1 and housing 2. The growth of this blood clot is illustrated in Figures 3 and 4. From Figure 4 the blood clot is shown extending vertically down housing 2 and any further increase in size in clot 4 could seriously impair the function of the replacement valve 10.

Figure 6 illustrates blood clot 4 initially formed at junction 3 between sewing ring 1 and valve housing 2. Additionally a further clot 8 is shown surrounding knot 7 of suture 6. Figure 7 illustrates the growth of blood clots 4, 8 following a further period of time, and as illustrated the clots 4, 8 have merged into a single merged blood clot 9 which extends over housing 2, junction 3 and a large portion of sewing ring 1, including knot 7. The risk that a portion of clot 9 will become detached, thus creating thrombosis or emboli problems within the patient, is high.

Figure 8 illustrates a portion of sewing ring 1 of a conventional heart valve 10 in cross-section and treated with a layer 14 of a hydrophilic polymer composition. As illustrated only a portion of sewing --...-.r 1 r.z.3 z = =.:. .raated w:::. :;.= ?._j'z.rzpc.!m. .z pc.ymer composition, and coating 14 extends across the surface of sewing ring 1 which is particularly vulnerable to initiating blood clot formation. In coating 14 the hydrophilic polymer composition is in fact a composite of three separate layers, each containing a different hydrophilic polymer. Layer 11 which is immediately exposed to the patient's immune system is selected to biodegrade over a three day period and comprises an anti-thrombogenic agent and/or an antibiotic which is controllably released over that timescale to combat blood clot and emboli formation. Intermediate layer 12 is designed to biodegrade within a two week period and contains a lesser amount of a pharmaceutically active agent, for example an anti-thrombogenic agent. Layer 13 is designed to biodegrade over a six month time scale. The triple-layer coating illustrated in Figure 8 is a preferred embodiment of the invention since this arrangement permits a high degree of control immediately following implantation, whilst avoiding unnecessary release of the anti-thrombogenic agent over a much longer timescale, for example over six months. Once coating 14 has completely biodegraded, the patient's immune system will have adapted to the presence of the heart valve 10 and the liklihood of thrombogenesis or emboli formation at that stage is much reduced. Instead of a coating 14, it is also possible for the heart valve 10 to be partially impregnated with a hydrophilic polymer composite.

It is also possible for a single or dual layer hydrophilic polymer composition to be used, rather than the triple-layer coating illustrated in Figure 8.

Likewise other mechanical prostheses for cardiac, coronary or vascular surgery may be impregnated or coated with suitable hydrophilic polymer composition(s) .

Claims

1. A cardiac, coronary or vascular prosthesis having a coating of hydrophilic polymer or at a part thereof and/or being at least partially impregnated with a hydrophilic polymer composition.

2. A prosthesis as claimed in Claim 1 wherein at least a part of the surface to be contacted by body fluids is coated or impregnated with siad hydrophilic polymer composition.

3. A prosthesis as claimed in Claim 2 wherein substantially all of the surface to be contacted by body fluids is coated or impregnated with said hydrophilic polymer composition.

4. A prosthesis as claimed in any one of Claims 1 to 3 which is a heart valve.

5. A prosthesis as claimed in Claim 4 wherein the sewing ring and/or the junction between the sewing ring and heart valve housing is coated or impregnated with said hydrophilic polymer composition.

6. A prosthesis as claimed in any one of Claims 1 to 3 which is suitable for coronary bypass operations or vascular surgery.

7. A prosthesis as claimed in Claim 6 capable of use as a coronary artery bypass graft or an arterial graft.

8. A prosthesis as claimed in any one of Claims 1 to 7 wherein said hydrophilic polymer composition contains of from 1% to 99% by weight of water.

9. A prosthesis as claimed in Claim 8 wherein said hydrophilic composition contains of from 40 to 95% by weight of water.

10. A prosthesis as claimed in any one of Claims 1 to 9 wherein said hydrophilic polymer composition comprises a polyurethane.

11. A prosthesis as claimed in any one of Claims 1 to 10 wherein said hydrophilic polymer composition is biodegradable.

12. A prosthesis as claimed in any one of Claims 1 to 11 wherein said hydrophilic polyer composition also contains a pharmaceutically active agent.

13. A prosthesis as claimed in Claim 12 wherein said agent has an anti-coagulant, anti-thrombogenic or a thrombolytic activity.

14. A prosthesis as claimed in any one of Claims 1 to 13 impregnated or coated with two or more hydrophilic polymer compositions which may be the same or different.

15. A prosthesis as claimed in Claim 14 having a triple-layer coating.

16. A method of treating a cardiac, coronary or vascular prosthesis to reduce thrombogenesis following implantation in a paitent, said method comprising treating said prosthesis with a hydrophilic polymer composition.

17. A method as claimed in Claim 16 wherein said hydrophilic polymer composition is as defined in any one of Claims 8 to 13.

18. The use of a hydrophilic polymer composition as claimed in any one of Claims 8 to 13 to coat or impregnate at least a portion of a cardiac, coronary or vascular prosthesis.

19. The use of a hydrophilic polymer composition as claimed in any one of Claims 8 to 13 manufacture a cardiac, coronary or vascular prosthesis for implantation in a patient to relieve coronary or vascular dysfunction.

20. Use as claimed in either one of Claims 18 and 19 wherein said prosthesis is a heart valve.