AU712268B2

AU712268B2 - Medical device treated with a hydrophilic polymer composition

Info

Publication number: AU712268B2
Application number: AU51544/96A
Authority: AU
Inventors: Edward Mcdaid; James Gordon Wright
Original assignee: Aortech Europe Ltd
Current assignee: Aortech Europe Ltd
Priority date: 1995-03-28
Filing date: 1996-03-27
Publication date: 1999-11-04
Anticipated expiration: 2016-03-27
Also published as: BR9607909A; GB9506769D0; WO1996030060A1; EP0817652A1; CA2216639A1; JPH11502734A; AU5154496A

Description

WO 96/30060 PCT/GB96/00725 1 1 "Medical Device Treated with a Hydrophilic Polymer 2 Composition" 3 4 The present invention relates to medical implants and equipment having a hydrophilic polymer composition 6 coating. In particular, the present invention is 7 concerned with cardiac implants and vascular 8 prostheses.

9 In mammals the heart is a vital organ responsible for 11 maintaining an adequate flow of blood (and hence oxygen 12 and nutrients) to all parts of the body. Essentially 13 the heart acts as a mechanical pump, forcing the blood 14 delivered to it via veins out along arteries at higher pressure. The blood is prevented from flowing 16 backwards through the heart by the presence of valves 17 located therein.

18 19 Dysfunction of one or more of the valves in the heart can have serious medical consequences. Dysfunction of 21 heart valves may be the result of a congenital defect, 22 or of disease-induced damage or degeneration.

23 Dysfunction frequently results from stenosis or 24 narrowing of the valve aperture, preventing sufficient blood through-flow. Further, dysfunction also WO 96/30060 PCT/GB96/00725 2 1 frequently results from valve insufficiency. In 2 addition to cardiac valve replacement operations, 3 operations for coronary bypass are also frequently 4 required.

6 To date, the only solution to treat severe heart valve 7 dysfunction is to replace the malfunctioning valve.

8 Such a valve replacement operation, in addition to 9 being extremely costly, requires complex open-heart surgery. There is a also a finite number of times that 11 a heart valve can be replaced successfully for any 12 particular patient, making the design and operational 13 lifetime of any replacement valve extremely important.

14 Mechanical valves have been developed and used for 16 heart valve replacement operations. Whilst such valves 17 exhibit excellent operational lifetimes, they suffer 18 from a higher incidence of thrombosis (blood clotting) 19 due to the trigger of clotting in the blood as the material of the valve is recognised by the immune 21 system as being "foreign" to the body. Suitable heart 22 valves are manufactured, for example, by Aortech Europe 23 Limited, Strathclyde, UK under the name ULTRACOR (Trade 24 Mark). Heat valves manufactured by St Jude Medical, CarboMedics, Medtronic or ATS Medical, USA are all 26 suitable as are valves manufactured by Sorin, Italy 27 28 Currently mechanical valve implants are estimated at 29 110,000 implants worldwide with an average price of between US$2,000 and $3,000 retail to the hospital.

31 The one major clinical problem facing mechanical valves 32 is anti-coagulation. It is currently believed that the 33 majority of emboli and clots initially grow from the 34 junction of the sewing ring with the metal or pyrolite housing. Also suture material and large knots put in -3place 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 20 recipient.

It has 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 at least one coating of a biodegradable, non-abrasion resistant, hydrophilic polymer composition on at least a part thereof and/or being at least partially impregnated with said composition, said composition containing terminal hydroxyl groups prepared by reacting an aliphatic diisocyanate with 3 polyoxyalkylene glycols, and said composition also containing, but not disposed -4within the interstices thereof, a pharmaceutically active agent, wherein the active agent is released as the said coating is degraded.

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 wherein the hydrophilic polymer composition contains terminal hydroxyl groups and is prepared by reacting an aliphatic diisocyanate with polyoxalkylene glycols.

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 15 coated or impregnated with a hydrophilic polymer composition wherein the *°°.hydrophilic polymer composition contains terminal hydroxyl groups and is prepared by reacting an aliphatic diisocyanate with polyoxalkylene glycols.

rl In coronary bypass operations surgeons currently harvest the saphenous vein 20 from the patient's leg, which often causes the patient post-operatively more pain t: ;problems than the thoracotomy. It is estimated that after ten years a significant ID number of all coronary artery bypass grafts are either grossly inefficient at S* 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-thrombogenic 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

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1 ring with the metallic part of the valve housing. Suitable 2 sewing ring material which may be coated according to the 3 present invention includes Teflon.

4 Optionally, the hydrophilic polymer composition may coat or be used to impregnate substantially all of the surfaces of 6 the coronary prostheses or vascular grafts.

7 8 The hydrophilic polymer composition may contain from 1% to 9 99% water (by weight), for example said composition may contain 20% to 99% water, especially 40 to 95% water. The 11 composition will normally be liquid at ambient temperature 12 and may be sprayed or painted onto the device of the 13 present invention. Alternatively the device may be dipped 14 into the composition and allowed to dry thereon.

16 Desirably, the hydrophilic polymer has low surface adhesion 17 properties, thus reducing the incidence or risk of 18 thrombogenesis.

19 Suitable hydrophilic polymers are described in US-A- 21 4,256,066; US-A-4,156,067; US-A-4,255,550;; US-A-4,359,588; 22 US-A-4,408,023; US-A-4,424,305; US-A-4,490,432;

US-A-

23 4,496,535; US-A-4,729,914; US-A-4,743,673; US-A-4,780,512; 24 US-A-4,789,720; US-A-4,798,876; US-A-4,810,582;

US-A-

25 5,000,955 and US-A-4,789,720 all of Tyndale Plains Hunter 26 Ltd, Princeton, New Jersey.

27 28 In particular, the hydrophilic polymers may be 29 polyurethanes, as described in US-A-5,120,816 and in US-A- 30 4,789,720. The polymers exemplified in US-A-4,789,720 and 31 in US-A-5,120,816 are especially suitable.

32 33 The advantageous biomedical properties of the hydrophilic 34 polymers suitable for use in the present invention (for 35 example as disclosed in US-A-4,789,720 and in US-A- 36 5,120,816) derive from the structure of the polymers which 7 are prepared by reacting an aliphatic diisocyanate with different polyoxyalkylene glycols, usually with a majority -6- 1 of polyoxethylene glycols. The polymers contain terminal 2 hydroxyl groups and can be made to different molecular 3 weights and degrees of hydrophilicity by adjusting the 4 ratio of hydrophilic to hydrophobic glycol. The hydrophilicity of these polymers can be varied over a wide 6 range, from extremely hydrophilic to hydrophobic polymers 7 as required. Preferably, the polymer composition contains 8 of from 50 to 95% water. The polymer will normally have an 9 average molecular weight range of about 10,000 to 200,000.

11 In one embodiment, the hydrophilic polymers are 12 biodegradable. Mention may be made of the polyurethane 13 polymers of US-A-4,789,720 and of US-A-5,120,816 which are 14 degraded over time to produce urea, which is then excreted from the body in urine. The time taken for the polymer to 16 be degraded and thus the operational lifetime of the 17 polymer composition may be varied by adjusting or modifying 18 the chemical nature of the polymer structure. Such 19 modification can be carried out during manufacture of the polymer, or may be a post-production modification to the 21 polymer.

22 23 Alternatively, a polymer which is viewed as non- 24 biodegradable within the art may be used and this may be 25 preferred in certain aspects.

26 27 In a further embodiment, the hydrophilic polymer 28 composition may be used as a carrier for pharmaceutically 29 active agents. Suitable agents include immuno-suppressant 930 drugs (to reduce the risk of prosthesis rejection or to 31 combat such rejection reactions); anti-bacterial agents, 32 such as antibiotics (to reduce the risk of infection or to 33 combat infection introduced during the operation to implant 34 the prosthesis), growth factor regulators and anti- 35 coagulant, anti-thrombogenic or thrombolytic drugs (to 36 reduce the risk or to combat thrombosis and emboli b formation). Mention may be made of heparin, heparin fragments tissue-type plasminogen activator (tPA), -7- 1 urokinase (uPA), anti-thrombosis agents (such as Hirudan) 2 and albumin, as examples of suitable anti-coagulant agents 3 to combat thrombosis. Also suitable are anti-coagulant 4 agents which are antibodies (for example antibodies directed against platelet receptor GPIb and/or GPIb, 6 against platelet receptor GPIIb/IIIa, and/or against von 7 Willebrand Factor (vWF)) and also such agents with 8 vasoactive properties (such as Prostacyclin and Nitric 9 Oxide)- With regard to pharmaceutically active agents which act as growth factor regulators particular mention may be 11 made of antibodies, such as antibodies directed against 12 Platelet-derived Growth Factor (PDGF), Fibroblastic Growth 13 Factor (FGF), Transforming Growth Factor beta (TGF), 14 Insulin-like Growth Factor (IGF), Interleukins (IL1-8), Endothelin, Thrombin, and/or Endothelial adhesion molecules 16 eg ICAM-1. Also suitable are angiotension converting 17 enzyme (ACE) inhibitors (for example Captopril), and 18 endothelial cell growth factor (ECGF). In certain aspects 19 use of anti-sense oligonucleotides or antibodies to particular mRNAs may be advantageous, for example anti- 21 sense oligonucleotides to a -myc, PCNA and the like or 22 antibodies to the mRNA molecules encoding for growth 23 factors.

24 Suitable antibiotics which may advantageously be present in 26 the polymer of the invention include Penicillins, 27 Cephaolsporins, Aminoglycosides, Tetracyclines, Macrolides, 28 Glycopeptides eg Vancomycin, Teicoplanin, Sulphonamides 29 and/or Anti-fungals eg Fluconazole. More than one 30 pharmaceutically active agent may be present.

31 32 The pharmaceutically active agent may be chemically bound 33 (for example via a covalent or ionic bond) to the 34 hydrophilic polymer. Alternatively, the pharmaceutically 35 active agent may be physically entrapped within the polymer 36 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 20 intermediate layer may be designed to release an amount of anti-thrombogenic agent over the danger period (extending for approximately 10 days) for producing ag 0blood 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 •a cardiac, coronary or vascular prosthesis to reduce thrombogenesis following implantation in a patient, said method comprising treating said prosthesis with a biodegradable hydrophilic polymer composition containing terminal hydroxyl groups and prepared by reacting an aliphatic to diisocyanate with polyoxyalkylene glycols, and also containing a pharmaceutically active agent pus which is released as the polymer coating is degraded. Generally, said -9prostheses 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 wherein the hydrophilic polymer composition contains terminal hydroxyl groups and is prepared by reacting an aliphatic diisocyanate with polyoxalkylene glycols as hereinbefore described.

In a yet further aspect the present invention provides the use of prostheses (especially a mechanical heart valve, coronary artery bypass grafts and arterial grafts) coated and/or impregnated with a hydrophilic polymer composition wherein the hydrophilic polymer composition contains terminal hydroxyl groups and is prepared by reacting an aliphatic diisocyanate with polyoxalkylene glycols 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.

20 Viewed from another aspect the present invention provides the use of a hydrophilic polymer composition as hereinbefore described in the manufacture of cardiac, oo aoS o ,s o:

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1 coronary or vascular prostheses for implantation in a 2 patient to relieve coronary or vascular dysfunction.

3 4 Figure 1 is a schematic view in partial cross-section of a conventional heart valve prosthesis.

6 7 Figure 2 is a detailed cross-section of the junction 8 between the sewing ring and heart valve housing of the 9 heart valve prosthesis shown in Figure 1 following implantation into a patient.

11 12 Figures 3 and 4 are schematic partial cross-sections of the 13 conventional heart valve prosthesis of Figure 1 at 14 different stages after implantation in the patient.

16 Figure 5 is a cross-section giving details of the 17 attachment of a conventional heart valve to patient tissue.

18 19 Figures 6 and 7 are cross-sections of the heart valve illustrated in Figure 5 following different periods of 21 implantation in the patient.

a a.

a WO 96/30060 PCT/GB96/00725 11 1 ring of the heart valve following treatment with a 2 hydrophilic polymer composition.

3 4 In more detail, Figures 1 to 7 illustrate conventional heart valves as currently used in heart valve 6 replacement surgery. The heart valves illustrated are 7 mechanical prostheses, likely to initiate blood clot 8 formation as shown in Figures 2, 3, 4, 6 and 7.

9 Conventional mechanical heart valve 10 comprise sewing ring 1 which completely surrounds the outer ring of the 11 valve housing 2. There is a junction 3 between the 12 sewing ring 1 and valve housing 2.

13 14 As is illustrated in Figure 5 sewing ring 1 is used to attach the mechanical heart valve 10 into the patient 16 by means of sutures, staples or the like. As 17 illustrated, a suture 6 has been used to extend through 18 sewing ring 1 and a flap of patient tissue 5. The 19 suture 6 is securely fastened with knot 7. Alternative means of attachment of the heart valve 10 into the 21 patient may also be used.

22 23 Following implantation of mechanical heart valve 24 into a patient, the heart valve 10 is exposed to the patient's immune system and its near presence within 26 the patient may initiate blood clotting as a form of 27 immune reaction. Blood clotting may be initiated in 28 two locations, in particular the junction 3 between 29 sewing ring 1 and valve housing 2 and also surrounding the suture knot 7. Figure 2 illustrates an initial 31 blood clot 4 which has become established at junction 3 32 between sewing ring 1 and housing 2. The growth of 33 this blood clot is illustrated in Figures 3 and 4.

34 From Figure 4 the blood clot is shown extending vertically down housing 2 and any further increase in 36 size in clot 4 could seriously impair the function of WO 96/30060 PCT/GB96/00725 12 1 the replacement valve 2 3 Figure 6 illustrates blood clot 4 initially formed at 4 junction 3 between sewing ring 1 and valve housing 2.

Additionally a further clot 8 is shown surrounding knot 6 7 of suture 6. Figure 7 illustrates the growth of 7 blood clots 4, 8 following a further period of time, 8 and as illustrated the clots 4, 8 have merged into a 9 single merged blood clot 9 which extends over housing 2, junction 3 and a large portion of sewing ring 1, 11 including knot 7. The risk that a portion of clot 9 12 will become detached, thus creating thrombosis or 13 emboli problems within the patient, is high.

14 Figure 8 illustrates a portion of sewing ring 1 of a 16 conventional heart valve 10 in cross-section and 17 treated with a layer 14 of a hydrophilic polymer 18 composition. As illustrated cnlv a portion of sewing n S,..S...:aated .r:pi c ,ymer composition, and coating 14 extends across the surface 21 of sewing ring 1 which is particularly vulnerable to 22 initiating blood clot formation. In coating 14 the 23 hydrophilic polymer composition is in fact a composite 24 of three separate layers, each containing a different hydrophilic polymer. Layer 11 which is immediately 26 exposed to the patient's immune system is selected to 27 biodegrade over a three day period and comprises an 28 anti-thrombogenic agent and/or an antibiotic which is 29 controllably released over that timescale to combat blood clot and emboli formation. Intermediate layer 12 31 is designed to biodegrade within a two week period and 32 contains a lesser amount of a pharmaceutically active 33 agent, for example an anti-thrombogenic agent. Layer 34 13 is designed to biodegrade over a six month time scale. The triple-layer coating illustrated in Figure 36 8 is a preferred embodiment of the invention since this WO 96/30060 PCT/GB96/00725 13 1 arrangement permits a high degree of control 2 immediately following implantation, whilst avoiding 3 unnecessary release of the anti-thrombogenic agent over 4 a much longer timescale, for example over six months.

Once coating 14 has completely biodegraded, the 6 patient's immune system will have adapted to the 7 presence of the heart valve 10 and the liklihood of 8 thrombogenesis or emboli formation at that stage is 9 much reduced. Instead of a coating 14, it is also possible for the heart valve 10 to be partially 11 impregnated with a hydrophilic polymer composite.

12 13 It is also possible for a single or dual layer 14 hydrophilic polymer composition to be used, rather than the triple-layer coating illustrated in Figure 8.

16 17 Likewise other mechanical prostheses for cardiac, 18 coronary or vascular surgery may be impregnated or 19 coated with suitable hydrophilic polymer composition(s).

Claims

1. A cardiac, coronary or vascular prosthesis having at least one coating of a biodegradable, non-abrasion resistant, hydrophilic polymer composition on at least a part thereof and/or being at least partially impregnated with said composition, said composition containing terminal hydroxyl groups prepared by reacting an aliphatic diisocyanate with polyoxyalkylene glycols, and said composition also containing, but not disposed within the interstices thereof, a pharmaceutically active agent, wherein the active agent is released as the said coating is degraded.

2. A prosthesis as claimed in claim 1 wherein the polyoxyalkylene glycols comprise at least 50% polyoxyethylene glycols. *o

3. A prosthesis as claimed in claim 1 or claim 2 wherein at least a part of the surface to be contacted by body fluids is coated or impregnated with said biodegradable hydrophilic polymer composition. a15 4. A prosthesis as claimed in claim 3 wherein substantially all of the surface to *be contacted by body fluids is coated or impregnated with said biodegradable hydrophilic polymer composition.

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

6. A prosthesis as claimed in claim 5 wherein the 1 sewing ring and/or the junction between the sewing 2 ring and heart valve housing is coated or 3 impregnated with said polymer composition. 4

7. A prosthesis as claimed in any one of claims 1 to 6 4 which is suitable for coronary bypass operations 7 or vascular surgery. 8 9 8. A prosthesis as claimed in claim 7 capable of use as a coronary artery bypass graft or an arterial 11 graft. 12 13 9. A prosthesis as claimed in any one of claims 1 to 14 8 wherein said biodegradable hydrophilic polymer composition contains of from 1% to 99% by weight 16 of water. 17 18 10. A prosthesis as claimed in claim 9 wherein said 19 biodegradable hydrophilic composition contains of from 40 to 95% by weight of water. 21 22 11. A prosthesis as claimed in any one of claims 1 to 23 10 wherein said biodegradable hydrophilic polymer 24 composition comprises a polyurethane. i 26 12. A prosthesis as claimed in any one of Claims 1 to 27 11 wherein said agent has an anti-coagulant, anti- 28 thrombogenic or a thrombolytic activity. 29 30 13. A prosthesis as claimed in any one of claims 1 to 31 12 impregnated or coated with two or more S- 32 biodegradable hydrophilic polymer compositions 33 which may be the same or different. 34 35 14. A prosthesis as claimed in Claim 13 having a -16- 1 triple-layer coating. 2 3 15 A method of treating a cardiac, coronary or vascular prosthesis to reduce 4 thrombogenesis following implantation in a patient, said method comprising treating said prosthesis with a biodegradable, non-abrasion resistant, 6 hydrophilic polymer composition containing terminal hydroxyl groups and 7 prepared by reacting an aliphatic to diisocyanate with polyoxyalkylene 8 glycols, and said composition also containing, but not disposed within the 9 interstices thereof, a pharmaceutically active agent which is released as the said coating is degraded. 11 12 16. A method as claimed in claim 15 wherein said biodegradable hydrophilic 13 polymer composition is as defined in any one of claims 9 to 12. 14

17. The use of a biodegradable hydrophilic polymer composition as claimed in 16 any one of claims 9 to 12 to coat or impregnate at least a portion of a 17 cardiac, coronary or vascular prosthesis. 18 19 18. The use of a biodegradable hydrophilic polymer composition as claimed in t: 20 any one of claims 9 to 12 to manufacture a cardiac, coronary or vascular 21 prosthesis for implantation in a patient to relieve coronary or vascular 22 dysfunction. oO*o 23 24 19. Use as claimed in either one of claims 17 and 18 wherein said prosthesis is a heart valve. 26 27 20. A prosthesis substantially as herein described with reference to Figure 8. P