WO1979000638A1

WO1979000638A1 - A method of producing thrombosis-resistant surfaces

Info

Publication number: WO1979000638A1
Application number: PCT/SE1979/000035
Authority: WO
Inventors: A Bergstroem; B Soedervall
Original assignee: Thin Conductive Coating Oester; A Bergstroem; B Soedervall
Priority date: 1978-02-17
Filing date: 1979-02-16
Publication date: 1979-09-06
Also published as: DK427079A; EP0015909A1; JPS55500091A

Abstract

A method of treating surfaces of medical devices which are to be brought into contact with blood or blood plasma for the purpose of rendering the surfaces resistant to thrombosis. The surfaces are treated with a wetting solution of a salt of a metal capable of causing peptide hydrogen ionisation and of forming complex compounds with heparin, hirudin and other anticoagulant proteins than hirudin, as a rhodium salt or a palladium salt, prior to applying thereto a coating of heparin, hirudin or other anticoagulant proteins than hirudin.

Description

_A METH_OD OF PR_ODUCING THROMBOSIS-RESISTANT SURFACES

The present invention relates to a novel method of effect¬ ively treating surfaces with heparin, hirudin and other anticoagulant proteins for the purpose of rendering said surfaces resistant to thrombosis. The method comprises the treatment of said surface with a palladium salt or a rhodium salt prior to heparising said surface.

In present day medicine and medical-care institutions a large number of treatments are carried out in which blood and blood plasma comes into contact with foreign surfaces, causing problems which are difficult to overcome clinically, for example when using vascular prostheses, catheters and the like. This problem originates from the fact that blood will coagulate when coming into contact with foreign bodies. Although it is not clearly understood why contact with a foreign body will cause blood to coagulate, it is known ^• that blood platelets will release substances which accele¬ rate the formation of thromboplastin upon adhesion and aggregation, which in turn initiates the formation of a thrombus. In this way there is formed a network which can result in the formation of a thrombus. It is thus logical to try to prevent blood platelets from adhering to such surfaces. To this end there has been devized a method which compares heparinizing the surface of polymeric materials.

Heparin, which is a mucopolysaccharide from D-glucoseamine and glucuronic acid with a molecular weight of about 17000, has the ability of preventing the aforementioned formation of a thrombus. It is essential that a heparinized surface is stable and that the heparin is firmly bound to the surface of the object. In an article by Olsson et al en¬ titled "Prevention of Platelet Adhesion and Aggregation by a Glutardialdehyde-Stabilized Heparin Surface", Thrombos, Hae ostas (Stuttgart) (1977) 37, pages 274-283 and Larsson et al " " (1976) there is described a rnulti-

-stage method of heparinizing a surface, which method, in addition to washing stages, comprises treating the surface with hexadecyl amine hydrochloride heparin, an aminesoluti _tglutaraldehyde and cooking salt. The product is considerab better than one whose surfaces have not been treated. The layers produced when applying this method tend to be uneve and are also liable to be washed-off by the blood flowing thereagainst, consequently, there is a need of improving the method. Heparin shares this property with hirudin and other anticoagulant proteins. Hirudin is a protein having a molecular weight of 16000 - 1000.

When applying the method of the invention there is obtaine an extraordinarily uniform and dense coating which adheres with such good effect that it is not removed by the blood flowing thereacross.

When reference is made herein to heparin, it will be under stood that reference is also made to hirudin and like anticoagulant proteines.

When putting the method into effect a well cleansed surfac to be heparinised is treated with a wetting solution of a metal salt of a metal capable of causing peptide hydrogen ionisation, whereafter the surface, subsequent to being rinsed, is treated with a solution containing heparin, preferably 1,000-1,000 IE per litre, over a period of time of such length that a coherent heparin layer- is formed on said surface. It will be understood that lower or higher concentrations can be used.

The surface to be treated may be of practically any materi whatsoever, although preferably the surface is of metal, such as a stainless steel, a plastics material, such as polyvinyl chloride, polyolefins, acryl resins and co-poly¬ mers thereof, silicon plastics, rubber, particularly butyl rubber, and fluorocarbon plastics. When cleaning surfaces of fluoro carbon plastics, they should be treated with an etching substance to ensure a uniform layer on the plastics surface.

The treatment metal may be one of a number of different metals. Those metals tested in particular included palladium, rhodium, nickel, cobalt and copper. Among these metals palladium and rhodium take a particular position, owing to the fact that peptide hydrogen ionisation takes place at an optimal pH range of 3-4. The pH range in the case of nickel is 4-6, in the case of cobalt 6-8 and in the case of copper 8-10. With regard to these properties see E.W. Wilson and R.B. Martin, Inorg. Chem 9, page 528 (1970).

As before mentioned, the well-cleaned, and optionally etched surface is treated with a solution of a metal salt of the metal soluble in the solvent used, with a preferably pharmaceutically acceptable acid. As a suitable solvent there can be mentioned primarily water, and water in mix¬ tures with a polar solvent m-iscible therewith. Polar organic solvents can also be used. Among those polar solvents which can be used are alkanols, such as methanol and ethanol.

Examples of suitable salts are primarily chlorides, sul¬ phates, nitrates, acetates, citrates, although it lies within the expertise of one skilled in this art to select other suitable soluble salts of the metal used.

The use of palladium chloride in aqueous solution or palla¬ dium citrate in an ethonal-containing aqueous solution is particularly preferred. Rhodium can be used in the same manner.

The treatment with the metal salt takes only some seccnds up to some minutes, depending upon the temperature of the solution and its pH, and takes place at an ion strength o 0.3-3 mmol metal salt per litre, which in the case of the mentioned palladium salts corresponds to 0.1-0.5 grams of salt per litre. The temperature may be room temperature, although a temperature of 50-80^cC is preferred.

Subsequent to rinsing the surface, preferably with distill water, the surface is treated with a heparin solution containing 1000-10000 IE heparin per litre. The solution contains mainly water and other suitable substances such as sodium chloride and glucose. The treatment time also varies here, although normally requires a treatment time 15-45 minutes. Glucose can be added to stabilise the solu tion.

The treatment method proposed in accordance with the in¬ vention results in the formation of a heparin layer which, has been judged, on the tests carried out, to be some ten times better than a heparin layer produced in accordance with the present standpoint of technics. It is assumed th palladium binds to the amine group in the glucose amine part of the heparin molecule, possibly in combination with van den Waals bonds to oxygen atoms in the heparin chain and in the sulphone group which is bound to the amine gro in the glucose amine part of the molecule.

It lies within the scope of the expertise of one skilled in this art to vary the method when treating different surfaces, in dependence upon the nature of the surface to be treated and of the salt and the solvent used, by select ing suitable temperatures and times when treating with the metal salt and with the heparin solution. Thus, it is much easier to treat glass surfaces and also metal surfaces th it is to treat plastics surfaces, particularly surfaces comprising fluorocarbon plastics.

. _0MP ^■

Claims

CLAIMS :-

1. A method of treating surfaces which are to be brought into contact with blood which is passed to or returned to the blood circulatory system of a human being or an animal, comprising treating a well-cleansed surface with a wetting solution of a metal salt of a metal capable of causing peptide hydrogen ionisation and of forming complex compounds with heparin, hirudin and other anticoagulant proteins, and treating the surface with a solution containing heparin, hirudin or said, other anticoagulant protein in a manner such as to form a coherent layer of anticoagulant compound on said surface.

2. A method according to claim 1, characterised in that said metal having the ability of causing peptide hydrogen ionisation is palladium in the form of a soluble salt of a pharmaceutically acceptable acid.

3. A method according to claim 2, characterised in that the palladium salt is a palladium citrate in aqueous solution.

4. A method according to claim 1, characterised in that the heparin is used in aqueous solution containing 3-8% glucose.

5. A method according to claim 1, wherein said metal having the ability of causing peptide hydrogen ionisation is rhodium in the form of a soluble salt of a pharmaceutic¬ ally acceptable acid.