GB2534119A

GB2534119A - Novel process and products

Info

Publication number: GB2534119A
Application number: GB1421174.2A
Authority: GB
Inventors: Evans Delwyn
Original assignee: P2i Ltd
Current assignee: P2i Ltd
Priority date: 2014-11-28
Filing date: 2014-11-28
Publication date: 2016-07-20
Also published as: GB201421174D0

Abstract

A method of producing an anti-coagulant surface, said method comprising exposing the surface to a plasma comprising a monomer or a sequence of monomers, wherein the monomer or sequence of monomers are capable of forming an anti-coagulant polymer or a precursor thereof, and wherein at least one of said monomers contains an oxygen or nitrogen containing functional group, controlling the plasma conditions so that a layer of anticoagulant polymer or a precursor thereof is deposited on the surface, and then if necessary, converting any precursor of anti-coagulant polymer to anti-coagulant polymer. Also claimed is a method of producing an anti-coagulant surface wherein at least one of said monomers contains an oxygen or nitrogen containing functional group. Substrates obtainable using this method are also claimed, such as blood-bags, syringes, syringe needles, stents, implants or tubing components. Preferably a precursor of an anti-coagulant polymer with multiple hydroxyl groups on proximal carbon atoms is deposited on the surface and is converted to the anti-coagulant polymer in a subsequent plasma process step. The subsequent step may oxidise the hydroxyl groups to carboxylate groups.

Description

Novel Process and Products The present invention relates to processes for producing anticoagulant surfaces on medical devices and equipment which come into contact with blood both in-vitro and in-vivo. For example syringes, test tubes, blood bags and flexible tubes devices which have been treated to provide an anti-coagulant coating thereon.

Handling of blood, for example for diagnostic, analytical or transfusion purposes is not straightforward. Blood is not compatible with many materials as their surfaces can trigger the clotting response. This leads to the blood coagulating. Therefore, care needs to be taken in selecting materials used in containers or transport devices used in blood handling.

However, this can be difficult because the materials also need to have other properties that make them suitable for the purpose for which they are intended, for example, rigidity, flexibility, heat and cold resistance etc. To circumvent this problem, the surface of material having the desired structural or other characteristics can be treated with anti-coagulants to prevent blood clotting. An anticoagulant is a substance that prevents the clotting of blood, and so have many biomedical applications. However, they are also used on the surfaces of equipment that come into contact with blood e.g. test tubes, syringes and a range of other products designed for use in laboratories or medical applications.

The coating of such products generally requires the anticoagulant to be dissolved or suspended in a liquid before application. Application methods typically include dip coating, spraying, and painting. One development is the sub-atomisation of the anticoagulation solution/suspension before spraying onto the substrate (US 4,808,449 and US 6,626,874).

Wet chemistry coating methods of this type involve drying steps to remove carrier solvent and this leads to increases in manufacturing time. They can be particularly troublesome where multiple process stages are required. Furthermore, wet coating 5 methods produce waste. This can be the non-utilised actives in the solutions and the loss of solvent during drying. Also, the wet coating process may be inappropriate for a particular item or device (e.g. an assembled device with electronics inside).

Plasma polymerisation in particular is recognised as being a clean, dry technique that generates little waste compared to conventional wet chemical methods. Using this method, plasmas are generally generated from organic molecules, which are subjected to an electrical field. When this is done in the presence of a substrate, the radicals of the compound in the plasma react on the substrate to form a polymer film.

Conventional polymer synthesis tends to produce structures containing repeat units that bear a strong resemblance to the monomer species, whereas a polymer network generated using a plasma can be extremely complex due to extensive monomer fragmentation. The properties of the resultant coating can depend upon the nature of the substrate as well as the nature of the monomer used and conditions under which it is deposited.

Although plasma processing has been used to deposit layers with different functionality (silanes) to which anticoagulant layers may be added is described in US 6,361,819. Plasma polymerisation to deposit biocompatible coatings, for example of tetrafluoroethylene, is described in US Patent No. 5032265, and plasma techniques have been used to produce polymer layers that can bond with heparin in a wet coating process (US Patent No. 5336518). However, since most of the chemicals which have anticoagulant properties are non-volatile solids (heparin or derivatives thereof, citrate (sodium citrate or a sodium citrate/citric acid mix) or ethylenediamine tetraacetic acid (EDTA),their deposition using this technique is not apparent. The present inventors have found that by subjecting surfaces to a plasma under particular well-controlled conditions, anticoagulant coatings which are robust and reliable may be prepared, efficiently and with minimal waste.

According to one aspect, the invention provides a method for producing an anti-coagulant surface, said method comprising exposing the surface to a plasma comprising a monomer or a sequence of monomers, wherein the monomer or sequence of monomers are capable of forming an anti-coagulant polymer or a precursor thereof, and wherein at least one of said monomers contains an oxygen or nitrogen containing functional group, controlling the plasma conditions so that a layer of anticoagulant polymer or a precursor thereof is deposited on the surface, and then if necessary, converting any precursor of anti-coagulant polymer to anti-coagulant polymer.

By utilising plasma deposition as a means of applying or developing the anti-coagulant coating, close control may be maintained of the resultant polymer structure and therefore the density and availability of groups or moieties which have anticoagulant properties. The deposition mode can be controlled and varied for instance by controlling the power of the plasma, whether or not the plasma is continuous or pulsed, the deposition time, the concentration of the monomer etc. By controlling these factors, the degree of fragmentation and rate and nature of deposition of the monomer can be selected and any degradation of any anti-coagulant groups or precursors of these can be kept to a minimum, and thus the structure of the polymer formed on the surface can be controlled. The structure may even be varied as the polymer is grown.

In this way, a polymeric layer including multiple anti-coagulant functional groups at a suitable density and orientation may be achieved.

Using this method, plasmas are generated from organic molecules, which are subjected to an electrical field. When this is done in the presence of a substrate, the radicals of the compound in the plasma polymerise on the substrate. Conventional polymer synthesis tends to produce structures containing repeat units that bear a strong resemblance to the monomer species, whereas a polymer network generated using a plasma can be extremely complex. The properties of the resultant coating can depend upon the nature of the substrate as well as the nature of the monomer used and conditions under which it is deposited.

As used herein, the expression "sequence of monomers" refers to a process in which different monomers are introduced sequentially into the plasma. The means that what is effectively a copolymer can form on the surface, with the first monomer forming a preliminary layer on the surface which becomes modified or extended by the subsequent monomers. This may be particularly useful in the context of the present invention as a preliminary polymeric coating layer of a relatively robust and highly volatile monomer may be applied, and subsequently, a monomer comprising anticoagulant functional groups or precursors of these may then be added. Since the latter are likely to be more sensitive to the conditions found in a plasma, it may be preferable to ensure that these are applied as efficiently as possible. These multiple stages can he carried out in succession without the need for drying or removing the product from the plasma chamber. Generally however, the chamber will be evacuated between stages and then the subsequent monomer is fed in, so as to rationalise the polymer growth.

Conditions within the plasma at the various stages of the reaction will be controlled appropriately as discussed in more detail below.

As used herein, the term "precursor" means that the compound has the polymeric structural elements found in the final anticoagulant polymer. As a result, the steps required to convert any precursor of anti-coagulant polymer to anti-coagulant polymer are essentially procedures in which suitable functional groups, having anti-coagulant effects or which are haemocompatible, are produced on the surface.

Although these conversion reactions may be carried out in any suitable way, for example by contacting the surface with reagents in a liquid form and under conditions in which reaction occurs, preferably any such conversion reactions are carried out in a gas plasma process. This means that the advantages in terms of economic use of material and the reduction in waste is maintained throughout the process as the preparation of coating solutions is not required. Furthermore, enhanced process efficiency is maintained as there are still no drying requirements. There is no need to remove the substrate from the plasma chamber between steps.

For example, a volatile monomer such as, but not limited to, an acrylate, methacrylate, alkene or alkyne which may carry a reactive group which may withstand the conditions encountered in the plasma, may be deposited on the surface using a plasma polymerisation procedure as outlined further below. Thereafter, the reactive group may be modified by a gas plasma process, so as to generate a functional group as described above. For example, where the reactive group is an alcohol group, this may be oxidised to a carboxylic acid group using an oxidising plasma, for example an oxygen plasma. In this way for instance, a deposited polymer having multiple hydroxy groups on proximal carbon atoms, for example, a moiety of formula (I) n*

OH [I]

may be oxidised to a polymer with pendent carboxylic acid groups of formula (II). n*

OH

Such a polymeric group would be expected to have an 10 anticoagulant effect.

Heparin has the highest charge density of any known biomolecule and this can be attributed in part to the sulphate groups attached to the carbohydrate structure. In order to mimic this property using the method of the invention, monomers containing alcohol groups can again be used to produce polymers with hydroxy side groups which can subsequently be treated with a sulphur dioxide or sulphur dioxide/oxygen plasma to generate the sulphate groups.

Thus for example, polymers produced by plasma deposition and containing hydroxyl groups such as illustrated in formula (III) below, may be are converted to the corresponding polymers of formula (VII) by sulphur dioxide grafting as outlined in scheme 1.

Scheme 1 2 i R2 \,)

K

+ 02 + 2S02

HO OH

HO3SO OSO3H Grafting of sulphate groups onto preformed polymer layers to enhance blood compatibility is described for instance by Lv, Journal of Materials Science: Materials in Medicine, 15, 5, (2004) 6-7-611.

The oxidation of secondary hydroxyl groups can lead to the breaking up of the polymer chain. The conversion of the secondary hydroxyl groups to primary groups can be achieved by utilising an epoxide. Thus for example, a secondary hydroxyl containing polymer may be reacted with epoxide in the following general scheme 2 Scheme 2 1 (R2 2 / HO OH 0

OH OH (IV)

where one of RI or R2 is part of the polymeric structure, and the 20 other is also part of the polymer or another group. Thus Rl or R2 will generally be selected from optionally substituted hydrocarbyl groups, or terminal groups such as hydrogen.

As used herein, the expression "hydrocarbyl" refers to organic 25 groups which contain hydrogen and carbon atoms. Examples of such compounds include those which comprise alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkylcycloalkyl, aryl (such as phenyl or naphthyl), alkylaryl, arylalkyl, alkylcycloalkylalkyl, alkylarylalkyl, alkenylcycloalkyl, alkenylaryl, arylalkenyl, alkenylcycloalkylalkyl, alkylarylalkenyl, alkylcycloalkylalkenyl, alkenylarylalkyl, alkynylcycloalkyl, alkynylaryl, arylalkynyl, alkynylcycloalkylalkyl, alkylarylalkynyl, alkylcycloalkylalkynyl or alkynylarylalkyl groups.

Where such groups comprise alkyl, alkenyl or alkynyl chains, these may be straight or branched. Suitably hydrocarbyl groups contain from 1 to 30, suitably from 1 to 10 and preferably from 1 to 6 carbon atoms, depending upon the desired properties of the final polymeric product.

The epoxide may be reacted in the gas phase, but the reaction may be facilitated by energising the process for example by applying a suitable plasma.

Once additional primary hydroxyl groups have been created in this way, they may be oxidised, for example using an oxygen plasma to form the corresponding carboxylated polymer of formula (V) or sulphonated to form the corresponding sulphonated polymer, or sulphated to form the corresponding sulphate polymer of formula (VI).

(R2 (R2 0 0 0 0 OSO3H OSO3H (VI) (V) Alternatively, monomers comprising carboxylic acid groups may be deposited directly under specific controlled conditions as described below, and as illustrated for example in Zhange et al., Thin Solid Films, Volume 435, issues 1-2, 1 July 2003, p108-115; Proceedings of the Joint International Plasma Symposium of the 6h APCPST, the 15th SPSM and the 1l Kapra Symposia.

Monomers containing primary diol groups are suitable applied using a plasma polymerisation process under conditions in which the diol moiety is not significantly disrupted (as will be explained in more detail below), and once the polymer has been formed, the hydroxy groups may be oxidised, preferably in an oxidising gas plasma, to produce the oxalate-like functionality.

EDTA consists of four acetic acid groups attached to an ethylenediamine unit. A polymer emulating these functional groups can be produced by first preparing a plasma polymer deposition of a polymer with primary amine side groups. These amine groups can then be reacted with gaseous epoxide to produce an amine/alcohol unit which in turn is treated with an oxygen plasma to produce the final amine-acetic acid groups. The length of alkyl chain, and the spacing between side groups, can be tailored to optimise the haemocompatible properties.

An example of such a procedure is illustrated in Scheme 3.

Scheme 3 2 /0\ / H2N NH2 (IX) / \

HN NH

---- '-..

OH OH (X) (XI)

The surface treated using the method described above is suitably a surface of a device or the material used to form a device which is intended to come into contact with blood or blood products. The material may be pre-coated before the device is assembled, for example polymeric substances used to produce blood bags or the like, or a preformed device, such as a syringe, syringe needle, stent, implant or tubing component.

When preformed devices are treated, it is necessary that those surfaces such as internal surfaces which are likely to come into contact with blood or blood products in use are coated.

However, if convenient or required, additional surfaces or even the entire device may be so treated.

A particular advantage of the method is that it is very penetrating and so will be particularly useful for medical devices with small apertures and channels such as the interior surfaces of syringe needles. The process is pertinent for both disposable products and non-disposable medical devices (e.g. stents) with little need for change of hardware Any monomeric compound or gas which undergoes plasma polymerisation or modification of the surface to form an anticoagulant polymeric coating layer or surface modification on the surface may suitably be used. Suitable monomers which may be used include for example, monomers that can give polymers with pendant hydroxyl groups such as vinyls or acrylates having a primary and/or secondary hydroxyl group(s) as well as: * 5-Hexen-l-ol, 0 3-Butene-l-ol, * 3-Butene-2-ol, or * 3,4-dihydroxy-l-butene Monomers that can give polymers with pendant carboxylic acid 25 groups may also be used and these include: o vinyl acetic acid.

In the method, in general, the surface to be treated is placed within a plasma chamber together with one or more monomers, which are able to generate the target polymeric substance, in an essentially gaseous state, a glow discharge is ignited within the chamber and a suitable voltage is applied.

As used herein, the expression "in an essentially gaseous state" 35 refers to gases or vapours, either alone or in mixture, as well as aerosols.

Precise conditions under which the plasma polymerization takes place in an effective manner will vary depending upon factors such as the nature of the polymer, the substrate etc. and will 5 be determined using routine methods and/or the techniques.

Suitable plasmas for use in the method of the invention include non-equilibrium plasmas such as those generated by radiofrequencies (Rf), microwaves or direct current (DC). They may operate at atmospheric or sub-atmospheric pressures as are known in the art. In particular however, they are generated by radiofrequencies (Rf).

The anti-coagulant polymeric coating may be produced under both pulsed and continuous-wave plasma deposition conditions but pulsed plasma is preferred. Using pulsed plasmas, in which low average powers can be achieved, a highly controllable surface covering can be obtained with minimal deterioration of the monomer, which is particularly important when retention of the monomer structure and anti-coagulant functional groups in the target polymer is required.

Various forms of equipment may be used to generate gaseous plasmas. Generally these comprise containers or plasma chambers in which plasmas may be generated. Particular examples of such equipment are described for instance in W02005/089961 and W002/28548, but many other conventional plasma generating apparatus are available.

In general, the item to be treated is placed within a plasma chamber together with the material to be deposited in gaseous state, a glow discharge is ignited within the chamber and a suitable voltage is applied, which may be pulsed.

The gas used within the plasma may comprise a vapour of the monomeric compound alone, but it may be combined with a carrier gas, in particular, an inert gas such as helium or argon. In particular helium is a preferred carrier gas as this can minimise fragmentation of the monomer.

When used as a mixture, the relative amounts of the monomer vapour to carrier gas is suitably determined in accordance with procedures which are conventional in the art. The amount of monomer added will depend to some extent on the nature of the particular monomer being used, the nature of the substrate being treated, the size of the plasma chamber etc. Generally, in the case of conventional chambers, monomer is delivered in an amount of from 50-250mg/min, for example at a rate of from 100-150mg/min. Carrier gas such as helium (when required) is suitably administered at a constant rate for example at a rate of from 5-90, for example from 15-30sccm. In some instances, the ratio of monomer to carrier gas will be in the range of from 100:0 to 1:100, for instance in the range of from 10:0 to 1:100, and in particular about 1:0 to 1:10. The precise ratio selected will be so as to ensure that the flow rate required by the process is achieved.

In some cases, a preliminary continuous power plasma may be struck for example for from 0.01-10 minutes within the chamber. This may act as a surface pre-treatment step, ensuring that the monomer attaches itself readily to the surface, so that as polymerisation occurs, the coating "grows" on the surface. The pre-treatment step may be conducted before monomer is introduced into the chamber, in the presence of only an inert gas.

The plasma is then suitably switched to a pulsed plasma to allow polymerisation to proceed, at least when the monomer is present.

In all cases, a glow discharge is suitably ignited by applying a high frequency voltage, for example at 13.56MHz. This is applied using electrodes, which may be internal or external to the chamber, but in the case of larger chambers are internal.

Suitably the gas, vapour or gas mixture is supplied at a rate of at least 1 standard cubic centimetre per minute (sccm) and preferably in the range of from 1 to 100sccm.

In the case of the monomer vacour, this is suitably supplied at a rate of from 80-300mg/minute, for example at about 120mg per minute depending upon the nature of the monomer, whilst the pulsed voltage is applied.

Gases or vapours may be drawn or pumped into the plasma region. In particular, where a plasma chamber is used, gases or vapours may be drawn into the chamber as a result of a reduction in the pressure within the chamber, caused by use of an evacuating pump, or they may be pumped, sprayed, dripped, electrostatically ionised or injected into the chamber as is common in liquid handling.

Polymerisation is suitably effected using vapours of suitable monomers, for example alkenes or acrylates which carry at least one hydroxy substituent, such as those listed above, which are maintained at pressures of from 0.1 to 400mtorr, suitably at about 10-100mtorr.

The applied fields are suitably of power of from 20 to 500W, suitably at about 100W peak power, applied as a pulsed field. The pulses are applied in a sequence which yields very low average powers, for example in a sequence in which the ratio of the time on: time off is in the range of from 1:500 to 1:1500.

Particular examples of such sequence are sequences where power is on for 20-50ps, for example about 30ps, and off for from 1000ps to 300001.ts, in particular about 20000ps. Typical average powers obtained in this way are 0.01W.

The fields are suitably applied from 30 seconds to 90 minutes, preferably from 5 to 60 minutes, depending upon the nature of the monomer and the substrate.

Suitably a plasma chamber used is of sufficient volume to accommodate multiple substrates such as medical devices as detailed herein.

A particularly suitable apparatus for carrying out the method of 10 the invention is described in W02005/089961, the content of which is hereby incorporated by reference.

In particular, when using high volume chambers of this type, the plasma is created with a voltage as a pulsed field, at an average power of from 0.001 to 500w/m, for example at from 0.001 to 100w/m-and suitably at from 0.005 to 0.5w/m-.

These conditions are particularly suitable for depositing good quality uniform coatings, in large chambers, for example in chambers where the plasma zone has a volume of greater than 500cm', for instance 0.1m3 or more, such as from 0.5m'-10mr and suitably at about 1m3. The layers formed in this way have good mechanical strength.

The dimensions of the chamber will be selected so as to accommodate the particular material or device or sub-assembly being treated. For instance, generally cuboid chambers may be suitable for a wide range of applications, but if necessary, elongate or rectangular chambers may he constructed or indeed cylindrical, or of any other suitable shape.

The chamber may be a sealable container, to allow for batch processes, or it may comprise inlets and outlets for the substrate, to allow it to be utilised in a continuous process as an in-line system. In particular in the latter case, the pressure conditions necessary for creating a plasma discharge within the chamber are maintained using high volume pumps, as is conventional for example in a device with a "whistling leak". However it will also be possible to process substrates at atmospheric pressure, or close to, negating the need for "whistling leaks".

In some cases, the surface of the substrate may be subject to a pre-treatment or activation step, either to sterilise it or to make the surface receptive to the polymer deposition. Such steps may be readily carried out in the plasma chamber, using conditions which are conventional in the art. This can involve the use of plasmas of air, oxygen, nitrogen, helium or argon, or combinations thereof.

The processes described herein show how anticoagulant functionalities can be produced in a surface coating through the application of plasma technology. The use of this technology brings with it the traditional advantages of not requiring any solvent, no drying steps and low requirements of key chemicals.

This leads to a more streamline process and less waste.

Further according to the invention there is provided a substrate or device having a polymeric layer on at least one surface thereof, said polymeric layer having anti-coagulant reactive groups arranged thereon, so that the surface has anti-coagulant properties.

Such surfaces are obtainable using a method as described above thereon.

Suitable substrates or devices include any medical or analytical device which is intended to come into contact with blood, or the materials which may be formed into such devices. Examples of such devices include blood-bags, syringes, syringe needles, stents, implants or tubing components. Suitable materials include polymers (which may be rigid or flexible), glass, metal (such as titanium implants) etc. Suitable anti-coagulant reactive groups include citrate or 5 oxalate groups or salts of other derivatives thereof, as described above.

A second aspect of the invention comprises a method for producing an anti-coagulant surface, said method comprising exposing the surface to a plasma comprising a monomer or a sequence of monomers, wherein the monomer or sequence of monomers are capable of forming an anti-coagulant polymer, wherein at least one of said monomers contains a carboxylate functional group, or a precursor thereof, wherein at least one of said monomers contains a hydroxyl or amine functional group, controlling the plasma conditions so that a layer of anticoagulant polymer or a precursor thereof is deposited on the surface, and then if necessary, converting any precursor of anti-coagulant polymer to anti-coagulant polymer.

A third aspect of the invention comprises a method for producing an anti-coagulant surface, said method comprising exposing the surface to a plasma comprising a monomer or a sequence of monomers, wherein the monomer or sequence of monomers are capable of forming a precursor of an anti-coagulant polymer, and wherein at least one of said monomers contains an oxygen or nitrogen containing functional group, controlling the plasma conditions so that a layer of anti-coagulant polymer or a precursor thereof is deposited on the surface, and converting the precursor of anti-coagulant polymer to anti-coagulant polymer in a gas plasma process.

Preferred features of the second and third aspects of the invention may be as described above in connection with the first 35 aspect.

Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", mean "including but not limited to", and do not exclude other moieties, additives, components, integers or steps.

Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Other features of the present invention will become apparent from the following example. Generally speaking the invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims and drawings). Thus features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

Moreover unless stated otherwise, any feature disclosed herein may be replaced by an alternative feature serving the same or a similar purpose.

Example 1

A blood collection tube (for example a tube used to form a VacutainerS) can be placed into a plasma chamber with a processing volume of -300 litres. The chamber is connected to supplies of the required gases and or vapours, via a mass flow controller and/or liquid mass flow meter and a mixing injector or monomer reservoir as appropriate.

The chamber is evacuated to between 3 -10 mtorr base pressure before allowing helium or helium with monomer or monomer into the chamber at 20 so= until a pressure of 80 mtorr was reached.

A continuous power plasma is then struck for 4 minutes using RF at 13.56 MHz at 300 W. After this period, a monomer, 3,4-dihydroxy-l-butene is brought into the chamber at a rate of 120 milli grams per minute and the plasma switched to a pulsed plasma at 30 micro seconds on-time and 20 milli seconds off-time at a peak power of 100 W for 40 minutes. On completion of the 40 minutes the plasma power is turned off along with the processing gases and vapours and the chamber evacuated back down to base pressure.

Oxygen gas is then pumped into the chamber to a pressure of from 10-500 millitorr, and the plasma reignited. Either low power continuous wave or pulsed wave for example as described above are applied, the precise selection being made on the basis of the required level of oxidation, and whereby significant disruption of the polymer structure is avoided. After oxidation is complete, for example from 10 seconds to 10 minutes, the plasma power is turned off and the chamber evacuated back down to base pressure.

The chamber is then vented to atmospheric pressure and the tube removed.

It was found that the tube was covered with an anti-coagulant 25 layer which prevented blood from clotting when in contact with the surface.

Claims

Claims 1. A method for producing an anti-coagulant surface, said method comprising exposing the surface to a plasma comprising a 5 monomer or a sequence of monomers, wherein the monomer or sequence of monomers are capable of forming an anti-coagulant polymer, wherein at least one of said monomers contains a carboxylate functional group, or a precursor thereof, wherein at least one of said monomers contains a hydroxyl or amine functional group, controlling the plasma conditions so that a layer of anti-coagulant polymer or a precursor thereof is deposited on the surface, and then if necessary, converting any precursor of anti-coagulant polymer to anti-coagulant polymer.
2. A method according to claim 1 wherein a sequence of monomers is deposited, wherein a first monomer is deposited, and then subsequently a second monomer having comprising anticoagulant functional groups or precursors of these is then added.
3. A method according to claim 1 or claim 2 wherein a precursor of an anti-coagulant polymer is deposited on the surface, and this is converted to an anti-coagulant polymer in a subsequent step.
4. A method according to claim 3 wherein the subsequent step is a gas plasma process.
A method according to any one of claims 1 to 4 wherein the 30 precursor polymer contains multiple hydroxyl groups on proximal carbon atoms.
6. A method according to any of claims 3 to 5, wherein the precursor polymer is treated with an epoxide to create primary 35 hydroxyl functionalities.
7. A method according to any one of claims 4 to 6 wherein during the subsequent step, a hydroxyl group is oxidised to a carboxylate group.
8. A method according to any one of claims 4 to 7 wherein in the subsequent step, sulphur dioxide is grafted so as to convert hydroxyl groups to sulphonate and/or sulphate groups.
9. A method according to claim 3 or claim 4 wherein the anti-coagulant polymer precursor comprises primary amine side groups, which are subsequently reacted to with gaseous epoxide to produce an amine/alcohol unit which in turn is treated with an oxygen plasma to produce an amine-acetic acid group.
10. A method according to claim 1 or claim 2 wherein an anticoagulant polymer having multiple carboxylate groups is deposited in a single process.
11. A method according to any one of the preceding claims wherein the substrate is a preformed item selected from a blood bag, a syringe, syringe needle, stent, implant or tubing component, or a material intended for use in the manufacture of said item.
12. A method according to any one of the preceding claims wherein the substrate is placed within a plasma chamber together with one or more monomers, which are able to generate the target polymeric substance, in an essentially gaseous state, a glow discharge is ignited within the chamber and a.suitable voltage is applied.
13. A method according to any one of the preceding claims wherein the plasma is a pulsed plasma.
14. A method according to any one of the preceding claims wherein the substrate is subjected to a pre-treatment or activation step, either to sterilise it or to make the surface receptive to the polymer deposition.
15. A method according to claim 14 wherein the pre-treatment step uses a gas plasma of air, oxygen, nitrogen, helium or argon, or combinations thereof.
16. A substrate having a polymeric layer on at least one surface thereof, said polymeric layer having anti-coagulant reactive groups arranged thereon, so that the surface has anticoagulant properties, the polymeric layer being applied by the method of any of claims 1 to 15.
17. A substrate according to claim 16 which comprises a blood-15 bag, syringe, syringe needle, stent, implant or tubing component.
18. A substrate according to claim 16 which comprises a polymer, glass or a metal. 20
19. A method for producing an anti-coagulant surface, said method comprising exposing the surface to a plasma comprising a monomer or a sequence of monomers, wherein the monomer or sequence of monomers are capable of forming a precursor of an anti-coagulant polymer, and wherein at least one of said monomers contains an oxygen or nitrogen containing functional group, controlling the plasma conditions so that a layer of anti-coagulant polymer or a precursor thereof is deposited on the surface, and converting the precursor of anti-coagulant polymer to anti-coagulant polymer in a gas plasma process.
20. A method according to claim 19 wherein a sequence of monomers is deposited, wherein a first monomer is deposited, and then subsequently a second monomer comprising anticoagulant 35 functional groups or precursors of these is then added.
21. A method according to any one of claims 19 or 20 wherein the anti-coagulant polymer precursor comprises hydroxyl functional groups.
22. A method according to any one of clams 19 to 21 wherein the anti-coagulant polymer precursor comprises multiple hydroxyl groups on proximal carbon atoms.
23. A method according to claim 21 or claim 22, wherein the 10 precursor polymer is treated with an epoxide to create primary hydroxyl functionalities.
24. A method according to claim 22 or claim 23 wherein during the subsequent step, a hydroxyl group is oxidised to a carboxylate group.
25. A method according to claim 22 or claim 23 wherein in the subsequent step, sulphur dioxide is grafted so as to convert hydroxyl groups to sulphonate and/or sulphate groups.
26. A method according to claim 21 or claim 22 wherein the anti-coagulant polymer precursor comprises primary amine side groups, which are subsequently reacted to with gaseous epoxide to produce an amine/alcohol unit which in turn is treated with an oxygen plasma to produce an amine-acetic acid group.
27. A method according to any one of claims 19 to 26 wherein the substrate is a preformed item selected from a blood bag, a syringe, syringe needle, scent, implant or tubing component, or 30 a material intended for use in the manufacture of said item.
28. A method according to any one of the preceding claims wherein the substrate is placed within a plasma chamber together with one or more monomers, which are able to generate the target 35 polymeric substance, in an essentially gaseous state, a glow discharge is ignited within the chamber and a suitable voltage is applied.
29. A method according to any one of the preceding claims 5 wherein the plasma is a pulsed plasma.
30. A method according to any one of the preceding claims wherein the substrate is subjected to a pre-treatment or activation step, either to sterilise it or to make the surface 10 receptive to the polymer deposition.
31. A method according to claim 30 wherein the pre-treatment step uses a gas plasma of air, oxygen, nitrogen, helium or argon, or combinations thereof.
32. A substrate having a polymeric layer on at least one surface thereof, said polymeric layer having anti-coagulant reactive groups arranged thereon, so that the surface has anticoagulant properties, the anti-coagulant being applied according to the method of any of claim 19 to 31.
33. A substrate according to claim 32 which comprises a blood-bag, syringe, syringe needle, stent, implant or tubing component.
34. A substrate according to claim 32 which comprises a polymer, glass or a metal.