GB2140444A

GB2140444A - Block polymer of poly(alkylsiloxane) hard block polymer and polyethylene oxide polymer

Info

Publication number: GB2140444A
Application number: GB08407417A
Authority: GB
Inventors: Robert Stanto Ward
Original assignee: Thoratec LLC; Thoratec Laboratories Corp
Current assignee: Thoratec LLC
Priority date: 1980-02-29
Filing date: 1984-03-22
Publication date: 1984-11-28
Also published as: GB2140444B; MX159062A; JPS56136565A; AT385041B; IL62183A0; NL8100975A; FR2491938B1; ZA811107B; IT8120027A0; JPH0214062B2; GB2073219B; ATA83581A; FR2491938A1; AU6755181A; FR2497217B1; FR2497217A1; AU548194B2; GB2073219A; GB8407417D0; CA1206668A

Abstract

A blood-compatible polymer solid at 37 DEG C comprises a block polymer including a sequence of block segments represented by the formula (A) (B) (C), in which A is a poly(alkylsiloxane), B is a hard block polymer segment with a crystalline melting point above 37 DEG C or a glass transition temperature above 37 DEG C (such as a polyurethane), and C is a hydrophilic polymer consisting of polyethylene oxide or polyethylene oxide-copolypropylene oxide. The block polymer may be blended with at least 95% of a blood-incompatible base polymer, i.e. a good structural polymer such as a polyurethane, to lower the surface free energy and produce a blood-compatible polymer mixture suitable for use as a blood-contacting surface of a biomedical device.

Description

1 GB 2 140 444 A 1

SPECIFICATION

Block polymer of poly (alkylsiloxane), hard block polymer and polyethylene oxide polymer One widely accepted hypothesis regarding blood compatibility is that it is maximized within a narrow range of surface free energies which give rise to favorable interactions with plasma proteins. A com mon measurement of surface free energies. is by Zisman's critical surface tension (-yc). The optimum value has been found empirically to lie within the range of a -yc equal to about 20 to 30 dyne/cm., see, e.g., R.A. Baeir, Ann. N.Y. Acad. Sci- 17,283 (1977) Common polymers (e.g. polyurethane) which pro- 80 vide the desired physical properties forthe blood contact surfaces of biomedical devices often do not fall within this range of critical surface tensions.

Polysiloxanes are known to have a particularly low critical surface tension value and have been sug gested for incorporation into polyurethanes to im prove the surface characteristics of such materials.

However, polysiloxane by itself is known to have a tendency to exude from the polyurethane base polymer as illustrated in Reischl et aL, U.S. Patent 3,243,475.

Polysiloxane-polyurethane block copolymers have been suggested for use to modify the surface characteristics of blood contact surfaces of devices of biomedical devices as illustrated in Nyilas U.S.

Patent 3,562,352. The technique disclosed for such use includes fabricating the entire blood contact devices from such block copolymers or coating such devices with the copolymers. The block copolymers themselves have poor structural characteristics due 100 to a high proportion of polysiloxane. On the other hand, the coated materials are particularly expensive to form as they are not processable by thermoplastic methods such as injection molding and extrusion.

The manufacture of tubing, catheters and other 105 blood-contacting disposable devices from such materials is particularly expensive due to the neces sity of employing solution fabrication techniques.

Certain experimental work has been published relating to the blending of block copolymers of polydimethylsiloxane with homopolymers of higher critical surface tensions. These materials are known to produce films with high siloxane surface concen trations. See, for example, D.G. Legrand and R.L.Gaines, Jr., Polym Prepr. 11, 442 (1970); D.W.

Dwight et al., Polym. Prepr. 20, (1),702 (1979); and J.J. O'Malley, Polym Prepr. 18 (1977). However, all of these references describe the polymer blends in terms of scientific experiments without suggestion that the material would have any advantage for use in any biomedical application.

The invention relates to a polymer which may be added, as a polymer additive, to a blood incompatible base polymer to provide a blood compatible polymer mixture.

The present invention provides a blood compatible polymer solid at 37'C comprising a block polymer including sequence of block segments represented by the formula (A) (B) (C), in which A is a poly (alkylsiloxane), B is a hard block polymer 130 segment with a crystalline melting point above 37C or a glass transition temperature above 37'C, and C is a hydrophilic polymer selected from the group consisting of polyethylene oxide and polyethylene oxide-copoly-propylene oxide.

The polymer of the invention may be used to provide a technique for lowering the surface free energy of a good stuctural polymer to convert a surface formed from such material from one which is blood incompatible to one which is blood compatible. As used herein, the term "base polymer" will refer to the polymer whose surface characteristics is so modified. Typical base polymers whose surfaces may be improved by the presnt technique include polyurethanes, polysulfones, polycarbonates, polyesters, polyethylene, polypropylene, polystyrene, poly(acrylonitrile-butadiene-styrene), polybutadiene, polyisoprene, styrene-butadiene-styrene block copolymers, styrene-isoprene-styrene block copolymers, poly-4-methylpentene, polyisobutylene, polymethylmethacrylate, polyvinylacetate, polyacrylonitrile, polyvinyl chloride, polyethylene terephthalate, cellulose and its esters and derivatives, and the like.

The base polymer is of a type capable of being formed into a selfsupporting structural body, a self-supporting film, or deposited as a coating onto a self-supporting body. The end use of the final product may be the surface of a biomedical device or component thereof.

Another characteristic of the base polymer is that it displays a critical surface tension (,yc) in excess of that desirable for a blood contact surface and in excess of that of the polymer of the invention which reduces its -y, value. As defined herein, -y, measurements are performed by the direct method using a contact angle meter of the Kernco or RameHart type and series of seven solvents according to the Zisman procedure as set forth in A.W. Adamson, Physical Chemistry for Surfaces 339-357, 351 (3d Ed.). Measurements are made at room temperature using advancing angles on solvent castfilms annealed at 60'C forfour hours. The mean contact angles are fitted to a Zisman plot using a linear regression calculator program.

A base polymer of the foregoing type may be mixed with a polymer of the invention, as a polymer additive, as set out below to lower its surface free energy. The polymer additive with a substantially lower -y. value than that of the base polymer is thoroughly dispersed into the base polymer while in fluid form to form a fluid polymer admixture. Thereafter, the polymer mixture may be solidified and formed into the blood-contacting surface of a biomedical device or component. A suitable broad range of surface free energies of the polymer admixture is from 10 to 35 dyne/cm. while a preferred range is from 20 to 30 dyne/cm. An optimum range is 20-25 dyne/cm.

The polymer of the invention includes three different homopolymer chain components of different functional characteristics. One homopolymer chain, "A", is a poly(alkylsiloxane) and has a relatively lowyc value, less than that of both the base polymer and the second component "B" and causes 2 GB 2 140 444 A 2 reduction in the -yr of the polymer mixture as set out below. Such material typically has a tendency to exude from the base polymer in admixture.

To prevent exudation, the second homopolymer chain B is chemically bonded to the first component in the polymer additive to lower this tendency to exude. The second component is a "hard block" polymer segment useful in the preparation of thermoplastic block copolymers, e.g. as set out in A.

Noshay and J.E. McGrath, Block Copolymers Overview and Critical Survey (Academic Press 1977). The hard blocks are characterized by a crystalline melting point greater than about 37'C or a glass transition temperature also greater than about 37'C. This component B has a higher surface free energy than the component A. For compatibility, the component B is preferably formed of a polymer of the same type as the base copolymer.

The component B is linked to a segment C formed of a hydrophilic selected from the group consisting of polyethylene oxide and polyethylene oxide copolypropylene oxide. The component B links the poly (alkylsiloxane) component A and the hydrophilic component C.

It has been found that the homopolymer component of the additive with the lowest -yc value controls the -yc value of the entire polymer additive.

Suitable homopolymers; for the first component are those with a -yc value in the desired range to lower the value of the base polymer to that desired for blood compatibility. Thus, it is preferable that the component A be characterized by a -y, value less than 30 dyne/cm. One particularly effective homopolymer for this purpose is a polydimethylsiloxane with a -yc on the order of 22 dyne/cm. Techniques for forming siloxane copolymers for use in the present invention are known, e.g., as described in W. Noll, Chemistry and Technology of Silicones (Academic Press, 1968). Suitable first component homopolym- ers include other polydialkylsiloxanes.

A suitable number of repeating units of each homopolymer of the component A is that sufficient to retain the -y, value of the homopolymer as evidenced by retention of approximately the same glass transition temperature as its pure homopolym- 110 er. Typically, this number is on the order of 5to 10 units or more. Similarly, there should be a sufficient number of repeating units of the second component in a segment so that the polymer additive is solid at room temperature.

The preparation of block copolymers may be performed by several procedures which differ in the degree to which the structure of the resulting product may be defined.

One procedure involves the coupling of two (or more) preformed blocks which are prepared in separate reactions prior to the coupling reaction. This procedure involves a very well defined structure if the coupling reaction precludes like blocks from reacting with themselves but only allows dissimilar blocks to couple to one another.

A slightly less well defined structure results if the two preformed blocks possess the ability (via the coupling reaction) to react with themselves as well as with the dissimilar block.

An even less well defined structure results when a single (or more) preformed block is coupled with a second block created during the coupling reaction. In this case the initial length of the preformed block is known (by virtue of the separate reaction used to prepare it) but the sequence distribution of the copolymer is not known exactly since both coupling and chain growth is possible in the reaction which produces the second block. Suitable methods of forming these and other such copolymers for use in the present invention are set out in the aforementioned Noshay and McGrath publication.

In one excellent terpolymer, the first component is a poly(dialkylsiloxane), the second component is any of a broad group including polyurethane or polyureaurethane, and the hydrophilic component is either polyethylene oxide or polyethylene oxidecopolypropylene oxide. This terpolymer provides unexpectedly superior improvement in blood compatibility for abase polymer of the desired structural characteristics, such as a hard polymer of the same type as the second component.

As used herein, the term "polyurethane" encompasses polyetherurethaneureas, polyether urethanes, polyester urethanes, or any of the other known polyurethanes, e.g., as set forth in Nyilas U.S. Patent 3,562,352 (Col. 2, line 66-Col. 3, line 37). This copolymer may be blended with any base polymer of desired physical properties. It is particularly effective for use with the same type of base polymer as the component B to provide improved compatibility.

The ratio of first and second components in the polymer additive may vary to a considerable extent so long as there is sufficient amount of first component to reduce the -y, value and sufficient amount of second homopolymer to prevent exudation of the polymer additive. It is preferable that the polymer additive include at least about 20 volume % of the first component. A suitable ratio is from 20 to 80 volume % of the first type of component and about 20 to 80 volume % of the second type of polymer component.

The total amount of polymer additive required to reduce the -y. value of the base polymerto that desired for the polymer mixture is very low. For example, it has been found that less than 5 volume % and preferably less than 1 to 2 volume % of total polymer additive performs this function even though the first component typically comprises about half or less of the polymer additive. A suitable ratio of polymer additive to base polymers is on the order of 0.00002 to 2 volume % polymer additive based on the total polymer mixture. Experimental results have indicated that even though the polymer additive is initially mixed in bulk into the base polymer, it migrates to the surface to form an exceptionally thin (monomolecular) film which provides the desired surface characteristics. Sufficient polymer additive should be included to provide this uniform layer. The presence of an adequate amount of polymer additive is shown by a dramatic drop in the -y. value of the polymer admixture to approximately that of the first component. While the required amount varies from system to system, it is generally less than 1 volume 3 GB 2 140 444 A 3 % of the first component based on the total polymer mixture. It is advantageous to use such low amounts of polymer additive as large amounts of the first component can be detrimental to the physical 5 properties of the polymer mixture.

It has been found that the required minimum amount of polymer additive may be approximated by a knowledge of the film thickness of a polymer additive monolayer and the surface area to bulk volume ratio of the fabricated material. This is based on the simplifying assumption that prior to surface saturation, essentially all of the polymer additive migrates to the surface. By simple calculation, this minimum amount may be precalculated based on this knowledge.

A number of techniques may be employed for mixing the polymer of the invention as the polymer additive with the base polymer. In one technique, both the base polymer and polymer additive are thermoplastic and are melted at elevated temperatures to perform the mixing. Thereafter, the polymer is solidified by cooling. If desired, the bulk polymer may be simultaneously processed into the desired final form. Alternatively, the material may be soldi- fied for subsequent formation of the material into the desired form by thermoplastic methods such as injection molding and extrusion.

Another technique for mixing of the polymer additive and base polymer is by dissolving both of them in solvent and thereafter evaporating the solvent to form the solid product of the present invention. This product may also be subsequently processed by thermoplastic techniques if desired.

The polymer of the present invention must be thoroughly dispersed in the base polymer. For this purpose, it is preferable that the polymer additive be thermoplastic, soluble in organic solvents, and relatively uncrosslinked.

For most biomedical applications, the base polym- ers of the present invention should be thermoplastic so that they may be readily processed as desired. However, there are certain applications in which the polymers may be fabricated while fluid and thereafter solidified in the form of the fabricated part which cannot again be placed into the fluid form. For example, such base polymer may comprise thermosetting systems which are cured or vulcanized immediately following dispersion of the polymer additive. Such systems may include two component polyurethanes or epoxy resin systems.

One mode of pretreating a base polymer to lower its surface free energy is believed to be effective with a base polymer which includes high energy end groups, specifically ones capable of hydrogen bond- ing or reacting with protein. In this instance, the base polymer is first fractionated to remove a lower molecular weight fraction and thereby may reduce the hydrogen bonding capacity of the remaining base polymer. Suitable techniques for accom- plishing this are set out in Manfred J.R. Cantow, Polymer Fractionation, Academic Press (New York London 1967). Such techniques include liquid chromatography, particularly gel permeation chromatography.

It has been found that variations in processing conditions which would otherwise affect the surface free energy to a significant extent may be minimized as a factor in systems of the present invention by the use of a short heat treatment following surface formation.

It has further been found that the polarity of the environment of formation affects the -yc value of the surface. Thus an air equilibrated surface provides a lower y, than one which has been equilibrated in water.

The polymers of the present invention are particularly effective for use as a blood-contacting surface of a biomedical device or component. Such devices include auxiliary ventricles, intra-aortic balloons, and various types of blood pumps.

A further disclosure of the nature of the present invention is provided by the following specific examples of the practice of the invention. It should be understood that the data disclosed serve only as examples and are not intended to limit the scope of the invention.

Example 1

Atypical sythesis of Polydimethylsiloxane- Polyurethane Block Copolymer. To a 500 mi. four-necked flask equipped with stirrer, Dean and Stark trap, dropping funnel, drying tube, thermometer and inert gas inlet is placed a mixture of 50 ml. dimethylformamicle and 140 ml. of tetrahy- drofuran. The mixture is heated to reflux and approximately 40 ml. tetrahydrofuran is distilled off. The reaction mixture is cooled down and 12.513 gm (0.05 mole) of methylene bis (4-phenyl) isocyanate (MDI) is added to give a clear solution. From the dropping funnel 15.000 gm. (0.015 mole) of 3hydroxypropyl terminated polyclimethylsiloxane (Mol. wt 1,000) is added dropwise. The reaction mixture is heated at 105-1 OO'C for 1 hour, followed by dropwise addition of 3.15 gm (0.035 mole) of 1-4, butane diol over a period of 45 minutes. The polymerization is carried out for 15 minutes more, cooled down and precipitated by pouring into water in a blender. The slightly yellowish polymer is washed with water and finally with ethanol; dried in a vacuum oven at 50'C to afford - 30-31 gm of polymer (98-100%). [,q] in tetrahydrofuran at 25'C is 0.19.

Example 2

By replacing some of the hudroxyproplyterminated poly-dimethylsiloxane with polyethylene glycol, a polydimethyisiloxane/polyethylene oxide/ polyurethane terpolymer is prepared.

Example 3

By replacing the DM F solvent with di methylacetamide and substituting ethylene diamine for butane diol in Example 2 a polydimethylsiloxane/ polyethylene oxide/polyureaurethane terpolymer is prepared.

Claims

1. A blood-compatible polymer solid at 37'C comprising a block polymer including sequence of 4 GB 2 140 444 A 4 block segments represented by the formula (A) (B) (C), in which A is a poly (alkylsiloxane), B is a hard block polymer segment with a crystalline melting point above 370C or a glass transition temperature above 37'C, and C is a hydrophilic polymer selected from the group consisting of polyethylene oxide and polyethylene oxicle-copolypropolyene oxide.

2. A polymer as claimed in Claim 1 in which the component A is poly (dimethylsiloxane).

3. A polymer as claimed in Claim 1 in which the component A is a poly (dialkylsiloxane) and the component B is a polyurethane.

4. A polymeras claimed in anyone of the preceding claims blended with a blood-incompatible base polymer in the ratio of at least 95 volume % base polymer and no greater than 5 volume % polymer additive.

5. A polymer as claimed in Claim 4 in which the component B is formed of the same type of homo- polymer as the base polymer.

6. A polymer as claimed in Claim 4 orClaim 5 which is blended with the base polymer in an amount of from about 0.00002 to 2 volume % based on the total polymer mixture.

7. A polymer as claimed in Claim 1 substantially as hereinbefore described.

Amendments to the claims have been filed, and have the following effect:(b) New or textually amended claims have been filed as follows:- 6. A polymeras claimed in Claim 4orClaim 5 which is blended with the base polymer in an amount of from 0.00002 to 2 volume % based on the total polymer mixture.

Printed in the UK for HMSO, D8818935,10184,7102. Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.