Biocompatible compositions

Details Biocompatible compositions Biocompatible compositions

1998-08-05

2001-06-26

Szekely, Peter A. (Department: 1714)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Processes of preparing a desired or intentional composition...

C523S331000, C523S112000, C524S027000, C524S028000, C524S547000, C526S277000

Reexamination Certificate

active

06251964

ABSTRACT:

The present invention relates to novel biocompatible polymers, the use of these polymers to improve binding of mucopolysaccharides to substrates to improve their hemocompatibility and compositions containing mucopolysaccharides and the polymer.
In WO-A-93/01221 we describe various polymers and their use to coat surfaces to improve their biocompatibility. The polymers include zwitterionic groups and pendant groups which are capable of providing stable surface binding of the polymer to underlying substrate surfaces. The binding may be by provision of pendant hydrophobic groups which physisorb onto hydrophobic substrates, by counterionic attraction between pendant ionic groups on the polymer and oppositely charged groups at the substrate surface, by providing covalent attachment between coreactive pendant groups on the polymer and groups at the substrate surface or by crosslinking the polymer after coating. Post coating crosslinking may also be used to improve the stability of a polymer which is physisorbed, covalently bonded or counterionically bonded to the surface. The polymers have good hemocompatibility as indicated by the low platelet adhesion values reported in that specification.
It has also been shown that zwitterionic groups at substrate surfaces, for instance of contact lenses, show lower rates of deposition of proteins and lipids from biological liquids such as tear film. In WO-A-92/07885, reduced levels of protein deposition are described for contact lenses formed from a hydrogel of a crosslinked copolymer of copolymerisable zwitterionic monomer and non ionic comonomer.
In WO-A-93/21970 it is disclosed that microorganisms, especially bacteria, adhere to surfaces having pendant phosphoryl choline groups than to similar surfaces without such groups present.
Another way of reducing the thrombogenicity of surfaces has involved attachment or adsorption of anti-thrombogenic active compounds to substrate surfaces. For instance heparin may be attached through covalent or counterionic bonding to surfaces. In U.S. Pat. No. 3,634,123 the binding of heparin to a surface was increased by incorporation of cationic surfactant. A related process is described in EP-A-0350161, in which a surface is first coated with a cationic surfactant and subsequently with heparin. In EP-A-0086187 the surface is first coated with a cationic polymer and subsequently with heparin. In JP-A-53/137268 a cross-linked acrylic copolymer of a cationic monomer and a polyethyleneglycol monomer is blended with polyurethane and made into tubing which can be coated with heparin. In EP-A-0086186 heparin is attached to an underlying surface through a covalent bond via the end carbohydrate unit. In U.S. Pat. No. 5,342,621, a complex is formed of heparin with phosphatidyl choline and admixed with a polymer of caprolactone or L-lactic acid (both substantially unchanged overall) and subsequently used to coat medical devices.
The present inventors have discovered that the performance of heparin coated devices which are commercially available, for instance as components of extra corporeal devices, deteriorates after short periods of use, for instance half an hour. It is not known whether this is due to the heparin being removed from the surface or due to the surface becoming fouled by components of blood or other biological liquid in contact with the surface during use such that the heparin is masked. The present invention seeks to provide a substrate surface which is hemocompatible and retains its hemocompatible properties over longer term in use.
Generally patients who are undergoing complex operations requiring that their blood be directed through extra corporeal circuitry, require administration of heparin into the circulation to prevent the blood clotting. Subsequently the heparin has to be neutralised or removed from the blood stream. In order to remove heparin from the circulation without administering a further active compound to neutralise the heparin, it has been suggested to immobilise protamine, a cationic polypeptide used to neutralise heparin, at the surfaces of a filter used in an extra corporeal blood circuit, to scavenge heparin from a patient systemically heparinised.
In U.S. Pat. No. 3,861,948 pressure sensitive adhesives are copolymers of ionic monomer and alkylacrylate monomers. The ionic monomers may be cationic and/or zwitterionic. Zwitterionic monomers are sulpho or carboxy-betaines, and are used in combination with permanent cationic monomers and monomers with glycidyl groups which can be reacted after coating to cross-link the polymer.
A new terpolymer according to the invention has an overall cationic charge and is formed from ethylenically unsaturated monomers including
a) a zwitterionic monomer of the formula I
YBX  I
wherein
B is a bond or a straight or branched alkylene, alkylene-oxa-alkylene or alkylene-oligooxa-alkylene group, any of which optionally include one or more fluorine substituents;
X is an organic group having a zwitterionic moiety; and
Y is an ethylenically unsaturated polymerisable group;
b) a cationic monomer of the formula II
Y
1
B
1
Q
1
  II
wherein B
1
is a bond or a straight or branched alkylene, alkylene-oxa-alkylene or alkylene-oligooxa-alkylene group, any of which optionally includes one or more fluorine substituents;
Y
1
is an ethylenically unsaturated polymerisable group; and
Q is an organic group having a cationic or cationisable moiety; and
c) a termonomer of the formula III
Y
2
B
2
Q
2
  III
wherein
B
2
is a bond or a straight or branched alkylene, alkylene-oxa-alkylene or alkylene-oligooxa-alkylene group, any of which may optionally include one or more fluorine substituents;
Y
2
is an ethylenically unsaturated polymerisable group; and
Q
2
is an organic group having a hydrophobic group selected from alkyl groups having at least six carbon atoms, fluorine substituted alkyl groups and alkyl groups having at least one siloxane substituent.
The terpolymer may include pendant groups capable of providing covalent bonding at the substrate surface or cross-linking between polymer chains. Such groups are generally introduced by incorporation of additional reactive monomers into the monomer mixture. A termonomer may, for instance, comprise a covalent reactive group which is capable of forming a covalent bond with coreactive groups at the substrate surface. Alternatively the copolymer may be crosslinked after coating by subjecting a polymer having pendant crosslinkable groups to conditions such that crosslinking takes place.
A covalent reactive monomer may have the general formula IV:
Y
3
B
3
Q
3
  IV
wherein
B
3
is a bond or a straight or branched alkylene, alkylene-oxa-alkylene or alkylene-oligooxa-alkylene group, any of which optionally includes one or more fluorine substituents;
Y
3
is an ethylenically unsaturated polymerisable group; and
Q
3
is an organic group having a reactive group capable, on imposition of an external stimulus, of reacting with a coreactive group on the surface of a substrate or which is pendant on the polymer.
Reactive groups Q
3
may also provide crosslinkability on the polymer. For instance such groups may react with each other or may react with different coreactive groups as pendant groups on the copolymer, for instance amine or, more usually, hydroxyl groups. Examples of reactive groups capable of crosslinking with such pendant groups or of reacting to provide covalent binding to a surface, an aldehyde group or a silane or siloxane group containing one or more reactive substituents such as halogen, for example chlorine, or alkoxy, generally containing from 1 to 4 carbon atoms, for example methoxy or ethoxy, or, more preferably, Q3 is a hydroxyl, amino, carboxyl, epoxy, —CHOHCH
2
Hal, (in which Hal is a halogen atom such as chlorine, bromine or iodine) succinimido, tosylate, triflate, imidazole carbonyl-amino or optionally substituted triazine group. A preferred example of a reactive group is a trimethoxysilyl group which reacts either with other similar groups or with hydroxyl groups on the ter

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