Liquid purification or separation – Filter – Supported – shaped or superimposed formed mediums
Reexamination Certificate
1999-02-24
2001-07-17
Drodge, Joseph W. (Department: 1773)
Liquid purification or separation
Filter
Supported, shaped or superimposed formed mediums
C210S500430, C427S245000, C422S051000, C422S105000
Reexamination Certificate
active
06260715
ABSTRACT:
The present invention relates to membranes for biological purification of a biological fluid.
The terms purification or biological purification used here means the process of partial or complete elimination of an endogenous or heterologous molecule or macromolecule present in the biological fluid, the complete or partial elimination of which is desired; this molecule or macromolecule can be in a soluble isolated state or it can be complexed with other substances.
The present invention also relates to a multipurpose device for purification of a biological fluid. The device is constituted by a functionalized support which is hemocompatible when used in an extracorporeal circuit for treating blood. The particular feature of the device is that it can covalently bind any type of ligand which can be used to modify the activity or composition of a biological fluid.
The invention also relates to a process for producing and using a support either alone or integrated in a kit for extemporaneous preparation of a support which can carry a specific ligand.
Biocompatible semi-permeable membranes have been developed for dialysis of patients with kidney failure. Such supports can be in the form of flat membranes or hollow fibres. A number of membranes based on synthetic polymers or based on modified cellulose have been developed for users by manufacturers. The polymers used are rarely homopolymers, and no membrane has been exclusively constituted by polyacrylonitrile.
As an example, the PAN membrane from Asahi is constituted by a copolymer of acrylonitrile, methyl methacrylate and acrylic acid; that membrane has an asymmetric microporous structure formed by a dense layer in contact with the blood and a spongy wall on the dialysate side. The SPAN membrane from ENKA is also an asymmetric microporous membrane based on acrylonitrile, sodium methallyl sulphonate and methyl methacrylate.
The AN69 membrane produced and sold by HOSPAL (Meyzieu, France) is based on a copolymer of acrylonitrile and sodium methallyl sulphonate. That membrane is known for its transfer and biocompatibility properties. The number of anionic sites (from the sodium methallyl sulphonate co-monomer) of polymer AN69 is 600 mEq/kg. That of the membrane is about 180 Eq/kg (polymer content approximately 30%).
Other polymers, in particular polysulphone polymers, also have an asymmetric microporous structure; they are fundamentally hydrophobic and must be mixed with hydrophilic components such as polyvinylpyrrolidone to be able to provide dialysis membranes with sufficient diffusive properties.
Symmetrical hydrophilic supports, whether in the form of hollow fibres or of flat membranes depending on the desired usage, also have functional advantages regarding their biocompatibility in that they are low complement activators, they are non thrombogenic and they have a large diffusion capacity.
In general, any biocompatible anionic polymer such as acrylonitrile copolymers can provide supports which are functionalisable using the processes of the invention.
The present invention concerns two types of biological purification: firstly, non specific dialysis and/or hemofiltration type biological purification routinely used for renal dialysis; secondly, biological purification in which an undesirable molecule or macromolecule is eliminated from a biological fluid and by specific interaction of the molecule or macromolecules to be eliminated with one or more ligands covalently coupled to hydrophilic supports.
Dialysis and Hemofiltration
Apparatus for treating blood by extracorporeal circulation are used in a variety of medical or paramedical applications such as: treatment of kidney failure by dialysis or hemofiltration, plasmapheresis and apheresis for therapeutic and non therapeutic ends, blood oxygenation, immuno-purification, etc.
All of the materials used in the manufacture of such apparatus are selected so as to be as biocompatible as possible so that reactions (in particular coagulation) which occur when blood comes into contact with a foreign material do not occur or only occur at relatively benign levels.
Bulk or surface treatment of the materials which come into contact with blood can be treated to improve biocompatibility. Known treatments are carried out either during preparation of the solutions of polymers used to produce a particular part of the apparatus (bulk treatment) or after the different parts of the apparatus have been assembled and before sterilisation of the apparatus, or extemporaneously just before using the apparatus.
One problem which is particularly difficult to resolve occurs when the biocompatibility of the active element of an apparatus is to be improved (for example a dialysis membrane) while satisfying the following conditions:
1) The choice of substance used for the treatment and the treatment conditions must have the result of modifying a known active element, that modification improving the biocompatibility of the active element while preserving all of the known qualities (for example, for a dialysis/hemofiltration membrane: diffusive and convective transfer performances, adsorption capacity of undesirable substances, etc.);
2) Sterilization of the apparatus must not influence the treatment;
3) The treatment must not require particular processing by the user.
More specifically, the inventors propose a process for producing an apparatus which satisfies the above conditions and in which before treatment, the active element carries negative charges on its surface. When blood comes into contact with a negatively charged surface, it forms the seat of a biological phenomenon known as contact phase activation which manifests itself by the generation of active substances, kallikrein and factor XIIa, from inactive substances, prekallikrein and factor XII.
Phase contact activation in itself is benign, but when it occurs simultaneously with certain aggravating factors (the patient taking ACE (angiotensin converting enzyme) inhibitor type antihypertensive drugs, dilution of blood entering an apparatus filled with saline solution, with concomitant pH reduction), it appears to be the origin of undesirable reactions known as anaphylactoids which manifest themselves a few minutes after the start of the treatment in a variety of symptoms, among them a general sensation of heat, engorgement of fingers, lips or tongue, breathlessness, nausea, laryngeal oedema. Anaphylactoid reactions are not exclusively linked to the use of medical apparatus in which the blood compartment has a negatively charged internal surface. Such reactions have been observed with exchangers with membranes of different chemical compositions, both during first use, and after a number of uses when the exchangers, instead of being discarded after a single use, are re-used a number of times and are recycled after each use. An example of an exchanger in which first use is accompanied by an undesirable reaction is a dialyser with a polymethylmethacrylate and polyacrylonitrile membrane. Reactions associated with re-use of dialysers with a cellulose acetate and polysulphone membrane have been well documented (see Anaphylactoid Reactions Associated with Re-use of Hollow-fiber Hemodialyzers and ACE inhibitors in Kidney International, vol. 42 (1992), ppl 1232-1237).
Specific Biological Purification
A number of developments have been made as regards covalent binding of macromolecules to solid supports, more particularly developments intended to increase the specific degree of binding and to reduce the non specific degree of binding, for example by adsorption. International patent applications WO 92/07023, WO 92/07006 and WO 92/05201 are examples which develop a technique in which a support is coated with an uncharged hydrophilic polymer: epoxy PEG (polyethylene glycol), covalently bonded to a polyethylene imine (PEI). The process described in those three patent applications is carried out in a non polar reaction medium; the epoxy PEG forms a stable bond with the PEI which, by direct reaction by reducing the pH of the reaction medium, becomes bound to the insoluble
Moachon Nicolas
Quash Gerard
Simard Laurent
Thomas Michel
Drodge Joseph W.
Finnegan Henderson Farabow Garrett & Dunner
Hospal Industrie
LandOfFree
Means for the biological purification of a biological fluid does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Means for the biological purification of a biological fluid, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Means for the biological purification of a biological fluid will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2530528