Liquid purification or separation – Processes – Liquid/liquid solvent or colloidal extraction or diffusing...
Reexamination Certificate
2000-09-07
2002-07-23
Drodge, Joseph W. (Department: 1723)
Liquid purification or separation
Processes
Liquid/liquid solvent or colloidal extraction or diffusing...
C210S321690, C210S321890, C210S500240, C210S500430, C210S645000, C264S041000, C264S049000
Reexamination Certificate
active
06423232
ABSTRACT:
The present invention relates to the use of a neutral or cationic polymer, combined, before sterilization, with a semi-permeable membrane based on polyacrylonitrile bearing fixed negative charges, which is fitted in apparatus for the treatment of blood or plasma by extra-corporal circulation, to prevent activation of the contact phase of blood or plasma.
The subject of the present invention is also apparatus for the treatment of blood or plasma by extra-corporal circulation, which prevents activation of the contact phase of blood or plasma, as well as processes for manufacturing this apparatus.
Apparatus for the treatment of blood or plasma by extra-corporal circulation is used in various medical or paramedical applications, such as: treatment of renal insufficiency by dialysis or haemofiltration, plasmapheresis and apheresis for therapeutic and non-therapeutic purposes, oxygenation of the blood, immunopurification, etc.
Activation of the contact phase of blood or plasma appears to take place in particular when apparatus for the treatment of blood or plasma by extra-corporal circulation is used, which includes a negatively-charged semi-permeable membrane, without, in the absence of disruptive factors, the patients experiencing the slightest discomfort. Activation of the contact phase is described as a biological phenomenon which takes place in the case of patients undergoing blood (or plasma) treatment by extra-corporal circulation, when the blood comes into contact with the negatively charged surface of the membrane of certain apparatus for blood and plasma treatment. This biological phenomenon results in the generation of active substances, kallicrein and factor XIIa from inactive substances, prekallicrein and factor XII, kallicrein having a catalytic effect on the production of factor XIIa, and vice versa. In addition, kallicrein is the cause of the transformation of a plasma protein, high molecular weight kininogen, into a peptide substance, bradykinin.
When activation of the contact phase takes place simultaneously with certain disruptive factors such as, for example:
the presence, in the blood to be treated, of medicinal products for combating arterial hyper-tension by inhibition of the natural mechanism of vasoconstriction, these products being referred to generically as conversion enzyme inhibitors, or CEIs. These CEIs are also used for other therapeutic applications, in particular for treating certain forms of cardiac insufficiency,
dilution of the blood entering the apparatus filled with saline solution and concomitant lowering of the blood pH,
activation of the contact phase appears to be the cause of adverse reactions called anaphylactoid.
These anaphylactoid reactions develop, a few minutes after the start of the treatment, by various symptoms, including a generalized sensation of hotness, swelling of the fingers, the lips or the tongue, gasping for breath, nausea and laryngeal oedema.
Anaphylactoid reactions have been observed in particular in the case of renal insufficiency patients treated by haemodialysis, haemofiltration or haemodiafiltration with the aid of apparatus for the treatment of the blood in the form of a dialyser or exchanger containing a membrane.
Anaphylactoid reactions have been observed with exchangers containing membranes of various chemical compositions, sometimes during a first use, sometimes after several uses when the exchangers, rather than being discarded after a single use, are reused several times and recycled after each use. As examples of exchangers for which a first use has been accompanied by an adverse reaction, mention may be made of dialysers containing a membrane based on polymethyl methacrylate and on poly-acrylonitrile. Reactions associated with the reuse of dialysers containing a membrane based on cellulose acetate and on polysulphone have also been well documented (see the article entitled “Anaphylactoid reactions associated with reuse of hollow-fibber haemo-dialysers and ACE inhibitors” in “Kidney International”, vol. 42 (1992), pp. 1232-1237).
Anaphylactoid reactions are ascribed to an excessive concentration of bradykinin in the blood or in the plasma.
In order to avoid the generation of bradykinin at a concentration above 4000 pg/ml, European patent No. 0,561,379 recommends placing the blood or the plasma in contact only with semi-permeable membranes which have a limited surface charge density, i.e. an overall surface electrical charge of greater than or equal to −30 &mgr;eg/g of membrane, this electrical charge being measured by a method chosen from the group consisting of the dye adsorption method, the salt cleavage method, the method of titration to neutralization and the iodine method.
However, from the description of the invention claimed in European patent No. 0,561,379, in particular from the measuring methods proposed, it emerges that the surface electrical charge in fact corresponds to the overall ionic capacity of the semi-permeable membranes. Consequently, this European patent relates only to semi-permeable membranes with an overall ionic capacity of greater than or equal to −30 &mgr;eq/g of membrane, but not to semi-permeable membranes with an overall ionic capacity of very much less than −30 &mgr;eq/g of membrane, such as, for example, the membrane manufactured by the company Hospal from a copolymer of acrylonitrile and of sodium methallyl sulphonate, which is known under the trade name AN69.
Now, it is desirable not to modify the ionic capacity of membranes since this capacity gives rise to the adsorption and/or transfer of: certain proteins such as &bgr;2-microglobulin, inflammation mediators and complement factors; lipids. This is particularly true for membranes with a homogeneous, symmetrical structure.
Moreover, the Applicant has observed, that on several examples, that a membrane which has an overall ionic capacity of greater than −30 &mgr;eq/g of membrane can lead to activation of the contact phase, whereas, conversely, a membrane with an overall ionic capacity which is markedly less than −30 &mgr;eq/g of membrane cannot lead to activation of the contact phase.
Given the preceding observations, at the present time, a solution which is satisfactory, in both medical and economic terms, for preventing activation of the contact phase of blood or plasma which comes into contact with a negatively-charged semi-permeable membrane does not appear to be known.
SUMMARY OF THE INVENTION
One aim of the invention is thus to solve the abovementioned problem with apparatus for the treatment of blood or plasma by extra-corporal circulation, comprising a semi-permeable membrane based on polyacrylonitrile bearing fixed negative charges, which possesses two characteristics that have hitherto been considered antinomic, i.e.:
a negative overall ionic capacity, corresponding to an excess of negative charges, which simultaneously participates in the biocompatibility of the membrane and is a factor for triggering activation of the contact phase, and
a capacity not to produce activation of the contact phase under normal conditions for a first use.
Another aim of the invention is to solve the above-mentioned problem with sterilized apparatus for the treatment of blood or plasma by extra-corporal circulation, which has a capacity not to produce activation of the contact phase under normal conditions for a first use and which is stable in storage. Lastly, another aim of the invention is sterilized apparatus for the treatment of blood or plasma by extra-corporal circulation, which has a capacity not to produce activation of the contact phase under normal conditions for a first use and which is ready to use, i.e. which does not require any special manipulation on the part of the user of the apparatus, such as a special manipulation for the purposes of preventing the adverse effects of activation of the contact phase.
To this effect, the invention proposes the use of a neutral or cationic polymer for preventing activation of the contact phase of blood or plasma which comes into contact with a semi-per
Thomas Michel
Valette Pierre
Drodge Joseph W.
Hospal Industrie
Millen White Zelano & Branigan P.C.
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