Liquid purification or separation – Filter – Material
Reexamination Certificate
2001-05-08
2003-10-14
Kim, John (Department: 1723)
Liquid purification or separation
Filter
Material
C210S321780, C210S321870
Reexamination Certificate
active
06632359
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a blood purifying apparatus with high blood treating capabilities such as elimination of low molecular proteins and the like, and, particularly, to a blood purifying apparatus with reduced inflow of endotoxins from the dialyzate side.
BACKGROUND ART
Conventionally, a blood purifying apparatus used for hemodialysis, hemofiltration, and the like has an object of removing metabolic decomposition products and toxic substances accumulated in the blood by applying principle of diffusion or filtration. After development of a drum-type hemodialyzer by Kolff et al. in 1943, for example, membrane type dialyzers have been used for the therapy of patients who have partially or completely lost kidney function.
Metabolic decomposition products and toxic substances are generally eliminated through a membrane. Membranes made of regenerated cellulose or synthetic polymer such as polyethylene, polyacrylonitrile, polysulfone, or the like are known in the art. These materials are fabricated into membranes in the form of a sheet or hollow fiber. The hollow fiber membranes have become more popular in recent years due to the large blood contact area and high processing capacity.
If the membrane is in the form of a sheet, two or more sheets are layered and-filled into a plastic container; if hollow fibers, several hundred to several tens of thousands of pieces of fiber are bundled and filled into a cylindrical plastic container to make semi manufactured goods, which is sterilized and used as blood purifying apparatus. When processing blood using a hollow fiber blood purifying apparatus, blood is caused to flow inside hollow fibers and a dialyzate containing an inorganic electrolyte and the like is caused to flow outside the hollow fibers. Substances to be eliminated from blood are diffused or filtered through the hollow fiber membrane to the dialyzate side.
In the early stage, the materials to be eliminated by blood treatment other than water retained in the body were low molecular weight inorganic substances such as urea nitrogen, creatinine, uric acid, and the like. In 1965, Scribner proposed, in his middle molecular hypothesis, that it is necessary to eliminate substance having a certain large molecular weight for the maintenance of a normal state in patients who have lost kidney function. In the later half of the 1980's, &bgr;2 microglobulin (hereinafter referred to as &bgr;
2
-Mg) which is a protein with an estimated molecular weight of 11,200 was found in the arthrogenous area of a patient exhibiting dialysis amyloidosis which is a typical symptom of long-term dialysis patients. For these reasons, the recent main stream is a high performance blood purifying apparatus which is designed to eliminate low molecular weight proteins having a molecular weight from about ten thousand to several tens of thousands.
The intended elimination of low molecular weight proteins such as &bgr;
2
-Mg requires expansion of membrane pore sizes to a certain degree. Excessive pore size expansion, however, accompanies problems such as escape of albumin (molecular weight: 66,000), which is a useful protein, and reverse filtration of dialyzate from the outside of the hollow fibers to the inside where the blood flows. This may allow invasion of a very small amount of endotoxins contained in the dialyzate into the blood side and may cause anaphylactogenic symptoms. Therefore, in many clinical facilities an endotoxin adsorbent or an endotoxin elimination filter are provided immediately before the dialyzate side entrance of the dialyzer to control the dialyzate.
In dialyzers using an advanced high performance technology, however, these known technologies may encounter difficulties in sufficiently preventing the effect of endotoxins when the endotoxin elimination filter and the like deteriorate or joints of dialyzate lines and the dialyzer are contaminated.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a blood purifying apparatus having excellent blood-purification performance such as elimination performance of low molecular proteins and the like, and allowing only reduced inflow of endotoxins from the dialyzate side.
The inventors of the present invention have conducted extensive studies on the membrane structure and characteristics, and found that, even in a blood purifying apparatus with high elimination performance of low molecular weight proteins, it is possible to remarkably decrease endotoxin inflow from the dialyzate side by adjusting the membrane characteristics within certain specific values. This finding has led to the completion of the invention.
Specifically, an object of the present invention is to provide a blood purifying apparatus in which (1) the value obtained by dividing the solute permeability coefficient (&agr; value) which is obtained by the penetration test of a high weight moleculas substance, by the water permeability performance (Lp value) is 6×10
−7
or more, (2) the solute permeability coefficient (&agr; value) is in the range of 8×10
−5
to 1.5×10
−3
and the product of the solute permeability coefficient (&agr; value) and the water permeability performance (Lp value), which is obtained by the polymer penetration test, is 2.4×10
−2
or less, or (3) the invasion ratio obtained by the invasion test of a high molecular weight substance is 10% or less.
Another object of the present invention is to provide a blood purifying apparatus satisfying two or more of the above three conditions at the same time.
Still another object of the present invention is to provide a blood purifying apparatus satisfying any of the following conditions: the Lp value is in the range of 50 ml/Hr/mmHg/m
2
to 170 ml/Hr/mmHg/m
2
; an s value obtained by the invasion test of a high molecular weight substance is in the range of 1,000 to 5,000 and/or a p value obtained by the invasion test of a high molecular weight substance is 6% or less; and the blood purifying apparatus is made from an asymmetric hollow fiber membrane.
The blood purifying apparatus in the present invention is an artificial kidney which eliminates insoluble component in the blood by dialysis and/or filtration by causing the blood to contact with a dialyzate via a membrane such as a hemodialyzer, hemofilter, hemodialyis-filter, and the like.
The penetration test of high-molecular substance in the present invention is a test comprising causing a solution of a water soluble substance with a known high molecular weight to flow into the dialyzate side and detecting the amount of the dissolved substance permeating into the blood side through the membrane. Polyvinylpyrrolidone (hereinafter referred to as PVP) is used as the solute. PVP having a molecular weight distribution in the range of several thousand to about 300,000 which is made available by BASF under the trademark PVP(K-30) for example, is suitable for use in a test such as the present test in which the object of evaluation is permeability of proteins with a molecular weight of about several tens of thousand or permeability of endotoxins with a molecular weight of about several hundred of thousands. In the present test, PVP having a weight average molecular weight of 35,000 is used after confirming the molecular weight distribution using HPLC. The PVP may be from a single production lot or, if the molecular weight significantly differs from 35,000, two or more lots may be mixed to adjust the molecular weight distribution.
The method of conducting this test will now be described. A 20 ppm PVP solution is prepared using PVP with a known molecular weight and is fed to a blood purifying apparatus after discharge of a washing liquid used for previous washing according to a normal washing procedure. The PVP solution is caused to filtrate wholly from the dialyzate side to the blood side of the blood purifying apparatus at a rate of 100 ml/minute. The pressure difference between the dialyzate side and the blood side after five minutes from start of filtration is assumed to be &Dgr;
Uezumi Satoshi
Yoshida Makoto
Asahi Medical Co., Ltd.
Kim John
LandOfFree
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