Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Mixing of two or more solid polymers; mixing of solid...
Reexamination Certificate
2000-02-28
2002-01-08
Russel, Jeffrey E. (Department: 1653)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Mixing of two or more solid polymers; mixing of solid...
C210S692000, C424S078170, C530S359000, C604S005030
Reexamination Certificate
active
06337368
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a lipoprotein adsorbent. More particularly, it relates to a lipoprotein adsorbent for selectively adsorbing and removing lipoproteins, including apoB proteins, in particular low density lipoproteins (hereinafter, LDL) and very low density lipoproteins (hereinafter, VLDL), from blood constituents or the like.
BACKGROUND ART
Lipoproteins occurring in blood, in particular LDL and VLDL, commonly known as a villain cholesterol, contain a large amount of cholesterol and are known to be causative of atherosclerosis. On the other hand, the high density lipoprotein (hereinafter, HDL), commonly known as a goody cholesterol, is known to serve as an atherosclerosis retarding factor. Therefore, means is desired by which LDL and VLDL can be removed from blood constituents or the like without removing HDL therefrom.
As the methods currently in clinical use for removing LDL and VLDL, there can be mentioned plasma exchange therapy, double filtration membrane method, use of adsorbents (immobilized dextran sulfate, immobilized anti-apoB antibody, etc.) and HELP system, among others.
However, the membrane method brings about simultaneous removal of a considerable amount of HDL together with LDL and VLDL and therefore fails to satisfy the selectivity for lipoprotein. Further, there is a drawback that plasma proteins are partly removed simultaneously, hence such losses need to be repaired by supplementation.
As the removing method using an adsorbent, there can be mentioned, for example, the removing method using the so-called immunoadsorbent comprising an antibody or the like immobilized and the removing method using an adsorbent comprising a compound having affinity for LDL and VLDL (hereinafter, ligand) as immobilized according to the principle of the so-called affinity chromatography.
The removing method using an immunoadsorbent, however, has problems although it satisfies the selectivity for lipoprotein; thus, for example, the antibody to be used is not readily available or is poor in economy or storage stability or is difficult to sterilize.
In the removing method which uses an adsorbent based on the principle of affinity chromatography, heparin, dextran sulfate and the like are used as ligands of adsorbents. The adsorbents in which these ligands are used show good selectivity for lipoprotein and the ligands themselves are not very expensive. In cases where a ligand is used in large amounts, however, it is desired that said ligand is less expensive.
As an adsorbent for adsorbing and removing lipoproteins by using such an organic compound as phenyl glycidyl ether as a ligand and utilizing the hydrophobic interaction between the phenyl group and the hydrophobic sites of the lipoprotein surface, there is commercially available Phenyl Sepharose CL-4B (product of Pharmacia Fine Chemicals). However, this adsorbent, though it is inexpensive, adsorbs large amounts of HDL as well as LDL and VLDL and thus has a serious drawback from the standpoint of the selectivity for lipoprotein.
DISCLOSURE OF THE INVENTION
In view of the above-mentioned state of the art, the present invention has its objects to provide an adsorbent capable of efficiently adsorbing and removing LDL and VLDL from various lipoprotein-containing solutions, such as blood, serum, plasma, dilutions thereof, and solutions resulting from pretreatment of them for removal of blood corpuscles or serum protein or the like as well as a lipoprotein adsorber in which said adsorbent is used.
Japanese Kokai Publication Sho-62-186940 describes a lipoprotein adsorbent which comprises a water-insoluble carrier having aniline or an aniline derivative immobilized thereon and, in Japanese Kokai Publication Sho-63-208764, there is described a lipoprotein adsorbent comprising a water-insoluble matrix and, on the surface thereof, a group represented by the general formula —NR
a
R
b
in which R
b
is a group such that the corresponding compound R
b
H has a logarithmic value (log P) of 0 to 3.2, P being the partition coefficient in the water-octanol system, and it is disclosed that an inexpensive lipoprotein removing apparatus capable of removing LDL and VLDL selectively can be provided by using said adsorbent.
Referring to these technologies, the present inventors made further investigations and, as a result, found that when the lipoprotein adsorbents having a group represented by the above general formula —NR
a
R
b
further have a substituent in the meta position of R
b
, which is the aromatic ring-containing atomic group in said group —NR
a
R
b
, the selectivity for LDL and VLDL, in particular, is high, that when, in cases where R
b
is a group bound to an aromatic ring via an atom or atomic group, it is bound to the aromatic ring via a carbonyl group, the selectivity for LDL and VLDL is high; and that when R
b
has a specific functional group, the selectivity for LDL and VLDL is particularly high.
Thus, the present invention provides a lipoprotein adsorbent comprising a water-insoluble carrier having, on at least one part of the surface of said carrier, at least one group (other than p-nitrobenzoic acid) selected from the group consisting of groups represented by the general formula
(hereinafter also represented as “—NR
1
&phgr;
1
X”) (wherein R
1
represents a hydrogen atom or a methyl or ethyl group, &phgr;
1
represents an atomic group comprising an aromatic ring bound directly or via one atom to the nitrogen atom, X represents a substituent atom or atomic group bound to a meta position of said aromatic ring, and &phgr;
1
X represents an atomic group such that the compound represented by H&phgr;
1
X has a logP value (P being the partition coefficient in the water-octanol system) of 0 to 3.2), and groups represented by the general formula
(hereinafter also represented as “—NR
2
CO&phgr;
2
Y”) wherein R
2
represents a hydrogen atom or a methyl or ethyl group, CO represents a carbonyl group, &phgr;
2
represents an atomic group comprising an aromatic ring bound to the nitrogen atom via said carbonyl group, Y represents an atomic group bound to said aromatic ring, to the exclusion of the case where H&phgr;
2
Y is benzene, and CO&phgr;
2
Y represents an atomic group such that the compound represented by Y&phgr;
2
COH has a logP value of 0 to 3.2 (P being the partition coefficient in the water-octanol system). The present invention further provides a lipoprotein adsorber which comprises an adsorption section containing the lipoprotein adsorbent mentioned above, a liquid inlet section for a liquid to flow into said adsorption section and a liquid discharge section for the liquid that has flown into said adsorption section to flow out of said adsorption section.
DETAILED DESCRIPTION OF THE INVENTION
In the following, the present invention is described in detail.
The lipoprotein adsorbent of the present invention has, on at least one part of the surface of a water-insoluble carrier, at least one group selected from the group consisting of a group represented by the general formula —NR
1
&phgr;
1
X (wherein R
1
, &phgr;
1
and X are as defined above) and a group represented by the general formula —NR
2
CO&phgr;
2
Y (wherein R
2
, CO, &phgr;
2
and Y are as defined above).
In the above group —NR
1
&phgr;
1
X, R
1
represents a hydrogen atom, methyl group or ethyl group. The above-mentioned &phgr;
1
represents an atomic group comprising an aromatic ring bound to the nitrogen atom either directly or via an atom. The above-mentioned X represents an atomic group bound to the meta position of said aromatic ring. Further, &phgr;
1
X resulting from binding &phgr;
1
and X to each other is such that the compound represented by H&phgr;
1
X has a logP value of 0 to 3.2 (P being the partition coefficient in the water-octanol system).
The logP value, which is the logarithmic value of the partition coefficient in the water-octanol system, is a parameter indicative of the degree of hydrophobicity of a compound. A typical method of determining the partition coefficient P is as follows.
The compound is dissolved in octanol (or
Kobayashi Akira
Okuyama Tsutomu
Connolly Bove Lodge & Hutz LLP.
Kaneka Corporation
Russel Jeffrey E.
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