Liquid purification or separation – Filter – Material
Reexamination Certificate
2000-12-22
2003-10-14
Foelak, Morton (Department: 1711)
Liquid purification or separation
Filter
Material
C210S500420, C521S064000, C521S149000
Reexamination Certificate
active
06632361
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to shaped objects for pyrogen retention, processes for their manufacture, and use thereof.
2. Description of Related Art
It is well known that pyrogens are substances, such as lipopolysaccharide complexes, that in extremely small amounts (approximately 0.2 &mgr;g/kg body weight) cause fever in higher-order animals and humans after intravenous injection (Pschyrembel, “Klinisches Wörterbuch” (Clinical Dictionary), 257th Ed., de Gruyter (1994), p. 1279). For this reason, infusion media contaminated with pyrogens, for example, must be rendered pyrogen-free prior to use.
A further area of application in which the removal of pyrogens is important is kidney dialysis using so-called high-flux membranes. Here, the dialyzate must either be freed of pyrogens, using a separate membrane unit for example, to prevent pyrogens from being filtered back through the wall of the dialysis membrane and thus entering the blood of the dialysis patient, or it is also possible to use a dialysis membrane that itself does not pass pyrogens, thus also preventing the transition of pyrogens into the blood. In this case, the pyrogen retention may be effected by the membrane's separation characteristic, i.e., the pyrogens are retained due to their size. In many cases, the pyrogen retention is based on adsorptive effects.
EP-A 0 478 842 describes a membrane filter layer made from inert polymer materials such as polyethylene, polypropylene, nylon 6,6, polycaprolactam, polyester, or polyvinylidene fluoride, from which membranes with a pore size of 0.04 to 0.45 &mgr;m can be produced for pyrogen removal, whereby the polymer material for the membrane filter layer is preferably a cationically or anionically modified polymer since the deposition capacity can be attained more readily. One example of a cationically modified polymer is nylon 6,6, whose surface is modified with a thermally hardenable polymer having quaternary ammonium groups. For the anionically modified polymers, carboxyl groups are preferred as the source of negative charge.
It is well known that pyrogens include the endotoxins, which represent cell fragments of dead gram-negative bacteria. With respect to endotoxin removal, WO 94/17906 describes a hydrophilic, charge-modified, microporous membrane having a cross-linked structure comprising an interpenetrating polymer network, whereby the membrane comprises polyethersulfone, polyfunctional glycidyl ether, polymeric amine, and possibly a homopolymer made from vinylpyrrolidone or a quaternized copolymer made from vinylpyrrolidone and dimethylaminoethyl methacrylate quaternized with methyl sulfate.
WO 98/01208 describes cationically charged membranes suitable for removing endotoxins. According to this publication, the membranes are manufactured by bringing a hydrophobic polymer membrane, preferably made from polysulfone, polyarylsulfone, or polyethersulfone, into contact with a polymer wetting agent and thereby cross-linking at least one agent cationically modifying the membrane onto the membrane. In another embodiment of WO 98/01208, the membrane is cast from a solution comprising polyethersulfone, a copolymer of vinylpyrrolidone and a cationic imidazolinium compound, preferably methylvinylimidazolinium methyl sulfate, and a low-molecular organic acid, whereby weight percentages for the acid in the casting solution of 24 to 34% by weight are disclosed. For this reason, the system components coming into contact with the casting solution must be acid-resistant, thus making the system more expensive.
The prior art discloses charge-bearing structures for pyrogen or endotoxin removal. Charge-bearing structures are preferred at least in order to attain a retention effect beyond that of the sieve effect. It is often noted, however, that the action of membranes modified in this manner is not sufficient, i.e., the endotoxin retention attained thereby is not high enough. Therefore, a need still exists for a product with improved retention of pyrogens or endotoxins, and for a process for manufacturing such a product.
SUMMARY OF THE INVENTION
The present invention is directed to a hydrophilically acting shaped object for pyrogen retention comprising a synthetic polymer component and a copolymer additive made from vinylpyrrolidone and a vinylimidazole compound, and a method of making the same.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Surprisingly, it has been found that, due to the additive of the invention, the shaped object of the invention has an improved endotoxin retention capacity that is higher than that of a comparable charge-modified shaped object.
It is clear that the additive should be accessible to the pyrogens, i.e., present on the surface of the shaped object. Preferably, the additive is therefore either worked into the shaped object homogeneously, or, more preferably, present on the surface of the shaped object in increased concentration.
The shaped object of the invention may be pore-free. In this embodiment, the invention may be, for example, in the form of a correspondingly fine-grained powder used as an adsorption medium for pyrogen retention columns.
Preferably, however, the shaped object of the invention has a porous structure, and it is especially preferred for it to have a porous structure open toward the surface and thus to have a pore surface in addition to the geometrical surface. Such objects have a large surface area comprising the external geometric surface and the inner surface of the pores, whereby the additive is accessible both on the geometric and pore surfaces. Due to its pore size, the shaped object of the invention allows at least part of the pyrogens to pass. The additive of the invention, present on the pore surface, acts to retain these pyrogens.
It is especially preferred for the porous shaped object to be a semipermeable flat, tubular, or hollow-fiber membrane, whereby one skilled in the art will understand how large the dimension of the pores should be in order to maintain the pressure build-up within acceptable limits, yet understand how small the pores should be to maintain sufficient pore surface and thus sufficient load capacity of the membrane for the pyrogens or endotoxins.
The copolymer of the invention may have any known copolymer structure, such as, for example, a block copolymer. Preferably, the copolymer is a statistic copolymer.
In accordance with the invention, the molar ratio of the vinylimidazole compound to the vinylpyrrolidone in the copolymer may be selected from a broad range. Preferably, the ratio is from 10:90 to 90:10 mol/mol. A ratio of about 50:50 mol/mol is especially preferred.
In accordance with the invention, the vinylimidazole compound may be substituted at one or more of carbon atoms 2, 4, and 5, whereby the vinylimidazole compound is preferably 1-vinylimidazole substituted at carbon atoms 2 and/or 4 and/or 5 with a C
1
-C
5
-alkyl group. In another preferred embodiment of the invention, the vinylimidazole compound is 1-vinylimidazole.
For many of the applications of the shaped object of the present invention, the adsorptive adhesion of the additive on the synthetic polymer component is sufficient, such that no after-treatment is required to increase the additive adhesion. For other applications of the shaped object of the invention, in which, without after-treatment, a portion of the additive may be eluted (for example by sterilization, extraction, or another after-treatment step of the shaped object such as pre-flushing of the membrane, or by the pyrogen-contaminated liquids used) the shaped object of the invention may contain the additive in a form that sufficiently increases adhesion. Preferably, the additive is cross-linked to increase adhesion.
Since the pyrogen- or endotoxin-containing solutions are generally aqueous, the synthetic polymer component must act hydrophilically, no later than when the shaped object is used according to the invention. To this end, basically any structure is suitable that renders the geometric surface, and the porous surfac
Niklas Thorsten
Nothdurft Annekatrin
Wechs Friedbert
Foelak Morton
Membrana GmbH
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