U.S. patent application number 12/465005 was filed with the patent office on 2009-09-10 for macromolecular ketoaldehydes.
This patent application is currently assigned to Baxter International Inc.. Invention is credited to Henk Blom, Alex Odufu, Mitchell J. Poss, Robert Smakman.
Application Number | 20090223899 12/465005 |
Document ID | / |
Family ID | 32907892 |
Filed Date | 2009-09-10 |
United States Patent
Application |
20090223899 |
Kind Code |
A1 |
Poss; Mitchell J. ; et
al. |
September 10, 2009 |
MACROMOLECULAR KETOALDEHYDES
Abstract
Methods of producing macromolecular compositions and using same
are provided. The method includes preparing a resin material;
forming an acetyl group on the resin material; and oxidizing the
acetyl group via a one-step reaction including reacting a sulfoxide
and an acid with the acetyl group to form a ketoaldehyde group. The
macromolecular compositions are capable of removing an effective
amount of one or more constituents from a physiological solution,
such as urea during dialysis therapy.
Inventors: |
Poss; Mitchell J.; (Antioch,
IL) ; Blom; Henk; (Mundelein, IL) ; Odufu;
Alex; (Hoffman Estates, IL) ; Smakman; Robert;
(NW Nigtevecht, NL) |
Correspondence
Address: |
K&L Gates LLP
P.O. Box 1135
Chicago
IL
60690-1135
US
|
Assignee: |
Baxter International Inc.
Deerfield
IL
Baxter Healthcare S.A.
Zurich
|
Family ID: |
32907892 |
Appl. No.: |
12/465005 |
Filed: |
May 13, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10987331 |
Nov 12, 2004 |
7544737 |
|
|
12465005 |
|
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|
|
10376095 |
Feb 28, 2003 |
6861473 |
|
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10987331 |
|
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Current U.S.
Class: |
210/645 ;
210/321.6; 526/316 |
Current CPC
Class: |
B01J 39/20 20130101;
B01J 20/26 20130101; A61M 1/1696 20130101; B01J 20/265 20130101;
B01J 41/14 20130101; C08F 8/06 20130101; C08F 8/10 20130101; C08F
8/10 20130101; C08F 212/08 20130101; C08F 8/06 20130101; C08F 8/10
20130101; C08F 212/08 20130101 |
Class at
Publication: |
210/645 ;
526/316; 210/321.6 |
International
Class: |
B01D 61/00 20060101
B01D061/00; C08F 16/36 20060101 C08F016/36 |
Claims
1. A medical device comprising: a body defining an interior; an
inlet; an outlet; and a binder material, located in the interior of
the body, comprising a polystyrene, a spacer group attached to a
phenyl group on the polystyrene, and an alpha-ketoaldehyde group
attached to the spacer group, the binder material adapted to remove
one or more constituents from a medical fluid that flows into the
interior of the body.
2. The medical device of claim 1, wherein the binder material is a
urea binder material adapted to remove a therapeutically effective
amount of urea from a dialysis solution.
3. The medical device of claim 1, wherein the spacer group is
selected from the group consisting of a substituted or an
unsubstituted aliphatic group, a substituted or an unsubstituted
alicyclic group, a substituted or an unsubstituted aromatic group
and combinations thereof.
4. The medical device of claim 1, wherein the spacer group
comprises a methylene group.
5. The medical device of claim 1, wherein the binder material has a
layered configuration.
6. The medical device of claim 1, wherein the binder material is
provided in a chemical cartridge.
7. The medical device of claim 6, wherein the chemical cartridge
includes a urea binder material, a carbon layer, and a material
layer.
8. A medical device comprising: a body defining an interior; an
inlet; an outlet; and a chemical cartridge including a binder
material, a carbon layer and a material layer, the binder material
comprising a polystyrene, a spacer group attached to a phenyl group
on the polystyrene, and an alpha-ketoaldehyde group attached to the
spacer group, wherein the chemical cartridge is provided in the
interior of the body and is adapted to remove one or more
constituents from a medical fluid that is received within the
interior of the body.
9. A medical system comprising: a removal device comprising a body,
a binder material located within the interior of the body, the
binder material comprising a polystyrene, a spacer group attached
to a phenyl group on the polystyrene, and an alpha-ketoaldehyde
group attached to the spacer group, the binder material adapted to
remove one or more constituents from a medical fluid; and a fluid
pathway coupled to the removal device, the fluid pathway comprising
an inflow fluid path and an outflow fluid path for the medical
fluid.
10. The medical system of claim 9, the removal device further
comprising: an inlet configured to fluidly connect the inflow fluid
path to the body of the removal device, and an outlet configured to
fluidly connect the outflow fluid path to the body of the removal
device.
11. A binder material comprising: a cross-linked polystyrene having
a phenyl group, and an alpha-ketoaldehyde group attached to the
phenyl group.
12. The binder material of claim 11, further comprising one or more
activating groups attached to the phenyl ring.
13. The binder material of claim 11, further comprising at least
one additional component selected from the group consisting of a
hydrophilic group, an ion exchanging group or combinations
thereof.
14. The binder material of claim 11, further comprising a suitable
amount of a cross-linking agent.
15. The binder material of claim 14, the cross-linked polystyrene
further comprising up to about 25% by weight of the cross-linking
agent.
16. The binder material of claim 14, wherein the cross-linking
agent is divinylbenzene.
17. The binder material of claim 11, wherein the cross-linked
polystyrene is a porous bead.
18. A method for removing one or more constituents from a
physiological solution, the method comprising: passing a
physiological solution through a removal device comprising a binder
material, the binder material comprising a cross-linked polystyrene
having a phenyl group and an alpha-ketoaldehyde group attached to
the phenyl group, and removing one or more constituents from the
physiological fluid.
19. The method of claim 18, the binder material further comprising
one or more activating groups attached to the phenyl ring.
20. The method of claim 18, the binder material further comprising
at least one additional component selected from the group
consisting of hydrophilic groups, ion exchanging groups or
combinations thereof.
21. The method of claim 18, wherein the physiological fluid
includes dialysate that has been passed from a patient to the
removal device.
22. The method of claim 18, wherein the binder material is a urea
binder material.
23. The method of claim 18, wherein the binder material further
comprises at least one additional component selected from the group
consisting of hydrophilic groups, ion exchanging groups or
combinations thereof.
24. The method of claim 18, wherein the constituents are selected
from the group consisting of a nucleophilic moiety, an
electron-rich chemical group, a Lewis base, a Bronsted base, an
anion, including halides, molecules or radicals containing one or
more heteroatoms with a free electron pair including sulfur,
nitrogen, oxygen, urea, creatinine, uric acid, .beta.-2
microglobulin, metabolic waste, proteinaceous matter, biological
matter and combinations thereof.
25. A method for treating a patient requiring dialysis therapy, the
method comprising: removing a physiological solution from a
patient, passing the physiological solution through a removal
device comprising a binder material, the binder material comprising
a polystyrene, a spacer group attached to a phenyl group on the
polystyrene, and an alpha-ketoaldehyde group attached to the spacer
group; removing one or more constituents from the physiological
fluid, and returning the physiological solution to the patient.
26. The method of claim 25, wherein the physiological solution is a
dialysate solution.
27. The method of claim 25, wherein one of the constituents removed
from the physiological fluid is urea.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This patent application is a continuation of U.S. patent
application Ser. No. 10/987,331 filed Nov. 12, 2004, which is a
divisional of U.S. Pat. No. 6,861,473 filed on Feb. 28, 2003, the
entire disclosures of which are expressly incorporated herein by
reference.
BACKGROUND
[0002] The present invention relates generally to macromolecular
compositions. More specifically, the present invention relates to
methods of making and using macromolecular ketoaldehyde
compositions that have chemical binding properties.
[0003] In general, materials are known and used to remove
constituents from fluids for a number of different applications
including, for example, industrial, recreational, therapeutic,
diagnostic and/or the like. For example, cationic polymers, anionic
polymers and combinations thereof are typically used to purify a
variety of different aqueous streams, such as industrial process
streams, via ion exchange, flocculation or other suitable
mechanism. Other materials are generally known as sorbent
materials. The physiochemical properties of these types of
materials enable them to remove suitable types of constituents from
fluid via adsorption, absorbtion, chemisorption, chemical binding
and/or other suitable mechanisms.
[0004] In general, polymeric materials are known in the art that
are capable of removing nitrogen-containing compounds, such as
urea, creatinine, proteins, amino acids, glyco-proteins and/or
other metabolic waste in solution. These types of materials contain
a functional group(s) that chemically bind with urea or other like
compounds. For example, U.S. Pat. Nos. 3,933,753 and 4,012,317
disclose an alkenylaromatic polymer containing phenylglyoxal that
can function to chemically bind urea. As disclosed, the process for
making the glyoxal-functionalized polymer, in general, includes the
preparation of a poly-p-vinylacetophenone. Next, a phenacyl bromide
is formed. This is followed by a separate step that includes the
oxidation of the poly-p-vinylphenacetyl halide to form the
phenylglyoxal groups. See, for example, U.S. Pat. No. 3,933,753,
columns 7 and 8.
[0005] Another example of a polymeric material capable of removing
urea or the like in solution is disclosed in U.S. Pat. No.
4,897,200. This material includes a tricarbonyl functionality
commonly known as ninhydrin. The general formula of the polymeric
material (P-ninhydrin) is shown below:
##STR00001##
[0006] The ninhydrin-containing material may produce better urea
uptake levels as compared to, for example, the glyoxal-containing
materials discussed above. However, the ninhydrin product is
expensive to make due, in part, to the numerous reaction steps
necessary to carry out the reaction.
[0007] A need, therefore, exists to provide macromolecular
compositions made from improved methods with chemical binding
properties that can be effective even under physiological
conditions and that can be readily and easily made at reduced
costs, and easily adapted to existing systems, such as therapeutic
system.
SUMMARY
[0008] The present invention relates to macromolecular
compositions. In particular, the present invention relates to
improved methods of making and using macromolecular compositions
that have chemical binding properties. The macromolecular
compositions of the present invention include macromolecular
ketoaldehydes that can chemically bind with one or more suitable
constituents of any suitable fluid at enhanced uptake levels. As
used herein, the term "macromolecular composition" or other like
terms means a large molecule, such as a molecule that has a
molecular weight greater than 1000 amu including, for example,
synthetic polymers, natural polymers, and/or the like.
[0009] The present invention provides processes for producing
macromolecular compositions. The macromolecular composition can
include a composition prepared via a route of suitable conversions
from, for example, a (co)polymerisate of an ethylenically
unsaturated compound, such as an aromatic vinyl monomer; a
polycondensate, such as obtained, for example, from a Friedel
Crafts reactions of aromatic compounds; a natural macromolecular
material and modifications thereof; a macromolecular material, such
as carbon or other suitable macromolecular product prepared by
pyrolysis; an inorganic material, such as silica, alumina, zeolite,
sodium aluminum silicates or the like; or combinations thereof. For
example, the preparation of macromolecular composition can result
in the formation of a resin material composed of cross-linked
polystyrene. The macromolecular composition may have a relatively
high internal surface area.
[0010] The process of the present invention includes the
acetylation of the macromolecular composition. This results in the
formation of an acetylated macromolecular composition, such as an
acetylated polystyrene resin.
[0011] Oxidation of the macromolecular composition is performed
subsequent to acetylation, thus resulting in the formation of the
ketoaldehyde group. In an embodiment of the present invention, the
oxidation is performed in a single reaction step. This step
includes mixing the acetylated composition with an oxidizing
solvent, such as dimethylsulfoxide and/or the like to form a
reaction mixture. An acid, such as a hydrohalic acid including
hydrobromic acid and/or the like is added to the reaction mixture,
thus converting the acetyl groups into the ketoaldehyde groups.
Applicants believe that the process of the present invention
results in macromolecular ketoaldehydes with enhanced
functionalization. This can facilitate the binding capabilities of
the composition with respect to, for example, anions, molecules or
radicals containing heteroatoms with free electron pairs, such as
sulfur, nitrogen, oxygen, such as urea, creatinine, uric acid,
.beta.-2 microglobulin, proteins similar to .beta.-2 microglobulin,
other like metabolic waste, other suitable biological matter and/or
other suitable constituent.
[0012] In an embodiment, the macromolecular ketoaldehydes of the
present invention include a ketoaldehyde. Preferably, the
ketoaldehyde is a phenylglyoxal. In an embodiment, the ketoaldehyde
has a phenyl group and an .alpha.-ketoaldehyde group.
[0013] The macromolecular ketoaldehyde compositions of the present
invention can be effectively utilized in a variety of different
applications even under physiological conditions. For example, the
macromolecular compositions of the present invention can be
utilized to remove urea and/or the like from any suitable fluid at
effective uptake levels. Urea removal or removal of any nucleophile
is due to the reactive binding between the ketoaldehydes of the
macromolecular composition and one or both nitrogen atoms of urea
or one or more nitrogen atoms associated with any suitable
nucleophile.
[0014] This can be particularly beneficial as applied during
regenerative dialysis therapy where the dialysate is regenerated
prior to reuse, such as recirculation into, through and out of a
patient's peritoneal cavity during continuous flow peritoneal
dialysis. In this regard, the macromolecular compositions of the
present invention can be adapted in any suitable way to remove at
least a portion of urea, other suitable metabolic waste, suitable
other biological matter and the like from the dialysate prior to
reuse. It should be appreciated that the macromolecular
compositions of the present invention can be utilized in a variety
of different and suitable applications with respect to and in
addition to dialysis therapy.
[0015] An advantage of the present invention is to provide improved
methods for making macromolecular compositions.
[0016] Another advantage of the present invention is to provide
improved materials, devices, apparatuses and systems that utilize
macromolecular ketoaldehydes made according to an embodiment of the
present invention.
[0017] Yet another advantage of the present invention is to provide
improved macromolecular phenylglyoxals that can chemically bind
urea and/or the like.
[0018] Yet still another advantage of the present invention is to
provide improved macromolecular materials that can chemically bind
urea and/or the like under physiological conditions.
[0019] A further advantage of the present invention is to provide
improved macromolecular compositions that can remove urea and/or
the like from solutions used during medical therapy, such as
dialysis.
[0020] Additional features and advantages of the present invention
are described in, and will be apparent from, the following Detailed
Description of the Invention and the figures.
BRIEF DESCRIPTION OF THE FIGURES
[0021] FIG. 1 is a schematic illustration of a system including a
device containing a macromolecular composition according to an
embodiment of the present invention.
DETAILED DESCRIPTION
[0022] The present invention generally relates to macromolecular
compositions. More specifically, the present invention relates to
methods of making and using macromolecular compositions, such as
those containing ketoaldehydes with chemical binding
properties.
[0023] In general, the processes of the present invention include
the steps of preparing the macromolecular composition, such as a
cross-linked polystyrene resin; acetylation of the macromolecular
composition; and formation of a ketoaldehyde functional group via
oxidation of the acetylated macromolecular composition. The
oxidation step, in general, includes the formation of acetyl halide
groups and subsequent oxidation thereof to form the ketoaldehyde
groups (e.g., glyoxal) in a single reaction step as detailed below.
Applicants believe that the processes of the present invention can
produce ketoaldehyde-functionalized macromolecular compositions
with binding properties with respect to a variety of different
constituents in solution as previously discussed.
[0024] Applicants believe that the processes of the present
invention can result in a higher concentration of active chemical
binding sites which correspond to the number of glyoxals on the
phenyl ring of the macromolecular composition of the present
invention. This can also have the added effect of enhancing the
chemical reactivity of the compositions of the present invention
with respect to removing constituents, such as urea, from a
fluid.
[0025] As previously discussed, the process steps of the present
invention generally can be described as follows: 1) preparation of
resin material; and 2) glyoxalation of resin material. The
glyoxalation includes acetylation and subsequent oxidation. It
should be appreciated that the processes of the present invention
can include any suitable number and type of additional types of
reaction steps. For example, the processes of the present invention
can include alkylation of the macromolecular composition to provide
chemical groups in addition to the ketoaldehyde groups. The
additional chemical groups may effect the macromolecular
compositions to facilitate the binding properties thereof as
discussed above. It should be appreciated that glyoxalation and the
addition of the additional chemical groups can occur in any
suitable sequence including, for example, during the same process
step as described in detail below.
Resin Material Preparation
[0026] The present invention can include a variety of suitable
resin materials. In general, the resin material can include a
porous polymeric structure or non-porous polymeric structure. The
pore size can range from microporous to macroporous in size
depending on the application. In an embodiment, the resin materials
are composed of a porous bead material made from any suitable
polymer. Preferably, the resin material is made from cross-linked
styrene, such as styrene cross-linked with a suitable amount of a
cross-linking agent, such as divinylbenzene. In an embodiment, the
cross-linked resin material includes about 25% or less by weight of
the cross-linking agent. It should be appreciated that any suitable
type of material can be used as the resin material. For example,
the resin material can include a gel material. In general, this is
a polymeric material that is effectively non-porous.
[0027] The resin material of the present invention can be made in
any suitable way and/or may be commercially-available. In general,
cross-linked polystyrene beads can be made according to known
processes, such as suspension polymerization. In a typical
reaction, a styrene monomer, divinylbenzene and an initiator are
added to a reactor containing an aqueous phase with polymeric
and/or inorganic stabilizers. If macroporosity is desired, a
precipitant, such as an alkane, can be added to the monomer phase.
Optionally, a solvating agent, such as toluene, can be added too.
Also, a linear (monomer-soluble) polymer can be used. The reactants
are typically stirred and heated to an appropriate temperature to
carry out the polymerization reaction.
[0028] The resultant polymer can be characterized in a variety of
suitable ways. In an embodiment, the styrene content of the polymer
ranges from about 0.01% by weight to about 99.9% by weight; and the
divinylbenzene content (typically includes a mixture of
divinylbenzene and 3-ethyl styrene) ranges from about 0% by weight
to about 90% by weight. Preferably, the styrene content is higher
than the divinylbenzene content. In an embodiment, the
divinylbenzene content ranges from about 0.1% by weight to about
20% by weight. Additional other monomers or polymers in any
suitable amount can be present during polymerization. For example,
the polymer can include a hydrophilic monomer or its precursor or a
hydrophobic monomer in an amount ranging from about 0 to about 10
mole percent or greater. Depending on the application, the resin
material of the present invention can include any suitable pore
size, surface area and molecular weight.
Glyoxalation
[0029] As used herein, the term "glyoxalation" or other like term
means modifying a chemical moiety to produce a glyoxal group. For
example, modifying a phenyl ring to produce a phenylglyoxal.
[0030] In an embodiment, the phenyl group of the polystyrene resin
is modified to include the glyoxal group. This can proceed via any
suitable reaction mechanism, preferably acetylation via a Friedel
Crafts reaction and subsequent oxidation of the acetyl group to
form the glyoxal group attached to the phenyl ring. As detailed
below, the oxidation step, in an embodiment, can produce the
glyoxal group in a single reaction step. In an embodiment, this
includes the formation of an acetyl halide group and subsequent
oxidation of the acetyl halide group via a reaction with any
suitable oxidizing agent, such as, sulfoxide, aliphatic sulfoxides
including dimethyl sulfoxide and an acid, such as hydrohalic acid
including hydrogen bromide.
Additional Processing
[0031] As previously discussed, it should be appreciated that the
processes of the present invention are not limited to acetylation
and oxidation processing steps but can include any suitable number
and types of additional processing steps. For example, chemical
groups in addition to the glyoxal groups can be attached to the
phenyl ring as previously discussed. These additional other groups
can include, for example, electron withdrawing groups, steric
groups, chemical groups that can display both steric and electron
withdrawing effects, electron donating groups, halogen groups,
alkyl groups and/or the like discussed above.
[0032] The additional other chemical group(s) can be added to the
phenyl ring in any suitable way. For example, the alkyl group(s)
can be added to the phenyl ring via alkylation with a typical
Friedel Crafts catalyst, alone or in addition to other reaction
steps. In general, alkyl halides are known to alkylate benzene to
produce alkyl-benzene in the presence of a Lewis acid catalyst,
such as ferric chloride or aluminum chloride. Also alkenes in the
presence of, for example, hydrochloric acid, trifluoromethane
sulfonic acid and a Lewis acid catalyst can be used.
[0033] The macromolecular compositions of the present invention can
be sterilized in any suitable manner. In an embodiment, the
macromolecular compositions can be sterilized with gamma radiation.
In general, the composition is exposed to a suitable amount or dose
of gamma radiation sufficient for sterilization purposes. In an
embodiment, the macromolecular composition of the present invention
is exposed to about 5 Gky to about 50 Gky of gamma radiation during
sterilization. It should be appreciated that sterilization by gamma
radiation can be carried out in any suitable way.
[0034] In an embodiment, the macromolecular compositions of the
present invention include ketoaldehydes wherein the ketoaldehyde
includes a phenyl group and an .alpha.-ketoaldehyde group. The
produced composition displays chemical binding properties as
described below in greater detail. The macromolecular ketoaldehydes
can include a hydrated form and/or a non-hydrated form. A general
formula that represents a macromolecular phenylketoaldehyde
according to an embodiment of the present invention is provided
below as follows:
##STR00002##
[0035] The macromolecular ketoaldehydes of the present invention
can effectively remove any suitable number, type and amount of
constituents from a solution, such as a physiological solution. The
constituents suitable for removal can include, anions, molecules or
radicals containing heteroatoms with free electron pairs, such as
sulfur, nitrogen and oxygen, such as urea, creatinine, uric acid,
.beta.-2 microglobulin, other like metabolic waste, other suitable
biological matter and/or the like. It should be appreciated that
the macromolecular compositions of the present invention can
chemically bind the constituents of any suitable fluid existing in
liquid phase, gaseous phase, mixed liquid and gaseous phase,
supercritical systems and/or the like.
[0036] The chemical binding properties make the macromolecular
compositions of the present invention well suited for a variety of
different applications subject to physiological and/or
non-physiological conditions. In an embodiment, the macromolecular
ketoaldehydes of the present invention can be used to remove
metabolic waste, such as urea, creatinine, uric acid and/or other
like uremic toxins, biological matter, proteinaceous matter, and/or
the like from blood and/or solutions used to dialyze blood.
[0037] With respect to dialysis therapy, the present invention can
be used in a variety of different dialysis therapies to treat
kidney failure. Dialysis therapy as the term or like terms are used
throughout the text is meant to include and encompass any and all
forms of therapies to remove waste, toxins and excess water from
the patient. The hemo therapies, such as hemodialysis,
hemofiltration and hemodiafiltration, include both intermittent
therapies and continuous therapies used for continuous renal
replacement therapy ("CRRT"). The continuous therapies include, for
example, slow continuous ultrafiltration ("SCUF"), continuous
venovenous hemofiltration ("CVVH"), continuous venovenous
hemodialysis ("CVVHD"), continuous venovenous hemodiafiltration
("CVVHDF"), continuous arteriovenous hemofiltration ("CAVH"),
continuous arteriovenous hemodialysis ("CAVHD"), continuous
arteriovenous hemodiafiltration ("CAVHDF"), continuous
ultrafiltration periodic intermittent hemodialysis or the like. The
present invention can also be used during peritoneal dialysis
including, for example, continuous ambulatory peritoneal dialysis,
automated peritoneal dialysis, continuous flow peritoneal dialysis
and the like. Further, although the present invention, in an
embodiment, can be utilized in methods providing a dialysis therapy
for patients having chronic kidney failure or disease, it should be
appreciated that the present invention can be used for acute
dialysis needs, for example, in an emergency room setting. However,
it should be appreciated that the compositions of the present
invention can be effectively utilized with a variety of different
applications, physiologic and non-physiologic, in addition to
dialysis.
[0038] In an embodiment, the macromolecular compositions of the
present invention include macromolecular phenylglyoxals as
previously discussed. This type of macromolecular composition
includes a phenyl group and a glyoxal group attached to the phenyl
group.
[0039] It should be appreciated that the glyoxal group can be
attached directly or indirectly to the phenyl ring and in any
suitable position on the ring. When directly attached, the
.alpha.-carbon atom of the .alpha.-ketoaldehyde can be attached to
a carbon atom of the phenyl ring. When indirectly attached, the
.alpha.-carbon atom of the .alpha.-ketoaldehyde is attached to the
phenyl ring via a spacer group including, for example, an
aliphatic, an alicyclic, an aromatic, substituted or unsubstituted
group, and/or the like. In an embodiment, the spacer group includes
an aliphatic with 1 to 30 atoms, such as methylene (CH.sub.2) or
the like, connected to one or a combinations of other suitable
chemical groups, such as methyl, ethyl, decyl, phenyl, napthyl or
the like.
[0040] It should be appreciated that the macromolecular
compositions and materials of the present invention can include a
variety of other additional constituents in addition to the
ketoaldehydes. For example, the present invention can include
hydrophilic groups, ion exchanging groups and/or the like depending
on the desired application of the present invention, such as for
ion exchanging to remove, for example, potassium, controlling the
degree of acidity, increasing accessibility in fluid systems and/or
the like. To that end, there may be present strongly acid or weakly
acid groups or salts thereof, strongly basic or weakly basic groups
or salts thereof, and/or hydroxyl groups. Such materials may
optionally be pre-charged with, for instance, (earth)alkali(ne)
metal ions, such as sodium ions, potassium ions, calcium ions,
magnesium ions, chloride ions, bicarbonate ions, acetate ions
and/or the like.
EXAMPLES
[0041] By way of example and not limitation, the following examples
are illustrative of how to make the macromolecular compositions
according to an embodiment of the present invention and further
illustrate experimental testing conducted on macromolecular
compositions made in accordance with an embodiment of the present
invention.
[0042] Experiment 1a--General Procedure for the Preparation of
Polyvinylacetophenone from Polystyrene-Divinylbenzene Co-Polymer
Resin (0.5-80% PS/DVB, 5 .mu.m to 1 mm):
[0043] To a portion of polystyrene-divinylbenzene co-polymer resin
was added dichloroethane or other suitable solvent in a ratio of
1:20 to 1:100 (w/v), which was allowed to swell for a given period
of time. To the mixture may be added acetyl chloride during the
swelling period. During the swelling the mixture may be heated to
assist in swelling. After swelling, 1 to 10 mole equivalence to
resin was added acetyl chloride followed by the addition of 1 to 10
mole equivalence of aluminum chloride or other suitable
Friedel-Crafts reagent. The reaction was heated at 50.degree. C. to
65.degree. C. for 6 to 24 hours or until the evolution of HCl gas
stopped. The resin was isolated by filtration and rinsed with
acetone, water, concentrated HCl, water and acetone. The resin was
then dried in vacuo at 50.degree. C. to 80.degree. C.
[0044] Experiment 1b--General Procedure for the Preparation of
Polyvinylacetophenone from Polystyrene-Divinylbenzene Co-Polymer
Resin (0.5-80% PS/DVB, 5 .mu.m to 1 mm):
[0045] To a portion of polystyrene-divinylbenzene co-polymer resin
was added dichloroethane or other suitable solvent in a ratio of
1:20 to 1:100 (w/v), which was allowed to swell for a given period
of time. To the mixture may be added acetyl chloride during the
swelling period. The solvent was removed from the resin, which is
not dried. The resin was added to a solution of 1 to 10 mole
equivalence of prepared acetyl chloride with aluminum chloride in
dichloroethane or other suitable solvent. The reaction was heated
50.degree. C. to 65.degree. C. for 6 to 24 hours or until the
evolution of HCl gas as stopped. The resin was isolated by
filtration and rinsed with acetone, water, concentrated HCl, water
and acetone. The resin was then dried in vacuo at 50.degree. C. to
80.degree. C.
[0046] Experiment 2a--General Procedure for the Preparation of
.alpha.-Ketoaldehyde Polystyrene-Divinylbenzene Co-Polymer
Resin(0.5-80% PS/DVB, 5 .mu.m to 1 mm):
[0047] To a portion of polyvinylacetophenone
polystyrene-divinylbenzene co-polymer resin was added DMSO
(dimethylsulfoxide) solvent in a ratio of 1:1 to 1:100 (w/v), which
was allowed to swell for a given period of time. During swelling,
the mixture may be heated to assist in swelling. After swelling,
48% HBr (See, Floyd, M. B., et al. J. Org. Chem. 1985, 50,
5022-5027) was slowly added at room temperature, after which the
temperature was raised to 65.degree. C. to 95.degree. C. and the
DMS (dimethyl sulfide) was collected by distillation. After
complete distillation of DMS, the reaction was heated to 95.degree.
C. or refluxed for an additional 2 to 8 hours. The resin was
isolated by filtration, washed successively with water and acetone.
The resin was then dried under vacuum at 80.degree. C. for a
minimum of 1.5 hours.
[0048] Experiment 2b--General Procedure for the Preparation of
.alpha.-Ketoaldehyde Polystyrene-Divinylbenzene Copolymer Resin
(0.5-80% PS/DVB, 5 .mu.m to 1 mm):
[0049] To 12 g of a polyvinylacetophenone
polystyrene-divinylbenzene co-polymer resin was added 80 mL of
DMSO. Hydrobromic acid (20 mL) was then added at room temperature
under gentle stirring. The temperature was then increased to
85.degree. C. for about 8 hours after which time the resin was
washed in DMSO, DMSO/acetone mixtures, acetone and water. The resin
was dried in an oven at 60.degree. C.
[0050] Experiment 3--Urea Uptake Experiment (Batch):
[0051] .alpha.-ketoaldehyde polymer made in accordance to an
embodiment of the present invention was added to a urea solution
prepared at 60 mg/dL concentration. The ratio of
.alpha.-ketoaldehyde polymer to urea solution was kept at 1 gram of
.alpha.-ketoaldehyde polymer to 100 mL of urea solution. In
general, about 500 mg of .alpha.-ketoaldehyde polymer was added to
50 mL of urea solution in a sealed pyrex bottle which is mixed for
8 hours at 37.degree. C. The contents of the flask were allowed to
cool and the urea concentration of the solution is then measured
per Experiment 4 discussed below.
[0052] Experiment 4--Measurement of Urea Per Urease Method:
[0053] Urea concentration from aqueous samples was measured
according to the TALKE and SCHUBERT method (See, Talke H and
Schubert G E., Klin Wschr. 1965; 43:174), on a Boehringer
Mannheim/Hitachi analyzer.
[0054] Experiment 5--COCHO Quantitation:
[0055] Quantitation of .alpha.-ketoaldehyde groups was determined
by a known procedure (See, for example, U.S. Pat. No. 4,012,317;
Acta Chem. Scand., 4, 892-900 (1950); and J. Am. Chem. Soc., 94,
1434-1436 (1942). This method is an indirect method of measuring
.alpha.-ketoaldehyde content, by first converting all
.alpha.-ketoaldehydes into mandelic acid groups with excess sodium
hydroxide. The mmoles of mandelic acid groups is determined by back
titration of the excess base with hydrochloric acid to pH 7 and
calculating the difference between the amount of base used and the
amount titrated.
[0056] To 100 mg of resin was added 3 mL of DMSO and 3 mL of 0.5N
NaOH with stirring. After 15 minutes, 10 mL of distilled water was
added, followed by neutralization of the sodium hydroxide by
titration with 0.1N HCl, until the solution stabilized at pH 7.
[0057] Experiment 6--General Procedure for the Alkylation of the
Polystyrene-Divinylbenzene Co-Polymer Resin (0.5-80% PS/DVB, 5
.mu.m to 1 mm):
[0058] To a portion of polystyrene-divinylbenzene co-polymer resin
was added dichloroethane or other suitable solvent in a ratio of
1:1 to 1:100 (w/v). To the mixture was added 0.1% to 10%
nitromethane (v/v) to solvent, followed by the alkyl halide in 0.1
mole to 10 mole equivalence. The mixture was allowed to swell for a
given period of time, followed by the addition of AlCl.sub.3 (0.1
to 10 mole percent of the resin). The mixture was stirred for 2-4
hours with the temperature ranging from ambient to 50.degree. C.
The alkylated resin was isolated by filtration and rinsed with
solvent. Acetylation and oxidation to prepare the alkyl
.alpha.-ketoaldehyde polymer was completed as in Experiments 1b and
2 discussed above. Urea uptake by the resin was completed and
measured per Experiments 3 and 4 as previously discussed.
[0059] Experiment 7--.alpha.-Ketoaldehyde
Polystyrene-Divinylbenzene Co-Polymer Resin Beads (3% PS/DVB, 5
.mu.m to 1 mm Per Experiment 1a):
[0060] Acetyl chloride (10 mL), 75 mL of dichloroethane, and 10.918
g of resin beads were combined and allowed to swell. The resin
beads are commercially available and included 3% by weight of
divinylbenzene at a particle size that ranged from 5 .mu.m to 1 mm.
The solvent and acetyl chloride were filtered and the resin was
combined with 100 mL of dichloroethane, 12 mL of acetyl chloride
and 15.310 g of AlCl.sub.3. The reaction was heated for 6 hours and
the acetylated polymer beads were isolated by filtration, washed
with 500 mL of water and 200 mL of acetone. The beads were air
dried. 6.200 grams of the acetylated polymer beads were added to
150 mL of DMSO and heated to 80.degree. C., followed by the
dropwise addition of 48% HBr. The reaction was heated for 3 hours,
and the resin isolated by filtration, rinsed with 200 mL of water
and 200 mL of acetone. After air drying, urea uptake value of 47.3
mg of urea/gram of resin was obtained according to Experiments 3
and 4 discussed above.
[0061] Experiment 8--.alpha.-Ketoaldehyde
Polystyrene-Divinylbenzene Co-Polymer Resin Beads (70-80% PS/DVB
Per Experiment 1a):
[0062] 100 g of wet polystyrene resin beads (Supelco, Amberlite
XAD-4) were dried by eluting THF through the resin beads. The resin
beads are commercially available and included 70% by weight to 80%
by weight of divinylbenzene at a particle size that ranged from 5
.mu.m to 1 mm. The resin beads were then rinsed with 2.times.150 mL
portions of dichloroethane. The resin beads were swollen with 300
mL of dichloroethane and 50 mL of acetyl chloride. The solution was
decanted and 500 mL of fresh dichloroethane with 100 mL of acetyl
chloride were combined with the resin followed by 147.38 grams of
AlCl.sub.3. The reaction was heated to 42.degree. C. for 48 hours.
The resin beads were isolated by filtration and rinsed with 4 L
water containing 750 mL concentrated HCl over a period of 3 to 5
hours. The resin was rinsed with 2 L of water followed by 1 L of
DMSO. The resin beads were transferred to a reaction flask with 500
mL of DMSO, and 200 mL of 48% HBr. The mixture was heated to reflux
and mixed for 24 hours. The resin beads were isolated by
filtration, rinsed with 4 L of water over 2 hours, and dried at
80.degree. C. in vacuum for 3 hours. After drying, urea uptake
value of 8.8 mg of urea/gram of resin was obtained as performed by
Experiments 3 and 4.
[0063] Experiment 9--.alpha.-Ketoaldehyde
Polystyrene-Divinylbenzene Co-Polymer Resin Beads (PS/1% DVB, Per
Experiment 1b):
[0064] Preparation of the polystyrene-divinylbenzene co-polymer
beads was accomplished by placing the polymer resin beads (2.5 g)
in a dry 300 mL three necked flask with 40 mL of dichloroethane,
and 15 mL of acetyl chloride for 3 hours. The swelled polymer was
rinsed with excess dichloroethane and isolated by filtration. To a
separate dry round bottom 300 mL flask was added 25 mL of
dichloroethane, 7 g of AlCl.sub.3, and 4.5 mL of acetyl chloride.
The mixture was allowed to dissolve, followed by the addition of
the previously swelled resin. The mixture was allowed to react at
65 to 75.degree. C., for 14 hours with constant stirring. The resin
was isolated by filtration, and rinsed by the following procedure.
First with 300 mL of dichloroethane, 400 mL of acetone, 300 mL of
water, 300 mL of water with 90 mL of concentrated HCl, 600-800 mL
of water and a final rinse with 150 mL of acetone. The acetylated
polymer was dried in vacuo. The acetylated resin was transferred
into 250 mL flask with 30 mL of DMSO (dimethylsulfoxide), and
soaked at 80-90.degree. C. for 30-45 minutes. To the reaction was
added 10 mL of HBr dropwise, and heated for 2 hours. The reaction
was refluxed for another two hours, cooled, rinsed with DMSO,
water, acetone and isolated by filtration. The .alpha.-ketoaldehyde
PS/1% DVB polymer beads were dried in vacuo had a urea uptake of 45
mg of urea/gram of .alpha.-ketoaldehyde polymer according to
Experiments 3 and 4.
[0065] Experiment 10--Scale-Up Acetylation of 1% PS/DVB Beads to
Produce Polyacetophenone:
[0066] Preparation of the polystyrene-divinylbenzene (1% PS/DVB, 75
to 150 mesh) co-polymer beads was accomplished by placing the
polymer resin beads in a dry 1 L three necked flask with 600 mL of
dichloroethane, 200 mL of acetyl chloride, and 45 g of the polymer.
After 3 hours, the polymer resin was isolated by filtration and
washed with excess dichloroethane. To a dry round bottom 1 L flask
was added 500 mL of dichloroethane, 146 g of AlCl.sub.3, and 100 mL
of acetyl chloride. The mixture was allowed to dissolve, followed
by the addition of 100 mL of dichloroethane at 65 to 75.degree. C.
The previously swelled resin was slowly added to the solution and
allowed to react at 65 to 75.degree. C., for 14 hours with gentle
stirring. The resin was isolated by filtration, and rinsed with
dichloroethane. The resin was washed and isolated by filtration
with 600 mL of dichloroethane, excess acetone and 23% HCl solution.
The final water rinse was checked at neutral pH before the final
rinse with 500 mL of acetone.
[0067] Experiment 11--Preparation of .alpha.-Ketoaldehyde 1% PS/DVB
Beads:
[0068] To a dry 2 L 3-necked round bottom flask was added 240 mL of
DMSO (dimethylsulfoxide) and 16 grams of acetylated resin from
Experiment 10. The reaction mixture was mixed for 45-60 minutes at
80.degree. C. to 90.degree. C. under gentle stirring. To the
mixture was added 80 mL of 48% hydrobromic acid while distilling
off dimethylsulfide for two hours. The reaction was allowed to
reflux for an additional 2 hours. The reaction was allowed to cool
and the .alpha.-ketoaldehyde 1% PS/DVB beads were isolated by
filtration, washed successively with water and acetone. The resin
was then dried under vacuum at 80.degree. C. for a minimum of 1.5
hours. The .alpha.-ketoaldehyde PS/1% DVB polymer beads were dried
in vacuo and had a urea uptake of 39.6 mg of urea/gram of
.alpha.-ketoaldehyde polymer according to Experiments 3 and 4.
[0069] Experiment 12--Urea Uptake Test I:
[0070] Several polystyrene resin beads with varying amounts of DVB
were prepared according to Experiments 7, 8, and 9 with urea uptake
results according to Experiments 3 and 4. The results are shown
below in Table 1.
TABLE-US-00001 TABLE 1 Urea Uptake of .alpha.-ketoaldehyde resin
per experiment 12 Uptake of Urea mmol .alpha.- in mg/g of
ketoaldehyde per % DVB Experiment urea/polymer gram of resin
Content 8 8.8 2.45 70-80 7 20.8 3.1 3 9 47.3 3.1 3 9 45 5.9 1
[0071] Experiment 13--Gamma Radiation of .alpha.-Ketoaldehyde
Resins:
[0072] This experiment was conducted to determine the effect of
gamma radiation on urea uptake. A resin material made pursuant to
an embodiment of the present invention was determined to have an
urea uptake value of 43.8 mg of urea per gram of resin pursuant to
Experiments 3 and 4. The same resin material was exposed to about
40 Gky to about 50 Gky gamma radiation and an urea uptake value of
43.6 mg of urea per gram of resin was obtained according to
Experiments 3 and 4.
[0073] Experiment 14--Urea Uptake Test II:
[0074] To 50 mL of a 505.8 mg/dL urea solution was added 0.507 g of
.alpha.-ketoaldehyde polymer prepared similar to experiment 10. The
mixture was sealed in a pyrex bottle and heated to 50.degree. C.
with stirring for 24 hours. The urea concentration was measured as
per Experiment 4, and the .alpha.-ketoaldehyde polymer had a urea
uptake of 109 mg of urea per gram of .alpha.-ketoaldehyde
polymer.
[0075] Experiment 15--Urea Uptake Test III:
[0076] Urea uptake by the .alpha.-ketoaldehyde polymer prepared as
in Experiment 9 was measured per the procedure in Examples 11 to 15
according to U.S. Pat. No. 4,012,317. 100 mg of polymer and 15 mL
of an aqueous solution of urea of concentration 1 g/L, were mixed
with either a solution of 0.05 molar monopotassium phosphate (pH 7)
or a solution of 0.05 mol/L sodium carbonate and bicarbonate at pH
10. The contents of the sealed bottles were mixed for 15 hours at
37.degree. C. with samples prepared in duplicate and results
averaged. Urea uptake was measured per Experiment 4. The results
are shown below in Table 2.
TABLE-US-00002 TABLE 2 Urea Uptake Comparison - 1 g/L Urea Urea
Mmol of uptake in .alpha.-ketoaldehyde pH of .alpha.-ketoaldehyde
mg/g of per gram of urea Time polymer polymer resin solution
(hours) 1 3.2 3.3 7 2.5 1 19.8 3.3 7 15 1 4.0 3.3 10 2.5 1 12.8 3.3
10 15 2 7.5 3.6 10 15 1. .alpha.-ketoaldehyde polymer prepared
according to Experiment 9. 2. .alpha.-ketoaldehyde polymer prepared
according to example 3 of U.S. Pat. No. 4,012,317.
[0077] Experiment 16--Urea Uptake Test IV:
[0078] Urea uptake by the .alpha.-ketoaldehyde polymer prepared in
Experiment 9 was measured per the procedure in Example 5 from U.S.
Pat. No. 4,012,317. 25 mg of .alpha.-ketoaldehyde polymer was
combined with 5 mL of an aqueous solution of urea of concentration
of 1 mol/l and 5 mL of solution containing either 0.05 molar
monopotassium phosphate (pH 7) or 5 mL of a solution of 0.05 mol/L
sodium carbonate and bicarbonate at pH 10. The contents of the
sealed pyrex bottles were mixed for 15 hours at 37.degree. C.,
filtered and washed 10 times with 20 mL aliquots of water. The
resins were then dried under vacuo. Urea in the
.alpha.-ketoaldehyde polymer measured as percent nitrogen by
elemental analysis. Results in Table 3 provide a comparison of
results from the .alpha.-ketoaldehyde polymer prepared in U.S. Pat.
No. 4,012,317 as indicated below.
TABLE-US-00003 TABLE 3 Urea Uptake Comparison - 0.5 mol/L Urea
Concentration % Nitrogen mmol of Urea Measured .alpha.- .alpha.-
uptake in in the .alpha.- ketoaldehyde pH of ketoaldehyde mg/g of
ketoaldehyde per gram of urea Time polymer polymer Polymer resin
solution (hours) 1 90 3.48 3.14 7 15 1 79 3.05 3.14 10 15 2 17.15
2.4.sup.3 3.6 7 15 2 30 2.87.sup.3 3.6 10 15 1.
.alpha.-ketoaldehyde polymer prepared according to Experiment 9,
with a urea uptake of 47.3 mg urea/gram of polymer per Experiments
3 and 4. 2. .alpha.-ketoaldehyde polymer prepared in U.S. Pat. No.
4,012,317 according to example 3. .sup.3Percent Nitrogen Value
based on urea uptake from U.S. Pat. No. 4,012,317, example 6.
[0079] As previously discussed, the present invention provides
materials, devices, apparatuses and systems that can utilize
macromolecular ketoaldehyde compositions made pursuant to an
embodiment of the present invention. The macromolecular
compositions of the present invention are particularly suited for
removing urea or the like under physiological conditions, such as
from solutions used during dialysis therapy. The binder materials
of the present invention can include any suitable type of material
including, for example, a porous bead material composed of
cross-linked polystyrene that has been modified to include a phenyl
ring, an .alpha.-ketoaldehyde group and, optionally, one or more
activating chemical groups attached to the phenyl ring in proximity
to the .alpha.-ketoaldehyde group. In an embodiment, the urea
binder material of the present invention can remove urea from a
fluid, such as a dialysis fluid during dialysis therapy.
[0080] In an embodiment, the present invention includes devices
that utilize the urea binder material made pursuant to an
embodiment of the present invention to remove urea in solution. In
general, the device 10 includes a body 12 defining an interior 14
through which a fluid can pass into the device 10 via an inlet 16
and optionally flow out of the device via an outlet 18 as shown in
FIG. 1. The device 10 contains the urea binder material 20 of the
present invention in its interior 14. The device 10 can contain the
urea binder material in any suitable way, such as in a layered
configuration. As the fluid passes through the device, the urea
binder material acts to remove urea from the fluid.
[0081] As applied, the device is particularly suited for removal of
urea from a dialysis solution during dialysis therapy. In an
embodiment, the device includes a chemical cartridge coupled in any
suitable manner to a patient loop through which dialysate is
circulated into, through and out of the patient during dialysis
therapy, such as continuous flow peritoneal dialysis. In this
regard, the device can be used to remove a therapeutically
effective amount of urea from the dialysis solution as it
continually passes through the device prior to circulation into,
through and out of the patient. This can enhance dialysis clearance
and minimize the amount of dialysis fluid necessary to maintain
effective clearance levels during dialysis therapy. In an
embodiment, the urea binder device can remove urea from solution
used during medical therapy, such as dialysis. To achieve an
effective urea uptake, the device, in an embodiment, includes about
500 g or less of the macromolecular material made in accordance to
an embodiment of the present invention.
[0082] It should be appreciated that the chemical cartridge can
include any suitable number, type and amount of materials in
addition to a urea binder material in order to enhance treatment.
For example, the chemical cartridge can include a carbon layer for
removal of creatinine, .beta.2-microglobulin and/or the like, a
material layer to remove phosphate and/or the like and the urea
binder material to remove urea and/or the like.
[0083] As previously discussed, the present invention provides a
system capable of removing a constituent from a fluid. The system
can be applied in a variety of different applications including,
for example, therapeutic and diagnostic applications. In an
embodiment, the system 22 includes a fluid pathway through which
the fluid can flow that is coupled to the device 10 as discussed
above and as shown in FIG. 1. The fluid pathway at least includes
an inflow fluid path 24 allowing fluid to enter the device.
Optionally, a number of other suitable fluid pathways can be
coupled to the device, such as an outflow fluid path 26 allowing
the fluid to pass through and out of the device 10.
[0084] It should be understood that various changes and
modifications to the presently preferred embodiments described
herein will be apparent to those skilled in the art. Such changes
and modifications can be made without departing from the scope of
the present subject matter and without diminishing its intended
advantages. It is therefore intended that all such changes and
modifications be covered by the appended claims.
* * * * *