U.S. patent application number 10/949859 was filed with the patent office on 2005-02-17 for in vivo use of water absorbent polymers.
Invention is credited to Simon, Jaime, Strickland, Alan D..
Application Number | 20050036983 10/949859 |
Document ID | / |
Family ID | 22945717 |
Filed Date | 2005-02-17 |
United States Patent
Application |
20050036983 |
Kind Code |
A1 |
Simon, Jaime ; et
al. |
February 17, 2005 |
In vivo use of water absorbent polymers
Abstract
The subject invention is a method and material for removing
fluid from the intestinal tract of a host and may be useful in
treating animals or human patients suffering from fluid overload
states. In one embodiment, the subject method involves ingesting an
enterically coated non-systemic, non-toxic, non-digestible, water
absorbing polymer which absorbs fluid while passing through the
intestinal tract. The polymer is excreted in the feces wherein the
polymer and absorbed fluid is removed from the body. Preferred
polymers include super absorbent acrylic acid polymers, preferably
provided in bead form. The polymers may include functional groups
for selectively removing blood borne waste products, e.g. urea,
from the G.I. tract.
Inventors: |
Simon, Jaime; (Angelton,
TX) ; Strickland, Alan D.; (Lake Jackson,
TX) |
Correspondence
Address: |
THE DOW CHEMICAL COMPANY
INTELLECTUAL PROPERTY SECTION
P. O. BOX 1967
MIDLAND
MI
48641-1967
US
|
Family ID: |
22945717 |
Appl. No.: |
10/949859 |
Filed: |
September 24, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10949859 |
Sep 24, 2004 |
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10036989 |
Nov 6, 2001 |
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60249955 |
Nov 20, 2000 |
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Current U.S.
Class: |
424/78.27 |
Current CPC
Class: |
A61P 7/00 20180101; A61K
31/78 20130101; A61K 9/5073 20130101; A61K 31/716 20130101; A61P
7/10 20180101; A61P 39/02 20180101; A61P 13/12 20180101; A61P 1/00
20180101; A61K 31/715 20130101; A61K 9/1635 20130101; A61K 47/32
20130101; A61P 9/04 20180101; A61K 31/74 20130101; A61P 9/10
20180101; A61P 3/00 20180101 |
Class at
Publication: |
424/078.27 |
International
Class: |
A61K 031/785 |
Claims
What is claimed is:
1. A composition for removing fluid from the intestinal tract of a
host comprising an enterically coated, non-systemic, non-toxic,
water-absorbing polymer as the active ingredient, wherein the
water-absorbing polymer absorbs at least 20 times its weight in
physiological saline.
2. The composition of claim 1 wherein the polymer is capable of
absorbing at least 30 times its weight in physiological saline
3. The composition of claim 2 wherein the polymer is capable of
absorbing at least 40 times its weight in physiological saline.
4. The composition of claim 1 wherein the polymer is formed by
polymerizing acrylate containing monomers.
5. The composition of claim 1 wherein the polymer is formed by
polymerizing monomer comprising acrylic acid or salts thereof.
6. The composition of claim 1 wherein the polymer is a
polysaccharide.
7. The composition of claim 1 wherein the polymer is a crosslinked
polyally amine.
8. The composition of claim 1 wherein the polymer is provided in
bead form.
9. A method for removing fluid and waste products from the
intestinal tract of a host by directly delivering multiple polymers
to the intestinal tract.
10. The method according to claim 9 wherein the multiple polymers
comprise at least one water absorbent polymer capable of absorbing
at least 20 times its weight in physiological saline.
11. The composition of claim 10 wherein the polymer absorbs at
least 30 times its weight in physiological saline.
12. The composition of claim 11 wherein the polymer absorbs at
least 40 times its weight in physiological saline.
13. The composition of claim 10 wherein the water absorbent polymer
is formed by polymerizing acrylate containing monomers.
14. The composition of claim 10 wherein the water absorbent polymer
is formed by polymerizing monomer comprising acrylic acid or salts
thereof.
15. The composition of claim 10 wherein the water absorbent polymer
is a polysaccharide.
16. The composition of claim 10 wherein the water absorbent polymer
is a crosslinked polyallylamine.
17. The composition of claim 10 wherein the polymer is provided in
bead form.
18. A method for removing fluid from the intestinal tract of a host
by directly delivering a water absorbent polymer to the intestinal
tract through intestinal tubes, wherein the water absorbent polymer
absorbs at least 20 times its weight in physiological saline.
19. The composition of claim 18 wherein the polymer absorbs at
least 30 times its weight in physiological saline.
20. The composition of claim 19 wherein the polymer absorbs at
least 40 times its weight in physiological saline.
21. The composition of claim 18 wherein the polymer is formed by
polymerizing acrylate containing monomers.
22. The composition of claim 18 wherein the polymer is formed by
polymerizing monomer comprising acrylic acid or salts thereof.
23. The composition of claim 18 wherein the polymer is a
polysaccharide.
24. The composition of claim 18 wherein the polymer is a
crosslinked polyallylamine.
25. The composition of claim 18 wherein the polymer is provided in
bead form.
Description
CROSS-REFERENCE TO A RELATED APPLICATION
[0001] This Application is a continuation of copending application
Ser. No. 10/036,989 filed Nov. 6, 2001, which claims the benefit
under 35 USC 119(e) of U.S. provisional application No. 60/249,955
filed Nov. 20, 2000 incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Fluid overload states are associated with a number of
serious medical conditions. Many cardiac diseases can lead to
compromise in the heart's ability to pump blood. Myocardial
infarction frequently causes the replacement of heart muscle by
fibrotic tissue. This fibrotic tissue is not capable of pumping
blood and results in a decrease in the cardiac output.
Cardiomyopathy causes the heart muscle to have less strength
resulting in reduced cardiac output. These and other cardiac
diseases result in blood pooling in the pulmonary vasculature and
even in peripheral tissues such as the feet and legs. This
congestive heart failure can cause fluid to leak from the vascular
space into the extravascular space to cause edema of the tissue
involved, e.g. pulmonary edema, edema of the legs, etc. The reduced
cardiac output causes lowered blood flow to the kidneys which
decreases the urinary output. Diseases of the kidney can also lead
to fluid overload states. For example, nephrosis and nephritis
cause decreases in the ability of the kidney to excrete urine with
resultant fluid retention in the body and formation of edema. Acute
and chronic renal failure compromise or eliminate the production of
urine, resulting in fluid overload of the body. Intestinal or
nutritional disorders can result in decreased serum protein levels.
Particularly when the serum albumin levels are decreased, the
colloidal pressure in the vascular space is inadequate to retain
fluid in the blood vessels and tissue edema forms. These fluid
overload states can result from, among other diseases, kwashiorkor,
gluten-sensitive enteropathy, and deficiencies of such digestive
enzymes as chymotrysin or carboxypeptidase. Hepatic disease can
also lead to fluid overload states. Cirrhosis of the liver can
result from many liver diseases including any of the hepatitis
viruses, alcoholic liver disease, biliary obstructions,
hemochromatosis, Wilson's disease, mucopolysaccharidoses, and many
other genetic diseases. Cirrhosis of the liver results in decreased
synthesis of serum proteins such as albumin. It also causes
obstruction to blood flow from the body below the diaphragm to the
heart. This obstruction causes increased pressure the vasculature
with resultant edema formation below the diaphragm, ascites
formation, and decreased blood flow to the kidneys. Disorders of
other systems, such as the endocrine (e.g. preeclampsia, eclampsia,
etc.), neurological (e.g. angioneurotic edema, etc.), or immune
systems can also cause fluid overload states. Hormonal alterations,
such as the syndrome of inappropriate antidiuretic syndrome and
states with high progesterone levels, can result in fluid retention
and overload. Pulmonary diseases, such as pulmonary fibrosis and
chronic obstructive pulmonary diseases, also result in fluid
overload states. This listing of diseases and syndromes is merely
illustrative of some of the conditions which can cause fluid
overload states and is not intended to be exhaustive.
[0003] In addition to the fluid overload, many of these conditions
cause buildup of other substances. Any condition that compromises
urinary output can result in increases in urea, creatinine, other
nitrogenous waste products, and electrolytes or minerals such as
sodium, phosphate, and potassium. Hepatic diseases can result in
retention of water along with substances normally processed by the
hepatocytes such as ammonia and various organic acids. Cardiac
disorders can result in build up of lactic acid or lactates due to
ischemia of various tissues.
[0004] If untreated, the build up of water (i.e. fluid overload)
and other blood borne waste products can lead to unpleasant
symptoms and serious medical complications. Peripheral edema can be
painful and cause clothing to be too tight. The swelling from the
edema can compromise the blood flow to or from the tissues
resulting in infections or ulcers. Pulmonary edema causes
difficulty in absorbing enough oxygen to properly oxygenate
tissues. Ascites can be quite painful. Edema of the intestine
secondary to liver disease causes malabsorption of nutrients
leading to malnutrition. Disease of the kidney can cause build up
of uremic toxins such as putrescine, xanthine, and creatinine.
Ammonia retention can result in neurological damage. Any organic
acid in excess can cause metabolic acidosis with resultant
dysfunction of pH dependent processes such as enzymatic metabolic
reactions. Ischemic tissues with increased lactic acid can be
compromised in function or even necrose.
[0005] Treatment for fluid overload states involves both removal of
the excess fluid and remediation of the other waste products that
are accumulating in the body. Removal of the waste products may be
quite different from the treatment for removal of water and may
have a different degree of success. A common method of treatment
for removal of excess water is fluid restriction. When fluid intake
is less than the fluid output through urinary losses, fecal losses,
and insensible losses (e.g. sweat, moisture in the breath, etc.),
fluid is removed from the body and the fluid overload state can be
treated. This method of treatment is not usually adequate for fluid
removal and is not designed to remove other metabolic wastes. As
such, it is not usually the sole treatment of a fluid overload
state.
[0006] Another common treatment for fluid overload states is
administration of diuretic agents. Diuretic agents alter the normal
kidney function to either increase the amount of plasma filtrate
produced or decrease the reabsorption of tubular fluid. These
agents usually interfere with the normal renal handling of
electrolytes. For instance, furosemide interferes with normal
sodium reabsorption from the tubules and results in excessive
wasting of sodium and potassium. Increasing the dietary sodium
usually worsens the fluid overload state, but not increasing the
dietary sodium frequently results in decreased total body sodium
and decreased serum sodium concentrations. This eventually makes
the patient resistant to the diuretic. Diuretic resistance may also
result from the fluid overload being confined to the extravascular
space while the diuretic can only alter the retention of fluid in
the intravascular space.
[0007] Dialysis is a common treatment for those suffering from
fluid overload states and toxic accumulations of metabolic wastes.
Both compromised renal function and compromised hepatic function
have been treated with dialysis. Dialysis most commonly takes one
of two forms, hemodialysis or peritoneal dialysis. Both forms of
dialysis remove excess water and waste products (e.g. urea, salts,
etc.) from the body. However, hemodialysis and peritoneal dialysis
involve significant patient discomfort and/or inconvenience. In
addition, removal of water and wastes through dialysis is not
uniform for all substances. Sodium and potassium are easily removed
during either peritoneal dialysis or hemodialysis. Urea is
relatively easily removed. Creatinine and phosphate have lower
removal rates, and proteins such as beta-2-microglobulin have
markedly lower clearances. Removal rates for hepatic toxins are
quite low unless modifications are made to the typical hemodialysis
equipment and solutions. One method being used is to add albumin to
the dialysate to facilitate removal of toxins which are carried on
albumin in the bloodstream.
[0008] WO 98/17707 to Simon et. al. published Apr. 30, 1998
describes the therapeutic ingestion of functionalized, water
soluble, polyether glycol polymers for the selective absorption of
certain blood borne waste (i.e. phosphate and/or oxalate) from in
the gastrointestinal (GI) tract. However, the object of this
invention is to prevent the absorption of dietary phosphate and
oxalate and does not address fluid overload. This reference is
incorporated herein by reference.
[0009] Ingestion of oxystarch and coal for treatment of end stage
renal dialysis patients has been investigated by Friedman et. al.,
see Clinical Aspects of Uremia and Dialysis, pg. 671-687 (1977) and
see Friedman, et. al., "Combined oyxstarch-charcoal trial in
uremia: sorbent-induced reduction in serum cholesterol" Kidney
International 1976; 7: S273-6. The aldehydes on the oxystarch are
intended to remove urea and the charcoal is intended to remove
other organic substrates. However, the fluid capacity of these
polymers is limited and not clinically practical as a fluid
overload agent.
[0010] U.S. Pat. Nos. 5,679,717; 5,693,675; 5,618,530; 5,702,696;
5,607,669; 5,487,888 and 4,605,701 describe the ingestion of a
crosslinked alkylated amine polymers to remove bile salts and/or
iron from a patient. Again these polymers are limited in their
ability to absorb fluids and are not practical for treatment of
fluid overload.
[0011] U.S. Pat. No. 4,470,975 describes the elimination of water
from the gastrointestinal (GI) tract by ingesting an insoluble,
hydrophilic crosslinked polysaccharide which absorbs water from the
gastrointestinal (GI) tract and is subsequently excreted. This
patent is incorporated herein by reference. Unfortunately, the
described polysaccharides can be difficult to synthesize and
relatively expensive. Moreover, their ability to absorb water or
saline on a per-weight basis is limited; thus leading to very high
doses to the patient in order to obtain an effective treatment.
[0012] Imondi, A. R. and Wolgemuth, R. L reported in
"Gastrointestinal sorbents for the treatment of uremia. I. Lightly
cross-linked carboxyvinyl polymer" in Ann. Nutr. Metab. 1981; 25:
311-319 on studies of several insoluble resins, two polysaccharide
preparations, various oxystarch preparations, and a highly
swellable polyacrylic acid for oral use in treating uremia. They
note that the polyacrylic acid increased the fecal excretion of
urea and total nitrogen to the same extent as oxystarch. Ammonia,
sodium, potassium, calcium, and magnesium were removed by the
polyacrylic acid while phosphate, the only anionic species
investigated, was not removed by the polyacrylic acid. Oxystarch
and the polyacrylic acid increased fecal fluid excretion to the
same degree--which is inadequate for clinical utility, as revealed
above in the discussion of Friedman's articles on oxystarch.
[0013] Japanese Patent Application Kokai No. H10-59851 (Application
No. H8-256387) and Japanese Patent Application Kokai No. H10-130154
(Application No. H8-286446) disclose the oral administration of
alkali metal and alkaline earth salts of crosslinked polyacrylates
to treat kidney disease. These polymers are administered orally
from an oil emulsion. Thus, the water absorption effect of the
polymer begins within the stomach, just as is the case in the
experiments reported by Imondi and Wolgemuth. Such direct exposure
to stomach acid can lead to significant polymer degradation due to
the low pH environment. Moreover, the polymer tends to absorb
nutrients from the body via the stomach along with becoming
saturated with fluid just ingested rather than fluid containing
uremic wastes such as urea and creatinine. Thus, although the
disclosed polymers absorb significantly more water or saline than
polysaccharides on a per weight basis, direct exposure to stomach
acid can result in undesired polymer degradation, absorption of
nutrients, and polymer saturation with ingested fluid rather than
the absorption of excess fluid and waste from the intestinal
tract.
[0014] U.S. Pat. No. 4,143,130 discloses the oral administration of
lightly crosslinked polyacrylic acid for removing calcium from the
intestinal tract in order to treat kidney stones. The polymer may
be provided as a gel with hydroxyethylcellulose in a tablet,
capsule or pill form which may be enterically coated, although no
examples are provided. The aim of this invention was to remove
calcium from the body--not fluids. In fact the preferred method of
administration included adding water to the formulation prior to
administering to the patient. Thus, there was no suggestion that
this polymer could be used to treat fluid overload states or remove
metabolic waste products or fluid from the intestinal tract.
[0015] U.S. Pat. No. 5,051,253 discloses the oral administration of
polyacrylic acid for treating mucolytic protease activity in
patients with inflammatory bowel disease. The polymer may be
provided with a EUDRAGIT coating. The aim of this invention was to
administer small amounts of a gel to the colon to coat the mucosa
and protect it from degradation by protease. Treatment of fluid
overload was not suggested. Removal of metabolic wastes was not
anticipated or desired.
[0016] Polycarbophil is a synthetic oral bulk-producing laxative
based upon the calcium salt of polyacrylic acid. Calcium
polycarbophil can absorb up to 60 times its weight in water or 6
times its weight in 0.9% saline. Polycarbophil is known for use in
the treatment of constipation and diarrhea and is commonly orally
administered with 250 milliliters of water per 500 mg dose.
[0017] Although these literature references evidence attempts to
provide orally administered substances, such as polysaccharides,
polystarches, polyaldehydes, activated charcoal, and polyacrylic
acid compounds, none evidence a successful approach to removing
fluid from the GI tract. Most of the agents have had inadequate
fluid absorbing capacity. Agents with larger capacities for fluid
absorption, i.e. sodium polyacrylate or potassium polyacrylate,
were not disclosed as agents for treatment of fluid overload states
or for absorption of fluid from the GI tract. Calcium polyacrylate,
which does not absorb as much fluid (see Japanese Patent
Application Kokai No. H10-130154, Application No. H8-286446, see
claim 5 and Table 1) was chosen by one group. Polyacrylic acid,
which also does not absorb a large amount of fluid, was chosen by
the other group and was directed at prevention of renal stones
rather than treatment of fluid overload or removal of fluid from
the GI tract (see U.S. Pat. No. 4,143,130). No explanations of
these choices are given. The current investigators have found that
orally administered polyacrylates exposed to acidic conditions
common in the stomach do not absorb fluid as well after exposure to
acid, begin their absorption of fluid in the stomach where most
fluid is recently ingested fluid, and interfere with normal
absorption of nutrients and medications.
[0018] Therefore, there continues to be a need for an effective
means for removing fluid from the GI tract of a host, and for
treatments for fluid overload states. Such a treatment should
ensure fluid removal occurs substantially in the intestinal tract
rather than the stomach, thus avoiding polymer degradation,
absorption of nutrients and saturation with ingested fluid.
Furthermore, treatments are sought which can selectively remove
blood borne waste products, e.g. urea, phosphate, salts, etc.
SUMMARY OF THE INVENTION
[0019] The subject invention is a method and material for removing
fluid (e.g. water) from the intestinal tract of a host. The subject
method may be useful in the treatment of patients suffering from
fluid overload states. Fluid overload states can result from a
variety of conditions including, but not limited to, congestive
heart failure, cirrhosis of the liver, nephrosis, ascites, renal
disease, edema such as that associated with chemotherapy,
pre-menstrual fluid overload, and preeclampsia. The subject method
involves directly delivering a non-systemic, non-toxic,
non-digestible, fluid absorbing polymer to the intestinal tract
where it absorbs fluid as it passes therethrough and is
subsequently excreted. In one embodiment, the means for directly
delivering the polymer comprising enterically coating the polymer
and ingesting (orally administering) the polymer to the patient.
The enteric coating protects the polymer from exposure to the
stomach. After passing through the stomach of the host, the coating
breaks down wherein the polymer is exposed to the intestinal tract,
i.e. "directly delivered."
[0020] Applicable polymers include polyelectrolyte and
non-polyelectrolyte compounds. Polyelectrolyte polymers include,
but are not limited to, carboxylate containing polymers such as
polyacrylates, polyaspartates, polylactates, and the like,
sulfonate containing polymers, and physiologically quaternary or
cationic amine containing polymers such as polyallylamine or
polyethyleneimine. Non-polyelectrolyte polymers, or non-ionic
polymers, include such polymers as polyacrylamide gels, polyvinyl
alcohol gels, and polyurethane gels. Preferred polymers include
"super absorbent" acrylic polymers. The invention may include
mixtures of other polymers in addition to the water absorbing
polymers. Some polymers in this mixture may include functional
groups for selectively removing blood borne waste products e.g.
urea, from the G.I. tract. One modality of this invention involves
the use of multiple polymer components to remove water and a series
of waste products. The subject polymers may be enterically coated
such that they are protected from stomach acid but are exposed or
"released" in the intestinal tract. Alternatively, the subject
polymers may be administered through means, such as intestinal
tubes, which allow placement directly into the intestine.
[0021] The present invention can reduce the number of dialysis
treatments, amount of dialysis treatment time required and/or
completely alleviate the need for conventional dialysis. The
present invention can remove fluid from animals or patients with
congestive heart failure, ascites, and other fluid overload
conditions. The present invention can also remove waste products
from animals or patients.
[0022] The polymers of the subject invention are generally easy to
produce and many are commercially available.
[0023] The enteric coatings used to encapsulate or coat the subject
polymers ensure that fluid removal occurs substantially in the
intestine rather than the stomach. By preventing the polymers from
becoming active in the stomach, the present invention also allows
the polymers to absorb more fluid secreted into the intestinal
tract which contains metabolic waste products rather than recently
ingested dietary fluids. In contrast to previous art cited above,
the present invention protects the polymers from exposure to
gastric acid, thereby improving the fluid absorbing performance. By
preventing the polymers from absorbing fluid in the proximal small
intestine, the present invention has less interference with normal
absorption of nutrients and medications than the absorbents
mentioned in prior art.
DETAILED DESCRIPTION OF THE INVENTION
[0024] The subject invention involves directly delivering a
non-systemic, non-toxic, non-digestible, water-absorbing polymer to
the intestinal tract of a host to remove fluid therefrom. The term
"directly delivered" is intended to mean that the polymer is not
directly exposed to the stomach prior to deliver to the GI tract.
One preferred means of directly delivering the polymer to the GI
tract is via oral administration of an enterically coated polymer.
The enteric coating protects the polymer as it passes through the
stomach such that the polymer does not significantly degrade as a
result of exposure to stomach acid. Moreover, the enteric coating
prevents significant absorption or adsorption of nutrients or water
from the stomach. Upon reaching the intestinal tract, the enteric
coating exposes or "releases" the polymer where water and toxins
are then absorbed. The polymer is subsequently excreted in the
feces wherein the polymer, absorbed water and toxins are removed
from the body. Other non-limiting examples of direct delivery
include: introduction using an enema, a tube that is placed through
the nose or mouth and empties directly into the desired portion of
the intestine, a tube surgically implanted through the abdomen that
empties into the intestine, and via colonic lauage
administration.
[0025] The subject polymers include crosslinked polyacrylates which
are water absorbent such as those prepared from
.alpha.,.beta.-ethylenically unsaturated monomers such as
monocarboxylic acids, polycarboxylic acids, acrylamide and their
derivatives, e.g. polymers having repeating units of acrylic acid,
methacrylic acid, metal salts of acrylic acid, acrylamide, and
acrylamide derivatives (such as
2-acrylamido-2-methylpropanesulfonic acid) along with various
combinations of such repeating units as copolymers. Such
derivatives include acrylic polymers which include hydrophilic
grafts of polymers such as polyvinyl alcohol. Examples of suitable
polymers and processes, including gel polymerization processes, for
preparing such polymers are disclosed in U.S. Pat. Nos. 3,997,484;
3,926,891; 3,935,099; 4,090,013; 4,093,776; 4,340,706; 4,446,261;
4,683,274; 4,459,396; 4,708,997; 4,076,663; 4,190,562; 4,286,082;
4,857,610; 4,985,518; 5,145,906; and 5,629,377, which are
incorporated herein by reference. In addition, see Buchholz, F. L.
and Graham, A. T., "Modern Superabsorbent Polymer Technology," John
Wiley & Sons (1998). Preferred polymers of the subject
invention are polyelectrolytes. The degree of crosslinking can vary
greatly depending upon the specific polymer material; however, in
most applications the subject superabsorbent polymers are only
lightly crosslinked, that is, the degree of crosslinked is such
that the polymer can still absorb over 10 times its weight in
physiological saline (i.e. 0.9% saline). For example, such polymers
typically include less than about 0.2 mole percent crosslinking
agent.
[0026] Different morphological forms of the polymers are possible.
Polymers discussed in Buchholz, F. L. and Graham, A. T. "Modern
Superabsorbent Polymer Technology," John Wiley & Sons (1998)
are generally irregularly shaped with sharp corners. Other
morphological forms of crosslinked polyacrylates can be prepared by
techniques discussed in EP 314825, U.S. Pat. No. 4,833,198, U.S.
Pat. No. 4,708,997, WO 00/50096 and US 1999-121329 incorporated
herein by reference. These include several methods for preparing
spherical bead forms and films. The bead forms, as prepared by
methods similar to Example 1 of EP 314825 or Example 1 or Example 2
in WO 00/50096, are particularly advantageous for the present
invention because the uptake of fluid and the swelling are more
gradual (See Example 6 below). The irregularly shaped polymer
reaches its maximum fluid absorption within 2 hours of placement
into saline. Since the normal transit time through the stomach is
1.5 hours and the normal transit time through the small intestine
is 1.5 hours, most of the fluid absorption of this polymer would
occur in the small intestine. The bead form of the polymer swells
to its maximum extent 10 hours after being exposed to saline. This
allows the bead form of polymer to absorb more fluid in the distal
small intestine and colon than occurs with the irregularly shaped
polymer form. Absorbing more fluid in the distal portion of the
intestine prevents interference with the normal intestinal
absorption of nutrients and drugs while absorbing fluid that has a
higher concentration of waste products. Swelling of the polymer in
the colon also prevents feelings of fullness or bloating that may
occur when the swelling occurs in the stomach.
[0027] Many of these polymers, regardless of the morphological
form, are known for use as "super absorbents" and are commonly used
in controlled release applications and personal hygiene products.
For the subject invention, food and/or pharmaceutical grades of
materials are preferred. Although the alkali metal and alkaline
metal salts of these polymers can be used (e.g. calcium, potassium,
etc.); the sodium salt is particularly preferred.
[0028] Preferably the subject polymers are capable of absorbing at
least about 10 times their weight in physiological saline. In
several embodiments the subject polymers are capable of absorbing
more than 20 times, 30 times, and even above 40 times their weight
in physiological saline. For purposes of this document, the term
saline shall refer to physiological saline which comprises a 0.9%
saline solution, consistent with that found in the body.
[0029] Although less preferred due to their inability to absorb as
much fluid as the polymers described above, polysaccharides may be
used in the subject invention, so long as such polysaccharides are
directly administered to the intestinal tract and are not exposed
to the stomach. For example, the polysaccharides described in U.S.
Pat. No. 4,470,975 may be formulated as a tablet or provided within
a capsule which is enterically coated and orally administered. In
several embodiments of this invention, polysaccharide polymers are
specifically avoided.
[0030] In several embodiments, the subject polymer includes
functional groups which selectively bind with blood borne waste
products, e.g. urea, while passing through the gastrointestinal
tract. Such functional groups include, but are not limited to
aldehyde groups for binding urea, six to twelve carbon atom
hydrocarbon substituents for binding urea, polyaminoalkylene
substituents such as triethylenetetramine or tetraethylenepentamine
for binding oxalate. Additionally, amine functional groups, e.g.
ammonia, ethyleneamines, alkanol amines, C.sub.1-C.sub.10 alkyl
amines may be used for binding phosphate or oxalates. Thus, such
"functionalized" polymers can be designed to simultaneously absorb
water along with selectively binding with one or more blood borne
waste products. As part of a treatment regime, it may be desirable
to alternate or otherwise vary the use of some functionalized
polymers depending upon the need for removal of the target waste
product. Moreover, multiple polymers including different functional
groups may be used in combination, alternated or otherwise combined
for specialized treatment regimes.
[0031] In one embodiment of invention, the subject polymers are
coated or encapsulated with an enteric material which prevents the
release of polymer in the stomach and delivers the polymer to the
intestine. The preferred delivery site is the distal ileum or
colon. Examples of such suitable coatings include
hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose
phthalate, cellulose acetate phthalate, and sodium carboxyl methyl
cellulose. Other suitable coatings are known in the art, e.g.
polymers based on methacrylic acid and its derivatives, such as the
EUDRAGIT pH dependent copolymers, and are included within the scope
of the present invention. The polymer may be provided within a
capsule that is subsequently enterically coated. Multiple coatings
may be utilized. When provided in bead or tablet form, the polymer
may be directly coated. As previously mentioned, this invention
includes other methods of delivering the subject polymers to the
intestinal tract.
[0032] The quantity of water absorbent polymer utilized in a given
treatment varies depending upon the total amount of water the
patient normally excretes through the renal route or through
dialysis, along with the particular type of polymer utilized. Since
the water intake of patients varies greatly, the amount of water
that must be removed also varies. Thus, an effective amount of
water absorbent polymer will generally have a wide range, e.g. from
about 0.5 grams to about 40 grams per treatment but in some
instances can be as high as about 100 grams per treatment.
EXAMPLES
Example 1
[0033] A bead form of absorbent polymer based on a partial sodium
salt of lightly crosslinked polyacrylic acid was prepared in a
fashion similar to that given in Example 1 of EP 314825. Acrylic
acid, neutralized with sodium hydroxide and dissolved in water, was
mixed with the pentasodium salt of diethylenetriaminepentaacetic
acid and added to a reactor charged with Isopar L and Aerosil R972
held at 65.degree. C. Trimethylolpropane triacrylate and a solution
of sodium persulfate were added with vigorous stirring. The product
of the reaction was removed from the reactor, filtered, washed with
ethanol, and dried under vacuum. The resultant polymer had an
absorbance capacity of 45 gram 0.9% saline solution per gram of
polymer.
Example 2
[0034] The bead form of polymer from Example 1 was coated with a 5%
coating of hydroxypropylmethylcellulose followed by a subsequent
enteric coating of a 17.5% coating of Sureteric (polyvinyl acetate
phthalate).
Example 3
[0035] Six male beagle dogs underwent removal of the right kidney
and ligation of seven of the eight branches of the left renal
artery. Following one week of recovery time, the blood chemistries
revealed that all of the dogs were in renal failure. Two dogs were
then started on 1 gram of polymer from Example 1 per kg body weight
per day in two divided doses given with food. Two more dogs were
started on 1 gram of polymer as the enteric coated beads from
Example 2 in two divided doses given with food. Two dogs were
followed as controls. On the seventh and fourteenth day of
receiving the polymer, each dog was given capsules containing a
total of 73 mg ampicillin, 38 mg phenobarbital, and 8.8 mg zinc
simultaneously with the dose of polymer. Blood was drawn just
before and again two hours after the capsules were given. Serum
ampicillin rose to an average of 2.3 mg/L in the control dogs, 1.4
mg/L in the dogs given uncoated polymer, and 2.6 mg/L in the dogs
given the enteric coated polymer. Serum phenobarbital levels rose
to an average of 5.1 mg/L in the control dogs, 2.7 mg/L in the dogs
receiving uncoated polymer, and 5.0 mg/L in the dogs receiving the
enteric coated polymer. Serum zinc levels rose by 0.4 ppm in the
control dogs, fell by 0.8 ppm in the dogs receiving uncoated
polymer, and remained unchanged in the dogs receiving the enteric
coated polymer. Thus, uncoated polymer interfered with the normal
absorption of zinc, ampicillin, and phenobarbital; whereas the
enterically coated polymer did not interfere with absorption.
Example 4
[0036] Six male, 250 g, Sprague Dawley rats were placed on ad lib
regular rat chow and ad lib 10% aqueous ethanol solution. Each rat
was gavaged with a daily dose of 6.3 mg of cobalt(II) as an aqueous
solution of the acetate. All rats developed severe congestive heart
failure. All of the rats were given furosemide as a once per day
gavaged dose of 4 mg. All of the rats became resistant to the
diuretic effects of furosemide. After five days on furosemide,
three of the rats were additionally placed on polymer prepared as
in Example 2. The three control rats continued to retain fluid at a
rate of 1.5 g per day while the rats on the enterically coated
polymer increased the water excreted in their feces and had a net
fluid loss of 4.7 g per day.
Example 5
[0037] Nine male, 600 g, Sprague Dawley rats underwent bilateral
total nephrectomy. During the same surgery, gastric feeding tubes
were placed in all of the rats and three rats also had tubes placed
into the proximal to mid jejunum. All rats were then given normal
daily caloric intakes using a liquid rat diet gavaged through the
gastric feeding tubes. All rats had free access to water but
refused it. Three rats were followed as a control group receiving
only the liquid diet. Three rats were given the liquid diet and
also received 0.11 g of a polymer prepared by the aqueous reaction
of acrylic acid, sodium hydroxide, sodium persulfate, and
trimethylolpropane triacrylate similar to that described in
Buchholz, F. L. and Graham, A. T. "Modern Superabsorbent Polymer
Technology," John Wiley & Sons (1998). The polymer was
suspended in soy oil and gavaged into the stomach through the
gastric feeding tube. The three rats with the jejunal tubes
received the same polymer ("CLP") gavaged into the jejunum while
their liquid diet was gavaged through the gastric feeding tube. All
rats were followed with periodic sampling of blood for
determination of chemistries. The mean rate of rise of the blood
urea nitrogen (BUN) and serum creatinine were calculated for each
group:
1 BUN Creatinine (mg/dL/hr) (mg/dL/hr) Control rats 7.83 0.33
Gastric CLP rats 6.83 0.35 Jejunal CLP rats 4.50 0.19
[0038] Thus, the rate of increase of BUN after total nephrectomy is
81% of control rates for rats receiving CLP intragastrically and
57% of control rates for rats receiving CLP into the jejunum
without exposure to the stomach. Similarly, the rate of rise of
serum creatinine is 104% of control values for rats receiving CLP
via the stomach and 58% of control values for rats receiving CLP
directly into the jejunum.
Example 6
[0039] Three samples of a bead form polyacrylate polymer prepared
according to Example 1 were sealed into filter-paper bags and
immersed into a sodium phosphate/sodium chloride solution with pH
6.8 and weighed every thirty minutes to determine the extent of
fluid absorption. Three samples of an irregularly shaped
polyacrylate polymer prepared as described in Buchholz, F. L. and
Graham, A. T. "Modem Superabsorbent Polymer Technology," John Wiley
& Sons (1998) were sealed into filter-paper bags and immersed
into a sodium phosphate/sodium chloride solution with pH 6.8.
Weights were recorded to determine the extent of fluid absorption.
The irregularly shaped polymer reached its maximum fluid absorption
after two hours. The bead form of polymer reached its maximum fluid
absorption after 10 hours.
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