U.S. patent application number 10/158207 was filed with the patent office on 2003-05-08 for method for treating hypercholesterolemia with polyallylamine polymers.
This patent application is currently assigned to GelTex Pharmaceuticals, Inc.. Invention is credited to Burke, Steven K., Goldberg, Dennis I., Holmes-Farley, Stephen Randall, Mandeville, W. Harry III.
Application Number | 20030086898 10/158207 |
Document ID | / |
Family ID | 27420493 |
Filed Date | 2003-05-08 |
United States Patent
Application |
20030086898 |
Kind Code |
A1 |
Holmes-Farley, Stephen Randall ;
et al. |
May 8, 2003 |
Method for treating hypercholesterolemia with polyallylamine
polymers
Abstract
A method for removing bile salts from a patient that includes
administering to the patient a therapeutically effective amount of
a non-absorbable amine polymers characterized by a repeat unit
having the formula: 1 and salts thereof, where n is a positive
integer and x is zero or an integer between 1 and about 4.
Inventors: |
Holmes-Farley, Stephen Randall;
(Arlington, MA) ; Mandeville, W. Harry III;
(Lynnfield, MA) ; Burke, Steven K.; (Sudbury,
MA) ; Goldberg, Dennis I.; (Sudbury, MA) |
Correspondence
Address: |
HAMILTON, BROOK, SMITH & REYNOLDS, P.C.
530 VIRGINIA ROAD
P.O. BOX 9133
CONCORD
MA
01742-9133
US
|
Assignee: |
GelTex Pharmaceuticals,
Inc.
Waltham
MA
|
Family ID: |
27420493 |
Appl. No.: |
10/158207 |
Filed: |
May 29, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10158207 |
May 29, 2002 |
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08979096 |
Nov 26, 1997 |
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6423754 |
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08979096 |
Nov 26, 1997 |
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08927247 |
Sep 11, 1997 |
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08927247 |
Sep 11, 1997 |
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08878422 |
Jun 18, 1997 |
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Current U.S.
Class: |
424/78.27 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 9/10 20180101; A61P 3/00 20180101; A61K 31/785 20130101; A61P
3/06 20180101 |
Class at
Publication: |
424/78.27 |
International
Class: |
A61K 031/785 |
Claims
What is claimed is:
1. A method for removing bile salts from a patient comprising
administering to said patient a therapeutically effective amount of
one or more crosslinked polymers characterized by a repeat unit
having the formula: 3and salts, where n is a positive integer and x
is zero or an integer between 1 and about 4, said polymer
characterized in that the polymer is substantially free of
alkylated amine monomers.
2. The method of claim 1 wherein said polymer is crosslinked by
means of a multifunctional crosslinking agent, said agent being
present in an amount from about 0.5-25% by weight, based upon the
combined weight of monomer and crosslinking agent.
3. The method of claim 2 wherein said crosslinking agent is present
in an amount from about 2.5-20% by weight, based upon the combined
weight of monomer and crosslinking agent.
4. The method of claim 2 wherein said crosslinking agent comprises
epichlorohydrin.
5. The method of claim 1 wherein the polymer is a homopolymer.
6. The method of claim 5 wherein x is 1.
7. The method of claim 5 wherein x is 0.
8. A method of removing bile salts from a patient comprising
administering to said patient a therapeutically effective amount of
cross-linked homopolyallylamine.
9. The method of claim 8 wherein said cross-linked
homopolyallylamine is crosslinked by means of a multifunctional
crosslinking agent, said agent being present in an amount from
about 1-25% by weight, based upon the combined weight of monomer
and crosslinking agent.
10. The method of claim 9 wherein said crosslinking agent is
present in an amount from about 2.5-20% by weight, based upon the
combined weight of monomer and crosslinking agent.
11. The method of claim 10 wherein said crosslinking agent
comprises epichlorohydrin.
12. A method of removing bile salts from a patient comprising
administering to said patient a therapeutically effective amount of
cross-linked homopolyvinylamine.
13. The method of claim 12 wherein said cross-linked
homopolyvinylamine is crosslinked by means of a multifunctional
crosslinking agent, said agent being present in an amount from
about 1-25% by weight, based upon the combined weight of monomer
and crosslinking agent.
14. The method of claim 13 wherein said crosslinking agent is
present in an amount from about 2.5-20% by weight, based upon the
combined weight of monomer and crosslinking agent.
15. The method of claim 14 wherein said crosslinking agent
comprises epichlorohydrin.
Description
RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. application Ser.
No. 08/979,096, filed Nov. 26, 1997, which is a
Continuation-in-Part of U.S. application Ser. No.: 08/927,247,
filed Sep. 11, 1997 which is a Continuation of U.S. application
Ser. No.: 08/878,422, filed Jun. 18, 1997. The entire teachings of
the above application(s) are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Reabsorption of bile acids from the intestine conserves
lipoprotein cholesterol in the bloodstream. Conversely, blood
cholesterol levels can be diminished by reducing reabsorption of
bile acids.
[0003] One method of reducing the amount of bile acids that are
reabsorbed and, thus, reducing serum cholesterol is the oral
administration of compounds that sequester the bile acids and
cannot themselves be absorbed. The sequestered bile acids
consequently are excreted.
[0004] Compounds which have been suggested for bile acid
sequestration include various ion exchange polymers. One such
polymer is cholestyramine, a copolymer of divinylbenzene/styrene
and trimethylammonium methylstyrene. It has been long recognized
that this polymer is unpalatable, gritty, and constipating. More
recently, various polymers have been suggested which are
characterized by hydrophobic substituents and quaternary ammonium
radicals substituted upon an amine polymer backbone (Ahlers, et al.
U.S. Pat. No. 5,428,112 and U.S. Pat. No. 5,430,110 and McTaggert,
et al., U.S. Pat. No. 5,462,730, which are incorporated herein by
reference).
[0005] Thus, there is still a need to discover superior bile acid
sequestrants.
SUMMARY OF THE INVENTION
[0006] The invention relates to the unexpected discovery that a new
class of ion exchange resins have improved bile salt sequestration
properties resulting in reduced dosages, which improve patient
tolerance and compliance, thereby improving the palatability of the
composition and are relatively easy to manufacture. The polymers,
employed in the invention comprise non-absorbable, and optionally
cross-linked polyamines as defined herein. The properties of the
polymer which gave rise to the present invention were discovered
during clinical trials of the polymer for its use in binding
phosphate in patients suffering from hyperphosphatemia. The
polyamines of the invention are characterized by one or more
monomeric units of the formula: 2
[0007] and salts thereof, where n is a positive integer and x is 0
or an integer between 1 and about 4. The polymer can be
characterized by the substantial absence of one or more alkylated
amine monomers and/or the substantial absence of one or more
trialkylammonium alkyl groups. In preferred embodiments, the
polymer is crosslinked by means of a multifunctional crosslinking
agent.
[0008] The invention provides an effective treatment for removing
bile salts from a patient (and thereby reducing the patient's
cholesterol level), particularly in patients with a serum LDL level
of at least about 130 mg/dL. The invention also provides for the
use of the polymers described herein for the manufacture of a
medicament for the treatment of hypercholesterolemia or for bile
acid sequestration.
[0009] Other features and advantages will be apparent from the
following description of the preferred embodiments thereof and from
the claims.
BRIEF DESCRIPTION OF THE DRAWING
[0010] The FIGURE presents the effect of cross-linked
polyallylamine on LDL cholesterol relative to baseline LDL
cholesterol.
DETAILED DESCRIPTION OF THE INVENTION
[0011] As described above, the polymers employed in the invention
comprise, optionally cross-linked polyamines characterized by the
formula above. Preferred polymers are polyallylamine or
polyvinylamine. Importantly, the polymers can be characterized by
the substantial absence of substituted or unsubstituted alkyl
substituents on the amino group of the monomer, such as obtained in
the alkylation of an amine polymer. That is, the polymer can be
characterized in that the polymer is substantially free of
alkylated amine monomers.
[0012] The polymer can be a homopolymer or a copolymer of one or
more amine-containing monomers or non-amine containing monomers.
Where copolymers are manufactured with the monomer of the above
formula, the comonomers are preferably inert, non-toxic and/or
possess bile acid sequestration properties. Examples of suitable
non-amine-containing monomers include vinylalcohol, acrylic acid,
acrylamide, and vinylformamide. Examples of amine containing
monomers preferably include monomers having the Formula 1 above.
Preferably, the monomers are aliphatic. Most preferably, the
polymer is a homopolymer, such as a homopolyallylamine or
homopolyvinylamine.
[0013] Preferably, the polymer is rendered water-insoluble by
crosslinking. The cross-linking agent can be characterized by
functional groups which react with the amino group of the monomer.
Alternatively, the crosslinking group can be characterized by two
ore more vinyl groups which undergo free radical polymerization
with the amine monomer.
[0014] Examples of suitable crosslinking agents include acryloyl
chloride, epichlorohydrin, butanedioldiglycidyl ether,
ethanedioldiglycidyl ether, and dimethyl succinate.
[0015] A preferred crosslinking agent is epichlorohydrin because of
its high availability and low cost. Epichlorohydrin is also
advantageous because of it's low molecular weight and hydrophilic
nature, maintaining the water-swellability of the polyamine
gel.
[0016] The level of crosslinking makes the polymers insoluble and
substantially resistant to absorption and degradation, thereby
limiting the activity of the polymer to the gastrointestinal tract.
Thus, the compositions are non-systemic in their activity and will
lead to reduced side-effects in the patient. Typically, the
cross-linking agent is present in an amount from about 0.5-25%
(more preferably about 2.5-20% and most preferably 1-10%) by
weight, based upon total weight of monomer plus crosslinking
agent.
[0017] Typically, the amount of crosslinking agent that is reacted
with the amine polymer is sufficient to cause between about 0.5 and
twenty percent of the amines. In a preferred embodiment, between
about 0.5 and 20 percent of the amine groups react with the
crosslinking agent.
[0018] Preferred polymers of the invention are generally known in
the art. Holmes-Farley, et al. (U.S. Pat. No. 5,496,545), describes
the use of aliphatic amine polymers in the treatment of
hyperphosphatemia. These polymers have also been suggested for use
in the treatment of iron-overload (Mandeville, et al., U.S. Pat.
No. 5,487,888). The teachings of both of these patents are
incorporated herein by reference.
[0019] Non-cross-linked and cross-linked polyallylamine and
polyvinylamine are generally known in the art and/or are
commercially available. Methods for the manufacture of
polyallylamine and polyvinylamine, and cross-linked derivatives
thereof, are described in the above US Patents, the teachings of
which are incorporated entirely by reference. Harada et al. (U.S.
Pat. Nos. 4,605,701 and 4,528,347, which are incorporated herein by
reference in their entirety) also describe methods of manufacturing
polyallylamine and cross-linked polyallylamine.
[0020] As described above the polymer can be administered in the
form of a salt. By "salt" it is meant that the nitrogen group in
the repeat unit is protonated to create a positively charged
nitrogen atom associated with a negatively charged counterion.
[0021] The cationic counterions can be selected to minimize adverse
effects on the patient, as is more particularly described below.
Examples of suitable counterions include Cl.sup.-, Br.sup.-,
CH.sub.3OSO.sub.3.sup.-, HSO.sub.4.sup.-, SO.sub.4.sup.2-,
HCO.sub.3.sup.-, CO.sub.3.sup.-, acetate, lactate, succinate,
propionate, butyrate, ascorbate, citrate, maleate, folate, an amino
acid derivative, a nucleotide, a lipid, or a phospholipid. The
counterions can be the same as, or different from, each other. For
example, the reaction product can contain two different types of
counterions, both of which are exchanged for the bile salts being
removed.
[0022] The polymers according to the invention can be administered
orally to a patient in a dosage of about 1 mg/kg/day to about 1
g/kg/day, preferably between about 5 mg/kg/day to about 200
mg/kg/day (such as between about 10 mg/kg/day to about 200
mg/kg/day); the particular dosage will depend on the individual
patient (e.g., the patient's weight and the extent of bile salt
removal required). The polymer can be administrated either in
hydrated or dehydrated form, and can be flavored or added to a food
or drink, if desired to enhance patient acceptability. Additional
ingredients such as other bile acid sequestrants, drugs for
treating hypercholesterolemia, atherosclerosis or other related
indications, or inert ingredients, such as artificial coloring
agents can be added as well.
[0023] Examples of suitable forms for administration include
tablets, capsules, and powders (e.g., for sprinkling on food) or
mixing in water or juice). The tablet, capsule, or powder can be
coated with a substance capable of protecting the composition from
disintegration in the esophagus but will allow disintegration as
the composition in the stomach and mixing with food to pass into
the patient's small intestine. The polymer can be administered
alone or in combination with a pharmaceutically acceptable carrier
substance, e.g., magnesium carbonate, lactose, or a phospholipid
with which the polymer can form a micelle.
[0024] The invention can be used to treat patients, preferably
humans, with hypercholesterolemia, particularly patients with a
serum LDL level which exceeds about 130 mg/dL.
[0025] The invention will now be described more specifically by the
examples.
EXAMPLES
A. Polymer Preparation
1. Preparation of Poly(vinylamine)
[0026] The first step involved the preparation of
ethylidenebisacetamide. Acetamide (118 g), acetaldehyde (44.06 g),
copper acetate (0.2 g), and water (300 mL) were placed in a 1 L
three neck flask fitted with condenser, thermometer, and mechanical
stirred. Concentrated HCl (34 mL) was added and the mixture was
heated to 45-50.degree. C. with stirring for 24 hours. The water
was then removed in vacuo to leave a thick sludge which formed
crystals on cooling to 5.degree. C. Acetone (200 mL) was added and
stirred for a few minutes, after which the solid was filtered off
and discarded. The acetone was cooled to 0.degree. C. and solid was
filtered off. This solid was rinsed in 500 mL acetone and air dried
18 hours to yield 31.5 g of ethylidenebisacetamide.
[0027] The next step involved the preparation of vinylacetamide
from ethylidenebisacetamide. Ethylidenebisacetamide (31.05 g),
calcium carbonate (2 g) and celite 541 (2 g) were placed in a 500
mL three neck flask fitted with a thermometer, a mechanical
stirred, and a distilling heat atop a Vigroux column. The mixture
was vacuum distilled at 24 mm Hg by heating the pot to
180-225.degree. C. Only a single fraction was collected (10.8 g)
which contained a large portion of acetamide in addition to the
product (determined by NMR). This solid product was dissolved in
isopropanol (30 mL) to form the crude vinylacetamide solution used
for polymerization.
[0028] Crude vinylacetamide solution (15 mL), divinylbenzene (1 g,
technical grade, 55% pure, mixed isomers), and AIBN (0.3 g) were
mixed and heated to reflux under a nitrogen atmosphere for 90
minutes, forming a solid precipitate. The solution was cooled,
isopropanol (50 mL) was added, and the solid was collected by
centrifugation. The solid was rinsed twice in isopropanol, once in
water, and dried in a vacuum oven to yield 0.8 g of
poly(vinylacetamide), which was used to prepare
poly(vinylamine).
[0029] Poly(vinylacetamide) (0.79 g) was placed in a 100 mL one
neck flask containing water (25 mL) and conc. HCl (25 mL). The
mixture was refluxed for 5 days, after which the solid was filtered
off, rinsed once in water, twice in isopropanol, and dried in a
vacuum oven to yield 0.77 g of product. Infrared spectroscopy
indicated that a significant amount of the amide (1656 cm.sup.-1)
remained and that not much amine (1606 cm.sup.-1) was formed. The
product of this reaction (.about.0.84 g) was suspended in NaOH (46
g) and water (46 g) and heated to boiling (.about.140.degree. C.).
Due to foaming the temperature was reduced and maintained at
.about.100.degree. C. for 2 hours. Water (100 mL) was added and the
solid collected by filtration. After rinsing once in water the
solid was suspended in water (500 mL) and adjusted to pH 5 with
acetic acid. The solid was again filtered off, rinsed with water,
then isopropanol, and dried in a vacuum oven to yield 0.51 g of
product. Infrared spectroscopy indicated that significant amine-had
been formed.
2. Preparation of Poly(allylamine) Hydrochloride
[0030] To a 2 liter, water-jacketed reaction kettle equipped with
(1) a condenser topped with a nitrogen gas inlet, (2) a
thermometer, and (3) a mechanical stirrer was added concentrated
hydrochloric acid (360 mL). The acid was cooled to 5.degree. C.
using circulating water in the jacket of the reaction kettle (water
temperature=0.degree. C.). Allylamine (328.5 mL, 250 g) was added
dropwise with stirring while maintaining the reaction temperature
at 5-10.degree. C. After addition was complete, the mixture was
removed, placed in a 3 liter one-neck flask, and 206 g of liquid
was removed by rotary vacuum evaporation at 60.degree. C. Water (20
mL) was then added and the liquid was returned to the reaction
kettle. Azobis(amidinopropane) dihydrochloride (0.5 g) suspended in
11 mL of water was then added. The resulting reaction mixture was
heated to 50.degree. C. under a nitrogen atmosphere with stirring
for 24 hours. Additional azobis(amidinopropane)dihydrochloride (5
mL) suspended in 11 mL of water was then added, after which heating
and stirring were continued for an additional 44 hours.
[0031] At the end of this period, distilled water (100 mL) was
added to the reaction mixture and the liquid mixture allowed to
cool with stirring. The mixture was then removed and placed in a 2
liter separatory funnel, after which it was added dropwise to a
stirring solution of methanol (4 L), causing a solid to form. The
solid was removed by filtration, re-suspended in methanol (4 L),
stirred for 1 hour, and collected by filtration. The methanol rinse
was then repeated one more time and the solid dried in a vacuum
oven to afford 215.1 g of poly(allylamine) hydrochloride as a
granular white solid.
3. Preparation of Poly(allylamine) hydrochloride Crosslinked with
Epichlorohydrin
[0032] To a 5 gallon vessel was added poly(allylamine)hydrochloride
prepared as described in Example 2 (1 kg) and water (4 L). The
mixture was stirred to dissolve the hydrochloride and the pH was
adjusted by adding solid NaOH (284 g). The resulting solution was
cooled to room temperature, after which epichlorohydrin
crosslinking agent (50 mL) was added all at once with stirring. The
resulting mixture was stirred gently until it gelled (about 35
minutes). The crosslinking reaction was allowed to proceed for an
additional 18 hours at room temperature, after which the polymer
gel was removed and placed in portions in a blender with a total of
10 L of water. Each portion was blended gently for about 3 minutes
to form coarse particles which were then stirred for 1 hour and
collected by filtration. The solid was rinsed three times by
suspending it in water (10 L, 15 L, 20 L), stirring each suspension
for 1 hour, and collecting the solid each time by filtration. The
resulting solid was then rinsed once by suspending it in
isopropanol (17 L), stirring the mixture for 1 hour, and then
collecting the solid by filtration, after which the solid was dried
in a vacuum oven at 50.degree. C. for 18 hours to yield about 677 g
of the cross linked polymer as a granular, brittle, white
solid.
4. Preparation of Poly(allylamine) hydrochloride Crosslinked with
Butanedioldiglycidyl Ether
[0033] To a 5 gallon vessel was added poly(allylamine)hydrochloride
prepared as described in Example 2 (500 g) and water (2 L). The
mixture was stirred to dissolve the hydrochloride and the pH was
adjusted to 10 by adding solid NaOH (134.6 g). The resulting
solution was cooled to room temperature in the vessel, after which
1,4-butanedioldiglycidyl ether crosslinking agent (65 mL) was added
all at once with stirring. The resulting mixture was stirred gently
until it gelled (about 6 minutes). The crosslinking reaction was
allowed to proceed for an additional 18 hours at room temperature,
after which the polymer gel was removed and dried in a vacuum oven
at 75.degree. C. for 24 hours. The dry solid was then ground and
sieved to -30 mesh, after which it was suspended in 6 gallons of
water and stirred for 1 hour. The solid was then filtered off and
the rinse process repeated two more times. The resulting solid was
then air dried for 48 hours, followed by drying in a vacuum oven at
50.degree. C. for 24 hours to yield about 415 g of the crosslinked
polymer as a white solid.
5. Preparation of Poly(allylamine) hydrochloride Crosslinked with
Ethanedioldiglycidyl Ether
[0034] To a 100 mL beaker was added poly(allylamine)hydrochloride
prepared as described in Example 2 (10 g) and water (40 mL). The
mixture was stirred to dissolve the hydrochloride and the pH was
adjusted to 10 by adding solid NaOH. The resulting solution was
cooled to room temperature in the beaker, after which
1,2-ethanedioldiglycidyl ether crosslinking agent (2.0 mL) was
added all at once with stirring. The resulting mixture was stirred
gently until it gelled (about 4 minutes). The crosslinking reaction
was allowed to proceed for an additional 18 hours at room
temperature, after which the polymer gel was removed and blended in
500 mL of methanol. The solid was then filtered off and suspended
in water (500 mL). After stirring for 1 hour, the solid was
filtered off and the rinse process repeated. The resulting solid
was rinsed twice in isopropanol (400 mL) and then dried in a vacuum
oven at 50.degree. C. for 24 hours to yield 8.7 g of the
crosslinked polymer as a white solid.
6. Preparation of Poly(allylamine) hydrochloride Crosslinked with
Dimethylsuccinate
[0035] To a 500 mL round-bottomed flask was added
poly(allylamine)hydrochl- oride prepared as described in Example 2
(10 g), methanol (100 mL), and triethylamine (10 mL). The mixture
was stirred and dimethylsuccinate crosslinking agent (1 mL) was
added. The solution was heated to reflux and the stirring
discontinued after 30 minutes. After 18 hours, the solution was
cooled to room temperature, and the solid filtered off and blended
in 400 mL of isopropanol. The solid was then filtered off and
suspended in water (1 L). After stirring for 1 hour, the solid was
filtered off and the rinse process repeated two more times. The
solid was then rinsed once in isopropanol (800 mL) and dried in a
vacuum oven at 50.degree. C. for 24 hours to yield 5.9 g of the
crosslinked polymer as a white solid.
[0036] An aqueous solution of poly(allylamine hydrochloride) (550
lb of a 50.7% aqueous solution) was diluted with water (751 lb) and
neutralized with aqueous sodium hydroxide (171 lb of a 50% aqueous
solution). The solution was cooled to approximately 25.degree. C.
and acetonitrile (1340 lb) and epichlorohydrin (26.2 lb) were
added. The solution was stirred vigorously for 21 hours. During
this time, the reactor contents changed from two liquid phases to a
slurry of particles in a liquid. The solid gel product was isolated
by filtration. The gel was washed in an elutriation process with
water (136,708 lb). The gel was isolated by filtration and rinsed
with isopropanol. The gel was slurried with isopropanol (1269 lb)
and isolated by filtration. The isopropanol/water wet gel was dried
in a vacuum dryer at 60.degree. C. The dried product was ground to
pass through a 50 mesh screen to give a product suitable for
pharmacologic use (166 lb, 73%).
7. Effect on Serum Cholesterol Levels in Humans
[0037] Hemodialysis patients on stable doses of calcium and/or
aluminum based phosphate binders entered a one-week screening
period. The phosphate binders were discontinued.
[0038] Those patients developing hyperphosphatemia (serum
P04>6.0 mg/dL) during the wash-out period were eligible for drug
treatment. A RenaGel.RTM. binder (epichlorohydrin cross-linked
polyallylamine, GelTex Pharmaceuticals, Inc., Waltham, Mass.)
starting dose was based on the degree of hyperphosphatemia.
Starting doses were either two, three, or four 465 mg capsules
three times per day with meals. At the end of each of three
subsequent two week periods, the dose of RenaGel.RTM. binder was
increased by one capsule per meal as necessary to achieve a serum
phosphorus between 2.5 and 5.5 mg/dL, inclusive. If the serum
phosphorus fell to less than 2.5 mg/dL, the RenaGel.RTM. binder
dose was decreased by one to three capsules per day to elevate the
serum phosphorus to above 2.5 mg/dL.
[0039] When the serum calcium fell below normal (defined by the
central laboratory normal range) during the study, the serum
calcium level was returned to within the normal range by adding an
evening calcium supplement of up to 1,000 mg of elemental calcium
as the carbonate salt on an empty stomach at bedtime or the
dialysate calcium concentration was increased. TUMS EX.RTM. 750 mg
tablets containing 300 mg of elemental calcium were provided. Other
brands of calcium carbonate or calcium acetate were used if the
patient prefered another formulation.
[0040] At the conclusion of the treatment period, any remaining
RenaGel.RTM. capsules were retrieved and the patient was kept off
phosphate binder for two weeks. After this second wash-out period,
patients discontinued any evening calcium supplements and returned
to their original phosphate binders.
[0041] Weekly throughout this period, on Mondays (MWF patients) and
Tuesdays (TTS patients), the patients gave blood for the laboratory
studies just prior to dialysis. On the Wednesdays (MWF patients)
and Thursdays (TTS patients) of the same weeks, the investigator
inquired if the patient experienced any adverse events or had
changes in medications that might indicate adverse events and
reviewed the results of the laboratory tests.
[0042] Dietary intakes of phosphorus were assessed on selected days
in the first wash-out, treatment, and second wash-out periods by
24-hour recall methods by nutritionists from the University of
Massachusetts Medical Center.
[0043] Approximately 216 hemodialysis patients on stable doses of
phosphate binders were entered into the study. The patients had to
have well controlled serum phosphorus and not have any clinically
significant unstable medical conditions. Only those patients who
were hyperphosphatemic (serum P04<6.0 mg/dL) during the first
washout period (approximately 180 patients) received treatment.
[0044] The polymer was supplied as capsules containing 500 mg of
polymer. Each patient started on one of three doses of polymer: (i)
2 capsules (0.93 g) three times per day with meals; (ii) 3 capsules
(1.4 g) three times per day with meals; and (iii) 4 capsules (1.86
g) three times per day with meals.
1 Dose Level*** Overall Low Medium High Std Std Std Std Parameter
Visit N Mean Dev P-Value* N mean Dev N Mean Dev N Mean Dev
P-Value** Total Cholesterol -1 28 214.6 41.2 13 217.0 42.4 3 267.3
57.4 12 198.8 23.8 0.0978 (mg/dL) 2 29 221.7 35.6 13 216.5 35.0 4
261.8 46.1 12 214.0 25.1 0.0790 6 28 182.2 46.2 12 186.8 44.1 4
234.8 63.1 12 160.1 25.6 0.0222 10 25 184.7 48.5 12 195.5 47.7 4
223.5 52.9 9 153.1 29.0 0.0181 10/Final 25 184.7 48.5 12 195.5 47.7
4 223.5 52.9 9 153.1 29.0 0.0181 Change(10/Final-2) 25 -37.2 29.0
<0.0001 12 -22.3 27.3 4 -38.3 25.3 9 -56.7 22.3 0.0098 12 25
208.1 42.1 12 202.6 38.4 4 267.3 45.6 9 189.2 18.0 0.0291 Change
(12-10) 24 23.1 34.2 0.0006 12 7.1 40.7 4 43.8 12.9 8 36.8 16.2
0.0306 LDL Cholesterol -1 27 145.0 34.1 12 147.2 32.2 3 191.1 40.2
12 131.2 24.9 0.0494 (mg/dL) 2 29 154.6 27.4 13 147.4 16.3 4 184.6
46.2 12 152.3 25.3 0.1441 6 28 110.5 33.4 12 113.3 32.4 4 150.5
43.9 12 94.5 17.3 0.0085 10 25 109.0 37.7 12 109.5 34.6 4 141.0
45.6 9 94.2 32.7 0.1750 10/Final 25 109.0 37.7 12 109.5 34.6 4
141.0 45.6 9 94.2 32.7 0.1750 Change(10/Final-2) 25 -45.7 29.3
<0.0001 12 -38.0 29.0 4 -43.6 28.0 9 -56.8 29.9 0.2972 12 25
141.0 33.6 12 132.3 20.9 4 194.2 37.9 9 129.0 23.8 0.0221 Change
(12-10) 24 33.0 24.8 <0.0001 12 22.8 23.6 4 53.2 17.9 8 38.2
23.9 0.0503 HDL Cholesterol -1 27 37.6 9.4 12 39.6 10.1 3 32.7 4.7
12 36.8 9.6 0.5108 (mg/dL) 2 29 36.4 9.2 13 37.8 9.8 4 31.3 5.0 12
36.5 9.6 0.4077 6 28 38.5 10.5 12 40.3 13.1 4 37.0 7.4 12 37.3 8.6
0.6622 10 25 36.5 11.1 12 41.3 12.0 4 34.5 6.1 9 30.9 9.3 0.1053
10/Final 25 36.5 11.1 12 41.3 12.0 4 34.5 6.1 9 30.9 9.3 0.1053
Change(10/Final-2) 25 0.8 9.0 0.2823 12 2.8 10.3 4 3.3 3.0 9 -3.0
8.2 0.1000 12 25 38.6 11.3 12 42.0 10.1 4 35.5 5.3 9 35.6 14.2
0.1986 Change(12-10) 24 0.9 8.5 0.8018 12 0.7 7.7 4 1.0 2.7 8 1.3
11.8 0.7914 Triglycerides -1 28 165.8 80.5 13 164.7 93.9 3 217.7
113.0 12 153.9 55.3 0.5796 (mg/dL) 2 29 153.9 92.3 13 156.3 103.7 4
229.5 104.0 12 126.2 64.0 0.2165 6 28 165.5 89.5 12 165.7 80.8 4
236.5 123.4 12 141.7 80.7 0.2408 10 25 196.2 165.3 12 223.4 222.6 4
240.0 65.1 9 140.3 81.8 0.0994 10/Final 25 196.2 165.3 12 223.4
222.6 4 240.0 65.1 9 140.3 81.8 0.0994 Change(10/Final-2) 25 38.2
150.6 0.3161 12 64.3 214.4 4 10.5 55.2 9 15.8 41.0 0.9199 12 25
142.5 91.2 12 141.7 107.2 4 188.0 76.3 9 123.4 74.3 0.2964
Change(12-10) 24 -54.0 151.3 0.0135 12 -81.8 209.6 4 -52.0 34.7 8
-13.4 49.7 0.2320 *Wilcoxon Signed Rank Test **Kruskal-Wallis Exact
Test ***Dose level defined using the last actual dose during study
8. Effect in Healthy Young and Old, Male and Female Volunteers
[0045] Eight young (19-40 years of age) and eight old (65 years of
age and older) healthy volunteer male and female subjects received
2.325 grams of RenaGel.RTM. binder (epichlorohydrin cross-linked
polyallylamine) three times per day with meals for 32 days. All
drug doses were administered with meals served at a clinical
research center for the entire 32 day study. On day 0, a 10 mL
blood sample was drawn prior to the morning meal and analyzed for
plasma cholesterol levels. On day 32 a second 10 mL blood sample
was drawn prior to the morning meal. Subjects were released from
the study after the morning meal on day 32. Plasma triglycerides
and HDL were measured and LDL cholesterol was calculated by the
Friedewald formula.
[0046] The FIGURE presents the effect of the the polymer on LDL
cholesterol relative to baseline LDL cholesterol. The higher the
baseline cholesterol in these normal volunteers, the greater the
decline in LDL cholesterol. LDL cholesterol declined by a mean of
42 mg/dL for the entire 16 patient cohort. Five patients in the
study had baseline LDL cholesterol lower than 100 mg/dL. The
decline in LDL cholesterol in the 11 patients with baseline LDL
cholesterol>than 120 mg/dL was 52.5 mg/dL.
EQUIVALENTS
[0047] Those skilled in the art will know, or be able to ascertain,
using no more than routine experimentation, many equivalents to the
specific embodiments of the invention described herein. These and
all other equivalents are intended to be encompassed by the
following claims.
* * * * *